article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "A child with severe combined immunodeficiency (SCID) had an influenza A(H1N1)pdm09 infection with viral excretion longer than 6 months, during 2013-2014 influenza season, despite cord blood transplantation and antiviral treatments.\n\n\n\nConventional real-time RT-PCR methods were used to estimate viral load and to detect the presence of the common N1 neuraminidase (NA) H275Y substitution responsible for oseltamivir resistance. Next-generation sequencing (NGS) of influenza viruses was performed retrospectively to characterize viral quasispecies in specimens.\n\n\n\nThe patient was first treated with oral oseltamivir, leading to detection of low-levels of NA-H275Y substitution. Concomitant cord blood cell transplantation, intravenous administration of zanamivir and immunoglobulins led to an increase in white blood cells and influenza viral load decrease. A viral rebound occurred as soon as the antiviral treatment was discontinued. Eventually, influenza viral load was negated with immune reconstitution. NGS found influenza quasispecies harboring NA-E119A substitution (10.3%). Moreover, NGS showed that viral genomic diversity evolved under antiviral treatment and immune status.\n\n\n\nConventional virological techniques were sufficient for influenza infection follow-up but NGS performances allowed characterization of viral variants evolution in this specific case of prolonged influenza virus infection. New and efficient treatments against influenza in immunocompromised patients are needed.",
"affiliations": "Hospices Civils de Lyon, Centre National de Référence des virus des infections respiratoires, Laboratoire de Virologie, Institut des Agents Infectieux, Groupement Hospitalier Nord, F-69317, Lyon Cedex 04, France; Univ Lyon, CIRI, Inserm U1111, CNRS UMR5308, ENS, UCBL1, équipe Virpath, Faculté de Médecine Lyon Est, 7-11 Rue Guillaume Paradin, F-69372, Lyon Cedex 08, France.;Hospices Civils de Lyon, Centre National de Référence des virus des infections respiratoires, Laboratoire de Virologie, Institut des Agents Infectieux, Groupement Hospitalier Nord, F-69317, Lyon Cedex 04, France; Univ Lyon, CIRI, Inserm U1111, CNRS UMR5308, ENS, UCBL1, équipe Virpath, Faculté de Médecine Lyon Est, 7-11 Rue Guillaume Paradin, F-69372, Lyon Cedex 08, France.;Hospices Civils de Lyon, Centre National de Référence des virus des infections respiratoires, Laboratoire de Virologie, Institut des Agents Infectieux, Groupement Hospitalier Nord, F-69317, Lyon Cedex 04, France.;Hospices Civils de Lyon, Centre National de Référence des virus des infections respiratoires, Laboratoire de Virologie, Institut des Agents Infectieux, Groupement Hospitalier Nord, F-69317, Lyon Cedex 04, France; Univ Lyon, CIRI, Inserm U1111, CNRS UMR5308, ENS, UCBL1, équipe Virpath, Faculté de Médecine Lyon Est, 7-11 Rue Guillaume Paradin, F-69372, Lyon Cedex 08, France.;Hospices Civils de Lyon, Institut d'Hématologie et d'Oncologie Pédiatrique, Unité Protégée, 1 Place Joseph Renaut, F-69008, Lyon, France.;Hospices Civils de Lyon, Service de Réanimation Pédiatrique, Hôpital Femme Mère Enfant, Groupement Hospitalier Est, 59 Boulevard Pinel, F-69677, Bron, France.;Hospices Civils de Lyon, Laboratoire d'Immunologie, Groupement Hospitalier Edouard Herriot, 5 Place d'Arsonval, F-69437, Lyon Cedex 03, France.;Hospices Civils de Lyon, Laboratoire d'Immunologie, Groupement Hospitalier Edouard Herriot, 5 Place d'Arsonval, F-69437, Lyon Cedex 03, France.;Hospices Civils de Lyon, Centre National de Référence des virus des infections respiratoires, Laboratoire de Virologie, Institut des Agents Infectieux, Groupement Hospitalier Nord, F-69317, Lyon Cedex 04, France; Univ Lyon, CIRI, Inserm U1111, CNRS UMR5308, ENS, UCBL1, équipe Virpath, Faculté de Médecine Lyon Est, 7-11 Rue Guillaume Paradin, F-69372, Lyon Cedex 08, France.;Hospices Civils de Lyon, Centre National de Référence des virus des infections respiratoires, Laboratoire de Virologie, Institut des Agents Infectieux, Groupement Hospitalier Nord, F-69317, Lyon Cedex 04, France; Univ Lyon, CIRI, Inserm U1111, CNRS UMR5308, ENS, UCBL1, équipe Virpath, Faculté de Médecine Lyon Est, 7-11 Rue Guillaume Paradin, F-69372, Lyon Cedex 08, France.;Hospices Civils de Lyon, Service de Réanimation Pédiatrique, Hôpital Femme Mère Enfant, Groupement Hospitalier Est, 59 Boulevard Pinel, F-69677, Bron, France.;Hospices Civils de Lyon, Plateforme de séquençage diagnostique, Centre de Biologie et de Pathologie Est, Groupement Hospitalier Est, F-69677, Bron, France.;Hospices Civils de Lyon, Centre National de Référence des virus des infections respiratoires, Laboratoire de Virologie, Institut des Agents Infectieux, Groupement Hospitalier Nord, F-69317, Lyon Cedex 04, France; Univ Lyon, CIRI, Inserm U1111, CNRS UMR5308, ENS, UCBL1, équipe Virpath, Faculté de Médecine Lyon Est, 7-11 Rue Guillaume Paradin, F-69372, Lyon Cedex 08, France.;Hospices Civils de Lyon, Centre National de Référence des virus des infections respiratoires, Laboratoire de Virologie, Institut des Agents Infectieux, Groupement Hospitalier Nord, F-69317, Lyon Cedex 04, France; Univ Lyon, CIRI, Inserm U1111, CNRS UMR5308, ENS, UCBL1, équipe Virpath, Faculté de Médecine Lyon Est, 7-11 Rue Guillaume Paradin, F-69372, Lyon Cedex 08, France.;Hospices Civils de Lyon, Centre National de Référence des virus des infections respiratoires, Laboratoire de Virologie, Institut des Agents Infectieux, Groupement Hospitalier Nord, F-69317, Lyon Cedex 04, France; Univ Lyon, CIRI, Inserm U1111, CNRS UMR5308, ENS, UCBL1, équipe Virpath, Faculté de Médecine Lyon Est, 7-11 Rue Guillaume Paradin, F-69372, Lyon Cedex 08, France. Electronic address: vanessa.escuret@chu-lyon.fr.",
"authors": "Pichon|Maxime|M|;Picard|Caroline|C|;Simon|Bruno|B|;Gaymard|Alexandre|A|;Renard|Cécile|C|;Massenavette|Bruno|B|;Malcus|Christophe|C|;Monneret|Guillaume|G|;Morfin-Sherpa|Florence|F|;Valette|Martine|M|;Javouhey|Etienne|E|;Millat|Gilles|G|;Lina|Bruno|B|;Josset|Laurence|L|;Escuret|Vanessa|V|",
"chemical_list": "D000998:Antiviral Agents; D016756:Immunoglobulins, Intravenous; D014764:Viral Proteins; D053139:Oseltamivir; C487630:NA protein, influenza A virus; D009439:Neuraminidase; D053243:Zanamivir",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.antiviral.2018.10.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0166-3542",
"issue": "160()",
"journal": "Antiviral research",
"keywords": "Influenza A(H1N1)pdm09 virus; Intravenous zanamivir; NA-E119A substitution; NA-H275Y substitution; Next-generation sequencing; Oseltamivir resistance",
"medline_ta": "Antiviral Res",
"mesh_terms": "D000998:Antiviral Agents; D002648:Child; D036101:Cord Blood Stem Cell Transplantation; D024882:Drug Resistance, Viral; D014644:Genetic Variation; D006801:Humans; D016756:Immunoglobulins, Intravenous; D053118:Influenza A Virus, H1N1 Subtype; D007251:Influenza, Human; D020125:Mutation, Missense; D009439:Neuraminidase; D053139:Oseltamivir; D060888:Real-Time Polymerase Chain Reaction; D016511:Severe Combined Immunodeficiency; D019562:Viral Load; D014764:Viral Proteins; D053243:Zanamivir",
"nlm_unique_id": "8109699",
"other_id": null,
"pages": "1-9",
"pmc": null,
"pmid": "30315875",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Clinical management and viral genomic diversity analysis of a child's influenza A(H1N1)pdm09 infection in the context of a severe combined immunodeficiency.",
"title_normalized": "clinical management and viral genomic diversity analysis of a child s influenza a h1n1 pdm09 infection in the context of a severe combined immunodeficiency"
} | [
{
"companynumb": "FR-ROCHE-2224838",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IMMUNE GLOBULIN NOS"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nHead and neck dermatitis is a subtype of atopic dermatitis driven by Malassezia yeast.\n\n\nOBJECTIVE\nWe sought to evaluate the response of these patients to systemic azole antifungals.\n\n\nMETHODS\nWe queried the electronic medical records from our institution for patients that were referred for allergy patch testing, were ultimately given the diagnosis of head and neck dermatitis, and were treated with oral azole antifungals over a 2-year period.\n\n\nRESULTS\nTwenty-four patients met inclusion criteria and were analyzed. Most patients noted their characteristic flare beginning during their teenage, young adult, or adult years. All were noted to have some involvement of the head and neck, and 17 responded to treatment. The mean time taking an azole antifungal medication was 8 months, with a mean overall follow-up of 10 months.\n\n\nCONCLUSIONS\nThis was a retrospective descriptive study, from a single institution, of a limited number of patients, and did not use a validated scoring system.\n\n\nCONCLUSIONS\nItraconazole and other azole antifungals were an effective treatment for more than two-thirds of adult patients with head and neck predominant atopic dermatitis.",
"affiliations": "Division of Dermatology, Ohio State University College of Medicine, Columbus, Ohio; Ohio State University College of Medicine, Columbus, Ohio.;Ohio State University College of Medicine, Columbus, Ohio.;Division of Dermatology, Ohio State University College of Medicine, Columbus, Ohio; Ohio State University College of Medicine, Columbus, Ohio; Ohio State University Contact and Occupational Dermatitis Center, Columbus, Ohio. Electronic address: Matt.Zirwas@osumc.edu.",
"authors": "Kaffenberger|Benjamin H|BH|;Mathis|Jason|J|;Zirwas|Matthew J|MJ|",
"chemical_list": "D000935:Antifungal Agents; D001393:Azoles; D017964:Itraconazole",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0190-9622",
"issue": "71(3)",
"journal": "Journal of the American Academy of Dermatology",
"keywords": "Malassezia; atopic dermatitis; contact dermatitis; eczema; fluconazole; head and neck dermatitis; itraconazole; ketoconazole; occupational dermatitis; seborrheic dermatitis",
"medline_ta": "J Am Acad Dermatol",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents; D001393:Azoles; D003876:Dermatitis, Atopic; D009783:Dermatitis, Occupational; D012628:Dermatitis, Seborrheic; D003881:Dermatomycoses; D005260:Female; D006801:Humans; D017964:Itraconazole; D008290:Malassezia; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "7907132",
"other_id": null,
"pages": "480-3",
"pmc": null,
"pmid": "24925733",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A retrospective descriptive study of oral azole antifungal agents in patients with patch test-negative head and neck predominant atopic dermatitis.",
"title_normalized": "a retrospective descriptive study of oral azole antifungal agents in patients with patch test negative head and neck predominant atopic dermatitis"
} | [
{
"companynumb": "US-JNJFOC-20140908921",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "In this article, we report two cases from our centre: case A has the longest recovery period and case B is one of the most complex from a diagnostic and management perspective, highlighting how treatment resistance can be overcome depending on patient response and needs.",
"affiliations": "The London Psychiatry Centre, London W1G 7HG, UK.;The London Psychiatry Centre, London W1G 7HG, UK.;The London Psychiatry Centre, London W1G 7HG, UK.",
"authors": "Zamar|Andy|A|;Warrya|Gurvinder|G|;Kouimtsidis|Christos|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2054270417715567",
"fulltext": "\n==== Front\nJRSM OpenJRSM OpenSHRspshrJRSM Open2054-2704SAGE Publications Sage UK: London, England 10.1177/205427041771556710.1177_2054270417715567Case ReportHigh-dose levothyroxine for the management of bipolar affective disorder: two case reports Zamar Andy Warrya Gurvinder Kouimtsidis Christos 9490The London Psychiatry Centre, London W1G 7HG, UKChristos Kouimtsidis. Email: drckouimtsidis@hotmail.com05 9 2017 9 2017 8 9 2054270417715567© The Author(s) 20172017The Royal Society of MedicineThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.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).In this article, we report two cases from our centre: case A has the longest recovery period and case B is one of the most complex from a diagnostic and management perspective, highlighting how treatment resistance can be overcome depending on patient response and needs.\n\nclinicalmood disorders (including depression)psychiatryedited-statecorrected-proof\n==== Body\nCase A\nThis is a 57-year-old female patient with current diagnosis of severe bipolar affective disorder (unspecified). She was referred in 2008, with the diagnosis of recurrent depressive disorder and a two-month history of two episodes of hypo-mania and five episodes of depression following an admission to hospital due to suicidal ideation. She was on lithium carbonate 1000 mg daily. An electrocardiogram at screening showed first degree AV block and normal QTc.\n\nThe patient had experienced multiple episodes of depression alternating with hypo-manic episodes over several years. She has been suicidal on several occasions. She had deteriorated when treated with antidepressants only, marginally improved with courses of electroconvulsive therapy, could not tolerate olanzapine, quetiapine or lamotrigine.\n\nShe was prescribed levothyroxine 200 µg/day in addition to lithium carbonate. Within the first month, patient and family reported improved stability of mood. The dose of levothyroxine was increased to 250 µg/day. Following stability for two months, lithium carbonate was gradually reduced and discontinued at month 4. Thyroid function remained abnormal (free T4 was 49.1), with no clinical symptoms of hyperthyroidism other than a mild tremor. Regular reviews by Cardiologist and Endocrinologist with bone densitometry scans were performed. Over the past seven years the patient remains on levothyroxine 250 µg daily and she has not reported any mood instability.\n\nCase B\nThis is a 23-year-old male patient with 13-year history of increased anxiety, depressive symptoms alternating with periods of flight of ideas, pressured speech, agitation, loss of sleep and total breakdown in social functioning. Previous diagnoses in childhood included depression, Attention Deficit and Hyperactivity Disorder and Asperger’s syndrome. A variety of antidepressants and stimulant medication tried with little effect. The diagnosis of bipolar affective disorder was considered at the age of 18. Risperidone, quetiapine alongside sodium valproate were used for short periods and were discontinued on several occasions due to side effects. Family therapy and cognitive behavioural therapy were tried. There was strong family history (mother’s side) of bipolar affective disorder.\n\nAt the centre, a diagnosis of rapid cycling mood disorder was made. Over the following 12 months, Attention Deficit and Hyperactivity Disorder and antidepressant medication were gradually discontinued and quetiapine XL with sodium valproate (maximum dose of 2000 mg) started with improvement in mood symptoms, reduction in agitation but on-going sedation. Thyroid screening revealed hypothyroidism and sodium valproate levels exceeding normal limits. Sodium valproate dose was reduced to 1500 mg and levothyroxine 100 µg started. Low dose external Trigeminal Nerve Stimulation was started for one week only with increased agitation. Ziprasidone could not be tolerated. Electroconvulsive therapy for eight sessions was used with no effect. Mood fluctuations and agitation have continued.\n\nAt month 12, sodium valproate was changed to Epilim maximum dose, levothyroxine dose increased to 300 µg/day and repetitive Transcranial Magnetic Stimulation was started for six weeks. At month 14, levothyroxine was increased to 400 µg. Mood was reported low with anxiety and agitation but reduced fluctuations. Addition of benzodiazepines and/or antipsychotics were not effective; therefore, all medications but levothyroxine 400 µg were stopped. Regular reviews by Cardiologist and an Endocrinologist with bone densitometry scans were performed. No clinical signs of hyperthyroidism were reported or observed and bone densitometry was normal. Mood became stable and ‘best ever’ for months 17–20.\n\nDue to re-emergence of anxiety and low mood, repetitive Transcranial Magnetic Stimulation was re-started with levothyroxine 400 µg, with mixed results. During months 21 and 22, levothyroxine was increased to 500 µg and at month 24 to 600 µg. Twelve months since initiation of levothyroxine, mood became stable and continues to be for the past 18 months. Mood is reported as ‘far better than ever before’. The patient has recently completed his university degree (1st Class), he is in a relationship, lives independently and travels alone. He also is a regular gym user with a substantial muscle bulk and fitness now. Prior to this, he was mostly bed bound, isolated and living with his parents in need of constant reassurance on many issues. In addition to levothyroxine, maintenance treatment includes repetitive Transcranial Magnetic Stimulation and external Trigeminal Nerve Stimulation once monthly.\n\nDiscussion\nAn extensive literature links mood disorders to disturbances of the hypothalamic–pituitary–thyroid axis. Supra-physiological doses of T4 have been less extensively studied and used compared to physiological doses of T3 in patients with mood disorders.1,2 Small open studies suggest that supra-physiological doses of T4 (up to 500 µg/day) may offer benefit in the treatment of acute bipolar depression,3 in rapid cycling bipolar disorder4 and treatment resistant bipolar affective disorder.5 This paper discusses the management of two patients: case A supports the role of high-dose levothyroxine into the management of rapid cycling bipolar affective disorder4 and case B into the treatment resistant bipolar affective disorder.5\n\nThe observations reported in this paper are based on two cases only, and therefore, could not be generalised to other cases. Case reports though can inform clinical practice and provide guidance until randomised control trials provide the relevant evidence.\n\nAcknowledgements\nNone.\n\nDeclarations\nCompeting Interests\nNone declared.\n\nFunding\nNone declared.\n\nEthical approval\nWritten informed consent for publication was obtained from the patients.\n\nGuarantor\nCK\n\nContributorship\nAZ was the treating clinician and contributed to the write up of the paper. GW reviewed the case notes and prepared the early drafts of the paper. CK wrote the submitted version of the paper.\n\nProvenance\nNot commissioned; peer-reviewed by Jibowu Olubokun and Christine Walker.\n==== Refs\nReferences\n1 Bauer MS Whybrow PC Winokur A \nRapid cycling bipolar affective disorder I. Association with grade I hypothyroidism . Arch Gen Psychiatry \n1990 ; 47 : 427 –432 .2109970 \n2 Cowdry RW Wehr TA Zis AP Goodwin FK \nThyroid abnormalities associated with rapid-cycling bipolar illness . Arch Gen Psychiatry \n1983 ; 40 : 414 –420 .6404231 \n3 Bauer M London ED Rasgon N Berman SM Frye MA Altshuler LL et al. \nSupraphysiological doses of levothyroxine alter regional cerebral metabolism and improve mood in bipolar depression . Mol Psychiatry \n2005 ; 10 : 456 –469 .15724143 \n4 Mark S Bauer MD Peter C Whybrow MD \nRapid cycling bipolar affective disorder II. Treatment of refractory rapid cycling with high-dose levothyroxine: a preliminary study . Arch Gen Psychiatry \n1990 ; 47 : 435 –440 .2184796 \n5 Baumgartner A Bauer M Hellweg R \nTreatment of intractable non-rapid cycling bipolar affective disorder with high-dose thyroxine: an open clinical trial . Neuropsychopharmacology \n1994 ; 10 : 183 –189 .7916915\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2054-2704",
"issue": "8(9)",
"journal": "JRSM open",
"keywords": "clinical; mood disorders (including depression); psychiatry",
"medline_ta": "JRSM Open",
"mesh_terms": null,
"nlm_unique_id": "101625786",
"other_id": null,
"pages": "2054270417715567",
"pmc": null,
"pmid": "28904805",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports",
"references": "2184796;15724143;2109970;6404231;7916915",
"title": "High-dose levothyroxine for the management of bipolar affective disorder: two case reports.",
"title_normalized": "high dose levothyroxine for the management of bipolar affective disorder two case reports"
} | [
{
"companynumb": "GB-MYLANLABS-2019M1042007",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
"drugadditional": "1",
... |
{
"abstract": "Öncü-Öner T, Ünalp A, Porsuk-Doru İ, Ağılkaya S, Güleryüz H, Saraç A, Ergüner B, Yüksel B, Hız-Kurul S, Cingöz S. GPR56 homozygous nonsense mutation p.R271* associated with phenotypic variability in bilateral frontoparietal polymicrogyria. Turk J Pediatr 2018; 60: 229-237. Polymicrogyria is a disorder of neuronal migration characterized by excessive cortical folding and partially fused gyri separated by shallow sulci. Homozygous mutations in the GPR56 gene, which regulates migration of neural precursor cells, are associated with bilateral frontoparietal polymicrogyria (BFPP) syndrome including white matter changes, brainstem and cerebellar involvement. Herein, we describe three siblings of consanguineous parents with a homozygous germline mutation (p.R271*) located in the seventh exon of the GPR56 gene that was previously detected in only one Portuguese patient. Phenotypic/genotypic relationships were analysed according to the clinical characteristics in only index patient. While earlier reported patient was exhibiting seizures provoked by hot water, macrocephaly, cerebellar/brainstem hypoplasia and corpus callosum abnormalities, the index patient showed only hypoplasia of brainstem, focal onset bilateral tonic clonic seizure. Despite the phenotypic similarities in two patients, the potential causes of the variation in the expression of the p.R271* variant between the two affected families might be genetic or epigenetic factors beyond the GPR56 gene. Consequently, the present findings show that the same mutation in GPR56 gene can have different phenotypic effects. Therefore, additional functional studies are needed to detect the phenotypic spectrum of the p.R271* mutation in GPR56, and provide insight into the mechanism of normal cortical development and regional patterning of the cerebral cortex.",
"affiliations": "Departments of Medical Biology and Genetics, Dokuz Eylül University Faculty of Medicine, İzmir, Turkey.;Department of Pediatric Neurology, Dr. Behcet Uz Children's Hospital, İzmir, Turkey.;Departments of Medical Biology and Genetics, Dokuz Eylül University Faculty of Medicine, İzmir, Turkey.;Departments of Medical Biology and Genetics, Dokuz Eylül University Faculty of Medicine, İzmir, Turkey.;Departments of Pediatric Radiology, Dokuz Eylül University Faculty of Medicine, İzmir, Turkey.;Genetic Engineering and Biotechnology Institute, TUBITAK Marmara Research Center.;Advanced Genomics and Bioinformatics Research Center (İGBAM), The Scientific and Technological Research Council of Turkey (TUBITAK), BİLGEM, Kocaeli, Turkey.;Genetic Engineering and Biotechnology Institute, TUBITAK Marmara Research Center.;Departments of Pediatric Neurology, Dokuz Eylül University Faculty of Medicine, İzmir, Turkey.;Departments of Medical Biology and Genetics, Dokuz Eylül University Faculty of Medicine, İzmir, Turkey.",
"authors": "Öncü-Öner|Tülay|T|;Ünalp|Aycan|A|;Porsuk-Doru|İlknur|İ|;Ağılkaya|Sinem|S|;Güleryüz|Handan|H|;Saraç|Aydan|A|;Ergüner|Bekir|B|;Yüksel|Bayram|B|;Hız-Kurul|Semra|S|;Cingöz|Sultan|S|",
"chemical_list": "C118925:ADGRG1 protein, human; D018389:Codon, Nonsense; D043562:Receptors, G-Protein-Coupled",
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-4301",
"issue": "60(3)",
"journal": "The Turkish journal of pediatrics",
"keywords": "BFPP; GPR56 mutations; polymicrogyria; whole exome sequencing",
"medline_ta": "Turk J Pediatr",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000073537:Biological Variation, Population; D001921:Brain; D018389:Codon, Nonsense; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D054220:Malformations of Cortical Development; D058953:Neural Stem Cells; D010375:Pedigree; D043562:Receptors, G-Protein-Coupled; D000073359:Whole Exome Sequencing; D055815:Young Adult",
"nlm_unique_id": "0417505",
"other_id": null,
"pages": "229-237",
"pmc": null,
"pmid": "30511534",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "GPR56 homozygous nonsense mutation p.R271* associated with phenotypic variability in bilateral frontoparietal polymicrogyria.",
"title_normalized": "gpr56 homozygous nonsense mutation p r271 associated with phenotypic variability in bilateral frontoparietal polymicrogyria"
} | [
{
"companynumb": "TR-UCBSA-2018054008",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"drugadditional": "3",
"dr... |
{
"abstract": "The relationship between acute life stress and the development of atrial fibrillation (AF) has been noted in the literature. However, the use of integrative medicine (IM) in restoring cardiac rhythm has not been adequately studied. This case report describes how an IM approach was used in a patient with atrial fibrillation and acute pain. Spontaneous cardioversion to normal sinus rhythm occurred during the IM session, in addition to marked decreases in self-reported pain, anxiety, and nausea at the conclusion of IM treatment. These results provide initial support that for some cases of AF, IM therapies can help to reduce costs via avoidance of additional hospitalization, electrocardioversion, and general anesthesia.",
"affiliations": "Wendy S. Farrar, MSW, NCTMB, is an integrative health practitioner at Penny George Institute for Health and Healing and Allina Health/Abbott Northwestern Hospital, Minneapolis, Minnesota.",
"authors": "Farrar|Wendy S|WS|;Fyfe-Johnson|Amber L|AL|;Baechler|Courtney J|CJ|;Dusek|Jeffery A|JA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7453/gahmj.2012.1.2.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2164-9561",
"issue": "1(2)",
"journal": "Global advances in health and medicine",
"keywords": "India; Sinus rhythm; anxiety; aromatherapy; atrial fibrillation; cardiac; case reports; coronary heart disease; guided imagery; hypertension; massage; nausea; obesity; pain; stress",
"medline_ta": "Glob Adv Health Med",
"mesh_terms": null,
"nlm_unique_id": "101584936",
"other_id": null,
"pages": "22-5",
"pmc": null,
"pmid": "24278814",
"pubdate": "2012-05",
"publication_types": "D002363:Case Reports",
"references": "15336336;14533321;21589696;16368364;15878557;20347836;4810622;11343485;20807278;22130304;19944872;9543032;18607243;21177058;1560803;14607452;9002492;18596974;16310432;15687136;7971330;23375926;19552264;9502640;15478786;12032044;21663602;20004797;4130474",
"title": "Spontaneous normal sinus rhythm conversion using integrative medicine in atrial fibrillation.",
"title_normalized": "spontaneous normal sinus rhythm conversion using integrative medicine in atrial fibrillation"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP028745",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditiona... |
{
"abstract": "Progressive multifocal leukoencephalopathy (PML), a demyelinating disorder caused by brain infection with JC virus, is a neurological complication of immunocompromised states and immunosuppressive therapies. While most commonly seen in the HIV/AIDS population, patients with hematologic malignancies are also at risk following treatment protocols including monoclonal antibodies such as rituximab and after hematopoietic stem cell transplantation. Here, we present the case of PML following allogeneic HCT that highlights potential diagnostic difficulties. We also review the literature regarding PML following HCT and described therapies employed to attempt to treat this disorder.",
"affiliations": "Department of Medicine, Mayo Clinic, Rochester, MN, USA.",
"authors": "Kaufman|Gregory P|GP|;Aksamit|Allen J|AJ|;Klein|Christopher J|CJ|;Yi|Eunhee S|ES|;Delone|David R|DR|;Litzow|Mark R|MR|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/ejh.12208",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "92(1)",
"journal": "European journal of haematology",
"keywords": "allogeneic bone marrow transplantation; encephalitis; hematopoietic cell transplantation; immunocompromised host; progressive multifocal leukoencephalopathy",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000368:Aged; D001706:Biopsy; D001921:Brain; D017809:Fatal Outcome; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007577:JC Virus; D007968:Leukoencephalopathy, Progressive Multifocal; D008279:Magnetic Resonance Imaging; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D014184:Transplantation, Homologous",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "83-7",
"pmc": null,
"pmid": "24118404",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Progressive multifocal leukoencephalopathy: a rare infectious complication following allogeneic hematopoietic cell transplantation (HCT).",
"title_normalized": "progressive multifocal leukoencephalopathy a rare infectious complication following allogeneic hematopoietic cell transplantation hct"
} | [
{
"companynumb": "PHHY2015US110340",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"drugadditional": null,
"drug... |
{
"abstract": "One of the most serious known adverse effects of feminizing cross-sex hormone therapy (CSHT) is venous thromboembolism (VTE); however, no study has assessed the incidence of VTE from the hormone therapies used in the United States because previous publications on this topic have originated in Europe. CSHT in the United States typically includes estradiol with the antiandrogen spironolactone, whereas in Europe estradiol is prescribed with the progestin cyproterone acetate.\n\n\n\nTo estimate the incidence of VTE from the standard feminizing CSHTs used in the United States.\n\n\n\nA retrospective chart review of transgender women who had been prescribed oral estradiol at a District of Columbia community health center was performed.\n\n\n\nThe primary outcomes of interest were deep vein thrombosis or pulmonary emboli.\n\n\n\nFrom January 1, 2008 through March 31, 2016, 676 transgender women received oral estradiol-based CSHT for a total of 1,286 years of hormone treatment and a mean of 1.9 years of CSHT per patient. Only one individual, or 0.15% of the population, sustained a VTE, for an incidence of 7.8 events per 10,000 person-years.\n\n\n\nThere was a low incidence of VTE in this population of transgender women receiving oral estradiol.",
"affiliations": "Whitman-Walker Health, Washington, DC, USA; The George Washington University School of Medicine and Health Sciences, Washington, DC, USA. Electronic address: jarnold@gwu.edu.;Whitman-Walker Health, Washington, DC, USA.;Whitman-Walker Health, Washington, DC, USA.;Whitman-Walker Health, Washington, DC, USA.",
"authors": "Arnold|Justin D|JD|;Sarkodie|Eleanor P|EP|;Coleman|Megan E|ME|;Goldstein|Deborah A|DA|",
"chemical_list": "D000726:Androgen Antagonists; D004967:Estrogens; D012739:Gonadal Steroid Hormones; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D017373:Cyproterone Acetate; D004958:Estradiol",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jsxm.2016.09.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1743-6095",
"issue": "13(11)",
"journal": "The journal of sexual medicine",
"keywords": "Cross-Sex Hormone Therapy; Gender Identity; Hormone Replacement Therapy; Transgender Persons; Venous Thromboembolism",
"medline_ta": "J Sex Med",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000726:Androgen Antagonists; D017373:Cyproterone Acetate; D004219:District of Columbia; D004958:Estradiol; D004967:Estrogens; D005060:Europe; D005260:Female; D005783:Gender Identity; D012739:Gonadal Steroid Hormones; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D000451:Mineralocorticoid Receptor Antagonists; D012189:Retrospective Studies; D012307:Risk Factors; D013148:Spironolactone; D063106:Transgender Persons; D014189:Transsexualism; D020246:Venous Thrombosis",
"nlm_unique_id": "101230693",
"other_id": null,
"pages": "1773-1777",
"pmc": null,
"pmid": "27671969",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Incidence of Venous Thromboembolism in Transgender Women Receiving Oral Estradiol.",
"title_normalized": "incidence of venous thromboembolism in transgender women receiving oral estradiol"
} | [
{
"companynumb": "US-TEVA-726863USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SPIRONOLACTONE"
},
"drugadditional": "3",
"... |
{
"abstract": "BACKGROUND\nHypertension as a cardiovascular disease risk factor continues to take a heavy toll on the population despite efforts with containment. Poor control, even among those on treatment, is part of the challenge and results from patient, physician and health system factors. When the problem resides at patient level, adherence is largely responsible. An entity defined as multidrug intolerance (MDI) is hardly considered. A situation when a patient is willing to adhere but is compelled otherwise could frustrate both patient and physician. Encountering a few such cases prompted the author to audit his specialized hypertension service in order to evaluate the burden of MDI and its associations.\n\n\nMETHODS\nBetween 7 May and 30 July 2016 (to cover a 12-week cycle which ensured all attendees were captured), all patients attending follow up for blood pressure control had their records evaluated for intolerance to three or more different classes of anti-hypertensives, which defines MDI. Their ages, sex, control state and co-morbidities were extracted from the records.\n\n\nRESULTS\nA total of 489 patients with hypertension were seen over the period; 271 (55.4%) of whom were women and 248 (50.7%) were uncontrolled. Overall 15 (3.1%) satisfied the definition of MDI; 10 women and 5 men. All the men with MDI were uncontrolled while 7 out of the 10 women were uncontrolled; with two having premenstrual syndrome as co-morbidity. A total of four patients (three men, one woman) had history suggesting allergy and two (one man, one woman) were on treatment for anxio-depressive illness.\n\n\nCONCLUSIONS\nMDI does occur in sub-Sahara African patients with hypertension and should be considered before describing hypertension as resistant or considering alternative treatments including device therapy. Staggering doses or trying different formulations could be of benefit.",
"affiliations": "Cardiology Sub-Unit 1, Department of Medicine, Jos University Teaching Hospital, PMB 2076, Jos, Plateau, 930001, Nigeria.",
"authors": "Okeahialam|Basil N|BN|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2042098617705625",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2042-0986",
"issue": "8(8)",
"journal": "Therapeutic advances in drug safety",
"keywords": "Nigeria; drug; hypertension; intolerance; multiple; poor control",
"medline_ta": "Ther Adv Drug Saf",
"mesh_terms": null,
"nlm_unique_id": "101549074",
"other_id": null,
"pages": "253-258",
"pmc": null,
"pmid": "28781737",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article",
"references": "18844769;15157754;18391085;27695289;15508001;22777025;17718101;11899280;27601925;22289726;12622606;26306794;25517090;23690342;18025295;26254049;23799329",
"title": "Multidrug intolerance in the treatment of hypertension: result from an audit of a specialized hypertension service.",
"title_normalized": "multidrug intolerance in the treatment of hypertension result from an audit of a specialized hypertension service"
} | [
{
"companynumb": "NG-LUPIN PHARMACEUTICALS INC.-2017-04531",
"fulfillexpeditecriteria": "2",
"occurcountry": "NG",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ATENOLOL\\CHLORTHALIDONE"
},
... |
{
"abstract": "Lymphatic malformations (LMs) are challenging to manage, particularly those involving the cervicofacial region and airway. Traditional therapy is sclerotherapy and/or resection. We aim to establish the emerging therapeutic role of sirolimus.\n\n\n\nInstitutional review board-approved retrospective review.\n\n\n\nAll patients treated for cervicofacial LM with sirolimus at Boston Children's Hospital, Massachusetts, from November 2012 to October 2016 were included. Chart review included response to therapy (defined as reduction in LM bulk by clinical photographs and radiologic imaging), type of LM (microcystic, macrocystic, mixed), extent of disease, duration of therapy, patient/parent-reported quality-of-life, airway status (tracheostomy dependence), and complications (opportunistic infection, hemorrhage, other). Follow-up and clinical outcomes were included up until October 2016.\n\n\n\nNineteen patients were treated with sirolimus for cervicofacial LM from November 2012 to October 2016 at Boston Children's Hospital. Seven patients remain on uninterrupted sirolimus. Of 12 patients who stopped therapy, seven have resumed due to recurrence of symptoms. All patients demonstrated reduction in LM bulk, ranging from modest to significant. All patients with mucosal vesicles (n = 14) resolved or improved on sirolimus. Six patients developed cellulitis, and four had bleeding within the LM during treatment. No patients developed opportunistic or systemic bacterial infection.\n\n\n\nThe use of sirolimus in the management of cervicofacial LM often is efficacious, with limited adverse events. Long-term follow-up, durability of response, and coordination of sirolimus prior to procedural therapies need further study.\n\n\n\n4. Laryngoscope, 128:269-276, 2018.",
"affiliations": "Department of Otolaryngology and Communication Enhancement, Boston Children's Hospital, Boston, Massachusetts, U.S.A.;Department of Otolaryngology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, U.S.A.;Vascular Anomalies Center, Boston Children's Hospital, Boston, Massachusetts, U.S.A.;Department of Otolaryngology and Communication Enhancement, Boston Children's Hospital, Boston, Massachusetts, U.S.A.;Vascular Anomalies Center, Boston Children's Hospital, Boston, Massachusetts, U.S.A.;Vascular Anomalies Center, Boston Children's Hospital, Boston, Massachusetts, U.S.A.",
"authors": "Strychowsky|Julie E|JE|;Rahbar|Reza|R|;O'Hare|Meghan J|MJ|;Irace|Alexandria L|AL|0000-0003-4758-3146;Padua|Horacio|H|;Trenor|Cameron C|CC|",
"chemical_list": "D007166:Immunosuppressive Agents; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.1002/lary.26780",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0023-852X",
"issue": "128(1)",
"journal": "The Laryngoscope",
"keywords": "Sirolimus; lymphatic malformation",
"medline_ta": "Laryngoscope",
"mesh_terms": "D002675:Child, Preschool; D005145:Face; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D044148:Lymphatic Abnormalities; D008297:Male; D009333:Neck; D011788:Quality of Life; D012189:Retrospective Studies; D020123:Sirolimus; D014139:Tracheostomy; D016896:Treatment Outcome",
"nlm_unique_id": "8607378",
"other_id": null,
"pages": "269-276",
"pmc": null,
"pmid": "28782106",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Sirolimus as treatment for 19 patients with refractory cervicofacial lymphatic malformation.",
"title_normalized": "sirolimus as treatment for 19 patients with refractory cervicofacial lymphatic malformation"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/18/0096050",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe coincidental occurrence of a cardiac symptomatology (e.g. an acute coronary syndrome or a myocardial infarction), during an anaphylactic or anaphylactoid episode is known as Kounis Syndrome. A variety of drugs, substances, food and environmental exposures are associated with this reaction. There is an exponential increase in the number of published scientific articles reports on this syndrome, but since it is rare, the largest case series published so far included only 10 and 6 patients.\n\n\nMETHODS\nWe searched the global World Health Organization database called VigiBase™ to detect all cases of Kounis Syndrome ever reported (last update December 31st 2014).\n\n\nRESULTS\nWe identified 51 cases of Kounis Syndrome reported to International Pharmacovigilance Agency (VigiBase™). All these cases were reported in the period 2010-2014 and almost half cases (22 reports) belonged to the year 2014. Most cases occurred in the USA and non-steroidal anti-inflammatory drugs were the most frequent trigger drugs.\n\n\nCONCLUSIONS\nWe collected pharmacovigilance international data representing the largest case series ever published on the recently identified Kounis Syndrome.",
"affiliations": "Italian Medicines Agency, Rome, Italy.;IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. Electronic address: landoni.giovanni@hsr.it.;Italian Medicines Agency, Rome, Italy.;Department of Medical Sciences \"M. Aresu\", Cagliari University, Cagliari, Italy.;Department of Medical Sciences \"M. Aresu\", Cagliari University, Cagliari, Italy.;Italian Medicines Agency, Rome, Italy.;Italian Medicines Agency, Rome, Italy.;Italian Medicines Agency, Rome, Italy.",
"authors": "Renda|Francesca|F|;Landoni|Giovanni|G|;Trotta|Francesco|F|;Piras|Desiderio|D|;Finco|Gabriele|G|;Felicetti|Patrizia|P|;Pimpinella|Giuseppe|G|;Pani|Luca|L|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-5273",
"issue": "203()",
"journal": "International journal of cardiology",
"keywords": "Acute coronary syndrome; Coronary vasospasm; Drug hypersensivity; Miocardial infarction; Rare diseases",
"medline_ta": "Int J Cardiol",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000328:Adult; D000707:Anaphylaxis; D016208:Databases, Factual; D005260:Female; D014943:Global Health; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D060735:Pharmacovigilance; D013577:Syndrome",
"nlm_unique_id": "8200291",
"other_id": null,
"pages": "217-20",
"pmc": null,
"pmid": "26512841",
"pubdate": "2016-01-15",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Kounis Syndrome: An analysis of spontaneous reports from international pharmacovigilance database.",
"title_normalized": "kounis syndrome an analysis of spontaneous reports from international pharmacovigilance database"
} | [
{
"companynumb": "IT-THE MEDICINES COMPANY-IT-MDCO-16-00448",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BISOPROLOL"
},
"drugaddition... |
{
"abstract": "An 83-year-old man developed acute kidney failure after intra-articular use of gentamicin sponges for a periprosthetic hip infection. Haemodialysis was necessary for clearance of gentamicin, and for kidney function replacement. It is important to be aware that there is a risk of renal toxicity due to gentamicin when using a locally applied sponge.",
"affiliations": "Department of Geriatrics, Catharina Hospital, Eindhoven, the Netherlands; Current position: Geriatics, St Anna Hospital Geldrop, the Netherlands.",
"authors": "Gommans|E P A T|EPAT|;Aarnoudse|A L H J|ALHJ|;van Wensen|R J A|RJA|;van Erp-van Boekel|A A W|AAW|;Grouls|R J E|RJE|;van der Linden|C M J|CMJ|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005839:Gentamicins",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-2977",
"issue": "78(2)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000900:Anti-Bacterial Agents; D005839:Gentamicins; D006622:Hip Prosthesis; D006801:Humans; D008297:Male; D016459:Prosthesis-Related Infections",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "87-89",
"pmc": null,
"pmid": "32641561",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute kidney failure after intra-articular use of gentamicin sponge.",
"title_normalized": "acute kidney failure after intra articular use of gentamicin sponge"
} | [
{
"companynumb": "NL-PFIZER INC-2020295747",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GENTAMICIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSevere cutaneous adverse reactions (SCAR) are rare but important causes of morbidity and mortality. Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) are severe cutaneous drug reactions that can be potentially life threatening. Our study aims to look at the epidemiology of SCAR in the local setting in Singapore and the underlying characteristics of our patients that may influence the drug reaction seen.\n\n\nMETHODS\nData was collected retrospectively from in-patient records in the period of January 2007 to December 2011. We looked at several factors: (i) patient demographics including age, gender, ethnicity, comorbidities, (ii) culprit drug(s), (iii) latent period, (iv) drug reaction observed, (v) systemic complications, (vi) length of hospital stay, (vii) treatment given, and (viii) outcomes (mortality, morbidity).\n\n\nRESULTS\nWe collected data from 42 patients. The mean age of our patients was 51.8 years. Twenty-nine (69%) of the patients had underlying comorbidities. The most common culprit drug group was antibiotics. SJS was the most common SCAR observed (54.8%), followed by acute generalized exanthematous pustolosis (AGEP; 24%), TEN (11.9%), and DRESS (2%). Sixteen patients (38.1%) had complications, and there was one reported death. There was a weak correlation (correlation coefficient 0.29, P value = 0.15, 95% CI = 2.07) between early steroid therapy and the length of stay.\n\n\nCONCLUSIONS\nAntibiotics are the most common culprit drugs. The most common SCAR observed in our study was SJS. Early initiation of steroids may lead to a more favorable outcome.",
"affiliations": "National University Hospital Singapore, Singapore.",
"authors": "Su|Peiqi|P|;Aw|Chen Wee Derrick|CW|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000927:Anticonvulsants; D006074:Gout Suppressants; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D013256:Steroids; D000493:Allopurinol",
"country": "England",
"delete": false,
"doi": "10.1111/ijd.12118",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-9059",
"issue": "53(11)",
"journal": "International journal of dermatology",
"keywords": null,
"medline_ta": "Int J Dermatol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000493:Allopurinol; D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000927:Anticonvulsants; D002648:Child; D015897:Comorbidity; D063926:Drug Hypersensitivity Syndrome; D005260:Female; D006074:Gout Suppressants; D006764:Hospitals, Community; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D012846:Singapore; D013256:Steroids; D013262:Stevens-Johnson Syndrome; D055815:Young Adult",
"nlm_unique_id": "0243704",
"other_id": null,
"pages": "1339-45",
"pmc": null,
"pmid": "25070588",
"pubdate": "2014-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Severe cutaneous adverse reactions in a local hospital setting: a 5-year retrospective study.",
"title_normalized": "severe cutaneous adverse reactions in a local hospital setting a 5 year retrospective study"
} | [
{
"companynumb": "SG-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-101945",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"druga... |
{
"abstract": "Immune checkpoint inhibitor (ICI)-related pneumonitis is a relatively rare but clinically serious and potentially life-threatening adverse event. The majority of cases can be managed by drug discontinuation, with the administration of corticosteroids added in severe cases. However, worsening of pneumonitis can develop in a subset of patients despite treatment with high doses of corticosteroids. We herein report a case of steroid-refractory ICI-related pneumonitis in a recurrent non-small cell lung cancer (NSCLC) patient treated with pembrolizumab that was successfully improved by triple combination therapy (high-dose corticosteroids, tacrolimus, and cyclophosphamide). After 3 weeks of initial pembrolizumab administration, the patient was diagnosed with ICI-related pneumonitis. Chest computed tomography (CT) showed patchy distributed bilateral consolidation and ground-glass opacities (GGOs) with traction bronchiectasis and bronchiolectasis resembling the diffuse alveolar damage (DAD) radiographic pattern. Although methylprednisolone pulse therapy was initiated, worsening of respiratory failure resulted in the patient being transferred to the intensive care unit. Because of an insufficient therapeutic response to high-dose corticosteroids, tacrolimus and cyclophosphamide pulse therapy were additively performed as triple combination therapy according to the treatment strategy for pulmonary complications of clinically amyopathic dermatomyositis (CADM). In response to this triple combination therapy, the patient's respiratory condition gradually improved, and chest CT showed the marked amelioration of pulmonary opacities. This is the first report suggesting the efficacy of triple combination therapy (high-dose corticosteroids, tacrolimus, and cyclophosphamide) for steroid-refractory ICI-related pneumonitis complicated with respiratory failure.",
"affiliations": "Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-19-18 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan. hiro173@jikei.ac.jp.;Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-19-18 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-19-18 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-19-18 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-19-18 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-19-18 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-19-18 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-19-18 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-19-18 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-19-18 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-19-18 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.;Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-19-18 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.",
"authors": "Utsumi|Hirofumi|H|http://orcid.org/0000-0003-4845-0599;Araya|Jun|J|;Okuda|Keitaro|K|;Watanabe|Junko|J|;Takekoshi|Daisuke|D|;Fujita|Yu|Y|;Hashimoto|Mitsuo|M|;Wakui|Hiroshi|H|;Minagawa|Shunsuke|S|;Numata|Takanori|T|;Hara|Hiromichi|H|;Kuwano|Kazuyoshi|K|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; C582435:pembrolizumab; D016559:Tacrolimus",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00262-020-02600-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-7004",
"issue": "69(10)",
"journal": "Cancer immunology, immunotherapy : CII",
"keywords": "Immune checkpoint inhibitor; Non-small cell lung cancer; Pembrolizumab; Pneumonitis; Steroid-refractory; Triple combination therapy",
"medline_ta": "Cancer Immunol Immunother",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D002289:Carcinoma, Non-Small-Cell Lung; D003520:Cyclophosphamide; D004359:Drug Therapy, Combination; D006801:Humans; D007166:Immunosuppressive Agents; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011014:Pneumonia; D011379:Prognosis; D016559:Tacrolimus",
"nlm_unique_id": "8605732",
"other_id": null,
"pages": "2033-2039",
"pmc": null,
"pmid": "32415507",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of steroid-refractory immune checkpoint inhibitor-related pneumonitis with triple combination therapy: a case report.",
"title_normalized": "successful treatment of steroid refractory immune checkpoint inhibitor related pneumonitis with triple combination therapy a case report"
} | [
{
"companynumb": "JP-SGP-000013",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nFilgrastim-sndz, a granulocyte-colony stimulating factor (G-CSF), was introduced as a biosimilar to filgrastim in 2015, but real-world comparative effectiveness for filgrastim versus filgrastim-sndz has not been reported to date.\n\n\nOBJECTIVE\nTo (a) compare the incidence of febrile neutropenia for patients taking filgrastim versus those taking filgrastim-sndz and (b) compare the incidence of a potential serious adverse event for filgrastim versus filgrastim-sndz.\n\n\nMETHODS\nThis retrospective cohort study identified patients receiving a G-CSF following chemotherapy, using administrative claims from the Humana Research Database. Patients enrolled in a Medicare Advantage Prescription Drug plan with a claim for a G-CSF from October 1, 2015, through September 30, 2016, were identified. G-CSF use had to occur within 6 days of exposure to chemotherapy and without any subsequent chemotherapy within 14 days after G-CSF use. Febrile neutropenia requiring hospitalization was defined as hospitalization within 14 days after G-CSF use with (a) diagnosis of infection and/or neutropenia (broad definition) or (b) infection and neutropenia diagnoses (narrow definition). Serious adverse drug events (spleen rupture, acute respiratory syndrome, serious allergic reactions, capillary leak syndrome, thrombocytopenia, leukocytosis, cutaneous vasculitis, or bones and muscle ache) were also identified within 14 days after G-CSF use. An incidence difference of < 1% with 90% CI crossing zero qualified as support for noninferiority. Two-tailed chi-square tests were also used to investigate differences.\n\n\nRESULTS\nA total of 88 filgrastim and 101 filgrastim-sndz patients were identified. Filgrastim and filgrastim-sndz met the criteria for noninferiority based on an incidence difference of -0.6% (90% CI = -5.1%-4.0%; P = 0.84) for the broad definition of febrile neutropenia and a difference of -0.8% (90% CI = -3.8%-2.1%; P = 0.64) for the narrow definition. For the analysis of serious adverse events, an incidence difference of -2.5% (90% CI = -7.5%-2.5%; P = 0.42) for filgrastim compared with filgrastim-sndz was not sufficient to establish noninferiority.\n\n\nCONCLUSIONS\nThis study is one of the first analyses of real-world evidence regarding the noninferiority of filgrastim and filgrastim-sndz. The study results support noninferiority of filgrastim and filgrastim-sndz for prevention of febrile neutropenia requiring hospitalization. While noninferiority for serious adverse events was not supported, there was also no statistically significant difference between filgrastim and filgrastim-sndz. The study's small sample size could have limited the analysis of the relatively rare outcomes of febrile neutropenia requiring hospitalization and serious adverse events. A study including a larger numbers of patients taking filgrastim or filgrastim-sndz could provide additional insights.\nThis study received no outside funding. Douglas, Kennedy, and Slabaugh were employees of Humana Pharmacy Solutions at the time the study was conducted. Bowe, Schwab, and Lane were employees of Comprehensive Health Insights, a wholly owned subsidiary of Humana, at the time the study was conducted. Study concept and design were contributed by Douglas, Kennedy, Schwab, and Lane, along with Slabaugh and Bowe. Bowe took the lead in data collection, assisted by Schwab, and data interpretation was performed by Schwab, along with the other authors. The manuscript was written by Schwab, Lane, and Douglas and revised by Kennedy, Slabaugh, and Bowe, along with Schwab, Lane, and Douglas.",
"affiliations": "1 Humana Pharmacy Solutions, Humana, Louisville, Kentucky.;2 Comprehensive Health Insights, Humana, Louisville, Kentucky.;2 Comprehensive Health Insights, Humana, Louisville, Kentucky.;1 Humana Pharmacy Solutions, Humana, Louisville, Kentucky.;1 Humana Pharmacy Solutions, Humana, Louisville, Kentucky.;2 Comprehensive Health Insights, Humana, Louisville, Kentucky.",
"authors": "Douglas|Andrea G|AG|;Schwab|Phil|P|;Lane|Daniel|D|;Kennedy|Kenneth|K|;Slabaugh|S Lane|SL|;Bowe|Andy|A|",
"chemical_list": "D000970:Antineoplastic Agents; D059451:Biosimilar Pharmaceuticals; D006401:Hematologic Agents; D000069585:Filgrastim",
"country": "United States",
"delete": false,
"doi": "10.18553/jmcp.2017.23.12.1221",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "23(12)",
"journal": "Journal of managed care & specialty pharmacy",
"keywords": null,
"medline_ta": "J Manag Care Spec Pharm",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D059451:Biosimilar Pharmaceuticals; D064146:Chemotherapy-Induced Febrile Neutropenia; D015331:Cohort Studies; D005260:Female; D000069585:Filgrastim; D006401:Hematologic Agents; D006760:Hospitalization; D006801:Humans; D015994:Incidence; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013997:Time Factors; D055815:Young Adult",
"nlm_unique_id": "101644425",
"other_id": null,
"pages": "1221-1226",
"pmc": null,
"pmid": "29172983",
"pubdate": "2017-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "A Comparison of Brand and Biosimilar Granulocyte-Colony Stimulating Factors for Prophylaxis of Chemotherapy-Induced Febrile Neutropenia.",
"title_normalized": "a comparison of brand and biosimilar granulocyte colony stimulating factors for prophylaxis of chemotherapy induced febrile neutropenia"
} | [
{
"companynumb": "US-AMGEN-USASP2022046240",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "To date, the standard treatments for severe anticipatory nausea and vomiting is not well established. 5-HT3 antagonist is one of the effective drugs to reduce chemotherapy-induced nausea and vomiting, but had no effect on these symptoms for this patient. The patient could be successfully administered standard chemotherapy(FOLFOX or FOLFIRI, q2w)without adverse reactions by appropriate treatments in the form of increased doses of dexamethasone and normal dose administration of prochlorperazine. This report suggests a possibility that FOLFOX or FOLFIRI may be successfully treated by appropriate treatments for severe chemotherapy-induced vomiting colon cancer patients, and that this observation may lead to the improved prognosis of these patients.",
"affiliations": "Dept. of Pharmacy, Houju Memorial Hospital.",
"authors": "Mori|Mitsue|M|;Kiba|Takayoshi|T|;Oikawa|Mika|M|;Hokkoku|Kengou|K|;Watanabe|Yuri|Y|;Nakagawa|Takashi|T|;Shintaku|Kimiko|K|;Yoshimitsu|Yutaka|Y|;Sakuma|Hiroshi|H|;Ueda|Hiroshi|H|;Nakai|Masuo|M|",
"chemical_list": "D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "36(2)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009325:Nausea; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds; D012004:Rectal Neoplasms; D014839:Vomiting",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "325-7",
"pmc": null,
"pmid": "19223757",
"pubdate": "2009-02",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Report of a case effectively treated by appropriate therapy for severe anticipatory nausea and vomiting due to FOLFOX or FOLFIRI.",
"title_normalized": "report of a case effectively treated by appropriate therapy for severe anticipatory nausea and vomiting due to folfox or folfiri"
} | [
{
"companynumb": "PHHY2016JP099466",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Dimethyl fumarate (DMF) is a first line medication for multiple sclerosis. It has a favourable safety profile, however, there is concern regarding the occurrence of moderate-severe and sustained lymphopenia and the associated risk of progressive multifocal leukoencephalopathy. We carried out an extensive literature review to understand the molecular mechanisms underlying this adverse reaction. Dynamic changes in certain components of the immune system are likely to be important for the therapeutic effects of DMF, including depletion of memory T cells and decrease in activated T cells together with expansion of naïve T cells. Similar modifications were reported for the B cell components. CD8+ T cells are particularly susceptible to DMF-induced cell death, with marked reductions observed in lymphopenic subjects. The reasons underlying such increased sensitivity are not known, nor it is known how expansion of other lymphocyte subsets occurs. Understanding the molecular mechanisms underlying DMF action is challenging: in vivo DMF is rapidly metabolized to monomethyl fumarate (MMF), a less potent immunomodulator in vitro. Pharmacokinetics indicate that MMF is the main active species in vivo. However, the relative importance of DMF and MMF in toxicity remains unclear, with evidence presented in favour of either of the compounds as toxic species. Pharmacogenetic studies to identify genetic predictors of DMF-induced lymphopenia are limited, with inconclusive results. A role of the gut microbiome in the pharmacological effects of DMF is emerging. It is clear that further investigations are necessary to understand the mechanisms of DMF-induced lymphopenia and devise preventive strategies. Periodic monitoring of absolute lymphocyte counts, currently performed in clinical practise, allows for the early detection of lymphopenia as a risk-minimization strategy.",
"affiliations": "MRC Centre for Drug Safety Science and Wolfson Centre for Personalised Medicine, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, Liverpool, UK; Dept. of Healthcare Surveillance and Bioethics, Section of Pharmacology, Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore, Rome, Italy.;MRC Centre for Drug Safety Science and Wolfson Centre for Personalised Medicine, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, Liverpool, UK.;MRC Centre for Drug Safety Science and Wolfson Centre for Personalised Medicine, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, Liverpool, UK. Electronic address: munirp@liverpool.ac.uk.",
"authors": "Dello Russo|Cinzia|C|;Scott|Kathryn Anne|KA|;Pirmohamed|Munir|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.pharmthera.2020.107710",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-7258",
"issue": "219()",
"journal": "Pharmacology & therapeutics",
"keywords": "Dimethyl fumarate; Lymphopenia; Microbiome; Monomethyl fumarate; Multiple Sclerosis; Pharmacogenetics; Pharmacokinetics; Psoriasis",
"medline_ta": "Pharmacol Ther",
"mesh_terms": null,
"nlm_unique_id": "7905840",
"other_id": null,
"pages": "107710",
"pmc": null,
"pmid": "33091427",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Dimethyl fumarate induced lymphopenia in multiple sclerosis: A review of the literature.",
"title_normalized": "dimethyl fumarate induced lymphopenia in multiple sclerosis a review of the literature"
} | [
{
"companynumb": "DE-ALKEM LABORATORIES LIMITED-DE-ALKEM-2020-07802",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DIMETHYL FUMARATE"
},
... |
{
"abstract": "Oxaliplatin-based chemotherapy regimens are currently a standard of care for the treatment of colorectal cancer (CRC) in both the adjuvant treatment and metastatic disease settings. Significant improvements in outcomes have been achieved with oxaliplatin-based combinations in these settings when compared with administration of 5-fluorouracil alone. Pathologic evaluation of normal liver from patients undergoing neoadjuvant oxaliplatin treatment has identified histologic evidence of sinusoidal injury, although the effect of this finding on patient outcomes after hepatic resection appears to be minimal. This article describes the use of oxaliplatin-based chemotherapy in 6 patients with stage III or IV CRC who developed evidence of noncirrhotic portal hypertension. These patients developed complications of portal hypertension including esophageal or hemorrhoidal varices with bleeding, splenomegaly with associated thrombocytopenia, and ascites. In each case, oxaliplatin-induced hepatic sinusoidal injury was identified as the most likely factor contributing to the development of noncirrhotic portal hypertension. The literature on hepatic sinusoidal injury after oxaliplatin is reviewed and the proposed pathophysiology is discussed.",
"affiliations": "Department of Pharmacy, The University of Texas M. D. Anderson Cancer Center, Houston, 77030, USA.",
"authors": "Slade|Julian H|JH|;Alattar|Mona L|ML|;Fogelman|David R|DR|;Overman|Michael J|MJ|;Agarwal|Atin|A|;Maru|Dipen M|DM|;Coulson|Ryanne L|RL|;Charnsangavej|Chusilp|C|;Vauthey|J Nicolas|JN|;Wolff|Robert A|RA|;Kopetz|Scott|S|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"country": "United States",
"delete": false,
"doi": "10.3816/CCC.2009.n.038",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1533-0028",
"issue": "8(4)",
"journal": "Clinical colorectal cancer",
"keywords": null,
"medline_ta": "Clin Colorectal Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D015179:Colorectal Neoplasms; D005260:Female; D006801:Humans; D006975:Hypertension, Portal; D008099:Liver; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D016896:Treatment Outcome",
"nlm_unique_id": "101120693",
"other_id": null,
"pages": "225-30",
"pmc": null,
"pmid": "19822514",
"pubdate": "2009-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Portal hypertension associated with oxaliplatin administration: clinical manifestations of hepatic sinusoidal injury.",
"title_normalized": "portal hypertension associated with oxaliplatin administration clinical manifestations of hepatic sinusoidal injury"
} | [
{
"companynumb": "US-MYLANLABS-2015M1024486",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OLMESARTAN MEDOXOMIL"
},
"drugadditional": n... |
{
"abstract": "We report a case of Alternaria keratitis and hypopyon following clear-corneal cataract surgery. A 66-year-old woman presented with a painful red left eye several months after uneventful self-sealing clear-corneal phacoemulsification that was unresponsive to prolonged treatment with topical/oral quinolones and topical corticosteroids. A full-thickness stromal white dense infiltrate in the area of the intrastromal tunnel incision and a 2.0 mm hypopyon were observed. Culture from corneal scrapings revealed Alternaria species. Treatment included topical and subconjunctival injections of amphotericin-B (5 mg/mL) and 200 mg of oral ketoconazole. Complete resolution of the corneal infiltration and hypopyon was observed after 30 days of treatment, with no recurrence during 6 years of follow-up. To our knowledge, this is the first report of Alternaria species keratitis complicating self-sealing clear-corneal cataract surgery. Topical and subconjunctival injections of amphotericin-B and oral ketoconazole were effective in resolving the corneal abscess and anterior chamber inflammatory reaction.\n\n\nBACKGROUND\nNo author has a financial or proprietary interest in any material or method mentioned.",
"affiliations": "From the Department of Ophthalmology (Espósito, Maccio, Monti, Urrets-Zavalía), University Clinic Reina Fabiola, Catholic University of Córdoba and CIBICI-CONICET (Cervi, Serra), Faculty of Chemical Sciences, National University of Córdoba, Córdoba, Argentina.;From the Department of Ophthalmology (Espósito, Maccio, Monti, Urrets-Zavalía), University Clinic Reina Fabiola, Catholic University of Córdoba and CIBICI-CONICET (Cervi, Serra), Faculty of Chemical Sciences, National University of Córdoba, Córdoba, Argentina.;From the Department of Ophthalmology (Espósito, Maccio, Monti, Urrets-Zavalía), University Clinic Reina Fabiola, Catholic University of Córdoba and CIBICI-CONICET (Cervi, Serra), Faculty of Chemical Sciences, National University of Córdoba, Córdoba, Argentina.;From the Department of Ophthalmology (Espósito, Maccio, Monti, Urrets-Zavalía), University Clinic Reina Fabiola, Catholic University of Córdoba and CIBICI-CONICET (Cervi, Serra), Faculty of Chemical Sciences, National University of Córdoba, Córdoba, Argentina.;From the Department of Ophthalmology (Espósito, Maccio, Monti, Urrets-Zavalía), University Clinic Reina Fabiola, Catholic University of Córdoba and CIBICI-CONICET (Cervi, Serra), Faculty of Chemical Sciences, National University of Córdoba, Córdoba, Argentina.;From the Department of Ophthalmology (Espósito, Maccio, Monti, Urrets-Zavalía), University Clinic Reina Fabiola, Catholic University of Córdoba and CIBICI-CONICET (Cervi, Serra), Faculty of Chemical Sciences, National University of Córdoba, Córdoba, Argentina. Electronic address: julioaurrets@gmail.com.",
"authors": "Espósito|Evangelina|E|;Maccio|J Pablo|JP|;Monti|Rodolfo|R|;Cervi|Laura|L|;Serra|Horacio M|HM|;Urrets-Zavalía|Julio A|JA|",
"chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B; D007654:Ketoconazole",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0886-3350",
"issue": "40(2)",
"journal": "Journal of cataract and refractive surgery",
"keywords": null,
"medline_ta": "J Cataract Refract Surg",
"mesh_terms": "D000038:Abscess; D000284:Administration, Oral; D000368:Aged; D000528:Alternaria; D060487:Alternariosis; D000666:Amphotericin B; D000935:Antifungal Agents; D003315:Cornea; D003320:Corneal Ulcer; D015821:Eye Infections, Fungal; D005260:Female; D006801:Humans; D056965:Injections, Intraocular; D007654:Ketoconazole; D019654:Lens Implantation, Intraocular; D018918:Phacoemulsification; D014792:Visual Acuity",
"nlm_unique_id": "8604171",
"other_id": null,
"pages": "331-4",
"pmc": null,
"pmid": "24461506",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Alternaria keratitis and hypopyon after clear-cornea phacoemulsification.",
"title_normalized": "alternaria keratitis and hypopyon after clear cornea phacoemulsification"
} | [
{
"companynumb": "AR-MYLANLABS-2015M1013058",
"fulfillexpeditecriteria": "1",
"occurcountry": "AR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN\\DEXAMETHASONE"
},
"drugadditio... |
{
"abstract": "BACKGROUND Fear of falling syndrome is a rare and often-missed disorder among patients with new-onset gait abnormality. The disorder is often mistaken for an organic neurologic problem, with some considering it to be a medical emergency. CASE REPORT This case report presents a 70-year-old man who presented to the Emergency Department due to inability to rise from a chair or ambulate independently. Onset of his chief complaint occurred subsequent to a traumatic fall in a public location. He underwent extensive workup, and an organic neurologic cause was ruled out. He was subsequently diagnosed with fear of falling syndrome after obtaining a detailed fall history, as well as utilizing a verified survey (the Falls Efficacy Scale-International). After extensive inpatient treatment, the patient improved significantly. However, upon discharge to a skilled nursing facility, he was not offered the recommended treatment. When he was readmitted for an unrelated reason 3 months later, he had regressed to the state he was in at the time of prior admission. CONCLUSIONS This case presents a rare debilitating but reversible gait disorder, and highlights the importance of assessing \"fall history\" and fear of falling in older adults. Uniquely, this case presents the rapid fluctuation in outcomes dependent on treatment, and what happens when a patient fails to complete treatment regimens. The report also provides an overview of fear of falling with the corresponding gait disorder.",
"affiliations": "John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.;Department of Radiology, Tripler Army Medical Center, Honolulu, HI, USA.;Department of Medicine, Tripler Army Medical Center, Honolulu, HI, USA.;Department of Medicine, Tripler Army Medical Center, Honolulu, HI, USA.;John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.",
"authors": "Ghaffari-Rafi|Arash|A|;Horak|Richard D|RD|;Miles|Daniel T|DT|;Eum|Ki Suk|KS|;Jahanmir|Jay|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.918879",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3165914710.12659/AJCR.918879918879ArticlesCase Report on Fear of Falling Syndrome: A Debilitating but Curable Gait Disorder Ghaffari-Rafi Arash ABCDEF12Horak Richard D. ABE3Miles Daniel T. ABDE4Eum Ki Suk DEFG4Jahanmir Jay ABCDEF14\n1 John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, U.S.A.\n2 Queen Square Institute of Neurology, University College London, London, U.K.\n3 Department of Radiology, Tripler Army Medical Center, Honolulu, HI, U.S.A.\n4 Department of Medicine, Tripler Army Medical Center, Honolulu, HI, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Arash Ghaffari-Rafi, e-mail: arashgr@hawaii.edu2019 29 10 2019 20 1587 1591 20 7 2019 14 8 2019 © Am J Case Rep, 20192019This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 70\n\nFinal Diagnosis: Fear of falling syndrome\n\nSymptoms: Inability to get up from a chair and ambulate independently\n\nMedication: —\n\nClinical Procedure: Lumbar puncture\n\nSpecialty: Neurology\n\nObjective:\nRare disease\n\nBackground:\nFear of falling syndrome is a rare and often-missed disorder among patients with new-onset gait abnormality. The disorder is often mistaken for an organic neurologic problem, with some considering it to be a medical emergency.\n\nCase Report:\nThis case report presents a 70-year-old man who presented to the Emergency Department due to inability to rise from a chair or ambulate independently. Onset of his chief complaint occurred subsequent to a traumatic fall in a public location. He underwent extensive workup, and an organic neurologic cause was ruled out. He was subsequently diagnosed with fear of falling syndrome after obtaining a detailed fall history, as well as utilizing a verified survey (the Falls Efficacy Scale-International). After extensive inpatient treatment, the patient improved significantly. However, upon discharge to a skilled nursing facility, he was not offered the recommended treatment. When he was readmitted for an unrelated reason 3 months later, he had regressed to the state he was in at the time of prior admission.\n\nConclusions:\nThis case presents a rare debilitating but reversible gait disorder, and highlights the importance of assessing “fall history” and fear of falling in older adults. Uniquely, this case presents the rapid fluctuation in outcomes dependent on treatment, and what happens when a patient fails to complete treatment regimens. The report also provides an overview of fear of falling with the corresponding gait disorder.\n\nMeSH Keywords:\nAccidental FallsGaitNeurology\n==== Body\nBackground\nFear of falling (FOF) is a common disorder in older adults, but the debilitating presentation of fear of falling gait is often missed and is mistaken for organic neurologic conditions [1].\n\nIn 1982, Murphy and Isaacs identified a cohort of 36 patients in which, after a fall, several were unable to walk unsupported and presented with a significant proclivity to clutch and grab, along with increased short-term mortality [2]. Since then, fear of falling syndrome (FOF) has been better characterized as the psychological trauma endured after a fall, which results in perpetual anxiety about falling or loss of confidence in balance abilities [3–5]. This subsequently limits daily activities to the point that physical capabilities are lost [3–5].\n\nRecent research shows that FOF does not require one to have fallen; rather, the cause appears to be multifactorial, with an interplay of physical, psychological, and functional influences [6]. Moreover, FOF itself is suggested to be more pervasive and a more serious problem than falls in the elderly [6]. Missed diagnosis of post-fall syndrome and fear of falling syndrome can have detrimental consequences, with some considering FOF a medical emergency requiring immediate treatment [7].\n\nThis case report presents an often-missed disorder in patients with a new-onset gait abnormality. We present a case of a debilitating but rapidly reversible psychogenic gait disorder (FOF syndrome), which highlights the importance of assessing “fall history” and fear of falling in older adults. The report also provides an overview of FOF with the corresponding gait disorder.\n\nCase Report\nWe present the case of a 70-year-old man who presented to the Emergency Department, at the request of his daughter, due to an inability to get up from a chair and ambulate independently. He had no prior gait disorders or neurologic signs and symptoms. The disorder started 1 month prior to admission, when he experienced a traumatic fall in the lobby of a busy hospital. At the time of the fall, the patient tripped on his cane and spilled his coffee. This resulted in a false cardiac arrest code being called, which drew a rush of personnel to his side. He did not experience any injuries from the fall. Prior to this event, the patient was living independently and ambulating easily with a cane. He was able to shop, cook, and dress himself. The patient was now restricted to a wheelchair.\n\nHis past medical history was notable for hyperlipidemia (40 mg atorvastatin daily), diet-controlled diabetes mellitus type 2, asymptomatic bradycardia, hypertension (20 mg lisinopril daily), chronic kidney disease stage IV, and chronic hiccups (10 mg baclofen daily). His family history was unremarkable. His social history was notable for past heavy drinking per family (unquantifiable).\n\nHis physical exam results were notable for a blood pressure of 190/60 without orthostatic changes, and a pulse of 52. He was friendly and cooperative. His affect was appropriate to context, mood was euthymic (“okay”), and cognition was normal. A cardiac exam was notable for a 4/6 systolic crescendo-decrescendo murmur in the right upper sternal border. A neurologic exam demonstrated normal facial expressions, speech, and tone. Strength in all extremities was 5/5, without tremor, bradykinesia, or abnormal muscular tone. He had normal proprioception, vibration, and pain and temperature sensations. His reflexes were 2+ and he had flexor plantar reflexes (negative Babinski sign). He was unable to stand independently, requiring 2-person assistance. While walking with a 2-person assist, he gripped firmly to the 4-legged walker, and continuously sought reaffirmation he was being held and that he would not be released. He also continuously emphasized he could not stand/walk alone. Slower and shorter steps with broad-based stance were noted. He demonstrated extreme caution with each step, but he lifted his feet to an appropriate height.\n\nThe patient’s comorbidities were all extensively assessed and addressed, including stabilizing his blood pressure to baseline with lisinopril and furosemide. Hepatic function tests, blood glucose, metabolic panel, urinalysis, complete blood count with coagulation studies, thyroid function tests, vitamin B12 (545 ng/L), cardiac (including EKG), and pre-albumin tests were all within normal limits. A nephrologist consult further assessed the patient’s chronic kidney disease, and exacerbations due to diabetes were also ruled out.\n\nDue to presentation of a slightly broad-based gait, self-described “wobbliness,” and a history of recent forgetfulness per family (urinary incontinence could not be assessed as he had a long-term suprapubic catheter due to obstructive uropathy), he was evaluated for normal pressure hydrocephalus. MRI demonstrated dilated ventricles without cerebellar degeneration or evidence of prior cerebrovascular accident. Lack of improvement after cerebrospinal fluid removal through lumbar puncture reduced the likelihood of normal pressure hydrocephalus (but of note, the tap test does not rule out normal pressure hydrocephalus) [8]. A formal neurology consult did not find any neurologic deficit.\n\nThe patient scored 41/64 on the Falls Efficacy Scale-International (FES-I) scale [9]. When asked what he believed was holding him back from walking, he explicitly stated that he was afraid of falling. He attested “no one in the world has a greater fear of falling than I do.” He believed nothing was physically wrong with him, but rather his fear of falling was holding him back. He believed if he could overcome his fear of falling, he would be able to walk again. He asked to see a psychiatrist to help him overcome his fears.\n\nHe was started on escitalopram 5 mg daily at bedtime to manage his anxiety, which was continued after discharged and managed by an appropriate outpatient provider. He underwent daily cognitive behavioral therapy addressing his FOF and was provided encouragement. He also received skilled physical therapy 5–6 times per week.\n\nBy the third day of treatment, he showed remarkable improvement, requiring only single-person assistance for ambulatory support. By the end of 5 days, he had achieved a significant increase in walking distance (using a walker). He required minimal single-person assistance during walking and none during standing.\n\nAnother important aspect of treatment involved education of the family about FOF gait and the required treatment regimen. In particular, the family was educated about how the patient was not malingering and suffered from a true disorder, with a positive prognosis if treated appropriately. Upon discharge to a sub-acute rehabilitation facility, the patient was also set to begin group Tai Chi exercises for older adults. However, upon discharge to a skilled nursing facility, he was not offered the recommended treatment (cognitive behavioral therapy with skilled physical therapy). When he was readmitted for an unrelated reason 3 months later (as an elderly diabetic, he was admitted to the inpatient medicine ward for a urinary tract infection), he had regressed to the state he was in at the time of prior admission.\n\nDiscussion\nEpidemiology\nAmong older adults (65 years or above) in the United States, 36% were found to be moderately or very afraid of falling [10]. Those more likely to have FOF were women, those aged 75 or older, single, and with lower income [10–14]. Men were found to under-report FOF due to the associated stigma of reporting fears [5,15].\n\nResearch supports a temporal relationship between a recent fall and subsequent development of FOF [10,12,13,16,17]. After falling, 29–92% of older adults develop FOF [18,19]. Notably, injury from a fall does not increase risk of FOF [10,12,14,18,20,21]. There is also a cyclic effect that occurs after the initial fall, with fear of falling increasing the risk of a subsequent fall, and in turn further pushing the patient to self-limit functionality due to fear of standing or walking [12].\n\nHow to identify fear of falling: Falls Efficacy Scale-International\nThe initial workup of this patient first involved ruling out organic causes of his gait instability based on history and physical exam, which included a comprehensive neurological exam. Potential organic causes included alcoholic cerebellar degeneration, vascular dementia, and normal pressure hydrocephalus.\n\nPatients can be objectively assessed by the Falls Efficacy Scale-International (FES-I) scale [9]. The assessment expanded on the prior Falls Efficacy Scale (FES), adding 6 new questions (items 11–16) for individuals who are more active than most [9,22]. FES-I consists of 16 questions that assess concerns of falling during physical and social activities, with each question graded on a 4-point scale (1=not at all concerned, 2=somewhat concerned, 3=fairly concerned, 4=very concerned) [9]. The scores are summed to a total, ranging from 16 to 64, with higher scores indicating greater FOF [17]. Cut-points differentiate between low, moderate, and high concern about falling (low 16–19, moderate 20–27, and high 28–64), with the mean score and standard deviation being 22.6±6.4 for older adults, irrespective of falling history [23]. Our patient was approximately 3 standard deviations above the mean and was in the category of high concern for falling, with a score of 41.\n\nOverall, the FES-I target population is older adults either with or without FOF [9]. The FES-I has a Cronbach’s alpha of 0.96, indicating strong internal consistency, with the items on the test having shared covariance and measuring the same underlying concept [9]. Likewise, the test-retest reliability or inter-class correlation coefficient was 0.96, demonstrating excellent internal validity [9]. In addition to accurately predicting future falls, the FES-I accurately predicts physiological fall risk, muscle weakness, overall disability, and depressive symptoms [23].\n\nFES-I was developed by the Prevention of Falls Network Europe (ProFaNE), a group of European academic centers studying the psychology of falling and fall prevention [24]. Twenty-nine translations of the FES-I have been made by the University of Manchester and with the original can be found at https://sites.manchester.ac.uk/fes-i/.\n\nSpecific ambulatory traits of fear of falling gait\nWhen the term “cautious gait” or FOF gait was first coined by a team from the Institute of Neurology at University College London, several patterns in the ambulation were noted, including those observed in our patient [25]. Observed traits included a slightly lowered center of mass (crouched posture), broader base, and shorter stride – secondary to perceived postural instability [25–28]. No shuffling of feet and no diminishment of foot-floor clearance were observed in our patient [25].\n\nRecent controlled research has found that patients with FOF have a slower walking gait velocity, yet other balance and gait parameters were unaffected (e.g., stride-length variability, stride-time variability, mediolateral angular displacement, and mediolateral angular velocity) [29]. Overall, the study concluded that patients with FOF adapted their gait mechanism to enhance balance, without demonstrating decreased balance control [29]. One hypothesis, which accounted for the balance adaptation, noted that anxiety concurrent with FOF taxes the cognitive demands required for gait and balance control, yet the same study found the performance of dual tasks in FOF gait were unaffected, thus contradicting the hypothesis [29–31].\n\nIn contrast, for static patients, several studies have noted decreased balance and postural control – specifically, increased postural sway and stiffness [32–34]. Another study found retropulsion in stance and anxiety about movement to be the most common findings in FOF patients [7].\n\nManagement and treatment\nAppropriate interventions can curtail morbidity and mortality in patients with FOF gait. Although there is a dearth of clinical trials examining intervention efficacy, the overarching management plan involves patient education with reassurance, physical therapy, and treatment of the underlying anxiety (with psychology and pharmacology) [35].\n\nThe cornerstone of treatment involves establishing confidence and perceived control over falls [35]. Education involves counseling on fear of falling, managing falls, motivating the patient to overcome self-defeating thoughts, and instilling confidence in the patient’s abilities to control fear and to avoid falling [37–40]. Randomized controlled trials have found that patients undergoing appropriate cognitive-behavioral changes can reverse their cycle of activity restriction and gait abnormalities [37].\n\nWith education, patients should also engage in exercise and physical activity to reduce fall risk and increase perceived environmental control [37]. Performing a home safety checklist and conducting a home assessment with appropriate safety modifications has been found to improve a patient’s perceived environmental control [38,41]. Addressing other causes of falls is also vital, such as consolidating the patient’s medications to reduce the risk of drug-induced falls. Classes of medications associated with falls include: anticonvulsants, benzodiazepines, opioids, antipsychotics, sedative-hypnotics, anticholinergics, antihistamines, muscle relaxants, antihypertensives, and anti-depressants (tricyclics, fluoxetine, paroxetine, sertraline, fluvoxamine) [42,43]. Although not all medications that increase the risk of falls can be discontinued, an attempt should be made to either switch the patient to a safer alternative or limit the medication to the lowest effective dose [42,43].\n\nAdditionally, patients should be trained to be more assertive [6]. Assertiveness training involves learning to ask for assistance when in a fearful situation, as well as becoming comfortable discussing one’s fear, as encouragement by family/friends to be more open and assertive promotes better outcomes [6]. Those able to openly discuss their FOF with family, friends, and healthcare providers were found to more likely remain physically active [38].\n\nThe greatest benefits from overcoming FOF were found with community or home-based interventions continued for at least 4 months [44]. Physical therapy with eventual transition to long-term group fitness programs was found to significantly improve balance and mobility and to decrease fall risk [45]. Specific therapies such as daily group Tai Chi or chair exercises have also been found to be helpful [44–46]. In addition, medical issues contributing to falling should also be addressed, along with mental health problems such as anxiety and depression [47].\n\nConclusions\nOverall, through a multidimensional and multidisciplinary approach, emphasizing confidence building, cognitive-behavioral changes, education, assertiveness training, and environmental modification, FOF gait can be reversed. However, as uniquely noted in our case, without follow-through with treatment, patients are at significant risk for regression.\n\nMoreover, this report presents a commonly missed new-onset gait abnormality, which is debilitating but rapidly reversible. The case also highlights the importance of assessing “fall history” and fear of falling in older adults, while providing an overview of FOF with the parallel gait disorder.\n\nConflict of interests\n\nNone.\n==== Refs\nReferences:\n1. Kurlan R ‘Fear of falling’ gait Cogn Behav Neurol 2005 18 3 171 72 16175021 \n2. Murphy J Isaacs B The post-fall syndrome Gerontology 1982 28 4 265 70 7117852 \n3. Tinetti ME Powell L Fear of falling and low self-efficacy: A cause of dependence in elderly persons J Gerontol 1993 48 Special 35 38 8409238 \n4. Tinetti ME Speechley M Ginter SF Risk factors for falls among elderly persons living in the community N Engl J Med 1988 319 26 1701 7 3205267 \n5. Maki BE Holliday PJ Topper AK Fear of falling and postural performance in the elderly J Gerontol 1991 46 4 M123 31 2071833 \n6. Legters K Fear of falling Phys Ther 2002 82 3 264 72 11869155 \n7. Mathon C Beaucamp F Roca F Post-fall syndrome: profile and outcomes Ann Phys Rehabil Med 2017 60 Suppl. e49 e53 \n8. Marmarou A Bergsneider M Klinge P The value of supplemental prognostic tests for the preoperative assessment of idiopathic normal-pressure hydrocephalus Neurosurgery 2005 57 3 Suppl. S17 28 16160426 \n9. Yardley L Beyer N Hauer K Development and initial validation of the Falls Efficacy Scale International (FES-I) Age Ageing 2005 34 6 614 19 16267188 \n10. Boyd R Stevens JA Falls and fear of falling: Burden, beliefs and behaviours Age Ageing 2009 38 4 423 28 19420144 \n11. Fletcher PC Hirdes JP Restriction in activity associated with fear of falling among community-based seniors using home care services Age Ageing 2004 33 3 273 79 15082433 \n12. Friedman SM Munoz B West SK Falls and fear of falling: which comes first? A longitudinal prediction model suggests strategies for primary and secondary prevention J Am Geriatr Soc 2002 50 8 1329 35 12164987 \n13. Vellas BJ Wayne SJ Romero LJ Fear of falling and restriction of mobility in elderly fallers Age Ageing 1997 26 3 189 93 9223714 \n14. Arfken CL Lach HW Birge SL Miller JP The prevalence and correlates of fear of falling in elderly persons living in the community Am J Public Health 1994 84 4 565 70 8154557 \n15. McAuley EM Mihalko SL Rosengren K Self-efficacy and balance correlates of fear of falling in the elderly Journal of Aging and Physical Activity 1997 5 329 40 \n16. Fletcher PC Hirdes JP Restriction in activity associated with fear of falling among community-based seniors using home care services Age Ageing 2004 33 3 273 79 15082433 \n17. Scheffer AC Schuurmans MJ van Dijk N Fear of falling: Measurement strategy, prevalence, risk factors, and consequences among older persons Age Ageing 2008 37 1 19 24 18194967 \n18. Howland J Peterson EW Levin WC Fear of falling among the community-dwelling elderly J Aging Health 1993 5 229 43 10125446 \n19. Aoyagi K Ross PD Davis JW Falls among community-dwelling elderly in Japan Bone Miner Res 1998 13 1468 74 \n20. Bruce DG Devine A Prince RL Recreational physical activity levels in healthy older women: The importance of fear of falling J Am Geriatr Soc 2002 50 1 84 89 12028251 \n21. Cumming RG Salkeld G Thomas M Prospective study of the impact of fear of falling on activities of daily living, SF-36 scores, and nursing home admission J Gerontol 2000 55A M299 305 \n22. Tinetti ME Richman D Powell L Falls efficacy as a measure of fear of falling J Gerontol 1990 45 6 P239 43 2229948 \n23. Delbaere K Close J Mikolaizak AS The Falls Efficacy Scale International (FES-I). A comprehensive longitudinal validation study Age Ageing 2010 39 2 210 16 20061508 \n24. Prevention of falls network Europe Profane.Eu.Org 2018 http://www.profane.eu.org/ \n25. Nutt JG Marsden CD Thompson MD Human walking and higher-level gait disorders, particularly in the elderly Neurology 1993 43 268 79 8437689 \n26. Winter DA The biomechanics and motor control of human gait: Normal, elderly, and pathological 2nd ed. Waterloo, Ontario University of Waterloo Press 1991 \n27. Elble RJ Hughes L Higgens C The syndrome of senile gait J Neurol 1992 239 71 75 1552306 \n28. Sudarsky L Psychogenic gait disorders Semin Neurol 2006 26 3 351 56 16791781 \n29. Reelick MF van Iersel MB Kessels RPC The Influence of fear of falling on gait and balance in older people Age Ageing 2009 38 4 435 40 19451658 \n30. Gage WH Sleik RJ Polych MA The allocation of attention during locomotion is altered by anxiety Exp Brain Res 2003 150 385 94 12707746 \n31. Shumway-Cook A Woollacott M Attentional demands and postural control: the effect of sensory context J Gerontol A Biol Sci Med Sci 2000 55 M10 16 10719767 \n32. Adkin AL Frank JS Carpenter MG Peysar GW Fear of falling modifies anticipatory postural control Exp Brain Res 2002 143 160 70 11880892 \n33. Binda SM Culham EG Brouwer B Balance, muscle strength, and fear of falling in older adults Exp Aging Res 2003 29 205 19 12623729 \n34. Carpenter MG Frank JS Silcher CP Peysar GW The influence of postural threat on the control of upright stance Exp Brain Res 2001 138 210 18 11417462 \n35. Thenganatt MA Jankovic J Psychogenic movement disorders Neurol Clin 2015 33 1 205 24 25432730 \n36. Myers AM Fletcher PG Myers AH Sherk W Discriminative and evaluative properties of the Activities-Specific Balance Confidence (ABG) scale J Gerontol A Biol Sci Med Sci 1998 53 4 M287 94 18314568 \n37. Tennstedt S Howland J Lachman M A randomized, controlled trial of a group intervention to reduce fear of falling and associated activity restriction in older adults J Gerontol B Psychol Sci Soc Sci 1998 53 P384 92 9826971 \n38. Walker JE Howland J Falls and fear of failing among elderly persons living in the community: Occupational therapy interventions Am J Occup Ther 1991 45 119 22 2035588 \n39. Bhala RP O’Donnell Thoppil E Ptophobia; Phobic fear or falling and its clinical management Phys Ther 1982 62 187 90 6120526 \n40. Lawrence RH Tennstedt SL Kasten LE Intensity and correlates of fear of falling and hurting oneself in the next year: Baseline findings from a Roybal Center fear of falling intervention J Aging Health 1998 10 267 86 10342933 \n41. Yates SM Dunnagan TA Evaluating the effectiveness of a home-based fall risk reduction program for rural community-dwelling older adults J Gerontol A Biol Sci Med Sci 2001 56 4 M226 30 11283195 \n42. Martin RM Hilton SR Kerry SM Richards NM General practitioners’ perceptions of the tolerability of antidepressant drugs: A comparison of selective serotonin reuptake inhibitors and tricyclic antidepressants BMJ 1997 314 646 51 9066479 \n43. de Jong MR Van der Elst M Hartholt KA Drug-related falls in older patients: implicated drugs, consequences, and possible prevention strategies Ther Adv Drug Saf 2013 4 4 147 54 25114778 \n44. Jung D Lee J Lee SM A meta-analysis of fear of falling treatment programs for the elderly West J Nurs Res 2008 31 6 16 18667626 \n45. Shumway-Gook A Grtiber W Baldwin M Liao S The effect of multidimensional exercises on balance, mobility, and fall risk in community-dwelling older adults Phys Ther 1997 77 46 57 8996463 \n46. Sattin R Easley K Wolf S Reduction in fear of falling through intense Tai Chi exercise training in older, transitionally frail adults J Am Geriatr Soci 2005 53 7 1168 78 \n47. Harding S Gardner A Fear of falling Aust J Adv Nurs 2009 27 94 100\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "20()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000058:Accidental Falls; D000368:Aged; D001007:Anxiety; D015928:Cognitive Behavioral Therapy; D005239:Fear; D005684:Gait; D006801:Humans; D008297:Male; D004856:Postural Balance; D016896:Treatment Outcome; D014481:United States",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "1587-1591",
"pmc": null,
"pmid": "31659147",
"pubdate": "2019-10-29",
"publication_types": "D002363:Case Reports",
"references": "9223714;2035588;19420144;8437689;10342933;9826971;16791781;16175021;3205267;18667626;8409238;11869155;12623729;2071833;12707746;9066479;25432730;6120526;2229948;11283195;16267188;15082433;8996463;12164987;11880892;10719767;18194967;20061508;7117852;8154557;10125446;19451658;10819321;1552306;9738520;16108935;25114778;12028251;11417462;18314568;16160426",
"title": "Case Report on Fear of Falling Syndrome: A Debilitating but Curable Gait Disorder.",
"title_normalized": "case report on fear of falling syndrome a debilitating but curable gait disorder"
} | [
{
"companynumb": "NVSC2019US061954",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LISINOPRIL"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Attempts for identifying targeted therapy strategies in metastatic gastric and gastroesopheal junction cancer (upper-GI) revealed that the inhibition of human epidermal growth factor receptor-2 (HER2) by monoclonal antibody trastuzumab improves survival of these patients. Hence, adding trastuzumab to doublet chemotherapy has become the standard treatment in this setting. Although the patient survival is extended among clinical trials, the knowledge on the real-time setting is limited. With this retrospective, single center analysis of the patient data of the Medical University of Vienna, we sought to investigate the clinical characteristics and outcome of patients, who received trastuzumab-based chemotherapy for metastatic upper-GI tumor. All patients, who received trastzumab at least once were included to the analysis. Clinical and pathological data were recorded. This search revealed 33 patients. The demographic data was comparable with that of the previous clinical trials. Progression free survival (PFS) was 11 months, whereas overall survival (OS) was 21 months. OS was significantly associated with initially favorable response to treatment. Thirteen patients (39%) received trastuzumab as maintenance treatment with a median cycle number of 6. Toxicity profile was acceptable with only one patient detected to have cardiotoxicity. Taken together, trastuzumab based treatment induced a considerable PFS and OS in metastatic or advanced upper-GI tumors with acceptable toxicity profile. The maintenance therapy with trastuzumab was safe and effective in patients who had initially a favorable response to chemotherapy. The optimal duration of the maintenance therapy should be tested in future clinical trials.",
"affiliations": "a Department of Medicine I , Clinical Division of Oncology, Medical University of Vienna , Vienna , Austria.;b Department of Medicine III , Clinical Division of Endocrinology and Metabolism, Medical University of Vienna , Vienna , Austria.;c Department of Pathology , Medical University of Vienna , Vienna , Austria.;d Department of Medicine III , Clinical Division of Gastroenterology, Medical University of Vienna , Vienna , Austria.;e Department of Radiology , Medical University of Vienna , Vienna , Austria.;f Department of Surgery , Medical University of Vienna , Vienna , Austria.;a Department of Medicine I , Clinical Division of Oncology, Medical University of Vienna , Vienna , Austria.;c Department of Pathology , Medical University of Vienna , Vienna , Austria.;a Department of Medicine I , Clinical Division of Oncology, Medical University of Vienna , Vienna , Austria.",
"authors": "Ilhan-Mutlu|A|A|;Taghizadeh|H|H|;Beer|A|A|;Dolak|W|W|;Ba-Ssalamah|A|A|;Schoppmann|S F|SF|;Hejna|M|M|;Birner|P|P|;Preusser|M|M|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"country": "United States",
"delete": false,
"doi": "10.1080/15384047.2017.1414759",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-4047",
"issue": "19(3)",
"journal": "Cancer biology & therapy",
"keywords": "HER2; ToGA; esophagus; gastric; gastroesophageal; herceptin; trastuzumab; upper-GI",
"medline_ta": "Cancer Biol Ther",
"mesh_terms": "D000328:Adult; D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D001317:Austria; D066126:Cardiotoxicity; D004938:Esophageal Neoplasms; D004943:Esophagogastric Junction; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D000077982:Progression-Free Survival; D018719:Receptor, ErbB-2; D012189:Retrospective Studies; D013274:Stomach Neoplasms; D000068878:Trastuzumab",
"nlm_unique_id": "101137842",
"other_id": null,
"pages": "169-174",
"pmc": null,
"pmid": "29252101",
"pubdate": "2018-03-04",
"publication_types": "D016428:Journal Article",
"references": "22179434;26628478;18441328;25712681;15862270;21468783;24557541;18422971;16682732;24127447;19097774;20185938;26323641;17978289;25038874;28177437;22797858;22565005;27409420;27330770;16822992;27563438;20728210;27156933",
"title": "Correlation of trastuzumab-based treatment with clinical characteristics and prognosis in HER2-positive gastric and gastroesophageal junction cancer: A retrospective single center analysis.",
"title_normalized": "correlation of trastuzumab based treatment with clinical characteristics and prognosis in her2 positive gastric and gastroesophageal junction cancer a retrospective single center analysis"
} | [
{
"companynumb": "AT-ROCHE-2078921",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Bisphosphonates and receptor activator of nuclear factor kappa-B ligand inhibitors are currently the most widely used antiresorptive therapies in bone metabolism diseases treatment. Unfortunately they can evoke medication-related osteonecrosis of the jaws. The present case series study proposes to evaluate clinical features, evolution and the surgical therapeutic approaches in three patients affected by medication-related osteonecrosis of the jaw and to review the state of art regarding the management of this complication in light of the most recent literature.\nThree cases of medication-related osteonecrosis of the jaws are discussed, two related to bisphosphonates therapy (ibandronic acid) and one due to denosumab.\nAll three patients were aged female and had probably a dental trigger agent. The lesions located in posterior mandible were treated in one case with the surgical approach alone and, in the other case, with surgical approach associated with Erb-YAG laser. The lesion related to denosumab was treated with surgical approach and platelet rich fibrin application. A complete healing was always achieved.\nDentists should be aware of the potential risk of developing medication-related osteonecrosis of the jaws for patients who take or had taken antiresorptive drugs. The side effects of denosumab and bisphosphonates are partly overlapping and currently there is still no consensus about the therapeutic surgical options. Prevention and early detection of the lesions should be the primary strategy.",
"affiliations": "Maxillofacial and Dental Surgical Unit, Department of Medical, Surgical and Health Sciences, University of Trieste, TriesteItaly.;Maxillofacial and Dental Surgical Unit, Department of Medical, Surgical and Health Sciences, University of Trieste, TriesteItaly.;Pathological Anatomy and Histopathology Unit, Department of Medical, Surgical and Health Sciences, University of Trieste, TriesteItaly.;Maxillofacial and Dental Surgical Unit, Department of Medical, Surgical and Health Sciences, University of Trieste, TriesteItaly.;Maxillofacial and Dental Surgical Unit, Department of Medical, Surgical and Health Sciences, University of Trieste, TriesteItaly.;Maxillofacial and Dental Surgical Unit, Department of Medical, Surgical and Health Sciences, University of Trieste, TriesteItaly.;Maxillofacial and Dental Surgical Unit, Department of Medical, Surgical and Health Sciences, University of Trieste, TriesteItaly.",
"authors": "Vettori|Erica|E|;Pipinato|Giulia|G|;Bussani|Rossana|R|;Costantinides|Fulvia|F|;Nicolin|Vanessa|V|;Bevilacqua|Lorenzo|L|;Maglione|Michele|M|",
"chemical_list": null,
"country": "Lithuania",
"delete": false,
"doi": "10.5037/jomr.2021.12206",
"fulltext": "\n==== Front\nJ Oral Maxillofac Res\nJ Oral Maxillofac Res\nJORM\nJournal of Oral & Maxillofacial Research\n2029-283X\nStilus Optimus Kaunas, Lithuania\n\n34377383\nv12n2e6ht\n10.5037/jomr.2021.12206\nCase Report\nTherapeutic Approach in the Treatment of Medication-Related Osteonecrosis of the Jaw: Case Series of 3 Patients and State of the Art on Surgical Strategies\nVettori Erica 1\nPipinato Giulia 1\nBussani Rossana 2\nCostantinides Fulvia 1\nNicolin Vanessa 1\nBevilacqua Lorenzo 1\nMaglione Michele 1\n1 Maxillofacial and Dental Surgical Unit, Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste Italy.\n2 Pathological Anatomy and Histopathology Unit, Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste Italy.\nErica Vettori, Maxillofacial and Dental Surgical UnitDepartment of Medical, Surgical and Health SciencesUniversity of TriestePiazza dell’Ospitale 1, 34129, TriesteItaly+390403992020+390403992022evettori@units.it\nApr-Jun 2021\n30 6 2021\n12 2 e626 1 2021\n8 5 2021\nCopyright © Vettori E, Pipinato G, Bussani R, Costantinides F, Nicolin V, Bevilacqua L, Maglione M. Published in the JOURNAL OF ORAL & MAXILLOFACIAL RESEARCH (http://www.ejomr.org), 30 June 2021.\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open-access article, first published in the JOURNAL OF ORAL & MAXILLOFACIAL RESEARCH, distributed under the terms of the Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 UnportedLicense (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work and is properly cited. The copyright, license information and link to the original publication on (http://www.ejomr.org) must be included.\n\nABSTRACT\n\nBackground\n\nBisphosphonates and receptor activator of nuclear factor kappa-B ligand inhibitors are currently the most widely used antiresorptive therapies in bone metabolism diseases treatment. Unfortunately they can evoke medication-related osteonecrosis of the jaws. The present case series study proposes to evaluate clinical features, evolution and the surgical therapeutic approaches in three patients affected by medication-related osteonecrosis of the jaw and to review the state of art regarding the management of this complication in light of the most recent literature.\n\nMethods\n\nThree cases of medication-related osteonecrosis of the jaws are discussed, two related to bisphosphonates therapy (ibandronic acid) and one due to denosumab.\n\nResults\n\nAll three patients were aged female and had probably a dental trigger agent. The lesions located in posterior mandible were treated in one case with the surgical approach alone and, in the other case, with surgical approach associated with Erb-YAG laser. The lesion related to denosumab was treated with surgical approach and platelet rich fibrin application. A complete healing was always achieved.\n\nConclusions\n\nDentists should be aware of the potential risk of developing medication-related osteonecrosis of the jaws for patients who take or had taken antiresorptive drugs. The side effects of denosumab and bisphosphonates are partly overlapping and currently there is still no consensus about the therapeutic surgical options. Prevention and early detection of the lesions should be the primary strategy.\n\nantiresorptive drugs\nlaser therapy\noral surgery\nosteonecrosis\nplatelet-rich fibrin\n==== Body\nINTRODUCTION\n\nOsteonecrosis of the jaws (ONJ) is a severe bone disease related to various medicaments: antiresorptive drugs (including bisphosphonates and receptor activator of nuclear factor kappa-B ligand [RANKL] inhibitors) and antiangiogenic drugs [1].\n\nOsteoclasts activity is depressed by antiresorptive agents, therefore, bone resorption is inhibited. Among these agents bisphosphonates, denosumab and selective estrogen modulators are the most used, rather than hormone replacement therapy and calcictonin which are mostly abandoned [2]. Typical and frequent indications for the use of these drugs are postmenopausal osteoporosis, bone malignant lesions secondary to breast or prostate cancer, and multiple myeloma [3].\n\nBisphosphonates, classified as being non-nitrogenous (etidronate, tiludronate and clodronate) or nitrogen-containing (pamidronate, alendronate, risendronate, zolendronate, ibandronate and neridronate) [1,4], are currently the most widely used antiresorptive therapies for malignant and nonmalignant diseases characterized by various kinds of bone loss [3,5]. Oral administration of bisphosphonates is generally used to treat osteometabolic disease such as osteoporosis, osteopenia or more rare syndromes such as Paget’s disease and osteogenesis imperfecta. Intravenous administrations is used for cancer-related conditions such as breast, prostate or lung cancer metastases and for the management of multiple myeloma [1].\n\nSince 2003, Marx [6] report of bone necrosis induced by bisphosphonate-related osteonecrosis of the jaw (BRONJ) has generated great concern regarding the side effects of these drugs. Nitrogen-containing bisphosphonates are the only kind of bisphosphonates associated with osteonecrosis [1]. BRONJ is characterized by exposed necrotic bone in the maxillofacial region for more than 8 weeks in bisphosphonate users with no history of head and neck radiotherapy [4]. In the early stages of BRONJ there are often no symptoms and radiographic features may not be present, advanced stages, instead, are characterized by pain, paraesthesia, mucosal ulceration and exposed necrotic bone.\n\nIn 2006, a classification based on the clinical presentation of the disease has been proposed by American Association of Oral and Maxillofacial Surgeons (AAOMS) [7]. This classification defines three stages of BRONJ:\n\nStage I, asymptomatic necrotic bone exposure;\n\nStage II, bone necrosis with exposure, pain and infection;\n\nStage III, bone necrosis with exposure, pain, infection and pathological fractures, or cutaneous fistulas.\n\nThe site of major prevalence of BRONJ has been reported to be the mandible although the maxilla can also be involved and both maxillary bones can be affected [4,8].\n\nBecause of the side effects related to the use of bisphosphonates, other therapeutic strategies for osteoporosis and bone metastasis or particular bone pathologies (such as Paget’s disease) have been developed. The discovery of RANKL, that induces osteoclast differentiation, have led to the development of denosumab, a fully human monoclonal antibody that can bind and inhibit RANKL [5,9]. Like bisphosphonates, denosumab has been associated with ONJ [10]. In spite of bisphosphonates, whose side effects persist for years depending on the cumulative dose, the effects of RANK ligand inhibitors diminish rapidly after the end of administration [1].\n\nAlthough ONJ related to non-antiresorptive anticancer agents is rare, its incidence is increasing (from 0.8% to 12%) [7]. Antiangiogenetic agents do not block tumour cell growth, but interfere with new blood vessels formation.\n\nIn substance there are two types of drugs related to ONJ: one that inhibits the angiogenetic growth factor or its receptor (bevacizumab, a monoclonal antibody), and the other one is a molecule which binds the tyrosine kinase receptor (sunitinib and sorafenib) [1].\n\nONJ related to non-antiresorptive agents has a better prognosis in terms of percentage of healing and healing time compared to antiresorptive drugs, even though histology, radiology and management is similar [11].\n\nMedication-related osteonecrosis of the jaw (MRONJ) has been defined as exposed necrotic bone in the oral cavity that does not heal within 8 weeks in patients who had taken antiresorptive (e.g. bisphosphonates and denosumab) or antiangiogenetic (bevacizumab) drugs [12].\n\nFor the treatment of MRONJ different conservative therapeutic approaches have been established, reserving surgery to cases of necessity in light of a risk-benefit ratio. In 2014 the AAOMS [13] published an update on the position paper regarding the staging and relative treatment of MRONJ (Table 1). Treatment approaches for MRONJ are still controversial; the lack of consensus has led to the development of new therapeutic strategies such as the use of platelet-rich fibrin (PRF) and laser therapy [12].\n\nTable 1 American Association of Oral and Maxillofacial Surgeons MRONJ position paper 2014 update [13]\n\nMRONJ staging\tTreatment Strategies\t\nAt risk\ncategory\tNo apparent necrotic bone in patients who have been treated with either oral or intravenous (IV) bisphosphonates.\t- No treatment indicated.\n- Patient education.\t\n\t\nStage 0\tNo clinical evidence of necrotic bone, but non-specific clinical findings, radiographic changes and symptoms.\tSystemic management, including the use of pain medication and antibiotics.\t\n\t\nStage 1\tExposed and necrotic bone, or fistulae that probes to bone, in patients who are asymptomatic and have no evidence of infection.\t- Antibacterial mouth rinse.\n- Clinical follow-up on a quarterly bias.\n- Patient education and review of indications for continued bisphosphonate therapy.\t\n\t\nStage 2\tExposed and necrotic bone, or fistulae that probes to bone, associated with infection as evidenced by pain and erythema in the region of the exposed bone with or without purulent drainage.\t- Symptomatic treatment with oral antibiotics.\n- Oral antibacterial mouth rinse.\n- Pain control.\n- Debridement to relieve soft tissue irritation and infection control.\t\n\t\nStage 3\tExposed and necrotic bone or a fistula that probes to bone in patients with pain, infection, and one or more of the following: exposed and necrotic bone extending beyond the region of alveolar bone, (i.e., inferior border and ramus in the mandible, maxillary sinus and zygoma in the maxilla) resulting in pathologic fracture, extra-oral fistula, oral antral/oral nasal communication, or osteolysis extending to the inferior border of the mandible of sinus floor.\t- Antibacterial mouth rinse.\n- Antibiotic therapy and pain control.\n- Surgical debridement/resection for longer term palliation of infection and pain.\t\nMRONJ = medication-related osteonecrosis of the jaw.\n\nThis study proposes to evaluate clinical features, evolution and surgical therapeutic approaches in three cases of medication-related osteonecrosis of the jaw and to review the state of art regarding the management of medication-related osteonecrosis of the jaw in light of the most recent literature.\n\nCASE DESCRIPTION AND RESULTS\n\nThree different cases of MRONJ were diagnosed and treated at the Maxillofacial and Dental Surgical Unit (Department of Medical, Surgical and Health Sciences, University of Trieste) between June 2014 and December 2016.\n\nAn informed written consent was obtained from each patient to use data for the research that was conducted in agreement with the guidelines of the Helsinki Declaration as revised in 1975 and amended in October 2003.\n\nFor each case pain assessment has been made with Numeric Rating Scale (NRS) which is an unidimensional measure of pain intensity whereby the patients rates the pain from 0 (no pain) to 10 (worst possible pain) [14].\n\nCase 1\n\nA 77-years old woman was admitted at the Dental Emergency Unit because of an unresolved perimplantitis in the site of left mandibular second premolar, with local pain (reported as 6 in NRS), gingiva swelling, dysesthesia of the left side of the lower lip and purulent discharge. The infection signs persisted despite of a long antibiotic therapy (about one month) and the dental implant removal done one month before.\n\nThe medical history showed hypertension, gastritis, hypercholesterolemia and osteoporosis.\n\nThe patient had taken alendronate - Fosamax® (Merck Sharp & Dohme B.V.; Haarlem, The Netherlands) from 2010 until 2015 following by a therapy with ibandronic acid - Bonviva® (F. Hoffmann-La Roche Ltd.; Basel, Switzerland).\n\nAn orthopantomography (OPG) and a computed tomography (CT) were executed and revealed an osteolytic lesion with a bone sequestrum around the left mandibular second premolar site.\n\nClinical and radiographic features are shown in Figure 1.\n\nFigure 1 Case 1. A = orthopantomography before surgery; B = preoperative clinical features; C = surgical debridement; D = 8-months follow-up.\n\nAntibiotic therapy with amoxicillin and clavulanic acid 875 mg/125 mg - Neoduplamox® (GlaxoSmithKline; London, United Kingdom) Ter In Die (TID) and chlorhexidine mouthwashes (Curasept S.p.A.; Varese, Italy) were prescribed. Surgical intervention was performed under local anaesthesia (mepivacaine chlorohydrate with epinephrine 1 : 100000 - Molteni Dental S.r.l.; Firenze, Italy), the left mandibular first premolar and the implant in the site of left mandibular first molar were extracted. Sequestrectomy and debridement of the necrotic tissue were executed until a bleeding bone was observed. Interrupted sutures with silk were applied.\n\nThe biopsy of the necrotic bone was performed. Histologic examination revealed the presence oral mucosa with massive reacutized chronic phlogosis and micro-abscessual areas (Figure 2). Diagnosis of MRONJ at Stage 2 was made. Antibiotic therapy was continued for one week after surgery.\n\nFigure 2 Case 1. Oral mucosa with massive reacutized chronic phlogosis and micro-abscessual areas. Hematoxylin and eosin stain: A = original magnification x2.5; B = original magnification x10; C = original magnification x10.\n\nAll along follow-up’s span, presence of paraesthesia was evaluated asking the patient about sensibility of tongue, lip and chin; tests like 2-point discrimination, light touch and pinprick have been performed [15].\n\nAfter three weeks, the debrided region was covered by normal mucosa. Dysesthesia of the left side of the lower lip improved.\n\nAfter 8 months, a new CT was performed revealing a radiolucent area with well-defined borders and without surrounding periosteal reaction. There were no infections signs. Paraesthesia at the lower lip was the same as the one before the surgical debridement, but pain has regressed.\n\nCase 2\n\nA 66-years old woman was admitted at the Emergency Unit of the Dental School because of pain, bad breath and exposed necrotic bone in the anterior lower jaw (Figure 3). Three months before the woman underwent inferior tooth extraction, she had eight teeth extracted in the inferior incisal and right molar region by her dentist.\n\nFigure 3 Case 2. A = Orthopantomography before surgery; B = preoperative clinical features; C = surgical debridement; D = 12-months follow-up.\n\nThe review of the patient’s medical history revealed that for 21 months she had received monoclonal antibody therapy with denosumab - Prolia® (Amgen; Singapore) because of bone metastases from breast cancer diagnosed two years before.\n\nThe OPG showed a wide osteolytic area without defined borders in the anterior lower jaw (Figure 3). CT was requested to plan the surgery.\n\nAntibiotic therapy with amoxicillin and clavulanic acid 875 mg/125 mg - Neoduplamox® TID and chlorhexidine mouthwashes were prescribed. Surgical resection of bone necrosis was performed in operating room under local anaesthesia (mepivacaine chlorohydrate - Molteni Dental S.r.l.). Patient underwent bone surgical toilette and debridement until a bleeding bone was observed. The biopsy of necrotic bone were performed. Two swabs of macroscopically health bone were executed. PRF was used on the remaining bone in order to provide growth factors and improve wound healing and bone regeneration. Absorbable interrupted sutures with Vicryl® (Henry Schein Inc.; Melville, New York, USA) were placed. Antibiotic therapy was continued for one week after surgery.\n\nHistologic examination revealed the presence of necrotic bone with chronic inflammatory cell infiltrate and muscle-connective tissue with stromal lymphoplasmacellular infiltrates and hemorrhagic imbibition (Figure 4). Stage 2 MRONJ diagnosis was made.\n\nFigure 4 Case 2. Necrotized and regressed bone tissue with intense reacutized chronic phlogosis Hematoxylin and eosin stain: A = original magnification x2.5; B = original magnification x2.5; C = original magnification x10.\n\nAfter 2 weeks a wound dehiscence was observed and a new CT (performed after 5 weeks from the first one) revealed a well-defined area of surgical resection with clear areas where bone bleeding was obtained.\n\nAfter 7 weeks the debrided region was covered by normal mucosa.\n\nOPG performed after about one year from the surgery revealed a good bone healing. The surgical wound was definitively healed, even if the patient has always reported discomfort with NRS = 3 in the operated area.\n\nCase 3\n\nA 80-years old woman was admitted at the Dental Emergency Unit because of a paraesthesia of the left lower lip and pain reported as 5 in NRS scale. In her medical history it was reported she was suffering by hypertension, hypothyroidism, diabetes type II and osteoporosis.\n\nSymptoms appeared after dental extractions approximately 3 years before.\n\nAn accurate review of her medical history was performed and it was emerged that she had started a therapy with Bonviva® - ibandronic acid 150 mg once per month, 8 years before.\n\nClinical examination revealed abnormal posture of the left lower lip associated with low thermic and pain sensitivity. Mandibular profile was altered because of the presence of a non-mobile hard swelling without defined borders. Intraoral examination revealed the presence of a dental implant in 3.6 site with clinical evidence of purulent discharge and the presence of a vestibular soft mucosal swelling (Figure 5).\n\nFigure 5 Case 3. A = Orthopantomography before surgery; B = preoperative clinical features; C = surgical debridement; D = 18-months follow-up.\n\nThe OPG showed a large osteolytic lesion without defined borders; the bone inside this area had a cotton wool appearance (Figure 5).\n\nAntibiotic therapy with amoxicillin and clavulanic acid 875 mg/125 mg - Neoduplamox® TID was prescribed and a biopsy of the sick bone was performed. A head and neck CT was requested to plan the surgery.\n\nPatient underwent bone surgical toilette under general and local anaesthesia (mepivacaine chlorohydrate - Molteni Dental S.r.l.) and contextual removal of the implant with sequestrectomy and debridement until a bleeding bone was observed; the residual cavity was also treated with Er:YAG laser device (2940 nm, LightWalker AT - Fotona; Ljubljana, Slovenia).\n\nAntibiotic therapy was continued for one week after surgery.\n\nHistologic examination revealed the presence of necrotic bone with chronic inflammatory cell infiltrate, hyperplasia and parakeratosis of stratified squamous epithelium with underlying hyperplastic granulation tissue (Figure 6). Diagnosis of Stage 2 MRONJ was performed.\n\nFigure 6 Case 3. Oral mucosa with intense phlogosis and aggregates of bacterial flora. Hematoxylin and eosin stain: A = original magnification x1; B = original magnification x10; C = original magnification x20.\n\nAfter three weeks the debrided region was covered by normal mucosa and a new CT (performed after 16 weeks from the first one) showed a radiolucent area with well-defined borders and without surrounding periosteal reaction. Hypoesthesia disappeared after surgery.\n\nAt one year follow-up no signs of relapse or recurrence appeared.\n\nDISCUSSION\n\nThanks to their antiresorptive properties, bisphosphonates reduce morbidity and mortality in malignant and non-malignant bone diseases.\n\nThese drugs have an effect on increasing apoptosis and osteoclastic inhibition by binding the mineral component of bone: this action is well known even though their mechanism is not yet fully understood.\n\nThe way bisphosphonates work is that they disrupt the osteoblast-osteoclast interaction so they interfere with the mechanism of bone remodelling [4,6,16]. Bisphosphonates can be administered orally, usually for the treatment of osteoporosis, or intravenously because of the higher power, generally in cases of bone metastases [4,7,17]. Like the bisphosphonates, denosumab has been associated with ONJ. Denosumab’s pharmacodynamics and pharmacokinetics differ from that of bisphosphonates, for this reason, denosumab-related-ONJ may resolve more rapidly.\n\nDenosumab is injected subcutaneously; the dosing ranges from 60 mg every 6 months in postmenopausal women to 120 mg every 4 weeks in the setting of malignant diseases. Instead of bisphosphonates, denosumab circulatory half-life is about 26 days, in fact its effect is reversible because it does not accumulate in the bone [3,4,18]. Denosumab prevents the interaction of RANKL (a cytokine secreted by bone marrow stromal cells, osteoblasts and T cells, essential to induce osteoclast differentiation) with RANK (receptors present on osteoclasts and their precursor cells), blocking the formation, functional ability and survival of osteoclastic cells. The indications of denosumab are principally similar to bisphosphonates, that bind to the calcium hydroxyapatite present in bone and reduce bone resorption by affecting the function and survival of osteoclasts. However they do not affect the formation of osteoclasts [9,19,20].\n\nThe side effect profile of denosumab and bisphosphonates is partly overlapping: ONJ occur with similar frequency under treatment with denosumab and zoledronic acid, the most potent among bisphosphonates [3,21,22]. The greater prevalence of osteonecrosis in the maxillary bones can be explained by the major concentration of antiresorptive drugs in these structures, because of the continuous bone remodelling resulting from the constant functional trauma [4,23]. The site of the greater prevalence of ONJ has been reported to be the mandible; maybe, the antiangiogenetic properties of bisphosphonates has a relevant effect in mandible because of its physiologic characteristic of elevate blood supply and high turnover [4,23].\n\nSeveral risk factors can be related to the onset of the disease, including the nature of the drugs, its potency and absorption rate, local and systemic factors and the duration of administration. Osteonecrosis can develop spontaneously; however, dental surgery is considered to be the main triggering factor, followed by prosthetic trauma, periodontal disease, and dental implant placement [4,24]. Regarding the treatment of ONJ, reported therapeutic options include the use of antiseptic agents as 0.12% chlorhexidine, systemic antibiotics, and surgical debridement, either alone or combined with biological modulators such as platelet-rich plasma, an high autologous platelet concentrated that provides a source of growth factors improving wound healing and bone regeneration [4].\n\nAlso PRF has proved to be useful after surgery, in fact PRF releases growth factors such as platet-derived growth factors, insulin-like growth factor and vascular endothelial growth factor which are important healing promoters [25].\n\nFernando de Almeida Barros Mourão et al. [26] in their study presented a series of patients treated with PRF applied after necrotic bone removal and showed a positive effect on promoting soft tissue healing and reducing post-operative pain.\n\nAlso Giudice et al. [27] in their paper found that the use of PRF to cover bone surface after surgical debridement of necrotic area brought to better short-term results in terms of mucosal healing and quality of life. Although long-term evaluation showed no statistical differences between using or not PRF after surgery, with the cited study they demonstrated a significant improvement in short-term quality of life and a reduction of necessity of re-intervention.\n\nSeveral studies [28-31] have described MRONJ surgical treatment performed with Er:YAG laser. Vescovi et al. [28] affirmed that a surgical approach performed with Er:YAG laser was associated with significantly better results when compared with traditional surgical treatment.\n\nEr:YAG laser emits a wavelength of 2940 nm which is highly affine to water and hydroxyapatite; laser technology allows an efficient ablation of hard tissues without producing important thermal increasing which could determine necrotizing effects on tissues [29-31].\n\nLaser works producing water vapour that expands increasing pressure until micro-explosions develop. The result is tissue removal and this process is called thermally-induced mechanical ablation [32].\n\nThe cold ablation produced by Er:YAG laser has been demonstrated to be effective and safe in removal of granulation tissue and root surface debridement. Furthermore it also promotes new bone formation in periodontal surgery also because of the lower increase of the temperature compared with rotary tools [30,31,33].\n\nDiscontinuing the drug after ONJ diagnosis is controversial: denosumab’s related ONJ, due to its different mechanism of pathogenesis, may resolve more rapidly after a drug holiday compared to BRONJ [10]. Usually, when a drug use causes a serious side effect, the drug is interrupted but, as these medications are also used to inhibit bone metastases growing, benefits of their continuation is almost always overweigh their risks.\n\nThere is still no consensus about the treatment of the ONJ because the pathological mechanism of disease is not fully understood, but there is agreement on the importance of prevention for bisphosphonate users. In the present study, all the analysed cases have been diagnosed after symptoms developing; this is according to literature’s findings that ONJ diagnosis is not easy during asymptomatic, reinforcing the importance of an accurate medical history and of prevention [34,35]. Clinical and radiographic evaluation of patient’s dental status is required before starting therapy with antiresorptive drugs, in order to identify and remove possible sites of infections, such as teeth with periodontal disease, residual roots, chronic infections. At risk patients must have acceptable oral health when antiresorptive therapy begins, for the purpose of avoid the necessity of tooth extractions during (and after) the antiresorptive therapy [36].\n\nIn our experience all the three surgical options used gave us good results; all patients were Stage 2 MRONJ and have been treated with surgery associated with antibiotic therapy and antimicrobial rinses as indicated by the AAOMS position paper [13]. Moreover, in one case Er:YAG laser was also used and in another one PRF was applied. Due to our results all the three strategies have been revealed to be effective in MRONJ treatment. The three cases presented in this paper are summarized in Table 2.\n\nTable 2 Personal and clinical characteristics of patients with MRONJ and treatment received (n = 3)\n\nCase\tSex\tAge\tAntiresorptive agent\tIndication for treatment\tTreatment duration (years)\tLesion site\tStage AAOM\tTriggering factor\tTreatment for MRONJ\tFollow-up outcome\t\n1\tF\t77\tIbandronic acid (alendronate)\tOsteoporosis\t(5) + 1\tMandible\t2\tImplant removal due to perimplantitis\tSurgical debridement\tGood wound healing, paraesthesia remained\t\n\t\n2\tF\t66\tDenosumab\tBone metastases (breast cancer)\t1\tMandible\t2\tDental extraction\tSurgical debridement\n+ PRF\tGood wound healing, remained discomfort\n(NRS = 3)\t\n\t\n3\tF\t80\tIbandronic acid\tOsteoporosis\t8\tMandible\t2\tDental extraction\tSurgical debridement\n+ Er:YAG laser\tGood wound healing, no more paraesthesia\t\nAAOM = American Association of Oral and Maxillofacial Surgeons; MRONJ = medication-related osteonecrosis of the jaw; F = female; PRF = platelet-rich fibrin; NRS = numeric rating scale.\n\nCONCLUSIONS\n\nMedication-related osteonecrosis of the jaw is a complication that can cause oncologic treatment interruptions and can deteriorate quality of life. It is necessary and very important for dentists to be aware of the potential risk of developing medication-related osteonecrosis of the jaw in patients who take or had taken in the past antiresorptive drugs. Prevention and a particular care toward these patients with periodic checks should be the primary strategies for antiresorptive drugs users. The use of platelet-rich fibrin and Erb:YAG laser seems promoting therapeutic options in the treatment of medication-related osteonecrosis of the jaw but more studies should be developed to establish a precise way to assess the medication-related osteonecrosis of the jaw risk and to define the more effective treatment strategies in light of a benefit-risk ratio.\n\nACKNOWLEDGMENTS AND DISCLOSURE STATEMENTS\n\nThe authors report no conflicts of interest related to this study. No external funding to declare.\n==== Refs\nREFERENCES\n\n1 Tenore G Palaia G Gaimari G Brugnoletti O Bove L Lo Giudice R Mohsen M Romeo U Medication-Related Osteonecrosis of the Jaws (MRONJ): Etiological update. Senses Sci. 2014 Dec;4(1):147-52. 10.14616/sands-2014-4-147152\n2 Novak S Antiresorptivni lijekovi u lijecenju osteoporoze [Antiresorptive agents in the treatment of osteoporosis]. Reumatizam. 2014;61(2):89-94. Croatian. 25427401\n3 Otto S Medication-Related Osteonecrosis of the Jaws: Bisphosphonates, Denosumab, and New Agents. Berlin Heidelberg; Springer: 2015. 10.1007/978-3-662-43733-9\n4 Mathias Duarte LF dos Reis HB Tucci R Dib LL Bisphosphonate-related osteonecrosis of the jaws: analysis of a case series at a dental school. Spec Care Dentist. 2014 Mar-Apr;34(2):77-83. 10.1111/scd.12023 23875734\n5 Baron R Ferrari S Russell RG Denosumab and bisphosphonates: different mechanisms of action and effects. Bone. 2011 Apr 1;48(4):677-92. 10.1016/j.bone.2010.11.020 21145999\n6 Marx RE Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003 Sep;61(9):1115-7. 10.1016/S0278-2391(03)00720-1 12966493\n7 Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg. 2007 Mar;65(3):369-76. 10.1016/j.joms.2006.11.003 17307580\n8 Ruggiero SL Fantasia J Carlson E Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006 Oct;102(4):433-41. 10.1016/j.tripleo.2006.06.004 16997108\n9 Benjamin B Benjamin MA Swe M Sugathan S Review on the comparison of effectiveness between denosumab and bisphosphonates in post-menopausal osteoporosis. Osteoporos Sarcopenia. 2016 Jun;2(2):77-81. 10.1016/j.afos.2016.03.003 30775470\n10 Malan J Ettinger K Naumann E Beirne OR The relationship of denosumab pharmacology and osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012 Dec;114(6):671-6. 10.1016/j.oooo.2012.08.439 23159111\n11 Nicolatou-Galitis O Kouri M Papadopoulou E Vardas E Galiti D Epstein JB Elad S Campisi G Tsoukalas N Bektas-Kayhan K Tan W Body JJ Migliorati C Lalla RV MASCC Bone Study Group. Osteonecrosis of the jaw related to non-antiresorptive medications: a systematic review. Support Care Cancer. 2019 Feb;27(2):383-394. 10.1007/s00520-018-4501-x 30353228\n12 Khan AA Morrison A Hanley DA Felsenberg D McCauley LK O'Ryan F Reid IR Ruggiero SL Taguchi A Tetradis S Watts NB Brandi ML Peters E Guise T Eastell R Cheung AM Morin SN Masri B Cooper C Morgan SL Obermayer-Pietsch B Langdahl BL Al Dabagh R Davison KS Kendler DL Sándor GK Josse RG Bhandari M El Rabbany M Pierroz DD Sulimani R Saunders DP Brown JP Compston J International Task Force on Osteonecrosis of the Jaw. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. 2015 Jan;30(1):3-23. 10.1002/jbmr.2405 25414052\n13 Ruggiero SL Dodson TB Fantasia J Goodday R Aghaloo T Mehrotra B O'Ryan F American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update. J Oral Maxillofac Surg. 2014 Oct;72(10):1938-56. 10.1016/j.joms.2014.04.031 25234529\n14 Krebs EE Carey TS Weinberger M Accuracy of the pain numeric rating scale as a screening test in primary care. J Gen Intern Med. 2007 Oct;22(10):1453-8. 10.1007/s11606-007-0321-2 17668269\n15 Fusaro F Costantinides F Maglione M Dalessandri D Vettori E DI Lenarda R Comparison of orthopantomography and CT accuracy in predicting inferior alveolar nerve injury following lower third molar surgical extraction. Minerva Stomatol. 2017 Oct;66(5):193-200. 10.23736/S0026-4970.17.04026-2 28880060\n16 Tubiana-Hulin M Spielmann M Roux C Campone M Zelek L Gligorov J Samson J Lesclous P Laredo JD Namer M Physiopathology and management of osteonecrosis of the jaws related to bisphosphonate therapy for malignant bone lesions. A French expert panel analysis. Crit Rev Oncol Hematol. 2009 Jul;71(1):12-21. 10.1016/j.critrevonc.2008.10.009 19070505\n17 Diz P Limeres J Fedele S Seoane J Diniz M Feijoo JF Is oral bisphosphonate-related osteonecrosis of the jaw an endemic condition? Med Hypotheses. 2012 Feb;78(2):315-8. 10.1016/j.mehy.2011.11.011 22136947\n18 Yee AJ Raje NS Denosumab, a RANK ligand inhibitor, for the management of bone loss in cancer patients. Clin Interv Aging. 2012;7:331-8. 10.2147/CIA.S14566 22977302\n19 Russell RG Watts NB Ebetino FH Rogers MJ Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int. 2008 Jun;19(6):733-59. 10.1007/s00198-007-0540-8 18214569\n20 Boyle WJ Simonet WS Lacey DL Osteoclast differentiation and activation. Nature. 2003 May 15;423(6937):337-42. 10.1038/nature01658 12748652\n21 Henry DH Costa L Goldwasser F Hirsh V Hungria V Prausova J Scagliotti GV Sleeboom H Spencer A Vadhan-Raj S von Moos R Willenbacher W Woll PJ Wang J Jiang Q Jun S Dansey R Yeh H Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011 Mar 20;29(9):1125-32. 10.1200/JCO.2010.31.3304 21343556\n22 Qi WX Tang LN He AN Yao Y Shen Z Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta-analysis of seven randomized controlled trials. Int J Clin Oncol. 2014 Apr;19(2):403-10. 10.1007/s10147-013-0561-6 23605142\n23 Marx RE Sawatari Y Fortin M Broumand V Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg. 2005 Nov;63(11):1567-75. 10.1016/j.joms.2005.07.010 16243172\n24 Assael LA Oral bisphosphonates as a cause of bisphosphonate-related osteonecrosis of the jaws: clinical findings, assessment of risks, and preventive strategies. J Oral Maxillofac Surg. 2009 May;67(5 Suppl):35-43. 10.1016/j.joms.2009.01.003 19371813\n25 Su CY Kuo YP Tseng YH Su CH Burnouf T In vitro release of growth factors from platelet-rich fibrin (PRF): a proposal to optimize the clinical applications of PRF. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009 Jul;108(1):56-61. 10.1016/j.tripleo.2009.02.004 19451002\n26 Fernando de Almeida Barros Mourão C Calasans-Maia MD Del Fabbro M Le Drapper Vieira F Coutinho de Mello Machado R Capella R Miron RJ Gomes Alves G The use of Platelet-rich Fibrin in the management of medication-related osteonecrosis of the jaw: A case series. J Stomatol Oral Maxillofac Surg. 2020 Feb;121(1):84-89. 10.1016/j.jormas.2019.02.011 30794883\n27 Giudice A Barone S Giudice C Bennardo F Fortunato L Can platelet-rich fibrin improve healing after surgical treatment of medication-related osteonecrosis of the jaw? A pilot study. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018 Nov;126(5):390-403. 10.1016/j.oooo.2018.06.007 30108028\n28 Vescovi P Giovannacci I Otto S Manfredi M Merigo E Fornaini C Nammour S Meleti M Medication-Related Osteonecrosis of the Jaw: An Autofluorescence-Guided Surgical Approach Performed with Er:YAG Laser. Photomed Laser Surg. 2015 Aug;33(8):437-42. 10.1089/pho.2015.3927 26226174\n29 Merigo E Cella L Oppici A Cristina rbasi M Clini F Fontana M Fornaini C Combined Approach to Treat Medication-Related Osteonecrosis of the Jaws. J Lasers Med Sci. 2018 Spring;9(2):92-100. 10.15171/jlms.2018.19 30026893\n30 Curti M Rocca JP Bertrand MF Nammour S Morpho-structural aspects of Er:YAG-prepared class V cavities. J Clin Laser Med Surg. 2004 Apr;22(2):119-23. 10.1089/104454704774076172 15165386\n31 Angiero F Sannino C Borloni R Crippa R Benedicenti S Romanos GE Osteonecrosis of the jaws caused by bisphosphonates: evaluation of a new therapeutic approach using the Er:YAG laser. Lasers Med Sci. 2009 Nov;24(6): 849-56. 10.1007/s10103-009-0654-7 19277823\n32 Vescovi P Manfredi M Merigo E Meleti M Fornaini C Rocca JP Nammour S Surgical approach with Er:YAG laser on osteonecrosis of the jaws (ONJ) in patients under bisphosphonate therapy (BPT). Lasers Med Sci. 2010 Jan;25(1):101-13. 10.1007/s10103-009-0687-y 19543768\n33 Mizutani K Aoki A Takasaki AA Kinoshita A Hayashi C Oda S Ishikawa I Periodontal tissue healing following flap surgery using an Er:YAG laser in dogs. Lasers Surg Med. 2006 Apr;38(4):314-24. 10.1002/lsm.20299 16568444\n34 Martins MA Martins MD Lascala CA Curi MM Migliorati CA Tenis CA Marques MM Association of laser phototherapy with PRP improves healing of bisphosphonate-related osteonecrosis of the jaws in cancer patients: a preliminary study. Oral Oncol. 2012 Jan;48(1):79-84. 10.1016/j.oraloncology.2011.08.010 21940198\n35 Diniz-Freitas M López-Cedrún JL Fernández-Sanromán J García-García A Fernández-Feijoo J Diz-Dios P Oral bisphosphonate-related osteonecrosis of the jaws: Clinical characteristics of a series of 20 cases in Spain. Med Oral Patol Oral Cir Bucal. 2012 Sep 1;17(5):e751-8. 10.4317/medoral.18041 22549688\n36 Hennedige AA Jayasinghe J Khajeh J Macfarlane TV Systematic review on the incidence of bisphosphonate related osteonecrosis of the jaw in children diagnosed with osteogenesis imperfecta. J Oral Maxillofac Res. 2014 Jan 1;4(4):e1. 10.5037/jomr.2013.4401 24478911\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2029-283X",
"issue": "12(2)",
"journal": "Journal of oral & maxillofacial research",
"keywords": "antiresorptive drugs; laser therapy; oral surgery; osteonecrosis; platelet-rich fibrin",
"medline_ta": "J Oral Maxillofac Res",
"mesh_terms": null,
"nlm_unique_id": "101552108",
"other_id": null,
"pages": "e6",
"pmc": null,
"pmid": "34377383",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "21145999;22549688;30353228;18214569;26226174;19451002;23159111;24478911;30794883;25234529;12748652;30775470;12966493;25414052;16243172;19070505;22136947;19371813;17668269;21343556;19543768;21940198;30026893;30108028;23875734;17307580;23605142;16997108;16568444;19277823;15165386;25427401;28880060;22977302",
"title": "Therapeutic Approach in the Treatment of Medication-Related Osteonecrosis of the Jaw: Case Series of 3 Patients and State of the Art on Surgical Strategies.",
"title_normalized": "therapeutic approach in the treatment of medication related osteonecrosis of the jaw case series of 3 patients and state of the art on surgical strategies"
} | [
{
"companynumb": "IT-AMGEN-ITASP2021127135",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MEPIVACAINE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "OBJECTIVE\nTo present the correlation between severe pre-eclampsia and peripartum cardiomyopathy in pregnancy.\n\n\nMETHODS\nA 41-year-old parturient, gravida 3, para 1, at 34 4/7 weeks' gestation, was diagnosed with severe pre-eclampsia. At the time of admission, a plain chest film disclosed bilateral pleural effusions. An emergent cesarean section was planned because of decreased fetal movement, heavy daily protein loss, and bilateral pleural effusions. During the cesarean section, she developed shock with acute respiratory failure. She underwent advanced cardiac life support and intubation with mechanical ventilator support. Peripartum cardiomyopathy was subsequently diagnosed by echocardiography.\n\n\nCONCLUSIONS\nThe presented case demonstrates that routine echocardiography is highly recommended for suspected peripartum cardiomyopathy in gravidas with severe pre-eclampsia and symptoms or signs of heart failure.",
"affiliations": "Department of General Medicine, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan.;Department of Obstetrics and Gynecology, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan.;Department of Obstetrics and Gynecology, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan.;Department of Obstetrics and Gynecology, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan.;Department of Obstetrics and Gynecology, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan.;Department of Obstetrics and Gynecology, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan. Electronic address: su108868@gmail.com.",
"authors": "Chou|Meng-Han|MH|;Huang|Hsin-Hui|HH|;Lai|Yu-Ju|YJ|;Hwang|Kwei-Shuai|KS|;Wang|Yu-Chi|YC|;Su|Her-Young|HY|",
"chemical_list": null,
"country": "China (Republic : 1949- )",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1028-4559",
"issue": "55(1)",
"journal": "Taiwanese journal of obstetrics & gynecology",
"keywords": "heart failure; peripartum cardiomyopathy; pleural effusion; severe pre-eclampsia",
"medline_ta": "Taiwan J Obstet Gynecol",
"mesh_terms": "D000328:Adult; D009202:Cardiomyopathies; D002585:Cesarean Section; D004452:Echocardiography; D004630:Emergencies; D005260:Female; D006323:Heart Arrest; D006801:Humans; D007431:Intraoperative Complications; D011225:Pre-Eclampsia; D011247:Pregnancy",
"nlm_unique_id": "101213819",
"other_id": null,
"pages": "125-7",
"pmc": null,
"pmid": "26927264",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cardiac arrest during emergency cesarean section for severe pre-eclampsia and peripartum cardiomyopathy.",
"title_normalized": "cardiac arrest during emergency cesarean section for severe pre eclampsia and peripartum cardiomyopathy"
} | [
{
"companynumb": "TW-MYLANLABS-2017M1013668",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BETAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Adrenocortical carcinomas (ACC) are rare with an incidence of 0.7-2 per million population per year and account for only 0.05%-2% of all malignant tumors. While majority of the functional ACC present as Cushing syndrome, recurrent hyperaldosteronism from metastatic ACC is exceedingly rare. We describe a 67-year old female presented with hypertensive urgency & hypokalemia as a result of hyperaldosteronism from an 8-cm right ACC. She underwent a radical right nephrectomy with adrenalectomy that normalized her blood pressure. However, a few years later she presented again with resistant hypertension from hyperaldosteronism, raising the suspicion of recurrence of ACC. A contrast-enhanced CT scan showed a normal left adrenal gland but revealed pulmonary metastases of ACC based on a lung biopsy. Chemotherapy was complicated with side effects leading to refusal of further chemotherapy, henceforth requiring high dose of spironolactone for blood pressure control. Despite curative surgery, metastatic functional ACC should be considered in patients presenting with secondary hypertension from recurrent hyperaldosteronism, due to its high recurrence rate. Besides standard cancer surveillance after a curative surgery, meticulous monitoring of blood pressure is a simple yet crucial way to detect cancer recurrence early.",
"affiliations": "University of Oklahoma, Department of Internal Medicine/Nephrology, Tulsa Schusterman Center, Tulsa, Oklahoma, USA, 74135.;University of Oklahoma, Department of Internal Medicine/Nephrology, Tulsa Schusterman Center, Tulsa, Oklahoma, USA, 74135.;Mercy Clinic, Critical Care Medicine, Rogers, Arkansas, USA, 72758.",
"authors": "Baradhi|Krishna Mohan|KM|;Tran|Thao|T|;Mittadodla|Penchala Swamy|PS|",
"chemical_list": null,
"country": "Uganda",
"delete": false,
"doi": "10.11604/pamj.2018.30.10.14015",
"fulltext": "\n==== Front\nPan Afr Med JPan Afr Med JPAMJThe Pan African Medical Journal1937-8688The African Field Epidemiology Network PAMJ-30-1010.11604/pamj.2018.30.10.14015Case Report’Malignant’ hypertension from hyperaldosteronism: a case report Baradhi Krishna Mohan 1&Tran Thao 1Mittadodla Penchala Swamy 2\n1 University of Oklahoma, Department of Internal Medicine/Nephrology, Tulsa Schusterman Center, Tulsa, Oklahoma, USA, 74135\n2 Mercy Clinic, Critical Care Medicine, Rogers, Arkansas, USA, 72758& Corresponding author: Krishna Mohan Baradhi, University of Oklahoma, Department of Internal Medicine/Nephrology, Tulsa Schusterman Center, Tulsa, Oklahoma, USA, 7413504 5 2018 2018 30 1001 10 2017 22 4 2018 © Krishna Mohan Baradhi et al.2018The Pan African Medical Journal - ISSN 1937-8688. This is an Open Access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Adrenocortical carcinomas (ACC) are rare with an incidence of 0.7-2 per million population per year and account for only 0.05%-2% of all malignant tumors. While majority of the functional ACC present as Cushing syndrome, recurrent hyperaldosteronism from metastatic ACC is exceedingly rare. We describe a 67-year old female presented with hypertensive urgency & hypokalemia as a result of hyperaldosteronism from an 8-cm right ACC. She underwent a radical right nephrectomy with adrenalectomy that normalized her blood pressure. However, a few years later she presented again with resistant hypertension from hyperaldosteronism, raising the suspicion of recurrence of ACC. A contrast-enhanced CT scan showed a normal left adrenal gland but revealed pulmonary metastases of ACC based on a lung biopsy. Chemotherapy was complicated with side effects leading to refusal of further chemotherapy, henceforth requiring high dose of spironolactone for blood pressure control. Despite curative surgery, metastatic functional ACC should be considered in patients presenting with secondary hypertension from recurrent hyperaldosteronism, due to its high recurrence rate. Besides standard cancer surveillance after a curative surgery, meticulous monitoring of blood pressure is a simple yet crucial way to detect cancer recurrence early.\n\nSecondary hypertensionhyperaldosteronismadrenocortical carcinomahypokalemia\n==== Body\nIntroduction\nAdrenocortical carcinomas (ACC) are rare malignancy with an incidence of 0.7-2 per million population per year [1]. While ~60% of ACC are functional, clinical manifestations of hyper-secretion are seen in only ~40% of the cases. Hormone-secreting ACC usually present as Cushing´s syndrome (45%), or a mixed Cushing's and virilization syndrome, (25%), whereas, aldosterone-producing tumors are exceptionally rare comprising only ~2.5% of ACC. Amongst these unfamiliar territories, hyperaldosteronism from metastatic adrenal carcinoma has rarely been reported. We herein present a first unique case of secondary hypertension as a result of hyperaldosteronism arising from lung metastasis of the previously resected ACC.\n\nPatient and observation\nThe patient is a 67-year-old Caucasian woman who presented with uncontrolled hypertension. Patient did not have major medical issues until her early 60s when she started noticing rise in blood pressure during her routine clinic visits. Physical examination was within the normal limits except her systolic blood pressure was consistently in the 200s. Laboratory evaluation was significant for hypokalemia of 2.7 meq/L, bicarbonate -24 meq/L and creatinine of 0.92 mg/dl. Further evaluation for possible etiology of secondary hypertension revealed high aldosterone-renin ratio. Computed tomography (CT) scan to evaluate hyperaldosteronism showed a large mass in right adrenal gland measuring 10 x 7.8 cm (Figure 1). Further FDG-PET scan showed a right adrenal mass and periceliac lymph nodes were positive. The patient underwent a radical right adrenalectomy with nephrectomy and lymph nodes dissection. Pathology revealed 14cm adrenal cortical carcinoma with two lymph nodes next to vena cava which were positive. She also completed adjuvant radiation and chemotherapy. Her blood pressure and serum potassium normalized after adrenalectomy. Follow up FDG-PET scan a year later, showed increase glucometabolism in a nodal mass of the left paratracheal region superior to the clavicle and underwent lymph node dissection. Biopsy again showed metastatic ACC of supraclavicular lymph node. Patient completed 3 cycles of carboplatin and etoposide. In addition, during this time, the patient also diagnosed with papillary thyroid carcinoma for which she underwent thyroidectomy and ablation. Blood pressure was within the normal limits during this period. Patient was lost to follow up for two years due to non-compliance until she presented back again with difficult to control blood pressure with associated hypokalemia similar to her prior presentation (Table 1). Her medications at this time included clonidine, metoprolol, Lisinopril, Torsemide, and potassium supplements. Despite these regimen, her systolic blood pressure remained in the 200s. Further testing revealed aldosterone-renin ratio of greater than 200, raising the red flag of possible recurrence of ACC. A CT abdomen showed normal left adrenal gland, however CT chest revealed multiple pulmonary lesions favoring metastasis as shown in the Figure 2. Initial bronchoscopy showed many atypical cells but no malignancy. Percutaneous lung biopsy unveiled these lesions to be of metastatic cancer of adrenocortical origin. She underwent chemotherapy again complicated with side effects leading to refusal of further chemotherapy, henceforth requiring high dose of spironolactone (400 mg daily) for blood pressure control.\n\nTable 1 Laboratory data\n\nChemistry\tInitial presentation\tRecurrent presentation\tUnits\t\nSodium\t136\t140\tmEq/L\t\nPotassium\t2.7\t3.1\tmEq/L\t\nChloride\t104\t106\tmEq/L\t\nBicarbonate\t24\t25\tmEq/L\t\nCalcium\t8.7\t8.8\tmEq/L\t\nCreatinine\t0.92\t1.13\tmEq/L\t\nBUN\t14\t15\tmg/dL\t\nGlucose\t133\t88\tmg/dL\t\nAldosterone/Renin ratio >200\n\nFigure 1 CT abdomen: (A) coronal section showing 8cm mass above the right kidney; (B) sagittal section showing the adrenal tumor\n\nFigure 2 CT chest showing bilateral pulmonary metastases\n\nDiscussion\nSecondary hypertension from aldosterone secreting ACC is not only uncommon but may also be unfamiliar to the practicing clinicians. Amongst these odd etiologies of hyperaldosteronism, pulmonary metastasis of previously resected ACC is a rare entity. Deckers et al reported a case of hyperaldosteronism from peritoneal dissemination of the previously removed ACC [2]. Calvo-Romero et al reported a case of resistant hypertension as a result of hyperaldosteronism from recurrent adrenal adenoma [3]. ACC usually affect middle aged group and are slightly more common in females [4]. The clinical presentation of aldosterone producing ACC is hypertension and hypokalemia. It is clinically indistinguishable from the Conn's syndrome presentation and pathological differentiation can be challenging. Both size and appearance on imaging are used to distinguish between benign and malignant adrenal mass. Tumors > 6cm are highly suspicious for malignancy and require surgical resection according to NIH [5]. For tumors between 4 and 6 cm, additional criteria should be considered before adjudicating to monitor or proceed to adrenalectomy [5]. In addition, Weiss criteria can also be used to distinguish between benign and malignant ACC. Weiss system mandates meeting three out of the nine histological features to be regarded as malignant [6]. Amongst them, the presence of atypical mitoses, capsular invasion, tumor weight greater than 250g, and size greater than 10cm each showed a statistical association with poor survival, compared to other features, such as nuclear grade, presence of necrosis or of venous /sinusoidal invasion, character of the tumor cell cytoplasm, or architectural pattern, showed no statistical significance in predicting survival [7].\n\nMineralocorticoid antagonists or adrenalectomy can be the option of treatment for classical causes of primary hyperaldosteronism, whereas the only potential lifesaving option for ACC is complete radical resection [8]. It is imperative that hormonal assessment is done prior to adrenalectomy. Despite surgical resection, there is a high recurrence rate of ACC, up to 74% recurrence rate either local or distant metastasis [9]. Hence, Fassnacht et al advocate periodic radiological and biochemical monitoring for at least 10 years post-surgery for ACC [4]. For aldosterone producing ACC, common sites of metastasis include liver, lung, abdominal lymph modes, contralateral adrenal and abdominal lymph nodes [10]. The prognosis of ACC depends on tumour stage and is generally poor. Interval between the initial resection of an adrenocortical carcinoma and recurrence can dictate prognosis [11]. The overall 5-year survival rate range between 16 and 38% and median survival for metastatic disease is less than 12 months [12,13]. Largest study to date indicated rates of response and progression-free survival were significantly better with etoposide plus mitotane than with streptozocin plus mitotane as first-line therapy for advanced ACC [14]. Our patient presented with recurrent metastatic ACC with resultant hyperaldosteronism leading to resistant hypertension and hypokalemia. Given the extent of her disease with multiple recurrences of metastasis, mitotane chemotherapy was offered to patient along with the etoposide. Unfortunately, as she succumbed to the side effects of therapy, patient decided against further treatment and required escalating doses of spironolactone to control her blood pressure.\n\nConclusion\nOur case highlights the importance of considering functional ACC in patients presenting with hyperaldosteronism. Clinicians should be cognizant of high rate of recurrence of ACC and incorporate blood pressure monitoring besides standard radiographic and laboratory surveillance after a curative surgery to detect recurrence of ACC early.\n\nCompeting interests\nThe authors declare no competing interests.\n\nAuthors’ contributions\nAll authors read and agreed to the final version of this manuscript and equally contributed to its content and to the management of the case.\n==== Refs\nReferences\n1 Allolio B Fassnacht M Clinical review: Adrenocortical carcinoma: Clinical update J Clin Endocrinol Metab 2006 91 6 2027 2037 16551738 \n2 Deckers S Derdelinckx L Col V Hamels J Maiter D Peritoneal carcinomatosis following laparoscopic resection of an adrenocortical tumor causing primary hyperaldosteronism Hormone Research 1999 52 97 100 10681640 \n3 Calvo-Romero JM Ramos-Salado JL Recurrence of adrenal aldosterone-producing adenoma Postgrad Med J 2000 76 893 160 161 10684327 \n4 Fassnacht M Kroiss M Allolio B Update in adrenocortical carcinoma J Clin Endocrinol Metab 2013 98 12 4551 24081734 \n5 National Institutes of Health NIH state-of-the-science statement on management of the clinically inapparent adrenal mass (\"incidentaloma\") NIH Consens State Sci Statements 2002 19 2 1 25 \n6 Weiss LM Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors Am J Surgical Pathology 1984 8 3 163 169 \n7 Weiss LM Medeiros LJ Vickery AL Jr Pathologic features of prognostic significance in adrenocortical carcinoma Am J Surgical Pathology 1989 3 13 3 202 6 \n8 Allolio B Hahner S Weismann D Fassnacht M Management of adrenocortical carcinoma Clinical Endocrinology 2004 60 3 273 87 15008991 \n9 Freire DS Siqueira SA Zerbini MC Wajchenberg BL Corrêa-Giannella ML Lucon AM Development and internal validation of an adrenal cortical carcinoma prognostic score for predicting the risk of metastasis and local recurrence Clinical Endocrinology 2013 79 4 468 475 23444945 \n10 Seccia TM Fassina A Nussdorfer GG Pessina AC Rossi GP Aldosterone-producing adrenocortical carcinoma: an unusual cause of conn's syndrome with an ominous clinical course Endocrine Related Cancer 2005 12 1 149 159 15788646 \n11 Simon G Pattou F Mirallié E Lifante JC Nominé C Arnault V de Calan L Caillard C Carnaille B Brunaud L Laplace N Caiazzo R Blanchard C Surgery for recurrent adrenocortical carcinoma: a multicenter retrospective study Surgery 2017 161 1 249 256 27855966 \n12 Luton JP Cerdas S Billaud L Thomas G Guilhaume B Bertagna X Laudat MH Louvel A Chapuis Y Blondeau P Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy New England Journal of Medicine 1990 322 17 1195 1201 2325710 \n13 Icard P Goudet P Charpenay C Andreassian B Carnaille B Chapuis Y Cougard P Henry JF Proye C Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons Study Group World Journal of Surgery 2001 25 7 891 897 11572030 \n14 Fassnacht M Terzolo M Allolio B Combination chemotherapy in advanced adrenocortical carcinoma N Engl J Med 2012 366 2189 2197 22551107\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "30()",
"journal": "The Pan African medical journal",
"keywords": "Secondary hypertension; adrenocortical carcinoma; hyperaldosteronism; hypokalemia",
"medline_ta": "Pan Afr Med J",
"mesh_terms": "D000306:Adrenal Cortex Neoplasms; D000315:Adrenalectomy; D018268:Adrenocortical Carcinoma; D000368:Aged; D001794:Blood Pressure; D005260:Female; D006801:Humans; D006929:Hyperaldosteronism; D006974:Hypertension, Malignant; D007008:Hypokalemia; D008175:Lung Neoplasms; D009392:Nephrectomy; D012008:Recurrence",
"nlm_unique_id": "101517926",
"other_id": null,
"pages": "10",
"pmc": null,
"pmid": "30123413",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "2325710;15788646;14768652;11572030;16551738;27855966;22551107;2919718;23444945;10681640;10684327;24081734;15008991;6703192",
"title": "'Malignant' hypertension from hyperaldosteronism: a case report.",
"title_normalized": "malignant hypertension from hyperaldosteronism a case report"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-038525",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METOPROLOL"
},
... |
{
"abstract": "To report a sinus bradycardia induced by metoprolol and terbinafine drug-drug interaction and its management. A 63 year-old Caucasian man on metoprolol 200 mg/day for stable coronary artery disease was prescribed a 90-day course of oral terbinafine 250 mg/day for onychomycosis. On the 49th day of terbinafine therapy, he was brought to the emergency room for a decrease of his global health status, confusion and falls. The electrocardiogram revealed a 37 beats/min sinus bradycardia. A score of 7 on the Naranjo adverse drug reaction probability scale indicates a probable relationship between the patient's sinus bradycardia and the drug interaction between metoprolol and terbinafine. The heart rate ameliorated first with a decrease in the dose of metoprolol. It was subsequently changed to bisoprolol and the heart rate remained normal. By inhibiting the cytochrome P450 2D6, terbinafine had decreased metoprolol's clearance, leading in metoprolol accumulation which has resulted in clinically significant sinus bradycardia.",
"affiliations": "Department of Pharmacy, Hôpital du Sacré-Coeur de Montréal, 5400 Boul. Gouin Ouest, Montreal, QC, H4J 1C5, Canada, emmanuel.bebawi@umontreal.ca.",
"authors": "Bebawi|Emmanuel|E|;Jouni|Suhail S|SS|;Tessier|Andrée-Anne|AA|;Frenette|Anne Julie|AJ|;Brindamour|Dave|D|;Doré|Maxime|M|",
"chemical_list": "D009281:Naphthalenes; D019389:Cytochrome P-450 CYP2D6; D000077291:Terbinafine; D008790:Metoprolol",
"country": "France",
"delete": false,
"doi": "10.1007/s13318-014-0205-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0378-7966",
"issue": "40(3)",
"journal": "European journal of drug metabolism and pharmacokinetics",
"keywords": null,
"medline_ta": "Eur J Drug Metab Pharmacokinet",
"mesh_terms": "D001919:Bradycardia; D019389:Cytochrome P-450 CYP2D6; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006339:Heart Rate; D006801:Humans; D008297:Male; D008790:Metoprolol; D008875:Middle Aged; D009281:Naphthalenes; D000077291:Terbinafine",
"nlm_unique_id": "7608491",
"other_id": null,
"pages": "295-9",
"pmc": null,
"pmid": "24894748",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16175144;17542770;15063083;19689286;10709776;9492672;19787032;18834373;7249508;1386652;15492763;17522596;16513452;23251210;7144837;17124578;12748199;19512959;12412819;8946473;12398564;6370541;7768074;10383919;21668517;2222517;1372222",
"title": "A metoprolol-terbinafine combination induced bradycardia.",
"title_normalized": "a metoprolol terbinafine combination induced bradycardia"
} | [
{
"companynumb": "CA-MLMSERVICE-20150911-0023130-1",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TERBINAFINE"
},
"drugadditional": "1",... |
{
"abstract": "BACKGROUND\nAcute pancreatitis is an uncommon complication that occurs in 0.85% to 4% of patients with systemic lupus erythematosus (SLE). In some patients, it occurs within days to weeks of starting medium-to-high dose corticosteroids. The authors have used the term 'corticosteroid-associated lupus pancreatitis' for these patients, and they report a case series and perform a systematic review of previously published reports.\n\n\nMETHODS\nFor the purpose of this study, corticosteroid-associated lupus pancreatitis was defined as occurrence of acute pancreatitis in patients with SLE (fulfilling the 1997 ACR), within 3 weeks of starting therapy with medium-to-high dose corticosteroids - either newly initiated or escalated from a lower dose. All patients with SLE admitted in the last 2.5 years in a North Indian university hospital were reviewed, and those with pancreatitis who fulfilled the above criteria were included in the case series. For the systematic review, a PUBMED search using the keywords 'lupus' and 'pancreatitis' was performed, and reports in English were reviewed for an association with corticosteroids.\n\n\nRESULTS\nAmong 420 admissions of SLE patients, six patients (1.4%) fulfilled criteria for corticosteroid-associated lupus pancreatitis. All were female, with mean age and disease duration of 19.7 ± 3.3 and 3.8 ± 2.5 years respectively. All had active disease and developed acute pancreatitis within 48-72 hours of newly initiating medium-to-high dose corticosteroids (in three patients) or escalating them to medium-high dose (in three patients). After the development of pancreatitis, corticosteroids were continued in all except one patient. In addition, two patients received pulse methylprednisolone, two received pulse cyclophosphamide and one was started on azathioprine. Three patients died during hospitalization, all with severe pancreatitis. On systematic review, among 451 cases of lupus pancreatitis reported, 23 (5%) fulfilled criteria for 'corticosteroid-associated lupus pancreatitis'. A majority of them had pancreatitis within 3 days of starting treatment with medium-to-high dose corticosteroids. The mortality in these patients was 37.5%.\n\n\nCONCLUSIONS\nIn a small but substantial proportion of patients with lupus who develop pancreatitis, it occurs within days to weeks of starting medium-to-high dose corticosteroids. Many of these patients continue to receive corticosteroids, and some receive more aggressive immunosuppression. However, they have significant mortality, and further studies are required to identify appropriate treatment in this subgroup of patients.",
"affiliations": "1 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;1 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;1 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;1 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;2 Department of Pathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;2 Department of Pathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;1 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;1 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;1 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;1 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.;1 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.",
"authors": "Dwivedi|P|P|;Kumar|R R|RR|;Dhooria|A|A|;Adarsh|M B|MB|;Malhotra|S|S|;Kakkar|N|N|;Naidu|S|S|;Sharma|S K|SK|https://orcid.org/0000-0002-8821-6652;Sharma|A|A|;Jain|S|S|;Dhir|V|V|https://orcid.org/0000-0002-3626-0694",
"chemical_list": "D000305:Adrenal Cortex Hormones; D003520:Cyclophosphamide; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.1177/0961203319844004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "28(6)",
"journal": "Lupus",
"keywords": "Pancreatitis; SLE; corticosteroid; lupus; prednisolone",
"medline_ta": "Lupus",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000305:Adrenal Cortex Hormones; D001379:Azathioprine; D003520:Cyclophosphamide; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D010195:Pancreatitis; D012720:Severity of Illness Index; D055815:Young Adult",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "731-739",
"pmc": null,
"pmid": "31023131",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article; D000078182:Systematic Review",
"references": null,
"title": "Corticosteroid-associated lupus pancreatitis: a case series and systematic review of the literature.",
"title_normalized": "corticosteroid associated lupus pancreatitis a case series and systematic review of the literature"
} | [
{
"companynumb": "CA-CASPER PHARMA LLC-2019CAS000240",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BACITRACIN ZINC\\HYDROCORTISONE\\NEOMYCIN SULFATE\\POLYM... |
{
"abstract": "OBJECTIVE\nIncarcerated gravid uterus is a rare obstetrical complication that leads to adverse outcomes, especially if the uterus remains incarcerated and the condition goes undiagnosed until delivery. However, there is no consensus regarding the optimal management of this complication because of its rarity. In this study, we aimed to elucidate the incidence of incarcerated gravid uterus, as well as its natural courses and perinatal outcomes.\n\n\nMETHODS\nWe retrospectively reviewed medical records of patients who had incarcerated gravid uterus and managed at Osaka City University Hospital between April 2011 and March 2021. Incarcerated gravid uterus was defined as a retroverted or retroflexed uterus after 16 weeks of gestation.\n\n\nRESULTS\nThere were 14 incarcerated cases among 6958 pregnant women, and 13 of them had some kind of gynecological complication and/or history. Spontaneous resolution of incarcerated gravid uterus after 16 gestational weeks was observed in six cases before the late second trimester and five cases at the late second trimester to early third trimester. Three cases remained incarcerated at term or near-term. One case with adenomyosis had severe abdominal pain, although it was difficult to ascertain whether the cause of pain was triggered by adenomyosis and/or incarceration. One case was misdiagnosed as placenta previa, and the uterine cervix was subsequently injured during cesarean delivery, resulting in massive hemorrhaging.\n\n\nCONCLUSIONS\nApproximately 1 in 2300 pregnancies continued to be in an incarcerated condition at term or near-term, and 78.5% of cases showed a spontaneous resolution after 16 weeks of gestation. Expectant management with careful attention to the incarcerated gravid uterus may be one option in situations where there are no severe symptoms related to the incarceration itself.",
"affiliations": "Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.;Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.;Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.;Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.;Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.;Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.;Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.;Department of Diagnostic and Interventional Radiology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.;Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.",
"authors": "Tachibana|Daisuke|D|0000-0001-9268-2747;Misugi|Takuya|T|;Kitada|Kohei|K|;Kurihara|Yasushi|Y|;Tahara|Mie|M|;Hamuro|Akihiro|A|;Nakano|Akemi|A|;Yamamoto|Akira|A|0000-0002-4567-9745;Koyama|Masayasu|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/diagnostics11091544",
"fulltext": "\n==== Front\nDiagnostics (Basel)\nDiagnostics (Basel)\ndiagnostics\nDiagnostics\n2075-4418\nMDPI\n\n10.3390/diagnostics11091544\ndiagnostics-11-01544\nArticle\nIncarcerated Gravid Uterus: Spontaneous Resolution Is Not Rare\nhttps://orcid.org/0000-0001-9268-2747\nTachibana Daisuke 1*\nMisugi Takuya 1\nKitada Kohei 1\nKurihara Yasushi 1\nTahara Mie 1\nHamuro Akihiro 1\nNakano Akemi 1\nhttps://orcid.org/0000-0002-4567-9745\nYamamoto Akira 2\nKoyama Masayasu 1\nLaganà Antonio Simone Academic Editor\n1 Department of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan; misutaku1975@infoseek.jp (T.M.); kafukafu0404@yahoo.co.jp (K.K.); kurikuri_1011@yahoo.co.jp (Y.K.); rxv13436@nifty.ne.jp (M.T.); hamuroa@med.osaka-cu.ac.jp (A.H.); m2037746@med.osaka-cu.ac.jp (A.N.); masayasukoyama@gmail.com (M.K.)\n2 Department of Diagnostic and Interventional Radiology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan; loveakirayamamoto@gmail.com\n* Correspondence: dtachibana@med.osaka-cu.ac.jp; Tel.: +81-6-6645-3862; Fax: +81-6-6646-5800\n25 8 2021\n9 2021\n11 9 154409 6 2021\n20 8 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nAim: Incarcerated gravid uterus is a rare obstetrical complication that leads to adverse outcomes, especially if the uterus remains incarcerated and the condition goes undiagnosed until delivery. However, there is no consensus regarding the optimal management of this complication because of its rarity. In this study, we aimed to elucidate the incidence of incarcerated gravid uterus, as well as its natural courses and perinatal outcomes. Methods: We retrospectively reviewed medical records of patients who had incarcerated gravid uterus and managed at Osaka City University Hospital between April 2011 and March 2021. Incarcerated gravid uterus was defined as a retroverted or retroflexed uterus after 16 weeks of gestation. Results: There were 14 incarcerated cases among 6958 pregnant women, and 13 of them had some kind of gynecological complication and/or history. Spontaneous resolution of incarcerated gravid uterus after 16 gestational weeks was observed in six cases before the late second trimester and five cases at the late second trimester to early third trimester. Three cases remained incarcerated at term or near-term. One case with adenomyosis had severe abdominal pain, although it was difficult to ascertain whether the cause of pain was triggered by adenomyosis and/or incarceration. One case was misdiagnosed as placenta previa, and the uterine cervix was subsequently injured during cesarean delivery, resulting in massive hemorrhaging. Conclusions: Approximately 1 in 2300 pregnancies continued to be in an incarcerated condition at term or near-term, and 78.5% of cases showed a spontaneous resolution after 16 weeks of gestation. Expectant management with careful attention to the incarcerated gravid uterus may be one option in situations where there are no severe symptoms related to the incarceration itself.\n\nincarcerated gravid uterus\nspontaneous resolution\nmanual reduction\ndiagnosis\nmanagement\n==== Body\npmc1. Introduction\n\nUterine retroversion or retroflex is observed in 15% of pregnant women during the first trimester, and a majority will spontaneously resolve before 14 weeks of gestation [1]. If the uterine fundus remains in the pelvic cavity without self-correction after 16 weeks, the condition is said to be incarcerated. Incarcerated gravid uterus is a rare condition, occurring in approximately 1 in 3000 pregnancies [2]. Proposed risk factors are endometriosis, pelvic inflammatory disease, previous abdominal or pelvic surgery, fibroid, uterine anomaly, and uterine retroversion prior to pregnancy [1,2]. Symptoms of uterine incarceration during pregnancy are thought to be non-specific, such as pelvic discomfort, urinary retention, and gastrointestinal symptoms, and some patients are asymptomatic altogether [1,3,4]. Diagnosis is sometimes difficult because the hints of this disease are quite ambiguous, such as a non-palpable cervix and/or pelvic mass in filling the posterior cul-de-sac upon vaginal examination [1,2]. If a gravid uterus remains to be incarcerated, adverse outcomes, such as urinary retention, renal failure, miscarriage, preterm labor, and thrombosis, can be anticipated [3,5,6,7,8].\n\nSome authors suggest the use of manual reduction for the incarcerated uterus after 16 weeks of gestation. However, these procedures require hospitalization and invasive stress, including anesthesia and even laparotomy [1,2,5,8]. Moreover, because incarceration itself potentially implies uterine adhesion to surrounding pelvic organs, which is difficult correctly judge by magnetic resonance imaging (MRI) and/or ultrasound during pregnancy, manual reduction itself may cause potentially severe complications [6,9,10,11]. As such, obstetricians may face the dilemma of deciding whether to perform the manual reduction or not, and the selection of cases suitable for reduction itself is quite difficult prior to the procedure.\n\nIn this study, we aimed to elucidate the incidence, natural courses, and perinatal outcomes for incarcerated gravid uterus.\n\n2. Methods\n\n2.1. Study Design, Ethical Approval, and Study Population\n\nThe medical records of pregnant women who had incarcerated gravid uterus and who delivered at Osaka City University Hospital between April 2011 and March 2021 were retrospectively reviewed. All patients gave their informed written consent, and the study protocol was approved by the institutional review board (No. 2021-067, May 2021).\n\n2.2. Definition of Incarcerated Gravid Uterus and Data Collection\n\nIncarcerated gravid uterus was defined as a retroverted or retroflexed uterus after 16 weeks of gestation. We obtained medical information as follows: age, gravida/parity, mode of conception, gynecological complication and history, diagnosed week of incarceration, weeks of estimated resolution, history of characteristic pregnancy course, and delivery outcomes. The estimated gestational week of resolution was indicated by the duration between the gestational week of the last recognition of an incarcerated uterus and the gestational week of the confirmation of resolution. The resolution was confirmed by vaginal examination, MRI, and/or ultrasound evaluation.\n\n3. Results\n\nDuring the observational period, there were 6958 deliveries at Osaka City University Hospital, and no cases were referred to our hospital with the diagnosis of incarcerated gravid uterus. Incarcerated gravid uterus after 16 gestational weeks was diagnosed in 14 cases, and spontaneous resolution was recognized in 11 cases. The incidence of incarcerated gravid uterus after 16 gestational weeks and spontaneous resolution in the observed period were 0.2% (14/6958) and 78.5% (11/14), respectively. In all of the cases except for one, which was not diagnosed until cesarean delivery, the initial finding of suspected uterine incarceration was a non-palpable and non-visualized cervix upon vaginal examination.\n\nTable 1 shows a summary of the cases. Thirteen women among them had some gynecological complication, such as fibroids, adenomyosis, history of peritonitis, endometriosis, and tubal pregnancy. Case 8 experienced abdominal pain that continued for about 4 h, potentially at the timing of spontaneous resolution and around 28 weeks of gestation.\n\nWe describe three cases in detail, all of which showed characteristic findings and pregnancy courses due to incarceration. Case 2, who was complicated with adenomyosis, was transferred to our hospital due to severe abdominal pain with elevated inflammation signs at 20 weeks of gestation (white blood cell count: 15,000/μL; C-reactive protein: 12.7 mg/dL), and tramadol hydrochloride, acetaminophen, and pentazocine hydrochloride were needed to control her abdominal pain. The incarcerated uterus was identified by MRI, and was found to have an enlarged fundus with adenomyosis (Figure 1a). Antibiotic administration was not effective and was discontinued after five days. However, the patient was slightly relieved from severe pain at 21 weeks; MRI revealed a spontaneous resolution of the incarcerated uterus, and the lesion of adenomyosis was recognized as somehow reduced from its fully swollen size (Figure 1b). Despite the uterine resolution, the patient intermittently needed painkillers. Cesarean delivery was performed with the diagnosis of breech presentation and labor onset at 29 weeks of gestation.\n\nCase 13, conceived by assisted reproductive technology, was strongly suspected to have severe adhesion of the Douglas’s pouch as a result of a previous history of peritonitis, an operation for endometrial ovarian cysts, and a tubal pregnancy. MRI showed placenta previa at the cranioventrally stretched internal cervical ostium at 33 weeks of gestation (Figure 2a); however, it was difficult to diagnose the adhesion behind the uterine cavity. A cesarean delivery was performed because of increased uterine contractions at 34 weeks of gestation. MRI after the delivery showed signs of adhesion [10], a retroflexed uterus, an elevated posterior vaginal fornix, and loss of the fatty layer at the posterior cul-de-sac between the posterior uterine wall and the rectum (Figure 2b–d).\n\nCase 14 had undergone cesarean delivery with a misdiagnosis of placental previa without the prior recognition of incarceration. As a result, the uterine cervix was incised by 3/4 of its total circumference, and the baby was born through the posterior uterine wall. Although the estimated blood loss amounted to 4.8 L, the amputated lesion of the cervix was successfully repaired by one-layer single knot suturing using 1-0 Vicryl, and the post-operative course was uneventful. This patient experienced two subsequent spontaneous pregnancies that resulted in uncomplicated pregnant courses, and cesarean deliveries were performed at term without incarceration.\n\nThe other 11 cases did not experience any severe abdominal pain, although they did complain about the frequency of urination and abdominal discomfort, which were thought to be within physiological ranges and did not necessitate any medical treatment.\n\n4. Discussion\n\nOur study demonstrated that roughly one pregnancy in 2300 deliveries remained complicated with incarcerated uterus, at term or near term, if manual reduction was not performed. In addition, an antenatal diagnosis was correctly made in 92.8% of cases, and spontaneous resolution after 16 gestational weeks was observed in 78.5%. However, severe operative injury was experienced in one case misdiagnosed as placenta previa. As far as we know, our study is the first to include such a large number of patients and to report on the natural courses of incarcerated gravid uterus after 16 weeks of gestation without any manual reduction.\n\nComplications that arise from an incarcerated uterus are thought to result in adverse perinatal outcomes [1,2,3,5,6,7,8]. Extreme dislocation of the uterine cervix causes compression of the urethra and anatomical distortion of the bladder, thus presenting symptoms like dysuria, urinary retention, and overflow incontinence, as well as abdominal pain and worsening constipation [1,2,8]. Reportedly, the most severe cases led to bladder atony, renal failure, hypertensive disorders of pregnancy, and pulmonary embolism [5,7,8]. For these reasons, some authors recommend attempting the reduction of the incarcerated uterus without any delay [8,12,13]. However, there is no consensus as to the optimal management of this complication due to its rarity.\n\nFour cases of spontaneous resolution in the third trimester have been reported so far [5,14,15,16]. Their corrections of uterine incarceration were observed between 30 and 36 weeks, and two cases among them were complicated with fibroids. Interestingly, three cases in these reports experienced resolution without any abdominal pain, and were incidentally diagnosed as corrected. Moreover, abdominal and micturition symptoms disappeared without any treatment as the gestation progressed, even while the uterus remained incarcerated. Regarding this phenomenon, Smalbraak et al. speculated that bladder symptoms may improve when the anterior wall of the uterus becomes thinly stretched in order to accommodate the growing fetus, and this condition is the so-called “uterine sacculation” [5,17]. However, presently, it is impossible to predict who has a higher chance for spontaneous resolution. In addition, it is also difficult to assume who is a candidate for manual reduction because of possible severe symptoms if the incarceration continues. In fact, as we showed in Case 13, it is difficult to evaluate the adhesion behind the uterine cavity during pregnancy. Furthermore, obstetricians should keep in mind that manual reduction may cause serious complications, possibly resulting in the rupture of membranes and intrauterine fetal death [6,9,10,11]. Taken together with these facts, intervention should be reserved for only highly symptomatic cases, and expectant management should be the standard of care. We also suggest a redefinition of uterine incarceration, since this term should be reserved for symptomatic cases, as asymptomatic cases seem to be variations of a normal anatomy.\n\nThe limitations of this study are the retrospective nature of the study design and the fact that the number of patients was too small to elucidate concrete evidence. Furthermore, we did not validate the efficacy of manual and/or passive reduction of the incarcerated gravid uterus [18]. However, as far as we know, this is the largest case series in the past three decades where diagnostic tools, including MRI and ultrasound, became prevalent in clinical practice to precisely diagnose incarceration of the uterus during pregnancy.\n\nIn conclusion, the first finding to suspect incarcerated gravid uterus is the difficulty in recognizing the uterine cervix by vaginal examination. For such cases, MRI and ultrasound should be undertaken to confirm the diagnosis. In cases where there are no severe symptoms, expectant management with careful monitoring might be an option. Our findings will provide helpful information for obstetricians in clinical practice.\n\nAuthor Contributions\n\nConceptualization, D.T.; data curation, T.M., K.K., Y.K., M.T., A.H. and A.N.; writing—original draft, D.T.; supervision, A.Y. and M.K. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThere is no funding for this study.\n\nInstitutional Review Board Statement\n\nThe present study was approved by the institutional review board of Osaka City University Graduate School of Medicine (No. 2021-067, May 2021).\n\nInformed Consent Statement\n\nThe patients were well-informed and written consent was submitted.\n\nData Availability Statement\n\nData available on request due to restrictions of privacy.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 Sagittal T2-weighted MR images of Case 2. An enlarged uterine fundus with adenomyosis was entrapped within the pelvic cavity, and the cervix was stretched cranioventrally at 20 weeks of gestation (a). However, at 21 weeks, spontaneous resolution was confirmed with the finding of a normal position of the cervix (b). The arrowhead indicates cervical internal ostium. P, placenta; §, the amount of ascites was relatively larger than the normal physiological amount during pregnancy; * adenomyosis.\n\nFigure 2 Sagittal T2-weighted MR images of Case 13. They showed placenta previa at the cranioventrally stretched internal cervical ostium (arrowhead) at 33 weeks of gestation (a). MRI after the delivery showed signs of severe adhesion (b); retroflexed uterus (c); elevated posterior vaginal fornix (d); loss of the fatty layer at the posterior cul-de-sac between the posterior uterine wall and the sigmoid colon (b–d). P, placenta. MRI imaging of the uterus without using contrast agent.\n\ndiagnostics-11-01544-t001_Table 1 Table 1 Characteristics of the patients.\n\nCase\tAge\tG/P\tMode of Conception\tGynecological Complication\tDiagnosis\n(Gestational Week)\tResolution\n(Gestational Week)\tOutcome\t\n1\t36\t1/0\tspontaneous\tfibroid (6 cm)\t16\t16 to 20\tVD at 38 weeks\t\n2\t41\t2/0\tspontaneous\tadenomyosis\t20 (severe pain)\t20 to 21\tCS at 29 weeks (labor onset, breech presentation)\t\n3\t37\t2/0\tspontaneous\tfibroid (11 cm)\t20\t20 to 21\tCS at 38 weeks (labor arrest)\t\n4\t33\t2/0\tspontaneous\tfibroid (9 cm)\t16\t21 to 23\tVD at 40 weeks\t\n5\t33\t1/0\tspontaneous\tfibroid (7 cm)\t16\t16 to 24\tVD at 41 weeks\t\n6\t31\t1/0\tspontaneous\tfibroid (7 cm)\t16\t24 to 26\tVD at 40 weeks\t\n7\t36\t2/0\tART\tnone\t16\t26 to 28\tVD at 39 weeks\t\n8\t36\t2/0\tART\tfibroid (4 cm)\t26\t28 to 29\tVD at 37 weeks\t\n9\t40\t2/0\tspontaneous\tfibroid (9 cm)\t19\t27 to 29\tCS at 36 weeks (breech presentation)\t\n10\t41\t1/0\tspontaneous\tfibroid (7 cm)\t20\t29 to 30\tCS at 38 weeks (labor arrest)\t\n11\t42\t1/0\tspontaneous\tfibroid (13 cm)\t20\t29 to 31\tCS at 37 weeks (breech presentation)\t\n12\t35\t1/0\tspontaneous\tfibroid (6 cm)\t37\tNot resolved\tCS at 38 weeks\t\n13\t41\t1/0\tART\tPeritonitis, ovarian endometrial cyst, and tubal pregnancy\t31\tNot resolved\tCS at 34 weeks\t\n14\t36\t2/0\tspontaneous\tfibroid (7 cm)\tMisdiagnosed as placenta previa\tNot resolved\tCS at 37 weeks\t\nG/P: gravida/para, ART: assisted reproductive technology, GW: gestational week, VD: vaginal delivery, CS: cesarean section, at: at.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Fadel H.E. Misenhimer H.R. Incarceration of the retroverted gravid uterus with sacculation Obstet. Gynecol. 1974 43 46 49 4808963\n2. O’Connell M.P. Ivory C.M. Hunter R.W. Incarcerated retroverted uterus—A non recurring complication of pregnancy J. Obstet. Gynaecol. 1999 19 84 85 10.1080/01443619966092 15512235\n3. Jackson D. Elliott J.P. Pearson M. Asymptomatic uterine retroversion at 36 weeks’ gestation Obstet. Gynecol. 1988 71 466 468 3279358\n4. Al Wadi K. Helewa M. Sabeski L. Asymptomatic uterine incarceration at term: A rare complication of pregnancy J. Obstet. Gynaecol. Can. 2011 33 729 732 10.1016/S1701-2163(16)34959-3 21749750\n5. Smalbraak I. Bleker O.P. Schutte M.F. Treffers P.E. Incarceration of the retroverted gravid uterus: A report of four cases Eur. J. Obstet. Gynecol. Reprod. Biol. 1991 39 151 155 10.1016/0028-2243(91)90080-5 2050256\n6. Lettieri L. Rodis J.F. McLean D.A. Campbell W.A. Vintzileos A.M. Incarceration of the gravid uterus Obstet. Gynecol. Surv. 1994 49 642 646 10.1097/00006254-199409000-00026 7991232\n7. Singh M. Payappagoudar J. Lo J. Prashar S. Incarcerated Retroverted Uterus in the Third Trimester Complicated by Postpartum Pulmonary Embolism Obstet. Gynecol. 2007 109 498 501 10.1097/01.AOG.0000218695.71256.cf 17267872\n8. Newell S.D. Crofts J.F. Grant S.R. The incarcerated gravid uterus: Complications and lessons learned Obstet. Gynecol. 2014 123 423 427 10.1097/AOG.0000000000000102 24413243\n9. Jacobsson B. Wide-Swensson D. Recurrent incarceration of the retroverted gravid uterus—A case report Acta Obstet. Gynecol. Scand. 1999 78 737 10468069\n10. Kataoka M.L. Togashi K. Yamaoka T. Koyama T. Ueda H. Kobayashi H. Rahman M. Higuchi T. Fujii S. Posterior Cul-de-Sac Obliteration Associated with Endometriosis: MR Imaging Evaluation Radiology 2005 234 815 823 10.1148/radiol.2343031366 15665220\n11. Inaba F. Kawatu T. Masaoka K. Fukasawa I. Watanabe H. Inaba N. Incarceration of the retroverted gravid uterus: The key to successful treatment Arch. Gynecol. Obstet. 2004 273 55 57 10.1007/s00404-004-0681-3 15551143\n12. Grossenburg N.J. Delaney A.A. Berg T.G. Treatment of a late second-trimester incarcerated uterus using ultrasound-guided manual reduction Obstet. Gynecol. 2011 118 436 439 10.1097/AOG.0b013e3182164864 21768846\n13. Gardner B. Kozakiewicz M.L. Whitecar P.W. Nitsche J.F. Brost B.C. Novel Approach to Reduction of an Incarcerated Uterus Obstet. Gynecol. 2018 132 1177 1179 10.1097/AOG.0000000000002934 30303919\n14. Hamod H. Chamberlain P.F. Moore N.R. Mackenzie I.Z. Conservative treatment of an incarcerated gravid uterus BJOG 2002 109 1074 1075 10.1111/j.1471-0528.2002.01124.x 12269687\n15. Policiano C. Araújo C. Santo S. Centeno M. Pinto L. Incarcerated gravid uterus: Early manual reduction vs. late spontaneous resolution Eur. J. Obstet. Gynecol. Reprod. Biol. 2014 180 201 202 10.1016/j.ejogrb.2014.05.019 24910317\n16. Takami M. Hasegawa Y. Seki K. Hirahara F. Aoki S. Spontaneous reduction of an incarcerated gravid uterus in the third trimester Clin. Case Rep. 2016 4 605 610 10.1002/ccr3.577 27398206\n17. Spearing G.J. Uterine sacculation Obstet. Gynecol. 1978 51 11s 13s 618466\n18. Han C. Wang C. Han L. Liu G. Li H. She F. Xue F. Wang Y. Incarceration of the gravid uterus: A case report and literature review BMC Pregnancy Childbirth 2019 19 1 7 10.1186/s12884-019-2549-3 30606156\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2075-4418",
"issue": "11(9)",
"journal": "Diagnostics (Basel, Switzerland)",
"keywords": "diagnosis; incarcerated gravid uterus; management; manual reduction; spontaneous resolution",
"medline_ta": "Diagnostics (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101658402",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34573886",
"pubdate": "2021-08-25",
"publication_types": "D016428:Journal Article",
"references": "10468069;24910317;17267872;27398206;15665220;30303919;15551143;15512235;4808963;3279358;2050256;618466;21768846;7991232;24413243;21749750;31703641;12269687",
"title": "Incarcerated Gravid Uterus: Spontaneous Resolution Is Not Rare.",
"title_normalized": "incarcerated gravid uterus spontaneous resolution is not rare"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-331573",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"d... |
{
"abstract": "BACKGROUND\nImprovement in renal function and decreases in serum uric acid (SUA) have been reported following prolonged high-intensity statin (HMG-CoA reductase inhibitor) therapy. This post hoc analysis of the SAGE trial examined the effect of intensive versus less intensive statin therapy on renal function, safety, and laboratory parameters, including SUA, in elderly coronary artery disease (CAD) patients (65-85 years) with or without chronic kidney disease (CKD).\n\n\nMETHODS\nPatients were randomized to atorvastatin 80 mg/day or pravastatin 40 mg/day and treated for 12 months. Patients were stratified using Modification of Diet in Renal Disease (MDRD) estimated glomerular filtration rates (eGFRs) in CKD (eGFR <60 mL/min/1.73 m(2)) and non-CKD populations.\n\n\nRESULTS\nOf the 893 patients randomized, 858 had complete renal data and 418 of 858 (49%) had CKD (99% Stage 3). Over 12 months, eGFR increased with atorvastatin and remained stable with pravastatin (+2.38 vs. +0.18 mL/min/1.73 m(2), respectively; p < 0.0001). MDRD eGFR improved significantly in both CKD treatment arms; however, the increased eGFR in patients without CKD was significantly greater with atorvastatin (+2.08 mL/min/1.73 m(2)) than with pravastatin (-1.04 mL/min/1.73 m(2)). Modest reductions in SUA were observed in both treatment arms, but a greater fall occurred with atorvastatin than with pravastatin (-0.52 vs. -0.09 mg/dL, p < 0.0001). Change in SUA correlated negatively with changes in eGFR and positively with changes in low-density lipoprotein cholesterol. Reports of myalgia were rare (3.6% CKD; 5.7% non-CKD), and there were no episodes of rhabdomyolysis. Elevated serum alanine and aspartate transaminase to >3 times the upper limit of normal occurred in 4.4% of atorvastatin- and 0.2% of pravastatin-treated patients.\n\n\nCONCLUSIONS\nIntensive management of dyslipidemia in older patients with stable coronary heart disease may have beneficial effects on renal function and SUA.",
"affiliations": "Cardiology Division, UCSF School of Medicine, 5th Floor, 2823 Fresno Street, Fresno, CA, 93703, USA. pdeedwania@fresno.ucsf.edu.;Brigham and Women's Hospital, Boston, MA, USA.;Pfizer, New York, NY, USA.;Pfizer, New York, NY, USA.;Relypsa, Redwood City, CA, USA.",
"authors": "Deedwania|Prakash C|PC|;Stone|Peter H|PH|;Fayyad|Rana S|RS|;Laskey|Rachel E|RE|;Wilson|Daniel J|DJ|",
"chemical_list": "D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014527:Uric Acid; D000069059:Atorvastatin; D017035:Pravastatin",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40266-015-0328-z",
"fulltext": "\n==== Front\nDrugs AgingDrugs AgingDrugs & Aging1170-229X1179-1969Springer International Publishing Cham 32810.1007/s40266-015-0328-zOriginal Research ArticleImprovement in Renal Function and Reduction in Serum Uric Acid with Intensive Statin Therapy in Older Patients: A Post Hoc Analysis of the SAGE Trial Deedwania Prakash C. +1 559-287-0885pdeedwania@fresno.ucsf.edu Stone Peter H. Fayyad Rana S. Laskey Rachel E. Wilson Daniel J. Cardiology Division, UCSF School of Medicine, 5th Floor, 2823 Fresno Street, Fresno, CA 93703 USA Brigham and Women’s Hospital, Boston, MA USA Pfizer, New York, NY USA Relypsa, Redwood City, CA USA 1 12 2015 1 12 2015 2015 32 1055 1065 © The Author(s) 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background\nImprovement in renal function and decreases in serum uric acid (SUA) have been reported following prolonged high-intensity statin (HMG-CoA reductase inhibitor) therapy. This post hoc analysis of the SAGE trial examined the effect of intensive versus less intensive statin therapy on renal function, safety, and laboratory parameters, including SUA, in elderly coronary artery disease (CAD) patients (65–85 years) with or without chronic kidney disease (CKD).\n\nMethods\nPatients were randomized to atorvastatin 80 mg/day or pravastatin 40 mg/day and treated for 12 months. Patients were stratified using Modification of Diet in Renal Disease (MDRD) estimated glomerular filtration rates (eGFRs) in CKD (eGFR <60 mL/min/1.73 m2) and non-CKD populations.\n\nResults\nOf the 893 patients randomized, 858 had complete renal data and 418 of 858 (49 %) had CKD (99 % Stage 3). Over 12 months, eGFR increased with atorvastatin and remained stable with pravastatin (+2.38 vs. +0.18 mL/min/1.73 m2, respectively; p < 0.0001). MDRD eGFR improved significantly in both CKD treatment arms; however, the increased eGFR in patients without CKD was significantly greater with atorvastatin (+2.08 mL/min/1.73 m2) than with pravastatin (−1.04 mL/min/1.73 m2). Modest reductions in SUA were observed in both treatment arms, but a greater fall occurred with atorvastatin than with pravastatin (−0.52 vs. −0.09 mg/dL, p < 0.0001). Change in SUA correlated negatively with changes in eGFR and positively with changes in low-density lipoprotein cholesterol. Reports of myalgia were rare (3.6 % CKD; 5.7 % non-CKD), and there were no episodes of rhabdomyolysis. Elevated serum alanine and aspartate transaminase to >3 times the upper limit of normal occurred in 4.4 % of atorvastatin- and 0.2 % of pravastatin-treated patients.\n\nConclusion\nIntensive management of dyslipidemia in older patients with stable coronary heart disease may have beneficial effects on renal function and SUA.\n\nhttp://dx.doi.org/10.13039/100004319Pfizerissue-copyright-statement© Springer International Publishing Switzerland 2015\n==== Body\nKey Points\nThis post hoc analysis of the SAGE trial suggests that intensive treatment of dyslipidemia over 1 year in older patients with stable coronary artery disease had beneficial effects on renal function, based on dual assessment of estimated glomerular filtration rate and on serum uric acid.\t\nConsistent with longer-term studies, relatively short-term treatment of dyslipidemia with high-dose statin (HMG-CoA reductase inhibitor) therapy appears to preserve renal function and slow progression of chronic kidney disease in a high-risk population of older patients.\t\n\n\nIntroduction\nFor nearly 100 years, dyslipidemia has been implicated as a cause or a contributing factor to renal injury [1]. Analyses of multiple clinical trials [2–9] and meta-analyses [1, 10–12] have suggested that, in addition to preventing and/or reducing cardiovascular events and mortality, intensive treatment of dyslipidemia with statins (HMG-CoA reductase inhibitors) may stabilize or improve renal function in patients with vascular disease, with or without pre-existing renal impairment. More specifically, stabilization or improvement in the estimated glomerular filtration rate (eGFR) has been observed in post hoc analyses across a broad range of patients with coronary heart disease (CHD) or vascular disease with or without chronic kidney disease (CKD) [2, 4–6], and in patients with CHD with or without prior stroke [13].\n\nSeveral reports have demonstrated that high-intensity statin therapy may have additional renoprotective effects in patients with cardiovascular disease, as statins have been shown to stabilize or preserve renal function, reduce the quantity of albuminuria and proteinuria, and reduce the occurrence of contrast-induced acute kidney injury [9, 14–16], without increasing serious renal-related adverse events (AEs) [17].\n\nIt has long been recognized that renal function declines with aging [18–21], and the prevalence of CKD is higher in older individuals [21, 22]. Analyses of large epidemiologic databases and clinical studies have indicated that at least 44 % of subjects aged 65 years and older have CKD [21, 22]; the prevalence being highest for those patients aged ≥80 years and for those older subjects with co-morbidities [21]. Importantly, declines in eGFR and worsening of CKD status have also been reported in these older cohorts of subjects [21]. A recent meta-analysis from the CKD Prognosis Consortium demonstrated that mortality and the risk of end-stage renal disease increase with a 10 % or greater reduction in eGFR over a 2-year period [23].\n\nFew clinical trials have examined the safety or impact of intensive statin therapy on renal function in an older high-risk cohort with established CHD and vascular disease. This post hoc analysis of the SAGE (Study Assessing Goals in the Elderly) trial was designed to examine the effect of statin therapy with atorvastatin 80 mg/day or pravastatin 40 mg/day on renal function and laboratory parameters, including changes in serum uric acid (SUA), in an older population with symptomatic CHD over 12 months of treatment.\n\nMethods\nThe design of the SAGE trial, including eligibility criteria, has been described fully elsewhere [24, 25]. The SAGE trial was conducted in compliance with the ethical principles originating from the Declaration of Helsinki (Revised South Africa, 1996) and in compliance with the institutional review board/independent ethics committee, informed consent regulations, and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. Participants were aged 65–85 years with a documented history of clinically stable coronary artery disease (CAD) and one or more episodes of myocardial ischemia with a total ischemia duration ≥3 min during 48-h ambulatory ECG at screening, and with baseline low-density lipoprotein cholesterol (LDL-C) 100–250 mg/dL [24, 25]. Patients who satisfied all recruitment criteria were randomized (double-blind) to atorvastatin 80 mg/day or pravastatin 40 mg/day for 12 months, with 48-h ambulatory ECG at 3 and 12 months after randomization [24, 25].\n\nSerum creatinine was measured at baseline and Month 12 from an eGFR and was analyzed at a central laboratory using a modified Jaffé alkaline picrate method using a Roche 747 analyzer [26]. The 4-component Modification of Diet in Renal Disease (MDRD) equation was used to calculate an eGFR based on serum creatinine [27]. MDRD was the recommended established standard used for assessment of eGFR at the time the study was conducted, in line with US National Kidney Foundation guidelines [28].\n\nFor the present analysis, the Kidney Disease Outcomes Quality Initiative (KDOQI) criteria for the classification and stratification of kidney disease [28, 29] were used and patients with an eGFR <60 mL/min/1.73 m2 at baseline were classified as having CKD. CKD was subcategorized according to KDOQI 2012 guidelines [29] as follows: Stage 3a = eGFR 45–59 mL/min/1.73 m2; Stage 3b = 30–44 mL/min/1.73 m2; Stage 4 = 15–29 mL/min/1.73 m2; and Stage 5 ≤15 mL/min/1.73 m2. No patients had Stage 5 CKD. Other biochemical parameters including SUA—measured by enzyme colorimetry using a Roche 747 analyzer—as well as sodium and potassium levels were measured at baseline and Month 12 at a central laboratory. Diabetes mellitus status was defined from either a history of diabetes or a baseline blood glucose value of >126 mg/dL.\n\nMean changes in eGFR between treatment groups, overall, and by CKD status, diabetes status, and sex, were compared in an analysis of covariance (ANCOVA) model, using treatment, baseline eGFR, sex, and study center as covariates. Additional analyses adjusted for the presence of hypertension and/or diabetes at baseline to assess whether these conditions had any impact on the primary observation (change in eGFR over 1 year). For the analysis by sex, the model included baseline eGFR and center as covariates. If 12-month data were unavailable, the last observation was carried forward.\n\nAn exploratory analysis investigated the effects of baseline LDL-C and changes from baseline LDL-C on treatment in models adjusted for these variables. The patient cohort was grouped according to quartiles of change in LDL-C values from baseline to Month 12. The effect of LDL-C change from baseline on change in eGFR was then evaluated by ANCOVA analysis with adjustments for baseline eGFR, sex, center, and LDL-C quartile. In another exploratory analysis, mean changes in SUA between treatment groups, overall, and by CKD status, diabetes status, and sex were compared using an ANCOVA model with treatment and baseline SUA as covariates. Pearson correlations were used to examine the association between changes from baseline in eGFR with LDL-C and with SUA, and between change in SUA and LDL-C.\n\nSafety was monitored throughout SAGE by assessment of AEs for all patients who took one or more doses of study medication and had follow-up information [25]. The incidence of AEs relating to kidney injury was determined through review of the AE database. We selected from a standardized list of AE terms to evaluate for safety outcomes consistent with the Medical Dictionary for Regulatory Activities (MedDRA®)/Pfizer Narrow Renal Standardised MedDRA Query (SMQ), including: “Renal impairment”, “Renal disorder”, “Renal failure”, “Renal failure acute”, “Nephritis”, “Nephropathy”, “Renal tubular disorder”, or “Renal tubular necrosis”.\n\nResults\nThis post hoc analysis of SAGE consisted of 858 participants who had both baseline and Month 12 eGFR measurements (Fig. 1). Thirty-five SAGE patients were excluded from the renal cohort due to incomplete data; the majority of discontinuations were due to AEs (n = 18, including five deaths [atorvastatin n = 1, pravastatin n = 4]) or due to non-compliance (n = 7) (see Fig. 1). The mean (±standard deviation) age of the renal cohort was 72.4 ± 5.1 years, with 262 patients (30.5 %) aged >75 years. At baseline 49 % of the participants had CKD (eGFR ≤60 mL/min/1.73 m2), with 99 % (415/418) classified as Stage 3 (eGFR 30–60 mL/min/1.73 m2) (Table 1). The majority of patients with Stage 3 CKD were categorized as Stage 3a (84 %), according to KDOQI criteria [29].Fig. 1 Patient enrollment in the SAGE trial and inclusion in the renal analysis cohort. *Includes two patients with cardiac events. CKD chronic kidney disease, eGFR estimated glomerular filtration rate\n\nTable 1 Demographic and clinical characteristics of patients included in the renal analysis cohort [patients with both baseline and Month 12 estimated glomerular filtration rate (eGFR) data]\n\nCharacteristics\tPatients without CKD (eGFR ≥60 mL/min/1.73 m2)\tPatients with CKD (eGFR <60 mL/min/1.73 m2)\t\np valueb\n\t\nAll (n = 440)\tAtorvastatin (n = 227)\tPravastatin (n = 213)\t\np valuea\n\tAll (n = 418)\tAtorvastatin (n = 206)\tPravastatin (n = 212)\t\np valuea\n\t\nAge (years)\t71.8 ± 5.0\t71.6 ± 4.9\t72.2 ± 5.1\t0.444\t73.1 ± 5.2\t73.2 ± 5.1\t73.0 ± 5.3\t0.825\t0.0002\t\nAge >75 years\t118 (26.8)\t58 (25.6)\t60 (28.2)\t0.536\t144 (34.5)\t71 (34.5)\t73 (34.4)\t0.995\t0.015\t\nMales\t365 (83.0)\t185 (81.5)\t180 (84.5)\t0.402\t230 (55.0)\t114 (55.3)\t116 (54.7)\t0.898\t<0.0001\t\nWhite\t430 (97.7)\t221 (97.4)\t209 (98.1)\t0.779\t402 (96.2)\t199 (96.6)\t203 (95.8)\t0.582\t0.092\t\nWeight (kg)\t77.3 ± 12.6\t78.5 ± 13.4\t76.0 ± 11.6\t0.043\t75.1 ± 12.1\t76.0 ± 12.9\t74.3 ± 11.2\t0.167\t0.011\t\nBMI (kg/m2)\t27.0 ± 4.0\t27.3 ± 4.5\t26.6 ± 3.3\t0.054\t27.3 ± 3.6\t27.4 ± 3.6\t27.2 ± 3.7\t0.511\t0.184\t\nBaseline eGFR (mL/min/1.73 m2)\t70.8 ± 7.9\t70.4 ± 7.8\t70.6 ± 7.9\t0.790\t51.8 ± 6.5\t51.6 ± 6.5\t52.0 ± 6.5\t0.530\t<0.0001\t\nSmoking status: current smoker\t27 (6.1)\t15 (6.6)\t12 (5.6)\t0.909\t25 (6.0)\t8 (3.9)\t17 (8.0)\t0.117\t0.0007\t\nBaseline lipids (mg/dL)\t\n LDL-C\t144.3 ± 29.3\t146.3 ± 29.1\t142.2 ± 29.4\t0.146\t147.7 ± 32.5\t148.9 ± 31.8\t146.4 ± 33.1\t0.431\t0.115\t\n HDL-C\t46.3 ± 10.9\t46.0 ± 11.5\t46.6 ± 10.2\t0.558\t45.9 ± 12.3\t44.9 ± 11.7\t46.8 ± 12.9\t0.111\t0.627\t\n Triglycerides\t149.8 ± 67.8\t151.3 ± 63.3\t148.2 ± 72.4\t0.629\t171.6 ± 79.8\t177.6 ± 77.4\t165.7 ± 81.9\t0.131\t<0.0001\t\n Total cholesterol\t220.6 ± 33.8\t222.6 ± 34.4\t218.6 ± 33.1\t0.219\t227.8 ± 38.4\t229.3 ± 38.7\t226.3 ± 38.2\t0.425\t0.004\t\nDiabetes mellitus\t99 (22.5)\t50 (22.0)\t49 (23.0)\t0.806\t101 (24.2)\t46 (22.3)\t55 (25.9)\t0.388\t0.565\t\nHypertension\t256 (58.2)\t135 (59.5)\t121 (56.8)\t0.571\t299 (71.5)\t152 (73.8)\t147 (69.3)\t0.314\t<0.0001\t\nMetabolic syndrome\t146 (33.2)\t87 (38.3)\t59 (27.7)\t0.018\t200 (47.9)\t103 (50.0)\t97 (45.8)\t0.3850\t<0.0001\t\nMedical history\t\t\t\t\t\t\t\t\t\t\n Premature CHD\t76 (17.3)\t41 (18.1)\t35 (16.4)\t0.6513\t68 (16.3)\t30 (14.6)\t38 (17.9)\t0.3519\t0.6938\t\n CVA\t13 (3.0)\t5 (2.2)\t8 (3.8)\t0.336\t20 (4.8)\t4 (1.9)\t16 (7.6)\t0.007\t0.164\t\n Angina\t414 (94.1)\t213 (93.8)\t201 (94.4)\t0.813\t392 (93.8)\t197 (95.6)\t195 (92.0)\t0.122\t0.849\t\n CABG\t139 (31.6)\t65 (28.6)\t74 (34.7)\t0.169\t113 (27.0)\t49 (23.8)\t64 (30.2)\t0.141\t0.143\t\n MI\t191 (43.4)\t94 (41.4)\t97 (45.5)\t0.382\t205 (49.0)\t103 (50.0)\t102 (48.1)\t0.700\t0.098\t\nStage 3 CKDc\n\t\t\t\t\t\t204 (99.0)\t211 (99.5)\t0.619\t\t\n Stage 3a\t\t\t\t\t\t172 (83.5)\t181 (85.4)\t\t\t\n Stage 3b\t\t\t\t\t\t32 (15.5)\t30 (14.1)\t\t\t\nStage 4 CKDd\n\t\t\t\t\t\t2 (1.0)\t1 (0.5)\t\t\t\nValues are given as number of patients (%) or mean ± standard deviation\n\n\nBMI body mass index, CABG coronary artery bypass graft, CHD coronary heart disease, CKD chronic kidney disease, CVA cerebrovascular accident, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, MI myocardial infarction\n\n\na\np value for atorvastatin vs. pravastatin\n\n\nb\np value for all patients with CKD vs. all patients without CKD\n\n\ncStage 3a = eGFR 45–59 mL/min/1.73 m2; Stage 3b = 30–44 mL/min/1.73 m2\n\n\n\ndStage 4 = 15–29 mL/min/1.73 m2\n\n\n\n\nBaseline triglycerides and total cholesterol were higher in patients with versus without CKD (Table 1), but lipids were similar across treatment arms within each CKD or non-CKD cohort. Across all patients in this renal cohort (both those with and without CKD), treatment with atorvastatin resulted in significantly greater decreases in total cholesterol (−40.9 vs. −21.7 %), LDL-C (−56.1 vs. −32.0 %), and triglycerides (−28.5 vs. −9.2 %) than did pravastatin after 3 months of follow-up (p < 0.001).\n\nThere were no significant differences in baseline eGFR between the treatment groups, or within treatment for patients with or without CKD (Table 1). Overall, eGFR increased over 12 months with atorvastatin (+2.38 mL/min/1.73 m2) and remained stable with pravastatin (+0.18 mL/min/1.73 m2) (Fig. 2; treatment difference p < 0.0001). In patients with CKD, eGFR improved in both treatment arms (atorvastatin: +2.8 mL/min/1.73 m2; pravastatin: +2.3 mL/min/1.73 m2) (treatment difference p = 0.474). In patients without CKD, a significant increase in eGFR from baseline was observed with atorvastatin (+2.08 mL/min/1.73 m2; p = 0.009) but not with pravastatin (−1.04 mL/min/1.73 m2; p = 0.196) (treatment difference p = 0.0003) (Fig. 2).Fig. 2 Changes in estimated glomerular filtration rate (eGFR) from baseline (least square mean ± standard error) following 12 months’ treatment with atorvastatin 80 mg/day or pravastatin 40 mg/day in all patients in the SAGE renal cohort and according to chronic kidney disease status. LDL-C low-density lipoprotein cholesterol\n\n\n\nIncreases in eGFR were seen with both treatments when analyzed by diabetes status; however, the difference between statin treatments was significant only in patients without diabetes (Table 2). The overall increase in eGFR was significantly greater among males than females (p = 0.003). A significant treatment effect with atorvastatin versus pravastatin was observed in males only (Table 2). No notable differences in the primary assessment (change in eGFR) were noted for patients with or without CKD when data were adjusted for baseline hypertension or diabetes status in addition to baseline eGFR and sex (data not shown).Table 2 Baseline estimated glomerular filtration rate (eGFR) and changes in eGFR following 12 months’ treatment with atorvastatin 80 mg/day or pravastatin 40 mg/day according to diabetes mellitus status and sex\n\neGFR\tPatients with diabetesa\n\tPatients without diabetes\tMales\tFemales\t\nAtorvastatin (n = 105)\tPravastatin (n = 119)\tAtorvastatin (n = 328)\tPravastatin (n = 306)\tAtorvastatin (n = 299)\tPravastatin (n = 296)\tAtorvastatin (n = 134)\tPravastatin (n = 129)\t\nBaseline eGFRb (mL/min/1.73 m2)\t61.8 ± 13.1\t60.4 ± 12.8\t61.3 ± 11.5\t61.7 ± 11.4\t64.0 ± 11.6\t63.3 ± 11.3\t55.6 ± 10.4\t56.7 ± 11.5\t\nChange in eGFRc (mL/min/1.73 m2)\t2.2 ± 1.0\t0.7 ± 1.0\t2.2 ± 0.5\t0.2 ± 0.5\t3.7 ± 0.6\t1.1 ± 0.5\t0.6 ± 0.8\t−0.1 ± 0.8\t\n\np valued\n\t0.3065\t0.0014\t0.0001\t0.4969\t\n\naMedical history of diabetes or baseline glucose >126 mg/dL\n\n\nbMean ± standard deviation\n\n\ncLeast square mean ± standard error\n\n\ndAll p values are for treatment effect of atorvastatin vs. pravastatin\n\n\n\nThere was a weak but significant correlation between change in eGFR and change in LDL-C (r = −0.11; p = 0.002). Increases in eGFR were significantly greater in the patients with greater reductions in LDL-C (p for trend = 0.049) (Fig. 3). After adjustment for baseline LDL-C or change in LDL-C, the treatment effect on eGFR remained significant.Fig. 3 Changes in estimated glomerular filtration rate (eGFR) from baseline (least square mean ± standard error) following 12 months’ treatment with atorvastatin 80 mg/day or pravastatin 40 mg/day, grouped by quartile ranges of changes in low-density lipoprotein cholesterol from baseline. CKD chronic kidney disease, eGFR estimated glomerular filtration rate\n\n\n\nBaseline SUA values were within a normal range in both treatment groups, and with treatment a significantly greater reduction in mean SUA was seen with atorvastatin than with pravastatin treatment (p < 0.0001). These findings were similar when analyzed by CKD status, diabetes status, and sex (Table 3). There was a significant (negative) correlation between the change in SUA and the change in eGFR, regardless of CKD status (CKD patients, r = −0.373; p < 0.0001; non-CKD patients, r = −0.344; p < 0.0001). There was also a positive correlation between the change in LDL-C versus change in SUA, regardless of CKD status (CKD patients, r = 0.181; p = 0.0002; non-CKD patients, r = 0.262; p < 0.0001).Table 3 Baseline serum uric acid (SUA) and changes following 12 months treatment with atorvastatin 80 mg/day or pravastatin 40 mg/day according to chronic kidney disease (CKD) status, diabetes mellitus status, and sex\n\n\tAtorvastatin\tPravastatin\tAtorvastatin\tPravastatin\t\n\t\nAll patients\n\t\n\nn\n\t433\t425\t\t\t\nBaseline SUAa (mg/dL)\t6.30 ± 1.34\t6.15 ± 1.36\t\t\t\nChange in SUAb (mg/dL)\t−0.52 ± 0.04\t−0.09 ± 0.04\t\t\t\n\np valuec\n\t<0.0001\t\t\n\t\nPatients without CKD\n\t\nPatients with CKD\n\t\n\nn\n\t227\t213\t206\t212\t\nBaseline SUAa (mg/dL)\t5.92 ± 1.14\t5.92 ± 1.32\t6.71 ± 1.41\t6.39 ± 1.35\t\nChange in SUAb (mg/dL)\t−0.43 ± 0.05\t−0.02 ± 0.06\t−0.61 ± 0.07\t−0.18 ± 0.07\t\n\np valuec\n\t<0.0001\t<0.0001\t\n\t\nPatients without diabetes\n\t\nPatients with diabetes\n\t\n\nn\n\t328\t306\t105\t119\t\nBaseline SUAa (mg/dL)\t6.33 ± 1.32\t6.15 ± 1.33\t6.19 ± 1.40\t6.15 ± 1.43\t\nChange in SUAb (mg/dL)\t−0.52 ± 0.05\t−0.085 ± 0.05\t−0.54 ± 0.09\t−0.10 ± 0.09\t\n\np valuec\n\t<0.0001\t<0.0001\t\n\t\nMales\n\t\nFemales\n\t\n\nn\n\t299\t296\t134\t129\t\nBaseline SUAa (mg/dL)\t6.40 ± 1.31\t6.40 ± 1.27\t6.07 ± 1.37\t5.59 ± 1.38\t\nChange in SUAb (mg/dL)\t−0.55 ± 0.05\t−0.14 ± 0.05\t−0.48 ± 0.09\t0.03 ± 0.09\t\n\np valuec\n\t<0.0001\t<0.0001\t\n\naMean ± standard deviation\n\n\nbLeast square mean ± standard error\n\n\ncAll p values are for treatment effect of atorvastatin vs. pravastatin\n\n\n\nSerum alanine transaminase (ALT) and aspartate transaminase (AST) levels ≥3 times the upper limit of normal were reported in 19 atorvastatin patients (11/214 [5.1 %] with CKD; 8/232 [3.4 %] without CKD) and one pravastatin patient without CKD (1/227 [0.4 %]). There were no persistent elevations in liver enzymes (AST, ALT), as levels returned to normal for all patients who were followed up for a repeat test, including for the one pravastatin patient who permanently discontinued study medication (not due to liver function abnormality).\n\nMyalgia was the most common muscle-related AE, which occurred in 25 patients without CKD (20 atorvastatin; five pravastatin) and 15 patients with CKD (three atorvastatin; 12 pravastatin). Myalgia led to discontinuation of six CKD (one atorvastatin; five pravastatin) and seven non-CKD (seven atorvastatin) patients. Myopathy was reported in one CKD patient receiving atorvastatin. Rhabdomyolysis was not reported.\n\nTwenty-six deaths were reported in the overall renal cohort during the study, with more deaths recorded for patients with CKD (n = 15 [3.48 %]) than without CKD at baseline (n = 11 [2.40 %]). A greater number of cardiovascular deaths were recorded in the CKD population (n = 12) than in the non-CKD population (n = 3). A higher number of deaths were recorded in the renal cohort in patients receiving pravastatin (n = 18) than in those receiving atorvastatin (n = 8), for patients with and without CKD, many of which were adjudicated as cardiovascular deaths (pravastatin: n = 10; atorvastatin: n = 5). Investigator-reported renal AEs were less frequent in the atorvastatin (n = 1 [renal failure]) than in the pravastatin arm (n = 5 [renal failure, n = 2; acute renal failure, n = 1; renal impairment, n = 2]) for CKD patients. Investigator-reported renal AEs were very infrequent in both treatment arms for non-CKD patients (atorvastatin: n = 0; pravastatin: n = 1 [acute renal failure]).\n\nDiscussion\nThis post hoc analysis of the SAGE trial demonstrated that 1 year of intensive atorvastatin therapy (80 mg/day) improved renal function in a high-risk cardiovascular population of older patients with stable CAD and silent ischemia, regardless of the presence of CKD or diabetes, while moderate therapy with pravastatin (40 mg/day) stabilized renal function over the same period of follow-up. This observation is consistent with other analyses which demonstrate that renoprotection varies between atorvastatin and other lipid-lowering agents in subjects with vascular disease [30–32].\n\nThe mechanism by which statin therapy may have a beneficial effect on renal function remains unknown, and may differ between statin type. We noted a weak correlation between increases in eGFR with atorvastatin-associated reduction in LDL-C, so that the greatest improvement in renal function was correlated with more intense lipid lowering. Pravastatin had a more modest effect on renal function, possibly secondary to a smaller effect on lipid lowering when compared with atorvastatin [25]. The stabilizing effect on eGFR with pravastatin also aligned with findings in patients with or at high-risk of CHD over follow-up of nearly 5 years [4]. However, statin-associated renoprotection may be related to other pleiotropic effects, and not directly related to lipid lowering. In agreement, in a recent analysis of the prospective evaluation of proteinuria and renal function in diabetic patients with progressive renal disease (PLANET) I and II trials, high-dose atorvastatin (80 mg) was deemed to be more renoprotective over a 1-year treatment period than high-dose rosuvastatin (40 mg), despite rosuvastatin lowering plasma lipid concentrations to a greater extent than atorvastatin 80 mg in both CKD patients with end-stage renal disease and diabetes [33]. Furthermore, in a post hoc analysis of statin type, atorvastatin 80 mg lowered the urine protein:creatinine ratio significantly more than both low- and high-dose rosuvastatin in these patients [33].\n\nThe hypothesis that different statins have different renal protective effects is further supported by both non-clinical and clinical observations [34–43]. Statins have been observed to modify endothelial cell and vascular physiology in animal models [36] and show anti-inflammatory properties [37], both of which could have renoprotective effects. We report that in patients with CKD, eGFR improved with atorvastatin or pravastatin, while in those without CKD, eGFR improved in atorvastatin-treated patients but was only stabilized with pravastatin treatment. This suggests that the renoprotective effects of statins are more prominent in CKD patients than in non-CKD patients. The reasons underlying these differences are unclear; however, a number of differences in cellular physiology are known between CKD and non-CKD patients that could affect the outcomes observed herein [38–43]. For example, patients with CKD have been reported to have higher levels of inflammatory markers, such as C-reactive protein, interleukin-1β, and tumor necrosis factor-α, than an age-matched control population with normal renal function [38]. Treatment with atorvastatin can significantly lower these inflammatory markers in patients with CKD; furthermore, atorvastatin treatment may improve endothelial function and stabilize plaque-limiting atheroembolic renal disease [38, 39]. However, other statins may not have the same effect. In certain populations, evidence suggests that statins may influence blood flow [34, 35, 40–43], and this potential effect may contribute to changes in eGFR. However, the literature is somewhat conflicting regarding any effect, with some studies indicating that statins increase blood flow, but only in patients with normal endothelial function [43], whereas other studies suggest no change in healthy subjects [41], patients with hypercholesterolemia [40] or patients with peripheral arterial disease [42]. Given the diversity of populations studied, the small number of patients in the trials, and the known influence of patient characteristics (including CKD) and other risk factors on hemodynamics and endothelial function (as discussed earlier), further study is needed to clarify any statin-mediated influence on blood flow in CKD and non-CKD patient populations.\n\nCKD progresses rapidly in patients with coexisting CHD, and this rapid progression leads to an increased risk of cardiovascular events [11, 15, 44, 45]. In our 12-month study of patients aged 65–85 years, the increase in eGFR observed with intensive atorvastatin therapy was in accordance with the renal benefits reported for the same regimen in longer trials of younger CHD populations [5, 6]. In addition, the improvement in renal function among patients with diabetes and/or CKD following intensive atorvastatin therapy is consistent with that reported in other post hoc analyses of atorvastatin treatment regimens over longer follow-up [7, 46], and including in patients with prior stroke or transient ischemic attack, both with and without CKD [13]. Statin-associated renoprotection was not seen in SHARP (Study of Heart and Renal Protection) [31, 32]. This prospective clinical study was designed to determine the effect of a statin–ezetimide combination on cardiovascular and renal endpoints, which included progression to end-stage renal disease, doubling of serum creatinine, and death, in patients with advanced CKD [31]. An exploratory SHARP renal analysis failed to show any benefit from a 1 mmol/L reduction in LDL-C on slowing progression of kidney disease in a wide variety of patients with CKD [32]. There are important differences between the patients studied in SHARP and our analysis of the SAGE trial. SHARP recruited a population of patients with well-characterized renal disease including patients with glomerulonephritis and cystic renal disease, and excluded subjects with prior myocardial infarction or coronary revascularization [31]. Patients with specific renal disease diagnoses were excluded from SAGE [25]. Another recent analysis of the SHARP cohort demonstrated that the type of kidney disease was a significant factor affecting progression of renal disease, as 23 % of patients with cystic renal disease versus 10 % with glomerulonephritis and 12 % with diabetic nephropathy progressed to end-stage renal disease [47]. The degrees of renal impairment differed at baseline and could be another factor that may account for the lack of renoprotection in SHARP, as nearly half of the patients in SHARP had an eGFR <15 mL/min/1.73 m2 [31], while there were only three such subjects in the SAGE renal cohort.\n\nGuidelines now recommend statins or statin/ezetimide for adults aged ≥50 years with eGFR ≤60 mL/min/1.73 m2 who are not receiving long-term dialysis or for those who have had a kidney transplant [48, 49]. Recommendations for lipid-lowering therapy were justified on the basis of the high cardiovascular risk status of patients with coexisting CHD/CKD. Further incremental increases in cardiovascular risk occur with aging [19] or coexisting co-morbid conditions such as diabetes and hypertension [18, 44]. Despite recognized evidence for the benefits of statin therapy in younger patients with coexisting CHD and CKD [1], data surrounding the benefits of statin therapy for older patients with these co-morbidities are less clear. Our data demonstrate that an intensive atorvastatin-based treatment regimen can stabilize or improve renal function in a high-risk population of older patients with stable CAD and silent ischemia, with or without CKD, and that renoprotection was evident after 1 year. Overall, atorvastatin was more effective than pravastatin in stabilizing or improving renal function; however, significant improvement in renal function was also observed with pravastatin in this cohort of patients with CKD.\n\nThe renal benefits seen with atorvastatin in SAGE are consistent with those reported in other trials that have examined the effect of atorvastatin on renal function [2, 5–7, 13, 33, 46]. Although older subjects with CKD are less likely than younger populations to progress to end-stage renal disease, attempts should be made to modify risk factors and stabilize renal function. Hemmelgarn and colleagues [18] examined the changes in renal function that occurred in a cohort of 10,184 subjects aged 66 years or older over a 2-year period. Absolute reductions in eGFR in the cohort of 3191 subjects with baseline eGFR between 30 and 59 mL/min/1.73 m2 were 5.1 and 7.2 mL/min/1.73 m2 in female and male patients, respectively, with CKD and co-morbid diabetes, compared with 2.0 and 3.5 mL/min/1.73 m2 for female and male CKD patients, respectively, without diabetes [18]. The current analysis suggests that lipid-lowering therapy may be an effective strategy for limiting the expected decline in renal function in older CHD subjects with CKD and with or without coexisting diabetes.\n\nImprovements in renal function following intensive atorvastatin treatment are further supported by dual assessment of change in eGFR alongside SUA. The observed small (−0.52 mg/dL) but statistically significant decrease in SUA with atorvastatin was also in agreement with those reported from CHD patients aged up to 75 years treated with atorvastatin (10–80 mg/day) [2]. The greater fall in SUA observed with atorvastatin treatment could be secondary to improved filtration, whereas only a stabilizing effect was observed with pravastatin treatment. A significant negative correlation was noted between the change in SUA and change in eGFR; thus, as eGFR improved, SUA fell. SUA has been reported as an independent risk factor for cardiovascular mortality, with risk increasing as SUA increases, even within the normal range [22, 50]. Although improvements in the glomerular filtration rate may account for the modest reduction in SUA, the exact mechanisms whereby atorvastatin and pravastatin lower SUA remain to be determined. In addition, given that the reduction in SUA was small, although statistically significant, over the 1-year study period, the clinical relevance of this observation needs to be confirmed.\n\nIn the entire SAGE population [25] and in this renal cohort, both atorvastatin 80 mg/day and pravastatin 40 mg/day were generally well-tolerated, and the AEs recorded were as expected in a cohort of older patients [51]. The current analysis also demonstrated that in this cohort of older CHD patients with CKD, there did not appear to be a greater risk of muscle-related AEs than in those without CKD. This is in line with a recently published analysis including 149,882 patient-years of follow-up that failed to show any increase in renal-related serious AEs with statins compared with controls [17]. Thus, although safety perceptions have been cited as a reason for not prescribing statin therapy to older patients with or without CKD [51], the findings of this study and others do not support the view that safety risks outweigh the cardiovascular benefits of intensive atorvastatin therapy for this high-risk elderly population [17, 52, 53]. Current guidelines for treating dyslipidemia in CKD acknowledge the potential benefits of high-dose statins in patients with diabetes and mild-to-moderate CKD (Stages 1–3); however, dose modification is also recommended for some statins and certain other lipid-lowering medicines in moderate-to-advanced CKD (Stages 3–5) [29].\n\nLimitations\nThis post hoc analysis of a randomized controlled prospective study comparing two treatment regimens has some limitations. CKD staging was based on eGFR because data on proteinuria were not available, and albuminuria data were not analyzed. There was no placebo arm for comparison, and patient numbers were relatively small. There were more male than female patients in the non-CKD cohort (83 % male); eGFR is known to differ by sex, and the Cockroft-Gault equation is adjusted accordingly. In addition, observations have been published suggesting that SUA is higher in male than in female subjects both in the general population [22] and in subjects (mean age 61 years) with CKD [54]. Although our analyses were adjusted for sex and baseline eGFR, the uneven male:female ratio may have influenced the observations from the non-CKD analyses. The findings of this analysis should, therefore, be interpreted accordingly. Nevertheless, the results were in accordance with longer analyses and similar trials of younger patient groups [2, 5–7, 13, 33, 46]. Finally, although a number of our observations were statistically significant, the clinical relevance in a larger patient sample cannot be inferred.\n\nConclusions\nThis post hoc analysis of the SAGE trial extended the observation of renal benefits with statins to a high-risk population of older patients with a history of stable CAD with silent ischemia, and in particular to those with co-existent CKD. These findings suggest that relatively short-term (1 year), intensive management of dyslipidemia in older patients with stable CAD might be associated with preservation of renal function and slowed CKD progression without increasing the risk of muscle symptoms or other renal AEs.\n\nFor the SAGE Investigators.\n\nThis study was sponsored by Pfizer. Medical writing support was provided by Karen Burrows, MPhil, CMPP and Shuang Li of Engage Scientific Solutions and was funded by Pfizer.\n\nCompliance with Ethical Standards\nConflict of interest\nPCD has received research grants and consulting fees/other remuneration from Pfizer, Amgen, and Sanofi/Regeneron. PHS has received research grants from Boston Scientific and AstraZeneca. RSF and REL are employees of Pfizer. DJW was an employee of Pfizer at the time the study was conducted.\n\nFunding source\nThis study was funded by Pfizer.\n==== Refs\nReferences\n1. Fried LF Orchard TJ Kasiske BL Effect of lipid reduction on the progression of renal disease: a meta-analysis Kidney Int 2001 59 1 260 269 10.1046/j.1523-1755.2001.00487.x 11135079 \n2. Athyros VG Elisaf M Papageorgiou AA Symeonidis AN Pehlivanidis AN Bouloukos VI Effect of statins versus untreated dyslipidemia on serum uric acid levels in patients with coronary heart disease: a subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study Am J Kidney Dis 2004 43 4 589 599 10.1053/j.ajkd.2003.12.023 15042535 \n3. Rahman M Baimbridge C Davis BR Barzilay J Basile JN Henriquez MA Progression of kidney disease in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin versus usual care: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Am J Kidney Dis 2008 52 3 412 424 10.1053/j.ajkd.2008.05.027 18676075 \n4. Tonelli M Isles C Craven T Tonkin A Pfeffer MA Shepherd J Effect of pravastatin on rate of kidney function loss in people with or at risk for coronary disease Circulation 2005 112 2 171 178 10.1161/CIRCULATIONAHA.104.517565 15998677 \n5. Shepherd J Kastelein JJ Bittner V Deedwania P Breazna A Dobson S Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study Clin J Am Soc Nephrol. 2007 2 6 1131 1139 10.2215/CJN.04371206 17942759 \n6. Koren MJ Davidson MH Wilson DJ Fayyad RS Zuckerman A Reed DP Focused atorvastatin therapy in managed-care patients with coronary heart disease and CKD Am J Kidney Dis 2009 53 5 741 750 10.1053/j.ajkd.2008.11.025 19216014 \n7. Colhoun HM Betteridge DJ Durrington PN Hitman GA Neil HA Livingstone SJ Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS) Am J Kidney Dis 2009 54 5 810 819 10.1053/j.ajkd.2009.03.022 19540640 \n8. Ridker PM MacFadyen J Cressman M Glynn RJ Efficacy of rosuvastatin among men and women with moderate chronic kidney disease and elevated high-sensitivity C-reactive protein: a secondary analysis from the JUPITER (Justification for the Use of Statins in Prevention-an Intervention Trial Evaluating Rosuvastatin) trial J Am Coll Cardiol 2010 55 12 1266 1273 10.1016/j.jacc.2010.01.020 20206456 \n9. Leoncini M Toso A Maioli M Tropeano F Villani S Bellandi F Early high-dose rosuvastatin for contrast-induced nephropathy prevention in acute coronary syndrome: results from the PRATO-ACS Study (Protective Effect of Rosuvastatin and Antiplatelet Therapy On contrast-induced acute kidney injury and myocardial damage in patients with Acute Coronary Syndrome) J Am Coll Cardiol 2014 63 1 71 79 10.1016/j.jacc.2013.04.105 24076283 \n10. Strippoli GF Navaneethan SD Johnson DW Perkovic V Pellegrini F Nicolucci A Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials BMJ 2008 336 7645 645 651 10.1136/bmj.39472.580984.AE 18299289 \n11. Palmer SC Craig JC Navaneethan SD Tonelli M Pellegrini F Strippoli GF Benefits and harms of statin therapy for persons with chronic kidney disease: a systematic review and meta-analysis Ann Intern Med 2012 157 4 263 275 10.7326/0003-4819-157-4-201208210-00007 22910937 \n12. Hou W Lv J Perkovic V Yang L Zhao N Jardine MJ Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidney disease: a systematic review and meta-analysis Eur Heart J 2013 34 24 1807 1817 10.1093/eurheartj/eht065 23470492 \n13. Amarenco P Callahan A 3rd Campese VM Goldstein LB Hennerici MG Messig M Effect of high-dose atorvastatin on renal function in subjects with stroke or transient ischemic attack in the SPARCL trial Stroke 2014 45 10 2974 2982 10.1161/STROKEAHA.114.005832 25147328 \n14. Han Y Zhu G Han L Hou F Huang W Liu H Short-term rosuvastatin therapy for prevention of contrast-induced acute kidney injury in patients with diabetes and chronic kidney disease J Am Coll Cardiol 2014 63 1 62 70 10.1016/j.jacc.2013.09.017 24076297 \n15. Nitta K Clinical assessment and management of dyslipidemia in patients with chronic kidney disease Clin Exp Nephrol. 2012 16 4 522 529 10.1007/s10157-012-0655-x 22722878 \n16. Hoshi T Sato A Kakefuda Y Harunari T Watabe H Ojima E Preventive effect of statin pretreatment on contrast-induced acute kidney injury in patients undergoing coronary angioplasty: propensity score analysis from a multicenter registry Int J Cardiol 2014 171 2 243 249 10.1016/j.ijcard.2013.12.017 24393575 \n17. Bangalore S Fayyad R Hovingh GK Laskey R Vogt L DeMicco DA Statin and the risk of renal-related serious adverse events: analysis from the IDEAL, TNT, CARDS, ASPEN, SPARCL, and other placebo-controlled trials Am J Cardiol 2014 113 12 2018 2020 10.1016/j.amjcard.2014.03.046 24793673 \n18. Hemmelgarn BR Zhang J Manns BJ Tonelli M Larsen E Ghali WA Progression of kidney dysfunction in the community-dwelling elderly Kidney Int 2006 69 12 2155 2161 10.1038/sj.ki.5000270 16531986 \n19. Cohen E Nardi Y Krause I Goldberg E Milo G Garty M A longitudinal assessment of the natural rate of decline in renal function with age J Nephrol. Epub 2014 \n20. Coresh J Selvin E Stevens LA Manzi J Kusek JW Eggers P Prevalence of chronic kidney disease in the United States JAMA 2007 298 17 2038 2047 10.1001/jama.298.17.2038 17986697 \n21. Stevens LA Li S Wang C Huang C Becker BN Bomback AS Prevalence of CKD and comorbid illness in elderly patients in the United States: results from the Kidney Early Evaluation Program (KEEP) Am J Kidney Dis 2010 55 3 Suppl 2 S23 S33 10.1053/j.ajkd.2009.09.035 20172445 \n22. Fang J Alderman MH Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971–1992. National Health and Nutrition Examination Survey JAMA 2000 283 18 2404 2410 10.1001/jama.283.18.2404 10815083 \n23. Coresh J Turin TC Matsushita K Sang Y Ballew SH Appel LJ Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality JAMA 2014 311 24 2518 2531 10.1001/jama.2014.6634 24892770 \n24. Deedwania PC Effect of aggressive versus moderate lipid-lowering therapy on myocardial ischemia: the rationale, design, and baseline characteristics of the Study Assessing Goals in the Elderly (SAGE) Am Heart J 2004 148 6 1053 1059 10.1016/j.ahj.2004.06.026 15632893 \n25. Deedwania P Stone PH Bairey Merz CN Cosin-Aguilar J Koylan N Luo D Effects of intensive versus moderate lipid-lowering therapy on myocardial ischemia in older patients with coronary heart disease: results of the Study Assessing Goals in the Elderly (SAGE) Circulation 2007 115 6 700 707 10.1161/CIRCULATIONAHA.106.654756 17283260 \n26. Junge W Wilke B Halabi A Klein G Determination of reference intervals for serum creatinine, creatinine excretion and creatinine clearance with an enzymatic and a modified Jaffe method Clin Chim Acta 2004 344 1–2 137 148 10.1016/j.cccn.2004.02.007 15149882 \n27. Levey AS Bosch JP Lewis JB Greene T Rogers N Roth D A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group Ann Intern Med. 1999 130 6 461 470 10.7326/0003-4819-130-6-199903160-00002 10075613 \n28. National Kidney Foundation K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification Am J Kidney Dis 2002 39 2 Suppl 1 S1 S266 11904577 \n29. National Kidney Foundation KDOQI clinical practice guideline for diabetes and CKD: 2012 update Am J Kidney Dis 2012 60 5 850 886 10.1053/j.ajkd.2012.07.005 23067652 \n30. Sandhu S Wiebe N Fried LF Tonelli M Statins for improving renal outcomes: a meta-analysis J Am Soc Nephrol 2006 17 7 2006 2016 10.1681/ASN.2006010012 16762986 \n31. Baigent C Landray MJ Reith C Emberson J Wheeler DC Tomson C The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial Lancet 2011 377 9784 2181 2192 10.1016/S0140-6736(11)60739-3 21663949 \n32. Haynes R Lewis D Emberson J Reith C Agodoa L Cass A Effects of lowering LDL cholesterol on progression of kidney disease J Am Soc Nephrol 2014 25 8 1825 1833 10.1681/ASN.2013090965 24790178 \n33. de Zeeuw D Anzalone DA Cain VA Cressman MD Heerspink HJ Molitoris BA Renal effects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I): a randomised clinical trial Lancet Diabetes Endocrinol. 2015 3 3 181 190 10.1016/S2213-8587(14)70246-3 25660356 \n34. Hafez K Inman S Stowe N Novick A Renal hemodynamic effects of lovastatin in a renal ablation model Urology. 1996 48 6 862 867 10.1016/S0090-4295(96)00314-7 8973668 \n35. van Dijk M Kamper A van Veen S Souverijn J Blauw G Effect of simvastatin on renal function in autosomal dominant polycystic kidney disease Nephrol Dial Transplant 2001 16 11 2152 2157 10.1093/ndt/16.11.2152 11682660 \n36. Zhou MS Jaimes EA Raij L Atorvastatin prevents end-organ injury in salt-sensitive hypertension: role of eNOS and oxidant stress Hypertension 2004 44 2 186 190 10.1161/01.HYP.0000136395.06810.cf 15238570 \n37. Yokota N O’Donnell M Daniels F Burne-Taney M Keane W Kasiske B Protective effect of HMG-CoA reductase inhibitor on experimental renal ischemia-reperfusion injury Am J Nephrol 2003 23 1 13 17 10.1159/000066301 12373076 \n38. Goicoechea M de Vinuesa SG Lahera V Cachofeiro V Gomez-Campdera F Vega A Effects of atorvastatin on inflammatory and fibrinolytic parameters in patients with chronic kidney disease J Am Soc Nephrol 2006 17 12 Suppl 3 S231 S235 10.1681/ASN.2006080938 17130267 \n39. Scolari F Ravani P Pola A Guerini S Zubani R Movilli E Predictors of renal and patient outcomes in atheroembolic renal disease: a prospective study J Am Soc Nephrol 2003 14 6 1584 1590 10.1097/01.ASN.0000069220.60954.F1 12761259 \n40. Ott C Ritt M Titze SI Schaufele T Schmieder RE Rosuvastatin does not affect intrarenal hemodynamics in patients with hypercholesterolemia J Nephrol. 2009 22 5 675 681 19810001 \n41. Paulsen L Holm C Bech JN Starklint J Pedersen EB Effects of statins on renal sodium and water handling: acute and short-term effects of atorvastatin on renal haemodynamics, tubular function, vasoactive hormones, blood pressure and pulse rate in healthy, normocholesterolemic humans Nephrol Dial Transplant 2008 23 5 1556 1561 10.1093/ndt/gfm807 18065809 \n42. Alnaeb ME Youssef F Mikhailidis DP Hamilton G Short-term lipid-lowering treatment with atorvastatin improves renal function but not renal blood flow indices in patients with peripheral arterial disease Angiology. 2006 57 1 65 71 10.1177/000331970605700109 16444458 \n43. Zhang L Gong D Li S Zhou X Meta-analysis of the effects of statin therapy on endothelial function in patients with diabetes mellitus Atherosclerosis. 2012 223 1 78 85 10.1016/j.atherosclerosis.2012.01.031 22326029 \n44. Shlipak MG Katz R Kestenbaum B Siscovick D Fried L Newman A Rapid decline of kidney function increases cardiovascular risk in the elderly J Am Soc Nephrol 2009 20 12 2625 2630 10.1681/ASN.2009050546 19892934 \n45. Rein P Saely CH Vonbank A Boehnel C Drexel H Usefulness of serial decline of kidney function to predict mortality and cardiovascular events in patients undergoing coronary angiography Am J Cardiol 2014 113 2 215 221 10.1016/j.amjcard.2013.08.032 24169005 \n46. Shepherd J Kastelein JP Bittner VA Carmena R Deedwania PC Breazna A Intensive lipid lowering with atorvastatin in patients with coronary artery disease, diabetes, and chronic kidney disease Mayo Clin Proc 2008 83 8 870 879 10.1016/S0025-6196(11)60763-5 18674471 \n47. Haynes R Staplin N Emberson J Herrington WG Tomson C Agodoa L SHARP Collaborative Group Evaluating the contribution of the cause of kidney disease to prognosis in CKD: results from the Study of Heart and Renal Protection (SHARP) Am J Kidney Dis. 2014 64 1 40 48 10.1053/j.ajkd.2013.12.013 24613056 \n48. Tonelli M Wanner C Lipid management in chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2013 clinical practice guideline Ann Intern Med 2014 160 3 182 10.7326/M13-2453 24323134 \n49. Food and Drug Administration. Summary minutes of the Endocrinologic and Metabolic Drugs Advisory Committee, November 2, 2011. Silver Spring, MD. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM290774.pdf. Accessed 26 Jun 2014.\n50. Kalaitzidis RG Bakris GL Serum creatinine vs. albuminuria as biomarkers for the estimation of cardiovascular risk Curr Vasc Pharmacol 2010 8 5 604 611 10.2174/157016110792006914 20507275 \n51. Jacobson TA Overcoming ‘ageism’ bias in the treatment of hypercholesterolaemia: a review of safety issues with statins in the elderly Drug Saf 2006 29 5 421 448 10.2165/00002018-200629050-00005 16689557 \n52. Wenger NK Lewis SJ Herrington DM Bittner V Welty FK Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease Ann Intern Med 2007 147 1 1 9 10.7326/0003-4819-147-1-200707030-00002 17606955 \n53. Koren MJ Feldman T Mendes RA Impact of high-dose atorvastatin in coronary heart disease patients age 65 to 78 years Clin Cardiol 2009 32 5 256 263 10.1002/clc.20448 19452483 \n54. Yoshitomi R Fukui A Nakayama M Ura Y Ikeda H Oniki H Sex differences in the association between serum uric acid levels and cardiac hypertrophy in patients with chronic kidney disease Hypertens Res 2014 37 3 246 252 10.1038/hr.2013.134 24089265\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1170-229X",
"issue": "32(12)",
"journal": "Drugs & aging",
"keywords": null,
"medline_ta": "Drugs Aging",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000069059:Atorvastatin; D008078:Cholesterol, LDL; D003327:Coronary Disease; D004311:Double-Blind Method; D050171:Dyslipidemias; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007668:Kidney; D008297:Male; D017035:Pravastatin; D051436:Renal Insufficiency, Chronic; D014527:Uric Acid",
"nlm_unique_id": "9102074",
"other_id": null,
"pages": "1055-65",
"pmc": null,
"pmid": "26625880",
"pubdate": "2015-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "19452483;24089265;19540640;19892934;20172445;20206456;20507275;21663949;22326029;22722878;22910937;23067652;23470492;24076297;24076283;24169005;24393575;24323134;24793673;24613056;24892770;24790178;25147328;25660356;24643437;17606955;17942759;10815083;11135079;11682660;11904577;12373076;12761259;15042535;15149882;15238570;8973668;10075613;15632893;15998677;16444458;16689557;16531986;16762986;17130267;17283260;17986697;18299289;18065809;18674471;18676075;19216014;19810001",
"title": "Improvement in Renal Function and Reduction in Serum Uric Acid with Intensive Statin Therapy in Older Patients: A Post Hoc Analysis of the SAGE Trial.",
"title_normalized": "improvement in renal function and reduction in serum uric acid with intensive statin therapy in older patients a post hoc analysis of the sage trial"
} | [
{
"companynumb": "US-UCBSA-2015042555",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"drugadditional": null,
... |
{
"abstract": "Cryptococcus. Neoformans (C. neoformans) is an encapsulated heterobasidiomycetous fungus responsible for opportunistic infections worldwide in immunocompromised patients. Clinical presentation ranges from asymptomatic respiratory tract colonization to disseminated infection in any human body part. The central nervous system (CNS) and pulmonary diseases garner most of the clinical attention. Secondary cutaneous cryptococcosis is an uncommon manifestation seen as a sentinel sign commonly in disseminated cryptococcal infection. Primary cutaneous cryptococcosis (PCC) is a rare manifestation seen in both immunocompromised and immunocompetent patients. It is a discrete infection with different epidemiological trends. Immunosuppressive therapy (corticosteroids, tacrolimus) predisposes a patient to acquire this clinical entity. We present a case of an elderly Caucasian male on fingolimod for relapsing-remitting multiple sclerosis with nonhealing scalp lesions for four years. He was a referral to our healthcare center for the presence of fungal elements seen on a scalp biopsy fungal stains. Final cultures returned positive for C. neoformans susceptible to fluconazole (MIC = 8 μg/mL). The CD4 count was 13 cells/uL, and workup for CNS and disseminated cryptococcal infection were negative. Fingolimod is an immunomodulator that acts on sphingosine 1-phosphate receptors, affecting the lymphocytes. Pubmed literature review revealed few case reports (< 5) with PCC in patients on fingolimod. To our knowledge, ours is the first case with scalp cryptococcosis, with the lowest CD4 count while being on fingolimod. No randomized controlled trial data exist for the treatment of PCC. Therapy initiated with oral luconazole for six months with significant improvement at three months.",
"affiliations": "Infectious Disease Department, University of Missouri Hospital and Clinic, 1 Hospital Dr, Columbia, MO 65212, USA.;Infectious Disease Department, University of Missouri Hospital and Clinic, 1 Hospital Dr, Columbia, MO 65212, USA.;Neurology Department, University of Missouri Hospital and Clinic, 1 Hospital Dr, Columbia, MO 65212, USA.;Infectious Disease Department, University of Missouri Hospital and Clinic, 1 Hospital Dr, Columbia, MO 65212, USA.;Infectious Disease Department, University of Missouri Hospital and Clinic, 1 Hospital Dr, Columbia, MO 65212, USA.",
"authors": "Patil|Sachin M|SM|;Beck|Phillip Paul|PP|;Arora|Niraj|N|;Acevedo|Bran Andres|BA|;Dandachi|Dima|D|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2020.e00810",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509 Elsevier \n\nS2214-2509(20)30118-9\n10.1016/j.idcr.2020.e00810\ne00810\nArticle\nPrimary cutaneous cryptococcal infection due to fingolimod – Induced lymphopenia with literature review\nPatil Sachin M. drssmp1@gmail.coma⁎ Beck Phillip Paul a Arora Niraj b Acevedo Bran Andres a Dandachi Dima a a Infectious Disease Department, University of Missouri Hospital and Clinic, 1 Hospital Dr, Columbia, MO 65212, USA\nb Neurology Department, University of Missouri Hospital and Clinic, 1 Hospital Dr, Columbia, MO 65212, USA\n⁎ Corresponding author. drssmp1@gmail.com\n15 5 2020 \n2020 \n15 5 2020 \n21 e0081014 3 2020 7 5 2020 7 5 2020 © 2020 Published by Elsevier Ltd.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Cryptococcus. Neoformans (C. neoformans) is an encapsulated heterobasidiomycetous fungus responsible for opportunistic infections worldwide in immunocompromised patients. Clinical presentation ranges from asymptomatic respiratory tract colonization to disseminated infection in any human body part. The central nervous system (CNS) and pulmonary diseases garner most of the clinical attention. Secondary cutaneous cryptococcosis is an uncommon manifestation seen as a sentinel sign commonly in disseminated cryptococcal infection. Primary cutaneous cryptococcosis (PCC) is a rare manifestation seen in both immunocompromised and immunocompetent patients. It is a discrete infection with different epidemiological trends. Immunosuppressive therapy (corticosteroids, tacrolimus) predisposes a patient to acquire this clinical entity. We present a case of an elderly Caucasian male on fingolimod for relapsing-remitting multiple sclerosis with nonhealing scalp lesions for four years. He was a referral to our healthcare center for the presence of fungal elements seen on a scalp biopsy fungal stains. Final cultures returned positive for C. neoformans susceptible to fluconazole (MIC = 8 μg/mL). The CD4 count was 13 cells/uL, and workup for CNS and disseminated cryptococcal infection were negative. Fingolimod is an immunomodulator that acts on sphingosine 1-phosphate receptors, affecting the lymphocytes. Pubmed literature review revealed few case reports (< 5) with PCC in patients on fingolimod. To our knowledge, ours is the first case with scalp cryptococcosis, with the lowest CD4 count while being on fingolimod. No randomized controlled trial data exist for the treatment of PCC. Therapy initiated with oral luconazole for six months with significant improvement at three months.\n\nKeywords\nPrimary cutaneous cryptococcosisGilenyaFingolimodCD4C. neoformans\n==== Body\nIntroduction\nCryptococcus. neoformans is a saprophytic yeast responsible for infections in both immunosuppressed and immunocompetent patients. The most commonly affected organs are the central nervous system (CNS), followed by lung and skin. The incidence of cryptococcosis in the pre-AIDS era was 0.8 cases per one million persons per year, and it increased to fifty cases per one million persons per year in several large cities in 1992. By the mid-1990s, due to the widespread use of fluconazole for oral candidiasis, the incidence rate diminished and stabilized to approximately 1 case per 100,000 persons per year [1]. The initiation of highly active antiretroviral therapy in HIV infected patients has further decreased the incidence. Cutaneous cryptococcosis (CC) accounts for 10 % of total cases and frequently as a manifestation of disseminated cryptococcosis (DC) [2]. Clinical diagnosis of Primary cutaneous cryptococcosis (PCC) can be challenging due to its varied skin manifestations [3].\n\nImmunosuppression due to HIV is responsible for most of the cases, whereas medication (corticosteroid) induced immunosuppression accounts for lesser cases [2]. Both result in a diminished cell-mediated immune response. Apart from corticosteroids, other medicines associated with CC are tacrolimus and fingolimod. A Pubmed literature search on fingolimod-induced cryptococcal infections revealed approximately 10 cases. Of 10 cases, only two had PCC. Fingolimod is the first oral disease-modifying agent for relapsing-remitting multiple sclerosis (MS) approved by the FDA in September It modulates sphingosine 1-phosphate receptor causing CNS lymphopenia and a decrease in inflammation. Here we report the first case of biopsy and culture-positive PCC on the scalp (caused by C. neoformans) in an MS patient who was on fingolimod for seven years. This case report highlights the importance of medication-induced cryptococcosis and its management.\n\nCase report\nA 63-year-old male presented to his dermatologist with a history of multiple nonhealing left occipital scalp lesions for four years. On clinical examination, the patient had two nonhealing lesions over the left occipital scalp and one over the right occipital scalp. Right occipital scalp (Fig. 1) revealed a 1.4 cm pink plaque lesion, left superior occipital scalp lesion (Fig. 2) revealed a 1 cm pink plaque, and the left inferior occipital scalp lesion (Fig. 3) revealed 1 cm ill-defined papule. Examination of the face revealed 1 cm pink plaque with central depression located over the right parietal scalp, a 5 mm erythematous papule over the right superior helix, and an ill-defined 2 cm pink plaque over the right preauricular cheek. Shave biopsy of all three scalp lesions performed and specimens sent to histopathology for further examination. The right occipital scalp lesion revealed solar elastosis and vascular ectasia at the margins, whereas the left superior occipital scalp lesion revealed an ulcer with numerous fungal yeast forms and granulomatous dermatitis at the margins. The left inferior occipital scalp lesion revealed an ulcer with multiple fungal yeast forms present at the margin.Fig. 1 Right occipital scalp lesion.\n\nFig. 1Fig. 2 Left superior occipital scalp lesion.\n\nFig. 2Fig. 3 Left inferior occipital scalp lesion.\n\nFig. 3\n\nDue to the abnormal histopathology report, two weeks later, he underwent a repeat biopsy of the left superior occipital scalp lesion for fungal tissue culture. Due to the presence of numerous fungal yeast forms on the biopsy patient referred to our University medical center for management. After reviewing his clinical history, a decision made to admit him to the internal medicine inpatient service for additional work-up. Past medical history was significant for MS diagnosed more than 30 years back, osteoarthritis of right knee status post right knee arthroscopy, and degenerative disc disease of low back status-post surgery. For MS, the patient was on fingolimod for seven years. The patient admitted receiving high-dose corticosteroids for MS exacerbation previously but none in the length of the fingolimod use. His last MS exacerbation was 18 years ago. He denied any other clinical symptoms. He denied any exposure to birds or farm animals and no recent significant travel history and was a retired lineman. Clinical concern was to rule out acute DC, as the patient was on fingolimod for MS. Morphology and histochemical properties of the organisms seen on histopathology specimens were consistent with Cryptococcus spp.\n\nOn the day of admission due to a lack of neurological symptoms and signs, CT head was not performed. Two sets of blood cultures obtained at the admission were negative. Complete blood counts, comprehensive metabolic panel, and prothrombin time were within normal limits. HIV 1–2 serology, hepatitis C serology, serum cryptococcal antigen, andCD4/CD8 lymphocyte subset were ordered. Cerebrospinal fluid (CSF) analysis was clear, colorless; the protein was 52 mg/dL; glucose was 59 mg/dL; White cell count was 0 cells/uL and red cell count was 19 cells/uL. CSF specimens sent for fungal and bacterial culture. On day three, serum cryptococcal antigen, HIV, and hepatitis C serology were nonreactive. CSF cryptococcal antigen testing was negative, and CSF bacterial and fungal cultures were negative for growth. He received no antifungal therapy during his hospitalization and was discharged on day three. Post-discharge day 1 CD4/CD8 lymphocyte subset results revealed CD4 of 13 cells/μL (5.1 %) and CD8 of 147 cells/μL (57.1 %). Due to low CD4 count, Sulfamethoxazole/trimethoprim double strength once a day started for pneumocystis prophylaxis, and fingolimod discontinued. A clinical diagnosis of PCC made due to a lack of CSF involvement, negative HIV serology, and fingolimod administration with lymphocytopenia. His neurologist notified so that he could resume treatment with an alternative medication for multiple sclerosis. For PCC, he was initiated on therapy with six months of oral fluconazole 400 mg daily. Five days post-discharge biopsy culture returned positive for C. neoformans (susceptible to fluconazole, MIC = 8 μg/mL) confirming the diagnosis. At three weeks follow up, an improvement in his scalp lesions(decreased itchiness and drainage) seen with no change in face lesions. In the tenth week, scalp lesions were healing (Fig. 4) with no new lesions. At three months, the CD4 count increased to 209 cells/μL, and Sulfamethoxazole/trimethoprim doublestrength was stopped.Fig. 4 Left occipital lesions at 3 months of therapy.\n\nFig. 4\n\nDiscussion\nIn cryptococcosis, 80 % of cases are due to immunosuppression, whereas the remaining 20 % have no underlying disease or risk factor [4]. Clinical presentation in classic cryptococcosis is dependent on a host's immune response to inhaled cryptococci. An efficient immune system eliminates it or produces a dormant small pulmonary lymph node complex via Th1 response, whereas immunosuppression leads to proliferation, dissemination resulting in disease [1]. The infection ranges from asymptomatic respiratory tract colonization to the spread of infection into any human body part. CC can be primary or secondary as in disseminated cryptococcosis [2]. Secondary cutaneous cryptococcosis (SCC) is an uncommon manifestation in 10–15% of disseminated cryptococcal infections attributed to hematogenous dissemination [2].\n\nPCC is a rare manifestation in both immunocompromised and immunocompetent patients. It is a separate clinical entity with different epidemiological trends. The clinical definition includes identification of the C. neoformans in the skin lesion biopsy specimen or by culture and either clinical criteria or histological criteria together with the absence of dissemination [3]. It results from direct inoculation via preceding trauma or occupational/hobby exposure to environmental sources with a predisposition to skin injury [2,3]. Skin lesions are solitary or confined to a limited area and located in unclothed areas in PCC; however, in SCC, they are multiple scattered, situated on both exposed and clothed areas. In both, the infection presents as a new skin lesion refractory to conservative or antibacterial therapy. Most typical skin lesions are nodular or granulomatous, followed by ulcerative lesions. In SCC, almost every type of skin lesion is seen, most often being umbilicated papules or cellulitic patterns. Overall the most common site of infection is the upper extremities. Lesions are located over the finger and face in immunocompetent, whereas they are on the trunk and lower extremities in immunocompromised patients [2]. Around one-half of patients with PCC were immunocompetent, whereas in the remaining, the most common risk factor being corticosteroids [2]. Significant geographical variation persists concerning the causative strain. In France, serotype D was responsible for 71 % of cases whereas, in Australia and New Zealand, it was serotype A and C. gatti in subtropical areas [2,5,6]. In the United States clinical series, serotyping done on only five patients returned positive for serotype D [2]. In solid organ transplant (SOT) patients, serotype A was responsible for most of the cases [7]. In PCC risk of dissemination of infection to other areas exists in immunocompromised patients. In immunocompetent patients, only one case of dissemination in a laboratory accident has been described [1].\n\nCompetent local immune response at the skin, underdiagnosis, or misdiagnosis can explain the lower incidence of PCC [3]. The average human skin temperature is 33 °C. Serotype D is dermatotropic due to its inability to grow at higher temperatures compared to serotype A. Calcineurin is essential for the growth of the cryptococcus at 37 °C. Tacrolimus (FK506) has an intrinsic antifungal activity due to calcineurin inhibition after binding to FKBP12 (FK506 binding\n\nprotein). It predisposes stable SOT patients to PCC as this activity is ineffective at lower skin temperatures [8]. Tacrolimus does confer protection against cryptococcal meningoencephalitis at an average body temperature of 37 °C [8]. Cyclosporine inhibits the growth of the cryptococcus by binding to cyclophilin A resulting in calcineurin inhibition at 37 °C but no effect at 24 °C. In vivo, the potent immunosuppressive effect of cyclosporine negates the anticryptococcal activity [9]. Corticosteroids alter the local cytokine milieu by repressing IL-12 and stimulating IL-4, IL -10 & IL-13, resulting in a Th2 response rather than a Th1 response. A Th1 response occurs due to an increase in IL-12 rich local cytokine milieu stimulating CD4 production of IL-2, IFN-ɤ & TNF-β conferring protection against fungal infections (Fig. 5) [10].Fig. 5 Summary of Th1/Th2 induction. Cytokines, hormones, and microbial antigens stimulate the innate immune system to produce either IL-12 or IL-4 in the local microenvironment around a newly activated T cell. IL-12 induces Th0 polarization to the Th1 phenotype and inhibits polarization to the Th2 phenotype, whereas IL-4 acts reciprocally. CMI, cell-mediated immunity; CpG, purine-purine-C-G-pyrimidine-pyrimidine DNA hexamer; DHEA, dehydroepiandrosterone; Epi/NE, epinephrine/norepinephrine; HSP, heat shock protein; LTA, lipoteichoic acid; LPS, lipopolysaccharide; PG, prostaglandin; estgn/pgstn, estrogen/progesterone; frust.phag., frustrated phagocytosis (Type 1/Type 2 Immunity in Infectious Diseases Brad Spellberg1 and John E. Edwards, Jr.) reproduced with permission from [10].\n\nFig. 5\n\nFingolimod (FTY720) is an oral disease-modifying agent approved by the FDA for relapsing-remitting MS. The FREEDOMS ‖ trial unfolded a single case of asymptomatic pulmonary cryptococcosis in a patient five months after discontinuation of the drug [11]. Clinical trials reported a marginal increase in the rate of lower respiratory and Herpes virus infections. Numerous AIDS-defining illnesses have occurred in patients on fingolimod, including cryptococcosis, histoplasmosis, PML (Progressive Multifocal Leukoencephalopathy), atypical mycobacterial infections, and Kaposi's sarcoma [12]. Cryptococcal infections seen with fingolimod are meningoencephalitis, disseminated cryptococcal infection, and PCC. The mean age at diagnosis was 56 years. The possibility of cryptococcal infection is higher after two years of therapy with fingolimod [11]. Natalizumab is the only other MS medication associated with cryptococcal infection.\n\nFingolimod binds with a high affinity to sphingosine 1 phosphate receptors (S1P1,3,4,5) with initial activation of Lymphocyte S1P1 followed by downregulation resulting in receptor internalization and lymphocyte entrapment in lymph nodes. Lymphocyte redistribution results in peripheral lymphopenia with sparing of the effector memory T cells. Autoreactive lymphocyte infiltration into the brain subsides due to lesser cells crossing the blood-brain barrier. Fingolimod dwindles circulating CD4 + T cells and, to a lesser extent, CD8 + T cells with no effect on antigen presentation, T or B cell activation, proliferation, differentiation, or effector function. It alters the Cytokine milieu and abates NK cell subsets resulting in switching the host immune response from Th1 to Th2 in cryptococcal infections [11]. Th1 immune response is crucial for fungal infection control. Long term fingolimod (51–64 months) culminates in a reversal of a healthy 2:1 ratio of CD4 to CD8 also seen in HIV AIDS patients and immunosenescence (elderly) [11]. The recommendation is to hold therapy if the lymphocyte count drops below 200 cells/uL for the immune rebuild before the reinitiation of therapy [12]. Immune system impact due to fingolimod does not return to normalcy immediately after cessation. Post cessation lymphocytes exceed the lower limit of normal by 6–8 weeks and recover to 80 % of their baseline level by three months [11]. A case of meningoencephalitis was described at eight weeks post discontinuation, as was a case of asymptomatic pulmonary cryptococcosis at five months after stopping (FREEDOMS ‖ trial). We concur with the likelihood of potentiation of fingolimod effects by a senescent immune system. Treatment span with fingolimod and age are important risk factors for the development of cryptococcal infection.\n\nHIV negative patients present with sparse signs and symptoms, insensitive serological testing, an occurrence leading to valuable hindrance in diagnosis and therapy institutions [4]. Nonmeningeal nonpulmonary cryptococcosis has the highest percentage of failed therapy and the worst prognosis [2,4]. Among these patients, fluconazole, when used alone, had a successful outcome. Mortality in PCC was 9.2 %, higher in immunocompetent compared to immunocompromised patients [2]. In SOT clinical series, the overall mortality of cutaneous cryptococcosis was 15.4 % (4/26),12.5 % in PCC (1/8) & 16.7 % (3/18) in DCC [7]. Predictors for mortality in PCC include male gender and organ failure syndrome [4].\n\nIn our case, the patient did not receive any high dose corticosteroids for the seven years he was on fingolimod. Other than his scalp lesions, he had no other clinical signs or symptoms which attests to the above-mentioned atypical presentations.\n\nIn the absence of other clinical manifestations, DC and meningoencephalitis evaluations were negative. The CD4 count was the lowest yet seen at 13 cells/uL. Biopsy and culture confirmed the diagnosis, and it was susceptible to fluconazole. After a PUBMED literature review, this is the second case with scalp involvement and the first case while being on fingolimod. The patient is a retired lineman, and environmental source exposure is a high possibility. Due to low CD4 count patient was placed on oral Sulfamethoxazole/trimethoprim double strength once a day for the next three months for Pneumocystis prophylaxis until CD4 counts were greater than 200 cells/uL. In a recent systemic review of PCC in immunocompetent patients [5], all cases treated with itraconazole, had a successful outcome. Due to the lack of randomized controlled clinical trials, expert opinion (based on clinical experience, descriptive studies, and case reports), the current clinical consensus is to follow IDSA guidelines for nonmeningeal nonpulmonary cryptococcosis treatment, which recommends using fluconazole at 400 mg per day for 6–12 months [13].\n\nConclusion\nAlthough fingolimod is a safe and effective drug for MS, there has been a recent increase in case reports of cryptococcal infection in patients on fingolimod. A literature review revealed less than 15 patients reported to date. Recommendations on how to screen or monitor these patients for infections are scant. Due to higher mortality in PCC, whether screening these patients regularly with serum cryptococcal antigen and CD4 counts will help in detecting these patients earlier is an unsolved dilemma currently. As several AIDS-defining illnesses have occurred in these patients, our suggestion is to monitor the CD4 counts regularly, and if they are less than 100 cells/uL, then obtain a serum cryptococcalantigen. Monitoring might cut short the unreasonable delays in diagnosis and institution of therapy. Monitoring will be an excellent additional supplement to the clinical questionnaire related to cryptococcosis and clinical examination. In PCC, itraconazole was successful in a few patients; we suggest to use fluconazole as per IDSA guidelines for at least 6–12 months.\n\nCredit statement of author’s contributions\nSachin M Patil, Phillip Paul Beck, and Niraj Arora worked on drafting, editing and reviewing the manuscript that was prepared for submission and performed a literature review for this project. Sachin M Patil, Bran Andres Acevedo, and Dima Dandachi were involved in the care of the patient being discussed. Bran Andres Acevedo and Dima Dandachi as faculty advisors, contributed by assisting in reviewing and editing of this case report and provided project supervision and administration. We confirm that the manuscript has been read and approved by all named authors. We further confirm that the order of authors listed in the manuscript has been approved by all of us\n\nEthics approval and consent to participate\nCare taken to ensure that all patient identifiers were removed in the process of creating this case report, and the patient was made aware of this case report.\n\nConsent for publication\nWritten and verbal informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAvailability of data and materials\nNot applicable.\n\nFunding\nThere are no sources of funding to report for this case report.\n\nDeclaration of Competing Interest\nThe authors declare that they have no competing interests.\n\nAcknowledgments\nNone.\n==== Refs\nReferences\n1 Mandell Perfect J.R. Douglas, and Bennett’s principles and practice of infectious diseases, cryptococcosis (Cryptococcus neoformans and Cryptococcus gattii) 9th ed. 2020 Elsevier Philadelphia 3146 3161 \n2 Christianson J.C. Engber W. Andes D. Primary cutaneous cryptococcosis in immunocompetent and immunocompromised hosts Med Mycol 41 3 2003 177 188 10.1080/1369378031000137224 12964709 \n3 Neuville S. Dromer F. Morin O. Dupont B. Ronin O. Lortholary O. Primary cutaneous cryptococcosis: a distinct clinical entity Clin Infect Dis 36 3 2003 337 347 10.1086/345956 12539076 \n4 Pappas P.G. Perfect J.R. Cloud G.A. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy Clin Infect Dis 33 5 2001 690 699 10.1086/322597 11477526 \n5 Du L. Yang Y. Gu J. Chen J. Liao W. Zhu Y. Systemic review of published reports on primary cutaneous cryptococcosis in immunocompetent patients Mycopathologia 180 1-2 2015 19 25 10.1007/s11046-015-9880-7 25736173 \n6 Marques S.A. Bastazini I. Martins A.L.G.P. Primary cutaneous cryptococcosis in Brazil: report of 11 cases in immunocompetent and immunosuppressed patients Int J Dermatol 51 7 2012 780 784 10.1111/j.1365-4632.2011.05298.x 22715820 \n7 Sun H.-Y. Alexander B.D. Lortholary O. Cutaneous cryptococcosis in solid organ transplant recipients Med Mycol 48 6 2010 785 791 10.3109/13693780903496617 20100136 \n8 Kanj S.S. Welty-Wolf K. Madden J. Fungal infections in lung and heart-lung transplant recipients. Report of 9 cases and review of the literature Medicine (Baltimore) 75 3 1996 142 156 10.1097/00005792-199605000-00004 8965683 \n9 Cruz M.C. Del Poeta M. Wang P. Immunosuppressive and nonimmunosuppressive cyclosporine analogs are toxic to the opportunistic fungal pathogen Cryptococcus neoformans via cyclophilin-dependent inhibition of calcineurin Antimicrob Agents Chemother 44 1 2000 143 149 10.1128/aac.44.1.143-149.2000 10602736 \n10 Spellberg B. Edwards J.E. Type 1/type 2 immunity in infectious diseases Clin Infect Dis 32 1 2001 76 102 10.1086/317537 11118387 \n11 Grebenciucova E. Reder A.T. Bernard J.T. Immunologic mechanisms of fingolimod and the role of immunosenescence in the risk of cryptococcal infection: a case report and review of literature Mult Scler Relat Disord 9 2016 158 162 10.1016/j.msard.2016.07.015 27645366 \n12 Grebenciucova E. Pruitt A. Infections in patients receiving multiple sclerosis disease-modifying therapies Curr Neurol Neurosci Rep 17 11 2017 88 10.1007/s11910-017-0800-8 28940162 \n13 Perfect J.R. Dismukes W.E. Dromer F. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of America Clin Infect Dis 50 3 2010 291 322 10.1086/649858 20047480\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "21()",
"journal": "IDCases",
"keywords": "C. neoformans; CD4; Fingolimod; Gilenya; Primary cutaneous cryptococcosis",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e00810",
"pmc": null,
"pmid": "32518753",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "12964709;8965683;25736173;22715820;20100136;12539076;20047480;10602736;27645366;11118387;28940162;11477526",
"title": "Primary cutaneous cryptococcal infection due to fingolimod - Induced lymphopenia with literature review.",
"title_normalized": "primary cutaneous cryptococcal infection due to fingolimod induced lymphopenia with literature review"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-250987",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FINGOLIMOD"
},
"drug... |
{
"abstract": "OBJECTIVE\nTo describe clinical outcomes in a cohort of adolescent female patients using tamoxifen for the treatment of bothersome etonogestrel implant-associated bleeding.\n\n\nMETHODS\nRetrospective chart review.\n\n\nMETHODS\nA tertiary children's hospital.\n\n\nMETHODS\nAdolescent female patients ages 12-21 seen between 8/2016 - 8/2019 with an etonogestrel (ENG) implant in place who received a tamoxifen prescription for the indication of implant-associated bleeding.\n\n\nMETHODS\nNone.\n\n\nMETHODS\nMain outcome measures were implant continuation rates, average time to implant discontinuation after tamoxifen prescription, reasons for implant removal, number of doses and timing of tamoxifen use, bleeding patterns, and adverse effects.\n\n\nRESULTS\nA total of 67 patients met inclusion criteria. The mean age of patients was 16.7 years old. Of the patients with available follow up data, 49 out of 60 (81.7%) were still using the implant at 12 months, 29 out of 53 (54.7%) at 24 months, and 9 out of 40 (22.5%) at 36 months. The average time from tamoxifen prescription to implant removal was 12.1 months. Bothersome bleeding was the primary reason for ENG implant discontinuation (68.6%). No side effects from tamoxifen use were reported.\n\n\nCONCLUSIONS\nTamoxifen was well-tolerated among this cohort of patients and can be considered as a treatment option to manage bothersome implant bleeding in adolescents.",
"affiliations": "University of Colorado Section of Obstetrics and Gynecology. Electronic address: julie.friedman@cuanschutz.edu.;Children's Hospital of Colorado Department of Pediatric and Adolescent Gynecology.;University of Colorado Anschutz Medical Campus.;University of Colorado Section of Obstetrics and Gynecology.;University of Colorado Section of Obstetrics and Gynecology; Children's Hospital of Colorado Department of Pediatric and Adolescent Gynecology.",
"authors": "Friedman|Julie|J|;Buyers|Eliza|E|;Laurin|Jaime|J|;Hampanda|Karen|K|;Alaniz|Veronica I|VI|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpag.2021.11.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-3188",
"issue": null,
"journal": "Journal of pediatric and adolescent gynecology",
"keywords": "Etonogestrel implant; adolescent; bothersome bleeding; tamoxifen",
"medline_ta": "J Pediatr Adolesc Gynecol",
"mesh_terms": null,
"nlm_unique_id": "9610774",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34780932",
"pubdate": "2021-11-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Tamoxifen for the treatment of etonogestrel implant associated bleeding in an adolescent gynecology practice.",
"title_normalized": "tamoxifen for the treatment of etonogestrel implant associated bleeding in an adolescent gynecology practice"
} | [
{
"companynumb": "US-ORGANON-O2112USA002691",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ETONOGESTREL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nIntentional overdose is a leading method of self-harm and suicide, and repeat attempts strongly predict eventual death by suicide.\n\n\nOBJECTIVE\nTo determine the risk of recurrence after a first intentional overdose. Secondary objectives included characterization of the temporal course and potential predictors of repeat overdose, a strong risk factor for death from suicide.\n\n\nMETHODS\n\n\n\nMETHODS\nPopulation-based cohort study.\n\n\nMETHODS\nOntario, Canada, from 1 April 2002 to 31 March 2013.\n\n\nMETHODS\nAll Ontario residents presenting to an emergency department after a first intentional overdose.\n\n\nMETHODS\nThe incidence and timing of recurrent overdose.\n\n\nRESULTS\nWe followed 81,675 patients discharged from hospital after a first intentional overdose. Overall, 13,903 (17.0%) returned with a repeat overdose after a median interval of 288 (inter-quartile range: 62 to 834) days. Of these, 4493 (5.5%) had multiple repeat episodes. Factors associated with repeat self-poisoning included psychiatric care in the preceding year (adjusted hazard ratio [aHR] 1.55; 95% confidence interval [CI] 1.50 to 1.61), alcohol dependence (aHR 1.41; 95% CI 1.35 to 1.46) and documented depression (aHR 1.39; 95% CI 1.34 to 1.44). Female sex, rural residence, lower socioeconomic status, ingestion of psychoactive drugs and younger age were also weakly associated with repeat overdose.\n\n\nCONCLUSIONS\nHospital presentation for repetition of intentional overdose is common, with recurrent episodes often far removed from the first. While several factors predict overdose repetition, none is particularly strong.\n\n\nCONCLUSIONS\nSecondary prevention initiatives should be implemented for all individuals who present to the emergency department and survive intentional overdose.",
"affiliations": "a Division of Emergency Medicine, Hospital for Sick Children, Faculty of Medicine , University of Toronto , Toronto , Canada ;;d The Institute for Clinical Evaluative Sciences , Toronto , Canada ;;d The Institute for Clinical Evaluative Sciences , Toronto , Canada ;;e Department of Emergency Medicine , Queen's University , Kingston , Canada ;;b Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Faculty of Medicine , University of Toronto , Toronto , Canada ;;g Applied Health Research Centre (AHRC) , Li Ka Shing Knowledge Institute of St. Michael's Hospital , Toronto , Canada ;;b Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Faculty of Medicine , University of Toronto , Toronto , Canada ;;d The Institute for Clinical Evaluative Sciences , Toronto , Canada ;",
"authors": "Finkelstein|Yaron|Y|;Macdonald|Erin M|EM|;Hollands|Simon|S|;Sivilotti|Marco L A|ML|;Hutson|Janine R|JR|;Mamdani|Muhammad M|MM|;Koren|Gideon|G|;Juurlink|David N|DN|;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2016.1177187",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "54(7)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Recidivism; self-poisoning; suicide",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000328:Adult; D000368:Aged; D002170:Canada; D015331:Cohort Studies; D062787:Drug Overdose; D004636:Emergency Service, Hospital; D005260:Female; D006760:Hospitalization; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D012008:Recurrence; D012307:Risk Factors; D016728:Self-Injurious Behavior; D013406:Suicide, Attempted; D055815:Young Adult",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "585-9",
"pmc": null,
"pmid": "27172384",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Repetition of intentional drug overdose: a population-based study.",
"title_normalized": "repetition of intentional drug overdose a population based study"
} | [
{
"companynumb": "CA-JNJFOC-20160820703",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "We report the case of a 61-year-old man with schizophrenia who was treated with carbamazepine, in whom electrocardiography showed transient Brugada-type ST elevation. He had been hospitalized our hospital's Department of Psychiatry and had been diagnosed with pneumonia. On the following day, electrocardiography showed coved-type ST elevation in the right precordial leads and a blood examination revealed that the patient's carbamazepine concentration was at the upper limit of the standard range, as well as hypothyroidism. The patient's electrocardiogram normalized after the withdrawal of carbamazepine. We demonstrated that the patient's carbamazepine concentration-and not hypothyroidism-was associated with the serial electrocardiographic changes by monitoring the patient's blood concentration of carbamazepine and his thyroid function.",
"affiliations": "Department of Cardiology, Hakodate Watanabe Hospital, Japan.;Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Japan.;Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Japan.;Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Japan.",
"authors": "Ota|Hisanobu|H|;Kawamura|Yuichiro|Y|;Sato|Nobuyuki|N|;Hasebe|Naoyuki|N|",
"chemical_list": "D002220:Carbamazepine",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.8875-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2914218910.2169/internalmedicine.8875-17Case ReportA Carbamazepine-induced Brugada-type Electrocardiographic Pattern in a Patient with Schizophrenia Ota Hisanobu 1Kawamura Yuichiro 2Sato Nobuyuki 2Hasebe Naoyuki 2\n1 Department of Cardiology, Hakodate Watanabe Hospital, Japan\n2 Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, JapanCorrespondence to Dr. Hisanobu Ota, hisa128@asahikawa-med.ac.jp\n\n15 11 2017 56 22 3047 3050 16 1 2017 29 1 2017 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).We report the case of a 61-year-old man with schizophrenia who was treated with carbamazepine, in whom electrocardiography showed transient Brugada-type ST elevation. He had been hospitalized our hospital's Department of Psychiatry and had been diagnosed with pneumonia. On the following day, electrocardiography showed coved-type ST elevation in the right precordial leads and a blood examination revealed that the patient's carbamazepine concentration was at the upper limit of the standard range, as well as hypothyroidism. The patient's electrocardiogram normalized after the withdrawal of carbamazepine. We demonstrated that the patient's carbamazepine concentration-and not hypothyroidism-was associated with the serial electrocardiographic changes by monitoring the patient's blood concentration of carbamazepine and his thyroid function. \n\nBrugada-type electrocardiographycarbamazepineschizophreniaantiepileptic drugsodium channel\n==== Body\nIntroduction\nBrugada syndrome is a cardiac channelopathy that is characterized by coved-type or saddleback-type ST segment elevation in the right precordial leads on electrocardiography. It has the potential to cause fatal ventricular arrhythmias (1). On the other hand, it has been reported that the mortality rate is elevated in patients with schizophrenia in comparison to the general population. Ischemic heart disease and drug-induced QTc interval prolongation are considered to be possible mechanisms (2-4). Furthermore, schizophrenia is reported to be associated with an increased risk of sudden cardiac death and a higher prevalence of Brugada-type electrocardiography findings (5,6). In addition, it was recently reported that antidepressants and other psychoactive drugs may provoke a Brugada-type electrocardiographic pattern (7). We encountered a case of schizophrenia in a patient who was treated with carbamazepine who presented with a transient coved-type Brugada electrocardiographic pattern and hypothyroidism. We herein discuss the possible mechanisms based on the findings of our case.\n\nCase Report\nThe patient was a 61-year-old man with schizophrenia who had been hospitalized in our hospital's Department of Psychiatry since December 2014. The patient's medications (all administered orally) included: carbamazepine (200 mg) and valproic acid (200 mg) twice a day, and olanzapine (10 mg), flunitrazepam (2 mg) and quazepam (15 mg) at bedtime. Thiamazole had also been prescribed since another physician had diagnosed the patient with hyperthyroidism 35 years previously. During hospitalization, the dose of the thiamazole was controlled by a psychiatrist because thiamazole-induced hypothyroidism emerged.\n\nAt the end of November, 2015, he developed fever and productive cough. He was diagnosed with pneumonia by chest computed tomography, and was treated with intravenous antibiotics. Since his blood examination data revealed abnormal creatinine phosphokinase elevation on the following day, electrocardiography was performed. During his hospitalization in the Department of Psychiatry, the patient had undergone electrocardiography at least once a month, and no Brugada-type waveforms had been seen (Fig. 1). On the electrocardiogram that was obtained after the diagnosis of pneumonia, however, coved-type ST segment elevation was observed in leads V1-3 (Fig. 2). He was therefore transferred to our department for a close examination and treatment.\n\nFigure 1. Electrocardiography was performed before the episode. No ST segment elevation was observed in the right precordial leads.\n\nFigure 2. A Brugada-type electrocardiographic pattern can be seen in the right precordial leads.\n\nA physical examination revealed mild wheezing, edema in the lower extremities, and ocular proptosis. The patient's blood pressure was 127/72 mmHg, his heart rate was 90 beats per minute, and his body temperature was 37.4℃. He had no previous episodes of syncope and no family history of sudden cardiac death. The patient's serum creatinine phosphokinase level was elevated (1,618 U/L), while his creatine kinase (CK)-MB level showed slight elevation (24.3 ng/mL). The patient's serum potassium level was 3.4 mEq/L, and his C-reactive protein level was 28.46 mg/dL. Hypothyroidism was reconfirmed based on a thyroid stimulating hormone (TSH) level of 23.49 μIU/mL and free-T4 level of <0.10 ng/dL. It was noteworthy that the patient's blood concentration of carbamazepine reached the upper limit of the standard range (11.9 μg/mL), while the blood concentration of valproic acid was relatively lower than the standard range (43 μg/mL).\n\nWe withdrew the administration of carbamazepine, valproic acid, and thiamazole. Thereafter, the coved-type ST segment elevation improved in proportion to the decrease in the blood concentration of carbamazepine. Although the thyroid function eventually normalized, it was not correlated with the serial electrocardiographic changes. Furthermore, the patient's body temperature (whether the patient was febrile or not) was not associated with the electrocardiographic changes (Fig. 3).\n\nFigure 3. The serial changes in the electrocardiographic findings, body temperature, the blood concentrations of carbamazepine and valproic acid, the thyroid function and the serum potassium levels are shown. The coved-type ST segment elevation improved in proportion to the decrease in the level of carbamazepine.\n\nDiscussion\nCarbamazepine is an antiepileptic drug that blocks the activity of the sodium channels. It is also used to treat aggressive symptoms in schizophrenia. There are few reports of carbamazepine-induced Brugada-type patterns on electrocardiography. The only published case involved a patient whose blood concentration of carbamazepine reached 338 μmol/L (80 μg/mL) after suffering poisoning due to the ingestion of 32 g of slow-release carbamazepine (8). In our case, the Brugada-type electrocardiographic pattern was correlated with the blood concentration of carbamazepine, despite the patient receiving a usual dosage. Valproic acid is also known to have a sodium channel blocking effect. However, the patient's blood concentration of valproic acid was not elevated during hospitalization. Unfortunately, we could not perform a genetic analysis to investigate channelopathy.\n\nPatients with schizophrenia are reported to be at increased risk of sudden cardiac death (5). Furthermore, Blom et al. reported that a Brugada-type electrocardiographic pattern is highly prevalent in patients with schizophrenia (6). They analyzed the electrocardiograms of a cohort of 275 patients with schizophrenia and compared it to an age-matched non-schizophrenic control group (n=179) and a control group composed of non-schizophrenic individuals who were 20 years older (n=1,168) and found that Brugada-type electrocardiographic patterns were significantly more prevalent in patients with schizophrenia cohort (11.6%) than they were in the age-matched cohort (1.1%) and the cohort that was 20 years older (2.4%). However, at the time of writing, there is no evidence of a tight association between schizophrenia and sodium channelopathy.\n\nIn our case, hypothyroidism was observed as an effect of thiamazole. Several cases of hypothyroidism associated with Brugada-type electrocardiographic patterns have been reported previously (9,10). It is possible that the Brugada-type electrocardiographic patterns in these patients were caused by a reduction in the INa and sympathetic nervous system activity in patients with a low thyroid function; however, there is no clear evidence. In our case, there was no close association between the thyroid function and the electrocardiographic morphology, as evidenced by the fact that the patient's electrocardiograms were normal before this episode, in spite of his hypothyroidism. However, it is possible that the patient's hypothyroidism might have played a complementary role in causing coved-type ST elevation, by enhancing the sodium channel blockade of carbamazepine.\n\nRecently, Ishizue et al. reported that polytherapy with sodium channel-blocking antiepileptic drugs may be associated with Brugada-type ST elevation and J-wave-like electrocardiographic abnormality in the patients with epilepsy (11). They mentioned that the use of phenytoin and polytherapy with sodium channel-blocking antiepileptic drugs was more frequent among the group of patients who were Brugada-type ST elevation-positive than it was among the group of patients who were Brugada type ST elevation-negative. However, the rate of carbamazepine administration did not differ to a statistically significant extent. In our case, only the carbamazepine concentration was tightly associated with the electrocardiographic changes in Brugada-type ST elevation.\n\nIn our case, the patient's serum carbamazepine concentration had been stable until the patient was diagnosed with pneumonia. This may be educational because we have to carefully monitor patients with schizophrenia or epilepsy for electrocardiographic changes, even when the carbamazepine concentration is within the normal range. When patients who are treated with carbamazepine show deterioration in their general condition, we remember to perform electrocardiography. If coved-type ST elevation is found in lead V1 or 2, we should monitor the serum concentration of carbamazepine and consider the indications for withdrawal. In order to prepare for such situations, electrocardiography should be periodically performed when the patient is in a stable condition.\n\nIn conclusion, we reported the case of a patient with schizophrenia who was treated with carbamazepine who presented with a transient coved-type Brugada electrocardiographic pattern and hypothyroidism. During the course of the patient's hospitalization, the monitoring of the blood concentration of carbamazepine and the thyroid function revealed that the level of carbamazepine was deeply associated with the serial electrocardiographic changes.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\nWe would like to express our gratitude to Tadashi Hasegawa, Kiyoshi Mizuseki, Katsuyoshi Sakyo, Akihiro Mikami, Masahiko Mikuni and the staff at Hakodate Watanabe Hospital for helpful suggestions and their support.\n==== Refs\n1. \nPriori SG , Wilde AA , Horie M , et al \nHRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013 . Heart Rhythm \n10 : 1932 -1963 , 2013 .24011539 \n2. \nReilly JG , Ayis SA , Ferrier IN , Jones SJ , Thomas SH \nQTc-interval abnormalities and psychotropic drug therapy in psychiatric patients . Lancet \n355 : 1048 -1052 , 2000 .10744090 \n3. \nSaha S , Chant D , McGrath J \nA systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? \nArch Gen Psychiatry \n64 : 1123 -1131 , 2007 .17909124 \n4. \nRoden DM \nThe Brugada ECG and schizophrenia . Circ Arrhythm Electrophysiol \n7 : 365 -367 , 2014 .24951569 \n5. \nIfteni P , Correll CU , Burtea V , Kane JM , Manu P \nSudden unexpected death in schizophrenia: autopsy findings in psychiatric inpatients . Schizophr Res \n155 : 72 -76 , 2014 .24704220 \n6. \nBlom MT , Cohen D , Seldenrijk A , et al \nBrugada syndrome ECG is highly prevalent in schizophrenia . Circ Arrhythm Electrophysiol \n7 : 384 -391 , 2014 .24591540 \n7. \nPostema PG , Wolpert C , Amin AS , et al \nDrugs and Brugada syndrome patients: review of the literature, recommendations, and an up-to-date website (www.brugadadrugs.org) . Heart Rhythm \n6 : 1335 -1341 , 2009 .19716089 \n8. \nMegarbane B , Leprince P , Deye N , et al \nExtracorporeal life support in a case of acute carbamazepine poisoning with life-threatening refractory myocardial failure . Intensive Care Med \n32 : 1409 -1413 , 2006 .16835785 \n9. \nKitahara A , Hirai R , Matsui Y , Ikeda Y , Nakamura H \nA case of hypothyroidism with Brugada electrocardiographic waveforms . Endocr J \n55 : 589 -594 , 2008 .18446000 \n10. \nTaira K , Fujino A , Watanabe T , Ogyu A , Ashikawa K , Shimizu W \nBrugada-type electrocardiogram in a patient with hypothyroidism . J Cardiol Cases \n2 : e147 -e150 , 2010 .\n11. \nIshizue N , Niwano S , Saito M , et al \nPolytherapy with sodium channel-blocking antiepileptic drugs is associated with arrhythmogenic ST-T abnormality in patients with epilepsy . Seizure \n40 : 81 -87 , 2016 .27371909\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "56(22)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Brugada-type electrocardiography; antiepileptic drug; carbamazepine; schizophrenia; sodium channel",
"medline_ta": "Intern Med",
"mesh_terms": "D053840:Brugada Syndrome; D002220:Carbamazepine; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D006801:Humans; D007037:Hypothyroidism; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "3047-3050",
"pmc": null,
"pmid": "29142189",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10744090;16835785;17909124;18446000;19716089;24011539;24591540;24704220;24951569;27371909;30532816",
"title": "A Carbamazepine-induced Brugada-type Electrocardiographic Pattern in a Patient with Schizophrenia.",
"title_normalized": "a carbamazepine induced brugada type electrocardiographic pattern in a patient with schizophrenia"
} | [
{
"companynumb": "JP-ABBVIE-17P-087-2180326-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHIMAZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "A 32-year-old nonlactational women with a nipple piercing and previous oral-to-breast contact presented with findings consistent with mastitis and abscess, however, the patient failed multiple courses of empiric antimicrobials. Needle aspiration was performed and the culture was positive for N. gonorrhoeae. She was successfully treated with intravenous ceftriaxone and transitioned to oral ciprofloxacin once susceptibilities were known. N. gonorrhoeae is an uncommon cause of nonlactational mastitis and abscess. A few cases have been reported in the context of sexual contact and nipple piercings. In an era of increasing antimicrobial resistance and with the risk of disseminated gonococcal infection, a high index of suspicion should be maintained within this clinical context.",
"affiliations": "Department of Internal Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, United States.;Department of Internal Medicine, Division of Hospital Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, United States.;Department of Internal Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, United States.",
"authors": "Ceniceros|Ashley|A|;Galen|Benjamin|B|;Madaline|Theresa|T|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2019.e00620",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(19)30236-710.1016/j.idcr.2019.e00620e00620ArticleGonococcal breast abscess Ceniceros Ashley aGalen Benjamin bMadaline Theresa tmadalin@montefiore.orga⁎a Department of Internal Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, United Statesb Department of Internal Medicine, Division of Hospital Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, United States⁎ Corresponding author at: Division of Infectious Diseases, Albert Einstein College of Medicine, Montefiore Medical Center, 111 East 210thSt, Bronx, NY 10467, United States. tmadalin@montefiore.org09 8 2019 2019 09 8 2019 18 e006205 8 2019 7 8 2019 7 8 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A 32-year-old nonlactational women with a nipple piercing and previous oral-to-breast contact presented with findings consistent with mastitis and abscess, however, the patient failed multiple courses of empiric antimicrobials. Needle aspiration was performed and the culture was positive for N. gonorrhoeae. She was successfully treated with intravenous ceftriaxone and transitioned to oral ciprofloxacin once susceptibilities were known.\n\nN. gonorrhoeae is an uncommon cause of nonlactational mastitis and abscess. A few cases have been reported in the context of sexual contact and nipple piercings. In an era of increasing antimicrobial resistance and with the risk of disseminated gonococcal infection, a high index of suspicion should be maintained within this clinical context.\n\nKeywords\nNeisseria gonorrhoeaeBreast abscess\n==== Body\nIntroduction\nMastitis is inflammation of the breast with or without infection. Mastitis with infection, in a woman, can be divided into lactational and nonlactational. Nonlactational mastitis leading to an abscess is uncommon [1]. Nearly 90% of nonlactational breast abscesses are subareolar and typically occur toward the end of a woman’s reproductive years. Risk factors identified include smoking, trauma, congenital malformations, and diabetes [2]. The most common organism cultured in nonlactational breast abscesses is S. aureus (including Methicillin-resistant S. aureus), followed by Streptococcus spp. and anaerobic organisms [3]. Piercing-related mastitis and abscesses have only been reported in case reports and series in the setting of recent (<1 year) piercing, and no predominant organisms have yet been identified [4].\n\nNeisseria gonorrhoeae is a gram negative diplococcus that primarily infects mucosal surfaces of the body. Abscess formation by N. gonorrhoeae is typically due to local spread from mucosal areas, leading to tubo-ovarian abscesses in women and periurethral abscesses in men. Diagnosing N. gonorrhoeae is of particular importance in view of the emergence of highly antimicrobial-resistant strains. Once a penicillin-susceptible organism, it has developed resistance to penicillin, cefiximine, and, most recently, fluoroquinolones. Ceftriaxone is now recommended as first-line treatment, however, as with penicillins, the recommended dose has increased over time [5].\n\nWe report a case of nonlactational mastitis and breast abscess due to N. gonorrhoeae. The patient initially failed empiric treatment for common causes of mastitis as initial antimicrobials did not treat N. gonorrhoeae. Successful treatment of this entity requires a high index of suspicion in patients with recent sexual contact and skin barrier breakdown.\n\nCase report\nA 32-year-old Dominican woman with no known medical problems was admitted to the hospital with 4 weeks of induration and erythema of the right breast with purulent discharge from a nipple piercing site. She had a recent history of two sexual encounters with two different partners, both approximately 2 weeks prior to symptom onset. She utilized barrier contraception with condoms in both encounters and both involved direct oral to breast contact. She was unsure of direct penile to breast contact. One partner reported recent negative test results for sexually transmitted infections (STI) and the patient was not aware of the STI status of the other partner. She reported treatment for chlamydia ten years prior and, again, seven months prior. She denied any other history of STIs. Her right nipple was pierced two years prior and had been without infectious complications or inflammation until this episode.\n\nThe patient’s history was relevant for a presentation to an urgent care clinic with induration and erythema of the right breast and purulent drainage. She was referred to the emergency department where an ultrasound study demonstrated a hypoechoic focus adjacent to the right nipple. She was prescribed trimethoprim-sulfamethoxazole 160–800 mg twice daily and referred to the breast surgery clinic. She was unable to obtain the antimicrobials and returned to urgent care five days later with worsening pain and induration of the right breast, subjective fevers, and chills. She was prescribed clindamycin 300 mg three times a day and completed a 10-day course of treatment; but the erythema of her right breast continued to expand. She returned to breast surgery clinic and aspiration of the area was performed with 3 mL of fluid removed and sent for cultures. She was prescribed an additional 10 days of clindamycin, which she took for only 1 day. When she returned for follow-up one week following aspiration, she reported no clinical improvement, and was noted to have fever of 38.8 degrees C. Repeat aspiration of the breast was attempted, but was unsuccessful. The wound culture from the initial aspiration resulted as N. gonorrhoeae using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, without susceptibilities available at that time. She was given an intramuscular injection of 1 g of ceftriaxone and a prescription for 1 g of azithromycin and was referred to an infectious disease clinic. She took the azithromycin, but reported an episode of emesis immediately following ingestion. Given the potential for resistance, duration and severity of symptoms, and inability to tolerate oral azithromycin, she was referred to the hospital for intravenous (IV) antimicrobials.\n\nOn examination in the emergency department, the patient’s temperature was 36.9 degrees C, blood pressure 111/64 mmHg, heart rate 82 beats per minute, and respiratory rate 18 per minute. Examination of right breast revealed an area of tender, warm, erythematous, periareolar fluctuance with surrounding induration. There was no purulence or drainage. The nipple ring had been removed. The left breast was without erythema, warmth, induration, or drainage. The remainder of the examination revealed no rashes, conjunctivitis, or joint abnormalities. Breast ultrasound revealed a 4.87 cm x 1.11 cm x 5.88 cm retroareolar fluid collection in the right breast (Fig. 1). The patient declined aspiration at that time. Complete blood count revealed WBC 7.7 × 1000/microL with 65% neutrophils. Serum syphilis IgG/IgM antibodies were negative. A 4th generation HIV Ag/Ab Combo Assay (Abbott ARCHITECT) was negative. Urine nuclear acid amplification test (NAAT) was negative for N. gonorrhoeae and C. trachomatis. Throat and rectal swabs were also negative for N. gonorrhoeae and C. trachomatis. The gonococcal isolate obtained at breast surgery clinic was found to be susceptible to ceftriaxone and ciprofloxacin.Fig. 1 Emergency department ultrasound revealing 4.87 cm × 1.11 cm × 5.88 cm hypoechoic retroareolar fluid collection in the right breast.\n\nFig. 1\n\nShe received 5 days of IV ceftriaxone. During the course of her hospitalization, she agreed to surgical management and underwent needle aspiration of the abscess with removal of 4 mL of serosanguinous fluid which was sent for culture. The aspiration was performed after two doses of IV ceftriaxone, and culture of this fluid was negative. Post-aspiration and following clinical improvement, antimicrobials were changed to oral ciprofloxacin 500 mg every 12 h. In total, she completed a 10-day course of appropriate antimicrobials. At a one month follow-up visit, the patient was asymptomatic, with resolution of the breast abscess. She confirmed that both partners were notified and treated appropriately.\n\nDiscussion\nPreviously, N. gonorrhoeae cutaneous abscesses in nongenital sites have been associated with disseminated gonococcal infection (DGI) [6]. These infections have no pathognomonic features, therefore physicians must maintain vigilance in obtaining proper testing and treatment. Cutaneous N. gonorrhoeae infections in the absence of DGI have been have reported on the abdomen, hand, and fetal scalp and are often proceeded by skin barrier breakdown [7].\n\nTo date, however, only three prior cases of gonococcal mastitis and subsequent breast abscess have been reported in the literature. The first was of a 42-year-old man from Australia with mastitis of the left breast due to N. gonorrhoeae. As described in the case report, it was probably acquired as a result of direct mouth-nipple contact [8]. The second case was of a 38-year-old man, also from Australia, who reported direct mouth-nipple contact approximately two weeks prior to presentation [9]. The third case was of a 21-year-old woman who reported direct mouth-nipple contact approximately one week prior to presentation [10]. All of the patients in these cases had prior, healed nipple piercings and no other organisms were isolated. This foreign body disrupts the skin barrier, predisposing to abscess formation upon exposure to N. gonorrhoeae.\n\nIn addition, the third case was the only other case to report using MALDI-TOF for identification of the organism. The advantage of MALDI-TOF is the ability to make a quick and accurate diagnosis with minimum growth. Specifically, it has been shown to have a positive predictive value of 99.3% and sensitivity of 99.9% in the identification of N. gonorrhoeae [11]. This case highlights the potential role for MALDI-TOF in abscess identification, particularly when N. gonorrhoeae is suspected.\n\nConclusion\nN. gonorrhoeae should be considered as a potential etiologic agent for mastitis and abscess. Patients with nipple piercings (recent or remote) and mastitis or breast abscess should be asked detailed questions about recent sexual contact. N. gonorrhoeae should be considered particularly if mastitis is refractory to appropriate empiric antimicrobial therapy. Mastitis due to N. gonorrhoeae is a potentially difficult disease to treat given escalating resistance of N. gonorrhoeae and the concern for disseminated disease. In cases of refractory mastitis and abscess, MALDI-TOF may be a powerful tool for the quick identification of unusual organisms. Careful antimicrobial management and source control are imperative.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nDeclaration of Competing Interest\nThe authors declare that there are no conflicts of interest.\n\nAcknowledgements\nThe authors thank Dr. Liise-anne Pirofski for her helpful discussion and critical review of the manuscript. We thank Dr. Wendy Szymczak for her assistance with review of the microbiology guidelines, practices, and findings.\n==== Refs\nReferences\n1 Lam E. Chan T. Wiseman S.M. Breast abscess: evidence based management recommendations Expert Rev Anti Infect Ther 12 7 2014 753 762 24791941 \n2 Versluijs-Ossewaarde F.N. Roumen R.M. Goris R.J. Subareolar breast abscesses: characteristics and results of surgical treatment Breast J 11 3 2005 179 182 15871702 \n3 Giamarellou H. Soulis M. Antoniadou A. Periareolar nonpuerperal breast infection: treatment of 38 cases Clin Infect Dis 18 1 1994 73 76 8054437 \n4 Lee B. Vangipuram R. Petersen E. Complications associated with intimate body piercings Dermatol Online J 24 7 2018 \n5 Hook E.W. 3rd Kirkcaldy R.D. A brief history of evolving diagnostics and therapy for gonorrhea: lessons learned Clin Infect Dis 67 8 2018 1294 1299 29659749 \n6 Ghosn S.H. Kibbi A.G. Cutaneous gonococcal infections Clin Dermatol 22 6 2004 476 480 15596318 \n7 Scott M.J. Jr. Scott M.J. Sr Primary cutaneous Neisseria gonorrhoeae infections Arch Dermatol 118 5 1982 351 352 7082029 \n8 Bodsworth N.J. Price R. Nelson M.J. A case of gonococcal mastitis in a male Genitourin Med 69 3 1993 222 223 8335316 \n9 Pendle S. Barnes T. Neisseria gonorrhoeae isolated from an unexpected site Sex Health 13 6 2016 593 594 27608066 \n10 Bateman A.C. Unusual cause of a wound infection J Appl Lab Med 2 3 2017 444 448 \n11 Buchanan R. Ball D. Dolphin H. Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry for the identification of Neisseria gonorrhoeae Clin Microbiol Infect 22 9 2016 815 e5-e7\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "18()",
"journal": "IDCases",
"keywords": "Breast abscess; Neisseria gonorrhoeae",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e00620",
"pmc": null,
"pmid": "31463197",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "30261561;27608066;29659749;24791941;8054437;8335316;7082029;15871702;27371346;15596318",
"title": "Gonococcal breast abscess.",
"title_normalized": "gonococcal breast abscess"
} | [
{
"companynumb": "US-PFIZER INC-2019373970",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN ANHYDROUS"
},
"drugadditional": n... |
{
"abstract": "BACKGROUND Three patients with stage IV esophagogastric junction cancer (EGJC) underwent extended resection to achieve a graphic/surgical R0 status (no visible remnant of viable tumor in imaging/surgical findings) and adjuvant chemotherapy from the early postoperative period. We also introduced use of our digestive reconstruction technique in these patients. CASE REPORT We used jejunal interposition for digestive reconstruction, which involved end-to-end jejunojejunostomy with a biofragmentable anastomosis ring. The mesojejunal autonomic nerves of the lifted jejunum were preserved. The first adenocarcinoma involved the perilesional lymph nodes (LNs). Graphic/surgical R0 resection was completed by para-aortic LN dissection. The diagnosis (Japanese Classification of Gastric Carcinoma) was stage IV [pM1(LYM)]. Adjuvant chemotherapy began on postoperative day (POD) 11. The second adenocarcinoma was accompanied by a solitary lung metastasis. Intraoperative cytology of ascitic fluid was positive, and cisplatin was intraperitoneally administered. Adjuvant chemotherapy began on POD 10. The solitary lung metastasis was then resected, and graphic/surgical R0 resection was achieved. The diagnosis was stage IV [pM1(PUL) and CY1]. The third adenocarcinoma was accompanied by multiple liver metastases and metastatic regional LNs. The diagnosis was stage IV [H1]. Systemic chemotherapy was repeated. Only a solitary liver metastasis remained and was treated by radiofrequency ablation. Conversion surgery was conducted, achieving graphic/surgical R0 resection. Systemic chemotherapy was continued from POD 10. CONCLUSIONS For patients with stage IV EGJC, extended resection to achieve a graphic/surgical R0 status is still controversial, and systemic chemotherapy is important. The results of the present study suggest that our physiological reconstruction technique does not affect the efficacy of other therapies, such as adjuvant chemotherapy.",
"affiliations": "Department of Digestive Surgery, Tenri Hospital, Tenri, Nara, Japan.;Department of Digestive Surgery, Tenri Hospital, Tenri, Nara, Japan.;Department of Digestive Surgery, Tenri Hospital, Tenri, Nara, Japan.;Department of Digestive Surgery, Tenri Hospital, Tenri, Nara, Japan.",
"authors": "Kitano|Taku|T|;Aisu|Yuki|Y|;Yasukawa|Daiki|D|;Hori|Tomohide|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.913960",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3095283110.12659/AJCR.913960913960ArticlesAggressive Graphic/Surgical R0 Resection and Jejunal Interposition with Preservation of Mesojejunal Autonomic Nerves in Patients with Stage IV Esophagogastric Junction Adenocarcinoma: A Report of 3 Cases Kitano Taku BDF*Aisu Yuki BFYasukawa Daiki FHori Tomohide ABCDEF*Department of Digestive Surgery, Tenri Hospital, Tenri, Nara, JapanAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\n* Taku Kitano and Tomohide Hori contributed equally to this report\n\nConflict of interest: None declared\n\nCorresponding Author: Tomohide Hori, e-mail: horitomo55office@yahoo.co.jp2019 06 4 2019 20 465 473 05 11 2018 26 1 2019 © Am J Case Rep, 20192019This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Case series\n\nPatients: Male, 54 • Male, 70 • Male, 59\n\nFinal Diagnosis: Esophagogastric junction adenocarcinoma\n\nSymptoms: Epigastralgia\n\nMedication: —\n\nClinical Procedure: Aggressive therapy\n\nSpecialty: Surgery\n\nObjective:\nUnusual clinical course\n\nBackground:\nThree patients with stage IV esophagogastric junction cancer (EGJC) underwent extended resection to achieve a graphic/surgical R0 status (no visible remnant of viable tumor in imaging/surgical findings) and adjuvant chemotherapy from the early postoperative period. We also introduced use of our digestive reconstruction technique in these patients.\n\nCase Report:\nWe used jejunal interposition for digestive reconstruction, which involved end-to-end jejunojejunostomy with a biofragmentable anastomosis ring. The mesojejunal autonomic nerves of the lifted jejunum were preserved. The first adenocarcinoma involved the perilesional lymph nodes (LNs). Graphic/surgical R0 resection was completed by para-aortic LN dissection. The diagnosis (Japanese Classification of Gastric Carcinoma) was stage IV [pM1(LYM)]. Adjuvant chemotherapy began on postoperative day (POD) 11. The second adenocarcinoma was accompanied by a solitary lung metastasis. Intraoperative cytology of ascitic fluid was positive, and cisplatin was intraperitoneally administered. Adjuvant chemotherapy began on POD 10. The solitary lung metastasis was then resected, and graphic/surgical R0 resection was achieved. The diagnosis was stage IV [pM1(PUL) and CY1]. The third adenocarcinoma was accompanied by multiple liver metastases and metastatic regional LNs. The diagnosis was stage IV [H1]. Systemic chemotherapy was repeated. Only a solitary liver metastasis remained and was treated by radiofrequency ablation. Conversion surgery was conducted, achieving graphic/surgical R0 resection. Systemic chemotherapy was continued from POD 10.\n\nConclusions:\nFor patients with stage IV EGJC, extended resection to achieve a graphic/surgical R0 status is still controversial, and systemic chemotherapy is important. The results of the present study suggest that our physiological reconstruction technique does not affect the efficacy of other therapies, such as adjuvant chemotherapy.\n\nMeSH Keywords:\nAdenocarcinomaAutonomic PathwaysChemotherapy, AdjuvantDrug TherapyEsophagogastric JunctionReconstructive Surgical Procedures\n==== Body\nBackground\nThe incidence of esophagogastric junction adenocarcinoma has been increasing worldwide [1]. However, a standardized surgical strategy for treatment of esophagogastric junction cancer (EGJC) has not been established [1]. Although optimal lymph node (LN) dissection in the treatment of EGJC is still controversial, the hiatal LNs (No. 19 and 20) and lower mediastinal LNs (No. 110, 111, and 112) are the target LNs of intentional dissection in the 2018 Gastric Cancer Treatment Guidelines issued by the Japanese Gastric Cancer Association [2].\n\nThe clinical significance of extended resection to achieve a graphic/surgical R0 status according to the Japanese Classification of Gastric Carcinoma [3] and 2018 Gastric Cancer Treatment Guidelines [2] (i.e., no visible remnant of viable tumor in imaging and surgical findings) is also controversial. Highly motivated physicians and surgeons have a strong desire to improve the poor prognosis of advanced EGJC.\n\nOral intake and performance status may be disturbed after surgery [4]. Although adjuvant chemotherapy for selected patients with stage IV cancer is recommended [5–12], some physicians may have concerns about smooth introduction of such chemotherapy after surgery.\n\nIn our institution, we employed jejunal interposition for digestive reconstruction, in which end-to-end jejunojejunostomy was performed with a biofragmentable anastomosis ring [13]. Moreover, the mesojejunal autonomic nerves of the lifted jejunum were preserved [13,14]. We managed 3 patients with stage IV EGJC (adenocarcinoma) who underwent extended treatments for graphic/surgical R0 resection and adjuvant chemotherapy from the early postoperative period. Here, we report the details of our surgical procedures of digestive reconstruction for these patients with EGJC and present 3 thought-provoking cases with a literature review.\n\nCase Report\nSurgical procedures for digestive reconstruction\nIntentional dissection of regional LNs (No. 1, 2, 3, 7, 8a, 9, 11p, 11d, 19, 20, 110, 111, and 112 according to the 2018 Gastric Cancer Treatment Guidelines [2]) was routinely performed. In our institution, the spleen and splenic LNs (No. 10, according to the Japanese Classification of Gastric Carcinoma [3]) were removed. Cholecystectomy was also routinely performed to prevent biliary complications due to postoperative vagal paralysis. Jejunal interposition was employed for reconstruction of the alimentary tract. Jejunojejunostomy was performed with a biofragmentable anastomosis ring in an end-to-end fashion.\n\nThe importance of preservation of mesojejunal autonomic nerves has been documented in the field of digestive surgery [15,16]. The interposing jejunum was harvested at a suitable point from the ligament of Treitz (Approximately 40 cm from the Treitz), and our surgical techniques for preservation of the mesojejunal autonomic nerves of the lifted jejunum are described in detailed elsewhere [13,14]. To preserve the physiological function of the autonomic nerves in the distal mesojejunum, the jejunum was sacrificed as close to the jejunal wall as possible (Figure 1A). Hence, the interposing jejunum could be lifted without even subtle tension on the lifted mesojejunum (Figure 1B); this provided better physiological conditions for the mesenteric autonomic nerves. Approximately 20 cm of the jejunum was sacrificed on the proximal side of the interposing jejunum, and approximately 10 cm was also sacrificed on the distal side (Figure 2). The interposing jejunum was lifted via the retrocolic route.\n\nAnvil heads were fixed to the duodenal bulb and esophagus. Circular staplers were used to perform jejunoduodenostomy (EEA Circular Stapler with DST Series Technology, 25 mm, 4.8 mm; Medtronic plc, Dublin, Ireland) and esophagojejunostomy (EEA Circular Stapler with DST Series Technology, 21 mm, 4.8 mm: Medtronic plc). Esophageal anastomosis was performed in the mediastinal space, and interrupted seromuscular sutures were circumferentially placed. The jejunal stump was closed with a linear stapler, and interrupted seromuscular sutures were placed to cover the staple line.\n\nJejunojejunostomy was performed in an end-to-end anastomosis fashion with a biofragmentable anastomosis ring (Valtrac, 25 mm, 1.5 mm; Medtronic plc) (Figure 3A), and 4 interrupted seromuscular sutures were placed as retention sutures.\n\nCase 1\nThe first case involved a 54-year-old man with inadequate oral intake and body weight loss. Diagnosis of advanced EGJC was made by endoscopic examination and imaging studies. Endoscopic biopsy revealed poorly differentiated adenocarcinoma, and the serum level of carbohydrate antigen 19-9 (188.7 U/ml) was elevated. He had no comorbidities, and his performance status was categorized as 0. Although distant metastasis was not detected in the imaging studies, the primary tumor might have involved perilesional LNs. The primary tumor extended into the esophagus (Figure 4A), and left thoracotomy was simultaneously performed (Figure 4B). The proximal margin of the thoracic esophagus was negative in rapid pathological examination. The regional LNs were completely dissected, and para-aortic LNs were also intentionally dissected. A graphic/surgical R0 status was achieved by extended resection with para-aortic LN dissection, and the patient’s tumor marker level (33.5 U/ml) was normalized immediately after surgery. The primary tumor seemed to involve the regional and para-aortic LNs (Figure 4C), and lymphoid metastasis was pathologically detected in one para-aortic LN. The definitive diagnosis based on the pathological findings of the resected specimens according to the Japanese Classification of Gastric Carcinoma [3] was pT3(SS) pN0 pM1(LYM) H0 P0 CY0 pStage IV. The postoperative course was uneventful. Adjuvant chemotherapy (S-1) began on postoperative day (POD) 11. No recurrence was detected 10 months after surgery.\n\nCase 2\nThe second case involved a 70-year-old man with epigastric pain. A diagnosis of advanced EGJC was made by endoscopic examination (Figure 4D) and imaging studies. Endoscopic biopsy revealed moderately differentiated adenocarcinoma, and the serum level of carbohydrate antigen 19-9 was elevated. He also had hypertension and diabetes. His performance status was categorized as 0. A solitary lung metastasis was detected in imaging studies (Figure 5A). Although the proximal margin of the thoracic esophagus was negative in rapid pathological examination, intraoperative cytology of ascitic fluid was positive (Figure 5B). Cisplatin was intraperitoneally administrated during surgery. The definitive diagnosis based on pathological and imaging findings according to the Japanese Classification of Gastric Carcinoma [3] was pT4a(SE) pN1 cM1(PUL) H0 P0 CY1 pStage IV. The postoperative course was uneventful. Adjuvant chemotherapy (S-1) began on POD 10. Three months after surgery, the solitary lung metastasis showed no change, and no other distant metastases were detected. After a temporary stop of chemotherapy, the solitary lung metastasis was thoracoscopically resected from the viewpoint of diagnostic therapy (i.e., rule out of primary lung cancer) at 4 months after the initial surgery, and the lung nodule was immunopathologically confirmed to be a metastatic tumor of EGJC. Graphic/surgical R0 resection was completed, and the tumor marker level was normalized immediately after lung resection. Thereafter, S-1 was resumed as adjuvant chemotherapy for 1 year after the initial chemotherapy. No recurrence was detected 14 months after the initial surgery.\n\nCase 3\nThe third case involved an asymptomatic 59-year-old man with no comorbidities. Tumor marker screening during his health check revealed a significantly elevated level of carcinoembryonic antigen. Endoscopic examination and imaging studies revealed advanced EGJC. Endoscopic biopsy revealed moderately differentiated adenocarcinoma, and human epidermal growth factor receptor 2 was negative. His performance status was categorized as 0. Multiple liver metastases (Figure 5C) and metastatic regional LNs were detected in imaging studies, including positron emission tomography/computed tomography. The clinical stage according to the Japanese Classification of Gastric Carcinoma [3] was cT3(SS) cN2 M0 H1 P0 CYX cStage IV. Three courses of systemic chemotherapy of S-1 plus oxaliplatin were completed with adverse effects (platelet depletion and edematous bowels), and imaging studies revealed that the swelling of the regional LNs had completely disappeared and that the multiple liver metastases were drastically down-regulated. Only a solitary liver metastasis remained, and the size of this persistent metastasis was reduced. Radiofrequency ablation (RFA) was performed for the remaining solitary metastasis (Figure 5D). The tumor marker level was drastically normalized after chemotherapy and RFA. Hence, conversion surgery was conducted to achieve a graphic/surgical R0 status. Both the proximal margin of the thoracic esophagus in rapid pathological examination and the intraoperative cytological examination of ascitic fluid were negative. The pathological diagnosis according to the Japanese Classification of Gastric Carcinoma [3] was ypT3 ypN1. The postoperative course was uneventful, and systemic chemotherapy of S-1 plus oxaliplatin was continued from POD 10. No recurrence was detected 12 months after surgery.\n\nDiscussion\nThe Murphy button was introduced by JB Murphy in 1892 [17] and was a major breakthrough in the field of intestinal surgery [17,18]. The biofragmentable anastomosis ring and dedicated forceps are currently available and are based on the concept of the Murphy button [17]. The biofragmentable ring (Valtrac, 25 mm, 1.5 mm; Medtronic plc) will break into pieces within 3 weeks, and we have a clear impression that jejunojejunostomy performed in an end-to-end fashion with a biofragmentable ring does not cause a postoperative passage obstruction. End-to-end anastomosis may not be easily detected in the postoperative examination because the anastomotic point does not show a caliber change. The actual finding of the intestinal examination at 3 months postoperatively is shown in Figure 3B.\n\nGastrectomy with D2 LN dissection is the standard treatment for curable gastric cancer [2]. The addition of para-aortic LN dissection does not improve the survival rate in patients with curable gastric cancer [19]. A Japanese nationwide prospective trial was conducted to determine the proportion of LN metastasis in esophagogastric cancers and identify the optimal extent of LN dissection in each type [1]. Metastasis to LNs other than regional LNs is defined as distant metastasis in EGJC [3], although the para-aortic LNs in upper gastric cancer were historically considered regional LNs in the previous Japanese Classification of Gastric Carcinoma. Para-aortic LN dissection offers marginal therapeutic value in patients with stage IV EGJC [20] and depends on the subtype of EGJC [21]. In selected patients who undergo neoadjuvant chemotherapy, intentional dissection of the para-aortic LNs may be effective if para-aortic LN metastasis is not massive [22,23].\n\nThe hiatal LNs (No. 19 and 20) and lower mediastinal LNs (No. 110, 111, and 112) are target LNs of intentional dissection for EGJC [24–29]. The left thoracoabdominal approach and abdominal-transhiatal approach to LN dissection have been compared [24]. The abdominal-transhiatal approach is recommended if the tumor size is <4 cm or the proximal side of the tumor is ≤3 cm from the esophagogastric junction [2,24]. In Case 1, we employed the left thoracoabdominal approach for intentional dissection of the para-aortic LNs to achieve surgical curability because the preoperative imaging findings suggested that the LNs near the EGJC might be metastatic.\n\nThe effectiveness of intraperitoneal administration of paclitaxel or cisplatin has been documented [30–32]. In our institution, cisplatin is intraperitoneally administrated for patients with positive cytologic examination of ascitic fluid and no visible dissemination nodules (P0 CY1 according to the Japanese Classification of Gastric Carcinoma [3]). Only in Case 2, cisplatin was intraperitoneally administrated during surgery.\n\nIn the field of gastric cancer, hepatectomy for liver metastases may be acceptable if the patient has a small number of metastases and no factors indicating unresectability [33–35]. The usefulness of RFA has been documented for liver metastasis of colorectal cancer [36–39], and RFA may be an alternative to hepatectomy in patients with gastric cancer [40–43]. RFA seemed to be effective in our patient (Case 3).\n\nIn the field of EGJC, the effects of chemotherapy alone versus chemotherapy followed by surgical resection have been investigated [44]. We understand that whether aggressive treatment should be performed to achieve a graphic/surgical R0 status (e.g., extended resection and RFA) is still controvertible. Although the number of patients was low and the follow-up duration was relatively short in the present report, both aggressive treatments to achieve a graphic/surgical R0 status and systemic chemotherapy after surgery seemed to well work for our patients with stage IV EGJC. Postoperative adjuvant chemotherapy is generally recommended for patients with stage IV cancer exhibiting positive ascites cytology (CY1) [5–8] and a surgical R0 status [6,9–12]. The clinical profiles of our 3 patients are summarized in Table 1; note that all patients received adjuvant chemotherapy from the early postoperative period (POD 10 or 11). Sufficient oral intake is important for excellent postoperative course [13,14,44,45]. Adequate intakes in each case were accomplished at each POD of start of meal intake, if adequate intake was defined as a dietary intake of more than half of meal [13,14,45]. Systemic chemotherapy is a key in the treatment of stage IV EGJC [20,46]. From the viewpoint of physiological postoperative function, jejunal interposition reconstruction with preservation of the mesojejunal autonomic nerves may play an important role in guaranteeing adequate oral intake and avoiding any disturbances of adjuvant chemotherapy in patients with stage IV EGJC. In our opinion, clinical decision-making regarding the timing of surgery is difficult. Our experience and follow-up term were insufficient to judge the disease process and to verify the validity of our management, and more studies are urgently needed.\n\nConclusions\nThe alimentary tract should be reconstructed once surgical graphic/surgical R0 resection is chosen. Physiological reconstruction by jejunal interposition with preservation of the mesojejunal autonomic nerves may be a key to avoiding any disturbances of the efficacy of other therapies, including adjuvant chemotherapy, in patients with stage IV EGJC. We hope our experiences will be informative in the field of advanced EGJC.\n\nTomohide Hori created original drawings of all schemas.\n\nConflict of interest\n\nNone.\n\nFigure 1. (A) To preserve the physiological function of the autonomic nerves in the distal mesojejunum, the resection line (green arrow) was set as close to the jejunal wall of the sacrificed jejunum (shaded area and red line) as possible. (B) The interposing jejunum could be lifted without even subtle tension on the lifted mesojejunum (red arrow).\n\nFigure 2. Approximately 20 cm of the jejunum was sacrificed on the proximal side of the interposing jejunum, and approximately 10 cm was sacrificed on the distal side (red arrows). The interposing jejunum was lifted via the retrocolic route. Jejunoduodenostomy (circular stapler, 25 mm) and esophagojejunostomy (circular stapler, 21 mm) were then performed. Esophageal anastomosis was performed in the mediastinal space, and the jejunal stump was closed with a linear stapler. Jejunojejunostomy was performed in an end-to-end anastomosis fashion using a biofragmentable anastomosis ring.\n\nFigure 3. (A) Biofragmentable anastomosis ring (Valtrac, 25 mm, 1.5 mm; Medtronic plc) and dedicated forceps are currently available. (B) Actual finding of intestinal examination 3 months after surgery. The anastomotic point did not show a caliber change (red arrow).\n\nFigure 4. (A) The primary tumor extended into the esophagus (yellow arrows). (B) Left thoracotomy was simultaneously performed. (C) The primary tumor appeared to involve the regional and para-aortic lymph nodes (red arrows). (D) Endoscopic findings revealed advanced esophagogastric junction cancer (yellow area).\n\nFigure 5. (A) A solitary lung metastasis was detected (yellow arrow). (B) Intraoperative cytological examination of ascitic fluid was positive (Papanicolaou stain). (C) Multiple liver metastases were detected by magnetic resonance imaging with gadoliniumethoxybenzyl-diethylenetriamine pentaacetic acid (red arrow). (D) The down-regulated solitary liver metastasis was treated by radiofrequency ablation (red area).\n\nTable 1. Clinical profiles.\n\nCase\t1\t2\t3\t\nAge\t57,1\t70,3\t59\t\nGender\tMale\tMale\tMale\t\nComorbidity\tNone\tDiabetes\tNone\t\nPerformance status\t0\t0\t0\t\nStage*\tIV\tIV\tIV\t\nDistant metastasis\tParaaortic lymph node\tAscites, lung\tLiver\t\nNeoadjuvant chemotherapy\tNo\tNo\tYes\t\nOperative time (minute)\t288\t247\t285\t\nBlood loss (ml)\t538\t505\t460\t\nAdditional therapy\tExtended lymph node dissection\tIntraperitoneal administration, lung resection\tLiver RFA\t\nGraphic R0**\tYes\tYes\tYes\t\nSurgical R0**\tYes\tYes\tYes\t\nStart of meal intake (POD)\t5\t4\t6\t\nAdjuvant chemotherapy\tYes\tYes\tYes\t\nStart of adjuvant chemotherapy (POD)\t11\t10\t11\t\nPostoperative hospital stay (day)\t12\t12\t12\t\nFollow-up term (month)\t10\t14\t12\t\nRecurrence\tNot detected\tNot detected\tNot detected\t\nTumor marker\tNormalized\tNormalized\tNormalized\t\nPrognosis\tAlive\tAlive\tAlive\t\n* Japanese Classification of Gastric Carcinoma;\n\n** Japanese Classification of Gastric Carcinoma and Gastric Cancer Treatment Guidelines 2018. POD – postoperative day.\n==== Refs\nReferences:\n1. Hashimoto T Kurokawa Y Mori M Doki Y Surgical treatment of gastroesophageal junction cancer J Gastric Cancer 2018 18 209 17 30275998 \n2. Japanese Gastric Cancer Association (Japan) Gastric Cancer Treatment Guidelines 5th edition Tokyo Kanehara 2018 \n3. Japanese Gastric Cancer Association Japanese Classification of Gastric Carcinoma 2017 15th edition Tokyo Kanehara \n4. Davis JL Ripley RT Postgastrectomy syndromes and nutritional considerations following gastric surgery Surg Clin North Am 2017 97 277 93 28325187 \n5. Bando E Yonemura Y Takeshita Y Intraoperative lavage for cytological examination in 1,297 patients with gastric carcinoma Am J Surg 1999 178 256 62 10527450 \n6. Kodera Y Ito S Mochizuki Y Long-term follow up of patients who were positive for peritoneal lavage cytology: Final report from the CCOG0301 study Gastric Cancer 2012 15 335 37 22527184 \n7. Kinoshita T Sasako M Sano T Phase II trial of S-1 for neoadjuvant chemotherapy against scirrhous gastric cancer (JCOG 0002) Gastric Cancer 2009 12 37 42 19390930 \n8. Cabalag CS Chan ST Kaneko Y Duong CP A systematic review and meta-analysis of gastric cancer treatment in patients with positive peritoneal cytology Gastric Cancer 2015 18 11 22 24890254 \n9. Tiberio GA Ministrini S Gardini A Factors influencing survival after hepatectomy for metastases from gastric cancer Eur J Surg Oncol 2016 42 1229 35 27134189 \n10. Qiu JL Deng MG Li W Hepatic resection for synchronous hepatic metastasis from gastric cancer Eur J Surg Oncol 2013 39 694 700 23579173 \n11. Sakuramoto S Sasako M Yamaguchi T Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine N Engl J Med 2007 357 1810 20 17978289 \n12. Bang YJ Kim YW Yang HK Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): A phase 3 open-label, randomised controlled trial Lancet 2012 379 315 21 22226517 \n13. Kimura Y Yasukawa D Aisu Y Hori T Imanaga’s first method for reconstruction with preservation of mesojejunal autonomic nerves during pylorus-preserving pancreatoduodenectomy Am J Case Rep 2018 19 608 13 29805155 \n14. Kitano T Yasukawa D Aisu Y Hori T Overlap anastomosis for digestive reconstruction during laparoscopic distal gastrectomy with intensive regional lymph node dissection: Physiological impact of preserving the mesenteric autonomic nerves in the lifted jejunal limb Surg Res Pract 2018 2018 4938341 30345344 \n15. Yamaguchi H Kaminishi M [Jejunal interposition reconstruction after total gastrectomy] Journal of Clinical Surgery 2000 55 685 90 [in Japanese] \n16. Yasuda T Imamoto H Shiozaki H [Current best surgical procedure for reconstruction after cervical esophagectomy] Journal of Japan Surgical Society 2008 109 249 55 [in Japanese] 18939457 \n17. Dietz UA Debus ES Hirt AL [From Murphy’s button to the Valtrac Ring. 100 years in search of a paradigm] Zentralbl Chir 1999 124 653 56 [in German] 10474881 \n18. Petersen W Üeber darmverschlingung nach der gastro-enterostomie Langenbecks Arch Klin Chir 1900 62 94 114 [in German] \n19. Sasako M Sano T Yamamoto S D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer N Engl J Med 2008 359 453 62 18669424 \n20. Munch S Habermehl D Agha A Perioperative chemotherapy vs . neoadjuvant chemoradiation in gastroesophageal junction adenocarcinoma: A population-based evaluation of the Munich Cancer Registry Strahlenther Onkol 2018 194 125 35 29071366 \n21. Hasegawa S Yoshikawa T Rino Y Priority of lymph node dissection for Siewert type II/III adenocarcinoma of the esophagogastric junction Ann Surg Oncol 2013 20 4252 59 23943020 \n22. Tsuburaya A Mizusawa J Tanaka Y Neoadjuvant chemotherapy with S-1 and cisplatin followed by D2 gastrectomy with para-aortic lymph node dissection for gastric cancer with extensive lymph node metastasis Br J Surg 2014 101 653 60 24668391 \n23. Ito S Sano T Mizusawa J A phase II study of preoperative chemotherapy with docetaxel, cisplatin, and S-1 followed by gastrectomy with D2 plus para-aortic lymph node dissection for gastric cancer with extensive lymph node metastasis: JCOG1002 Gastric Cancer 2017 20 322 31 27299887 \n24. Sasako M Sano T Yamamoto S Left thoracoabdominal approach versus abdominal-transhiatal approach for gastric cancer of the cardia or subcardia: A randomised controlled trial Lancet Oncol 2006 7 644 51 16887481 \n25. Yamashita H Seto Y Sano T Results of a nation-wide retrospective study of lymphadenectomy for esophagogastric junction carcinoma Gastric Cancer 2017 20 69 83 27796514 \n26. Yamashita H Katai H Morita S Optimal extent of lymph node dissection for Siewert type II esophagogastric junction carcinoma Ann Surg 2011 254 274 80 21772128 \n27. Sano T Sasako M Mizusawa J Randomized controlled trial to evaluate splenectomy in total gastrectomy for proximal gastric carcinoma Ann Surg 2017 265 277 83 27280511 \n28. Mine S Sano T Hiki N Lymphadenectomy around the left renal vein in Siewert type II adenocarcinoma of the oesophagogastric junction Br J Surg 2013 100 261 66 23180514 \n29. Tatsubayashi T Tanizawa Y Miki Y Treatment outcomes of hepatectomy for liver metastases of gastric cancer diagnosed using contrast-enhanced magnetic resonance imaging Gastric Cancer 2017 20 387 93 27155874 \n30. Shinkai M Imano M Chiba YH Intraperitoneal administration of paclitaxel followed by paclitaxel, cisplatin, and S-1 chemotherapy for cytology-positive gastric cancer: A feasibility study Anticancer Res 2018 38 5969 74 30275227 \n31. Shinkai M Imano M Hiraki Y Combination chemotherapy including intraperitoneal (IP) administration of paclitaxel (PTX) followed by PTX, CDDP and S-1 triplet chemotherapy for CY1 P0 gastric cancer Gan To Kagaku Ryoho 2017 44 1355 57 29394632 \n32. Murata S Yamamoto H Shimizu T 5-fluorouracil combined with cisplatin and mitomycin C as an optimized regimen for hyperthermic intraperitoneal chemotherapy in gastric cancer J Surg Oncol 2018 117 671 77 29266509 \n33. Kodera Y Fujitani K Fukushima N Surgical resection of hepatic metastasis from gastric cancer: A review and new recommendation in the Japanese gastric cancer treatment guidelines Gastric Cancer 2014 17 206 12 24022130 \n34. Oki E Tokunaga S Emi Y Surgical treatment of liver metastasis of gastric cancer: A retrospective multicenter cohort study (KSCC1302) Gastric Cancer 2016 19 968 76 26260876 \n35. Kinoshita T Kinoshita T Saiura A Multicentre analysis of long-term outcome after surgical resection for gastric cancer liver metastases Br J Surg 2015 102 102 7 25389030 \n36. Lee BC Lee HG Park IJ The role of radiofrequency ablation for treatment of metachronous isolated hepatic metastasis from colorectal cancer Medicine 2016 95 e4999 27684857 \n37. Wang LJ Zhang ZY Yan XL Radiofrequency ablation versus resection for technically resectable colorectal liver metastasis: A propensity score analysis World J Surg Oncol 2018 16 207 30322402 \n38. Kaganov OI Kozlov SV Orlov AE Blinov NV The results of the combine treatment of patients with liver bilobar metastases from colorectal cancer using radiofrequency ablation Indian J Surg Oncol 2018 9 175 80 29887697 \n39. Puijk RS Ruarus AH Vroomen L Colorectal liver metastases: Surgery versus thermal ablation (COLLISION) – a phase III single-blind prospective randomized controlled trial BMC Cancer 2018 18 821 30111304 \n40. Guner A Son T Cho I Liver-directed treatments for liver metastasis from gastric adenocarcinoma: Comparison between liver resection and radiofrequency ablation Gastric Cancer 2016 19 951 60 26231353 \n41. Lee JW Choi MH Lee YJ Radiofrequency ablation for liver metastases in patients with gastric cancer as an alternative to hepatic resection BMC Cancer 2017 17 185 28283024 \n42. Vogl TJ Emam A Naguib NN How effective are percutaneous liver-directed therapies in patients with non-colorectal liver metastases? Viszeralmedizin 2015 31 406 13 26889144 \n43. Tao F Lv J Wang W Jin K Clinical modalities for management of gastric cancer hepatic metastasis Int J Clin Exp Med 2015 8 19850 58 26884895 \n44. Winn JN Sathyamurthy A Kneib JL Synchronous gastrointestinal carcinoid tumor and colon adenocarcinoma: Case reports and literature review Am J Case Rep 2017 18 626 30 28584225 \n45. Hori T Oike F Furuyama H Protocol for laparoscopic cholecystectomy: Is it rocket science? World J Gastroenterol 2016 22 10287 303 28058010 \n46. Al-Batran SE Goetze TO Mueller DW The RENAISSANCE (AIO-FLOT5) trial: effect of chemotherapy alone vs . chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction – a phase III trial of the German AIO/CAO-V/CAOGI BMC Cancer 2017 17 893 29282088\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "20()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000714:Anastomosis, Surgical; D017024:Chemotherapy, Adjuvant; D004938:Esophageal Neoplasms; D004943:Esophagogastric Junction; D006801:Humans; D007582:Jejunostomy; D008197:Lymph Node Excision; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "465-473",
"pmc": null,
"pmid": "30952831",
"pubdate": "2019-04-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10474881;10527450;16887481;17978289;18669424;18939457;19390930;21772128;22226517;22527184;23180514;23579173;23943020;24022130;24668391;24890254;25389030;26231353;26260876;26884895;26889144;27134189;27155874;27280511;27299887;27684857;27796514;28058010;28283024;28325187;28584225;29071366;29266509;29282088;29394632;29805155;29887697;30111304;30275227;30275998;30322402;30345344",
"title": "Aggressive Graphic/Surgical R0 Resection and Jejunal Interposition with Preservation of Mesojejunal Autonomic Nerves in Patients with Stage IV Esophagogastric Junction Adenocarcinoma: A Report of 3 Cases.",
"title_normalized": "aggressive graphic surgical r0 resection and jejunal interposition with preservation of mesojejunal autonomic nerves in patients with stage iv esophagogastric junction adenocarcinoma a report of 3 cases"
} | [
{
"companynumb": "JP-ACCORD-121980",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GIMERACIL\\OTERACIL\\TEGAFUR"
},
"drugadditional": "3"... |
{
"abstract": "BACKGROUND Myxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously. CASE REPORT We report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient's blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465-4.680) mIU/ML, and free T4 0.3 ng/dL (0.8-2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m² (normal range 2.6-4.2 L/min/m²), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital. CONCLUSIONS Because of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.",
"affiliations": "Department of Cardiology, United Health Services Hospitals, Wilson Regional Medical Center, Johnson City, NY, USA.;Department of Internal Medicine, United Health Services Hospitals, Wilson Regional Medical Center, Johnson City, NY, USA.;Department of Internal Medicine, Ras Al Khaimah Medical Health and Sciences University, Ras al Khaimah, United Arab Emirates.;Department of Internal Medicine, United Health Services Hospitals, Wilson Regional Medical Center, Johnson City, NY, USA.;Department of Cardiology, United Health Services Hospitals, Wilson Regional Medical Center, Johnson City, NY, USA.",
"authors": "Braiteh|Nabil|N|;Senyondo|Godson D|GD|;Rahman|Mohammed Faraaz|MF|;Chaudhry|Raheel|R|;Kashou|Hisham|H|",
"chemical_list": "D013974:Thyroxine",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.929573",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n33690260\n10.12659/AJCR.929573\n929573\nArticles\nAn Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report\nBraiteh Nabil ABCDEF1\nSenyondo Godson D. ABCDEF2\nRahman Mohammed Faraaz ABEF3\nChaudhry Raheel ABEF2\nKashou Hisham ACD1\n1 Department of Cardiology, United Health Services Hospitals, Wilson RegionalMedical Center, Johnson City, NY, U.S.A.\n2 Department of Internal Medicine, United Health Services Hospitals, WilsonRegional Medical Center, Johnson City, NY, U.S.A.\n3 Department of Internal Medicine, Ras Al Khaimah Medical Health and Sciences University, Ras al Khaimah, United Arab Emirates\nCorresponding Author: Nabil Braiteh, e-mail: nabil.braiteh@nyuhs.org\nAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n2021\n10 3 2021\n22 e929573-1e929573-5\n01 11 2020\n07 1 2021\n01 2 2021\n© Am J Case Rep, 2021\n2021\nThis work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Male, 70-year-old\n\nFinal Diagnosis: Inferior STEMI • myxedema coma\n\nSymptoms: Chest pain • confusion • fatigue\n\nMedication: —\n\nClinical Procedure: Cardiac catheterization\n\nSpecialty: Cardiology • Endocrinology and Metabolic\n\nObjective:\n\nUnusual clinical course\n\nBackground:\n\nMyxedema coma is an endocrine emergency with a high mortality rate, defined as a severe hypothyroidism leading to hypotension, bradycardia, decreased mental status, hyponatremia, hypoglycemia, and cardiogenic shock. Although hypothyroidism and cardiac disease has been interlinked, ST elevation myocardial infarction in the setting of myxedema coma have not been reported previously.\n\nCase Report:\n\nWe report the case of a 70-year-old man who presented to the Emergency Department with chest pain and confusion. He also reported fatigue for the past week, which was progressively worsening. His past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemotherapy (axitinib and pembrolizumab). In the Emergency Department, an ECG revealed inferior ST elevations. Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection and was taken emergently for a cardiac catheterization, which failed to reveal an acute coronary occlusion. TSH was 60.6 mIU/L (0.465–4.680) mIU/ML, and free T4 0.3 ng/dL (0.8–2.2) ng/dL. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2), which confirmed cardiogenic shock due to myxedema coma. He was treated with levothyroxine (T4), liothyronine (T3), hydrocortisone, and multiple vasopressors but failed to respond and died 13 h after admission to the hospital.\n\nConclusions:\n\nBecause of its rarity and high mortality, early diagnosis of myxedema coma and initiation of treatment by cardiologists requires a high level of suspicion, especially when patients with a history of hypothyroidism present with a cardiac complaint (ie, acute coronary syndrome, or bradycardia) that does not completely fit the clinical picture. It is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock.\n\nKeywords:\n\nAcute Coronary Syndrome\nHypothyroidism\nShock, Cardiogenic\n==== Body\nBackground\n\nMyxedema coma is primarily a disorder of the thyroid gland, which eventually leads to slower functioning of multiple organs and is a medical emergency with a high mortality rate [1]. It is a form of severe hypothyroidism that leads to hypotension, bradycardia, decreased mental status, hyponatremia, and hypoglycemia [2]. Cardiac effects include decreased myocardial contractility and low cardiac output leading to hypotension. Pericardial effusion can also be present, but left ventricular ejection fraction is rarely affected.\n\nDecreased cardiac output occurs in hypothyroidism due to increase in vascular resistance and change in gene expression [3]. Vascular resistance is increased due to lack of T4 effect on initiating the release of endothelial-derived relaxing factor [4].\n\nThyroid disease and the cardiovascular system have an intricate relationship. Although patients with known stable angina will have less symptoms when they are in a hypothyroid state due to decreased activity and less oxygen demand, it is presumed that hypothyroidism is associated with accelerated coronary artery disease due to increased homocysteine levels, dyslipidemia, elevated concentrations of C-reactive protein, endothelial dysfunction, and increase in diastolic blood pressure [3,4].\n\nTo the best of our knowledge, a direct association between acute myocardial infarction and myxedema coma has not been previously reported. Herein, we report the case of a 70-year-old man who presented with ST elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma.\n\nCase Report\n\nA 70-year-old man presented to the Emergency Department with chest pain and confusion. The pain started 1 day prior to presentation, was centrally located, and radiated to his bilateral shoulders. He also reported fatigue for the past week, which was progressively getting worse.\n\nHis past medical history was significant for renal cell carcinoma with metastatic bone disease being treated with chemo-therapy (axitinib and pembrolizumab), a recent diagnosis of hypothyroidism, chronic kidney disease stage 2, benign essential hypertension, and paroxysmal atrial fibrillation.\n\nHis past surgical history was significant for a total nephrectomy. He denied tobacco, alcohol, or illicit drug abuse. His home medications were intravenous pembrolizumab 200 milligrams every 3 weeks, oral axitinib 7 milligrams twice daily, oral carvedilol 12.5 milligrams twice daily, and oral levothyroxine 25 micrograms once daily.\n\nUpon presentation to the Emergency Department, his vitals were significant for a blood pressure of 93/52 mmHg, heart rate of 96 beats per minute (bpm), oral temperature was 37.2 degrees Celsius with a 96% saturation on room air. Physical exam was significant for being altered, lethargic, and not oriented to time, place, and date, with a Glasgow coma scale of 11. Cardiac and lung exams were unremarkable. A 12-lead ECG showed ST elevations in leads II, III, and aVF, and a sinus rhythm with a first-degree AV block at a rate of 98 bpm (Figure 1). Shortly after presentation, the patient’s blood pressure was decreasing, he became bradycardic (sinus), and his mental status was getting worse, so he was intubated for airway protection. He was given 1 dose of 0.5 milligrams of intravenous atropine and was started on a norepinephrine and dopamine drip. Subsequently a STEMI code was called and he was started on acute coronary syndrome treatment and was transferred to the cardiac catheterization lab.\n\nPrior to dispatch to the cardiac catheterization lab, the patient had a brief episode of cardiac arrest preceded with sinus bradycardia that required a total of 2 min of cardiopulmonary resuscitation, and 1 dose of 0.5 milligrams intravenous epinephrine until return of spontaneous circulation was achieved.\n\nLeft and right heart catheterization was performed. A coronary angiogram showed no evidence of atherosclerotic coronary disease in the left main, left anterior descending artery, and in the left circumflex artery. There was evidence of a 60% concentric lesion in the distal right coronary artery (Figure 2) that was disproportionate to the clinical picture, so no intervention was done. The cardiac index was calculated to be 0.8 L/min/m2 (normal range 2.6–4.2 L/min/m2). During the procedure, the patient had another episode of cardiac arrest preceded by torsade de pointes that was treated with unsynchronized cardioversion with 150 Joules and 2 grams of intravenous magnesium.\n\nA transthoracic echocardiogram was performed, which revealed a normal ejection fraction estimated at 50–55% and a small pericardial effusion measuring 0.9 cm (Figure 3), with no significant valvular heart disease. His ST elevations resolved gradually within 2–3 h after admission. Laboratory data are listed in Table 1.\n\nArterial blood gas revealed a pH of 7.26 (7.35–7.55), PaCo2 33.8 (35.0–45.0) MMHG, PaO2 92 (80–100) MMHG, HCo3 14.6 (22.0–24.0) MEQ/L, saturation of 91.7% (92.0–100.0)% on assisted control mode ventilation, tidal volume of 550 ml, Fio2 of 100%, and respiratory rate of 16/min.\n\nA diagnosis of myxedema coma was immediately made, and 400 micrograms of intravenous levothyroxine (T4) and 20 micrograms of intravenous liothyronine (T3) were given first. Then, 100 milligrams of intravenous hydrocortisone were administered. The patient continued to deteriorate, requiring more vasopressors at high dosages (dopamine at 20 mcg/kg/min, norepinephrine at 200 mcg/min, epinephrine 100 mcg/min, and phenylephrine at 200 mcg/min). He was also started on empiric antibiotic treatment pending blood and urine culture results. Another transthoracic echocardiogram was performed 6 h after hospitalization, which did not show any new changes, with stable pericardial effusion.\n\nDespite all the above measures, the patient was not responding, and he dies 13 h after hospital admission.\n\nDiscussion\n\nA review of the literature did not identify any reported cases of acute myocardial infarction occurring in the setting of myxedema coma, which is thought to be a rather rare occurrence. Our patient had been on chemotherapy with Axitinib and Pembrolizumab for advanced renal cell cancer, which is likely the explanation of his new-onset worsening hypothyroidism, for which he was treated with a suboptimal dose of 25 micrograms of oral levothyroxine.\n\nAlthough the combination of pembrolizumab plus axitinib has proven to be effective in the treatment of advanced renal cell carcinoma in comparison to other alternatives, this combination has been strongly linked to hypothyroidism [5].\n\nOur patient presented with an inferior STEMI complicated with cardiogenic shock and bradycardia, leading to cardiac arrest, all in the setting of myxedema coma. The question to be answered is whether this was a coincidence or whether the myxedema coma led to the STEMI.\n\nThere are 2 hypotheses that could explain the patient’s presentation. First, the patient already had a chronic moderate-severe distal RCA lesion, which had progressed into a total occlusion in the setting of plaque rupture due to the stressful metabolic state of the body caused by myxedema coma. Likely, the plaque had dislodged peripherally or was broken. Intravenous ultrasound would have been useful to evaluate this further to rule out a plaque rupture; however, it was not done as the patient was in critical condition and it may not have changed outcome. We think that this theory is less likely since there was no evidence of inferior wall hypokinesis and no evidence of distal RCA thrombus by angiography.\n\nThe second hypothesis is that the patient already had a chronic moderate distal RCA lesion (60% occlusion) as identified by the coronary angiogram (Figure 2), and the stress of myxedema coma led to an acute coronary spasm in the RCA, causing inferior STEMI. This is the more likely theory considering that the coronary angiogram showed no evidence of atherosclerosis in other arteries, along with resolution of ST elevations. Known triggers of coronary spasm include thyroid dysfunction, collagen disorders, smoking, and abuse of drugs such as amphetamines and cocaine [6].\n\nIn addition, the mechanism of ST elevations would change management significantly. If it were due to a plaque rupture, then the patient should be treated with an acute coronary syndrome protocol that includes aspirin, P2Y12 inhibitors, anticoagulation, and percutaneous coronary intervention, while coronary spasm should be treated by reversing the inciting factor and the use of calcium channel blockers or nitrates.\n\nOur patient had severe bradycardia requiring a temporary transvenous pacer, small pericardial effusion, cardiogenic shock (cardiac index of 0.8 L/min/m2), severe lethargy leading to a comatose state, hyponatremia, evidence of severe hypothyroidism (TSH 60.6 mIU/L, free T4 of 0.3 mcg/dL), and secondary adrenal insufficiency (cortisol of 2.0 mcg/dl), all due to myxedema coma. In patients suspected to be in a myxedema coma, the history-taking should be focused on any new medications, treatments, and newly diagnosed diseases such as cancer. There are myriads of new chemotherapy medications and physicians should make an attempt to focus on serious life-threatening adverse effects of these drugs. Moreover, other causes of shock, such as infectious, cardiac, or hypovolemic factors, should be ruled out.\n\nOur patient was started on intravenous levothyroxine after coronary angiography, which was due to late diagnosis of myxedema coma considering the 2 life-threatening events. We recommend initiation of treatment with both intravenous levothyroxine and coronary angiography simultaneously in this scenario if both were diagnosed in a timely manner. However, the presence of STEMI can alter management due to its high mortality and the emergent need for cardiac catheterization.\n\nWhen myxedema coma is suspected, treatment should be initiated without waiting for laboratory confirmation. It is a medical emergency that carries a high mortality rate of 50–60% [7]. Treatment consists of thyroid hormone replacement, supportive measures, management of coexisting problems (ie, infection), and steroids (until coexisting adrenal insufficiency has been excluded) [8].\n\nConclusions\n\nOur case adds new data on cardiac complications of severe hypothyroidism (ie, myxedema coma) and presents a novel relationship between myxedema coma and ST elevation myocardial infarction. It also sets a platform for future research and publications exploring rare cardiac complications of thyroid disease.\n\nIt is of utmost importance for physicians to keep a wide differential diagnosis of other causes of ST elevation and/or persistent cardiogenic shock when a coronary angiogram and a transthoracic echocardiogram both fail to explain the full clinical picture. Obtaining a thorough history was key in pursuing another diagnosis (ie, myxedema coma) in our case.\n\nFigure 1. Electrocardiogram showing showed ST elevations in leads II, III, and aVF with a first-degree AV block at a heart rate of 98 beats/minute.\n\nFigure 2. Coronary angiogram of the right coronary artery (RCA) showing evidence of an approximately 60% lesion in the distal RCA (red arrow).\n\nFigure 3. Transthoracic echocardiogram showing a small pericardial effusion measured at 0.9 cm (red double arrow).\n\nTable 1. Laboratory data.\n\nLaboratory data\tValue\tNormal range\t\nSodium\t118 mmol/L\t(135–146) mmol/L\t\nPotassium\t3.2 mmol/L\t(3.5–5.3) mmol/L\t\nChloride\t85 mmol/L\t(98–107) mmol/L\t\nHCO3\t23 mmol/L\t(21–32) mmol/L\t\nGlucose\t568 mg/dL\t(65–99) mg/dL\t\nBUN\t13 mg/dL\t(7–23) mg/dL\t\nCreatinine\t1.4 mg/dL\t(0.5–1.2) mg/dL\t\nAST\t329 IU/L\t(5–40) IU/L\t\nALT\t160 IU/L\t(7–56) IU/L\t\nWBC\t11.7×109/L\t(4.0–10.5) K/UL\t\nHemoglobin\t13 g/dL\t(13.0–18.0) G/dL\t\nTSH\t60.6 mIU/L\t(0.465–4.680) mIU/ML\t\nFree T4\t0.3 ng/dL\t(0.8–2.2) ng/dL\t\nCortisol\t2.0 mcg/dl\t(1.7–14.1) mcg/dl\t\nTroponin I\t0.17 ng/ml (peaking at 21.8 ng/ml after 6 hours\t<0.01 ng/ml\t\n\nConflicts of Interest\n\nNone.\n==== Refs\nReferences:\n\n1. Elshimy G Correa R Myxedema StatPearls [Internet]. Treasure Island (FL) StatPearls Publishing 2020 https://www.ncbi.nlm.nih.gov/books/NBK545193/\n2. Klein I Thyroid hormone and the cardiovascular system Am J Med 1990 88 6 631 37 2189307\n3. Klein I Danzi S Thyroid disease and the heart Circulation 2007 116 15 1725 35 17923583\n4. Taddei S Caraccio N Virdis A Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy J Clin Endocrinol Metab 2003 88 8 3731 37 12915662\n5. Atkins MB Plimack ER Puzanov I A non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial Lancet Oncol 2018 19 3 405 15 29439857\n6. Hadi H D’souza S El-Omar M Hypovolemia-induced severe coronary spasm leading to acute myocardial infarction Exp Clin Cardiol 2012 17 2 74 76 22826651\n7. Ono Y Ono S Yasunaga H Clinical characteristics and outcomes of myxedema coma: outcomes of myxedema coma: Analysis of a national inpatient database in Japan J Epidemiol 2017 27 3 117 22 28142035\n8. Kwaku MP Burman KD Myxedema coma J Intensive Care Med 2007 22 224 17712058\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "22()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000368:Aged; D003128:Coma; D006801:Humans; D008297:Male; D009230:Myxedema; D000072657:ST Elevation Myocardial Infarction; D012770:Shock, Cardiogenic; D013974:Thyroxine",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "e929573",
"pmc": null,
"pmid": "33690260",
"pubdate": "2021-03-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17923583;22826651;12915662;2189307;17712058;28142035;29439857",
"title": "An Unusual Presentation of ST Elevation Myocardial Infarction Complicated with Cardiogenic Shock Due to Myxedema Coma: A Case Report.",
"title_normalized": "an unusual presentation of st elevation myocardial infarction complicated with cardiogenic shock due to myxedema coma a case report"
} | [
{
"companynumb": "US-MYLANLABS-2021M1025321",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
},
"drugadditional": null,
... |
{
"abstract": "Although intravenous (IV) bisphosphonates are first-line medications for the management of hypercalcemia, studies examining their use in patients with preexisting renal dysfunction are limited.\n\n\n\nThe objective of this study is to describe the safety and efficacy of pamidronate and zoledronic acid in the treatment of hypercalcemia in patients with baseline renal dysfunction.\n\n\n\nA retrospective analysis was conducted of IV pamidronate and zoledronic acid in adult patients with hypercalcemia and creatinine clearance (CrCl) <60 mL/min. The primary endpoint was incidence of all-grade serum creatinine (SCr) elevations. Secondary endpoints included refractory hypercalcemia, hypocalcemia, osteonecrosis of the jaw (ONJ), corrected serum calcium (CSC) decrease ≥1.0 mg/dL by day 7 of bisphosphonate administration, and normalization of CSC ≤10.5 mg/dL by days 10 and 30.\n\n\n\nA total of 113 patients were included (n = 55 pamidronate, n = 58 zoledronic acid). The primary endpoint of all-grade SCr elevation occurred in 28 (24.8%) patients. Grades 3/4 SCr elevations occurred in 10.9% of patients treated with pamidronate and 1.7% of patients receiving zoledronic acid. Approximately 16% and 14% of patients developed grades 1 and 2 hypocalcemia, respectively, and there were no cases of ONJ. Overall, 64.6% of patients achieved normalization of CSC by day 10, and there were no statistical differences between bisphosphonate type and renal function.\n\n\n\nThe analysis suggests an association between IV bisphosphonates and increased rates of SCr elevations among patients with preexisting renal dysfunction. Future prospective studies are necessary to elucidate these findings.",
"affiliations": "University of North Carolina Medical Center, Chapel Hill, NC, USA.;University of North Carolina Medical Center, Chapel Hill, NC, USA.;University of North Carolina, Chapel Hill, NC, USA.;University of North Carolina Medical Center, Chapel Hill, NC, USA.;University of North Carolina Medical Center, Chapel Hill, NC, USA.;University of North Carolina Medical Center, Chapel Hill, NC, USA.;University of North Carolina Medical Center, Chapel Hill, NC, USA.",
"authors": "Palmer|Shannon|S|0000-0002-4043-380X;Tillman|Frank|F|;Sharma|Preetika|P|;Auten|Jessica|J|;Owen|Kathryn|K|;Clark|Stephen M|SM|;Morgan|Katherine P|KP|",
"chemical_list": "D004164:Diphosphonates",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028020953501",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "55(3)",
"journal": "The Annals of pharmacotherapy",
"keywords": "bisphosphonate; hypercalcemia; pamidronate; renal dysfunction; zoledronic acid",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004164:Diphosphonates; D005260:Female; D006801:Humans; D006934:Hypercalcemia; D007674:Kidney Diseases; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012189:Retrospective Studies",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "303-310",
"pmc": null,
"pmid": "32847379",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety of Intravenous Bisphosphonates for the Treatment of Hypercalcemia in Patients With Preexisting Renal Dysfunction.",
"title_normalized": "safety of intravenous bisphosphonates for the treatment of hypercalcemia in patients with preexisting renal dysfunction"
} | [
{
"companynumb": "NVSC2021US055368",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": "3",
"... |
{
"abstract": "Anabolic steroid abuse adversely affects the endocrine system, blood lipids, and the liver, but renal injury has not been described. We identified an association of focal segmental glomerulosclerosis (FSGS) and proteinuria in a cohort of 10 bodybuilders (six white and four Hispanic; mean body mass index 34.7) after long-term abuse of anabolic steroids. The clinical presentation included proteinuria (mean 10.1 g/d; range 1.3 to 26.3 g/d) and renal insufficiency (mean serum creatinine 3.0 mg/dl; range 1.3 to 7.8 mg/dl); three (30%) patients presented with nephrotic syndrome. Renal biopsy revealed FSGS in nine patients, four of whom also had glomerulomegaly, and glomerulomegaly alone in one patient. Three biopsies revealed collapsing lesions of FSGS, four had perihilar lesions, and seven showed > or =40% tubular atrophy and interstitial fibrosis. Among eight patients with mean follow-up of 2.2 yr, one progressed to ESRD, the other seven received renin-angiotensin system blockade, and one also received corticosteroids. All seven patients discontinued anabolic steroids, leading to weight loss, stabilization or improvement in serum creatinine, and a reduction in proteinuria. One patient resumed anabolic steroid abuse and suffered relapse of proteinuria and renal insufficiency. We hypothesize that secondary FSGS results from a combination of postadaptive glomerular changes driven by increased lean body mass and potential direct nephrotoxic effects of anabolic steroids. Because of the expected rise in serum creatinine as a result of increased muscle mass in bodybuilders, this complication is likely underrecognized.",
"affiliations": "Columbia University College of Physicians and Surgeons, Department of Pathology, New York, NY 10032, USA.",
"authors": "Herlitz|Leal C|LC|;Markowitz|Glen S|GS|;Farris|Alton B|AB|;Schwimmer|Joshua A|JA|;Stokes|Michael B|MB|;Kunis|Cheryl|C|;Colvin|Robert B|RB|;D'Agati|Vivette D|VD|",
"chemical_list": "D045930:Anabolic Agents; D013256:Steroids",
"country": "United States",
"delete": false,
"doi": "10.1681/ASN.2009040450",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1046-6673",
"issue": "21(1)",
"journal": "Journal of the American Society of Nephrology : JASN",
"keywords": null,
"medline_ta": "J Am Soc Nephrol",
"mesh_terms": "D000328:Adult; D045930:Anabolic Agents; D001706:Biopsy; D005923:Glomerulosclerosis, Focal Segmental; D006801:Humans; D007668:Kidney; D008297:Male; D008875:Middle Aged; D011507:Proteinuria; D051437:Renal Insufficiency; D013256:Steroids; D019966:Substance-Related Disorders",
"nlm_unique_id": "9013836",
"other_id": null,
"pages": "163-72",
"pmc": null,
"pmid": "19917783",
"pubdate": "2010-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11560950;2915439;15886291;2658558;11522860;9761502;14750104;18680242;14749457;19019999;7617115;18004690;15660958;9734594;11373339;16939064;18514731;10966886;18923108;11260414;7861720;8258943;2121495;17495854;5527019;16437385;11209014;14579937;16875990;12397037;9813653;16971373;17268203;18184525;9192910;2351927;17989648;7062725",
"title": "Development of focal segmental glomerulosclerosis after anabolic steroid abuse.",
"title_normalized": "development of focal segmental glomerulosclerosis after anabolic steroid abuse"
} | [
{
"companynumb": "US-PFIZER INC-2020139533",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TESTOSTERONE ENANTHATE"
},
"drugadditional": "... |
{
"abstract": "We encountered a 60-year-old female patient who died of cerebral hemorrhage caused by disseminated aspergillosis during massive steroid therapy for overlap syndrome of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) and performed autopsy. Histologically, necrotizing vasculitis accompanied by Aspergillus hyphae was noted in the arterial wall of the region with cerebral hemorrhage and an abscess containing Aspergillus clumps was present in the lung, therefor we considered the cerebral hemorrhage caused by disseminated aspergillosis. For immunocompromised patients, it is desirable to perform treatment taking the possibility of deep mycosis into consideration, and when it is suspected, early therapeutic intervention may be useful.",
"affiliations": "The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan.;The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan.;The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan.;The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan.;The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan.;The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan.;The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan.;The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan.",
"authors": "Ueno|Masanobu|M|;Nakano|Kazuhisa|K|;Yoshinari|Hiroko|H|;Nakayamada|Shingo|S|;Iwata|Shigeru|S|;Kubo|Satoshi|S|;Miyagawa|Ippei|I|;Tanaka|Yoshiya|Y|",
"chemical_list": "D005938:Glucocorticoids",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.1226-18",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3056812010.2169/internalmedicine.1226-18Case ReportAn Autopsy Case with Cerebral Hemorrhaging due to disseminated Aspergillosis During Glucocorticoid Therapy for Overlap Syndrome of Systemic Lupus Erythematosus and Systemic Sclerosis Ueno Masanobu 1Nakano Kazuhisa 1Yoshinari Hiroko 1Nakayamada Shingo 1Iwata Shigeru 1Kubo Satoshi 1Miyagawa Ippei 1Tanaka Yoshiya 1\n1 The First Department of Internal Medicine, University of Occupational and Environmental Health, JapanCorrespondence to Dr. Yoshiya Tanaka, tanaka@med.uoeh-u.ac.jp\n\n18 12 2018 1 4 2019 58 7 1023 1027 22 3 2018 14 9 2018 Copyright © 2019 by The Japanese Society of Internal MedicineThe Internal Medicine 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/).We encountered a 60-year-old female patient who died of cerebral hemorrhage caused by disseminated aspergillosis during massive steroid therapy for overlap syndrome of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) and performed autopsy. Histologically, necrotizing vasculitis accompanied by Aspergillus hyphae was noted in the arterial wall of the region with cerebral hemorrhage and an abscess containing Aspergillus clumps was present in the lung, therefor we considered the cerebral hemorrhage caused by disseminated aspergillosis. For immunocompromised patients, it is desirable to perform treatment taking the possibility of deep mycosis into consideration, and when it is suspected, early therapeutic intervention may be useful. \n\ndisseminated aspergillosissystemic lupus erythematosussystemic sclerosiscerebral hemorrhage\n==== Body\nIntroduction\nAspergillosis often develops as an opportunistic infection in patients treated with steroids and immunosuppressors and also in immunocompromised patients, such as those with hematologic malignancy and acquired immunodeficiency syndrome (AIDS). Aspergillus is strongly angioinvasive and may cause disseminated aspergillosis, which rapidly spreads throughout the body. The prognosis is poor, especially in cases with concomitant central nervous system lesions (1). Early therapeutic intervention is desirable, but invasive tests cannot be performed in many patients because the symptoms are nonspecific and the patient's general condition is poor, leading to difficulty in achieving a diagnosis.\n\nWe encountered a patient who died of cerebral hemorrhaging caused by disseminated aspergillosis during massive steroid therapy for overlap syndrome of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) and performed an autopsy.\n\nCase Report\nThe patient was a 60-year-old woman with chief complaints of general malaise, abdominal pain, exertional dyspnea, and a cold sensation in the fingers and toes. Raynaud's symptoms appeared in the fingers and toes in October X-1, and the patient became aware of general malaise and exertional dyspnea in December. She visited a general hospital in January X. Cardiac dilatation and pericardial effusion were observed on computed tomography (CT), and she was diagnosed with pericarditis, for which the oral administration of 1 mg colchicine was initiated. Ulcers appeared on the fingertips in February, and the patient became aware of abdominal pain in March. Ascites and acalculous cholecystitis were observed on CT, and thrombocytopenia was also detected. The patient was admitted to our hospital for a close examination and treatment.\n\nOn a physical examination at admission, the second heart sound was promoted, bowel sounds were reduced, and Murphy's sign was positive. Cyanosis of the four extremities, swelling of the fingers, sclerema [modified Rodnan total skin thickness score (m-Rodnan TSS): 2], and fingertip ulcer scars were also observed, and pitting edema was present in the bilateral crura. On nailfold videocapillaroscopy, abnormal capillary vascular findings consistent with scleroderma were observed. On blood testing at admission, a decreased platelet count (5.2×104/μL, normal range; 15.8-34.8×104/μL), renal dysfunction [blood urea nitrogen (BUN)/Cr: 96/1.35 mg/dL, normal range; 8-20/0.46-0.79 mg/dL], and high brain-type natriuretic peptide (BNP) (7,263.8 pg/mL, normal range; 0-18.4 pg/mL) were detected (Table). On an immunological examination, the anti-nuclear antibody titer was 1,280-flod (Speckled pattern), and anti-ribonucleoprotein (RNP) antibody (≥550 U/mL) and platelet-related IgG (688 ng/107, normal range; 0-46 ng/107) were positive. On CT at admission, pleural effusion, ascites, and pericardial effusion were observed. The gallbladder was swollen, features of acalculous cholecystitis were observed, and concomitant interstitial pneumonia was also noted in the bilateral bases of the lung. Regarding the cardiac function, the left ventricular wall movement was diffusely reduced on echography [left ventricular ejection fraction (LVEF)=25-30%], and the estimated systolic pulmonary arterial blood pressure was elevated to 59 mmHg, suggesting a pericarditis-associated low cardiac output and concomitant pulmonary hypertension.\n\nTable. Blood Test at Hospitalization.\n\nHematology\tImmunology\t\nWBC\t\t5,700\t/μL\t\tIgG\t\t1,694\tmg/mL\t\nNeutro\t\t86\t%\t\tIgA\t\t84\tmg/mL\t\nLymph\t\t9.0\t%\t\tIgM\t\t43\tmg/mL\t\nEosi\t\t0\t%\t\tC3\t\t59\tmg/dL\t\nBaso\t\t0\t%\t\tC4\t\t10\tmg/dL\t\nMono\t\t4.0\t%\t\tCH50\t\t32\tU/mL\t\nMyelo\t\t1.0\t%\t\tANA\t\t×1,280\t\t\nRBC\t\t329×104\t/μL\t\tANA-type\t\tSpeckled\t\t\nHb\t\t11.3\tg/dL\t\tRF\t\t19.9\tU/mL\t\nPlt\t\t5.2×104\t/μL\t\tanti-ds-DNA antibody\t\t2.4\tU/mL\t\n\t\t\t\t\tanti-SM antibody\t\t2.6\tU/mL\t\nBiochemistry\t\tanti-RNP antibody\t\t≥550\tU/mL\t\nTP\t\t5.8\tg/dL\t\tanti-centromere antibody\t\t<5.0\tU/mL\t\nAlb\t\t3.1\tg/dL\t\tanti-Scl-70 antibody\t\t<1.0\tU/mL\t\nT.Bil\t\t1.1\tmg/dL\t\tPAIgG\t\t688\tng/107\t\nAST\t\t108\tIU/L\t\t\t\t\t\t\nALT\t\t51\tIU/L\t\tInfection\t\t\t\t\nLDH\t\t574\tIU/L\t\tHBs-Ag\t\t-\t\t\nALP\t\t192\tIU/L\t\tHCV-Ab\t\t-\t\t\nBUN\t\t96\tmg/dL\t\tT-SPOT\t\t-\t\t\nCr\t\t1.35\tmg/dL\t\tβ-D glucan\t\t<6.0\tpg/mL\t\neGFR\t\t31.73\tmL/min/1.73m2\t\t\t\t\t\t\nKL-6\t\t412\tU/mL\t\tUrine\t\t\t\t\nCRP\t\t0.14\tmg/dL\t\tU-pro /O.B.\t\t+1/+2\t\t\nESR\t\t9\tmm/hr\t\tcast\t\t+\t\t\nWBC: white blood cell, Neutro: neutrophil, Lymph: lymphocyte, Eosi: eosinophil, Baso: basocyte, Mono: monocyte, Myelo: myelocyte, RBC: red blood cell, Hb: hemoglobin, Plt: platelet, TP: total protein, Alb: albumin, T.Bil: total bilirubin, AST: aspartate aminotransferase, ALT: alanine aminotansferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, BUN: blood urea nitrogen, Cr: creatinine, eGFR: estimated glomerular filtration rate, KL-6: sialylated carbohydrate antigen KL-6, CRP: C-reactive protein, ESR: erythrocyte sedimentation rate, ANA: antinuclear antibody, RF: rheumatoid factor, PAIgG: platelet antibody, HBs-Ag: hepatitis B virus surface antigen, HCV-Ab: hepatitis C virus antibody, U-pro: urine protein, O.B.: occult blood\n\nThe present patient was definitively diagnosed with SLE because the following 4 of the 11 items of the diagnostic criteria (2012) of the Systemic Lupus International Collaborating Clinics were met: serositis and thrombocytopenia of I. Clinical items and anti-nuclear antibody-positive and hypocomplementemia of II. Immunological items. Scleroderma was definitively diagnosed because the score of the Classification Criteria for Systemic Sclerosis 2013 [American College of Rheumatology (ACR)/The European League of Against Rheumatism (EULAR)] was 10 (＞9): Fingertip ulcer scar, 3; swelling of the fingers, 2; abnormality in nail fold capillary blood vessels, 2; and Raynaud phenomenon, 3. The present patient had only a high anti-RNP antibody, which was mixed connective tissue disease (MCTD)-like. However both SLE and SSc could be definitively diagnosed, so we diagnosed the patient with overlap syndrome of SLE and SSc. The disease activity of SLE was high [SLE Disease Activity Index (SLEDAI): 13, British Isles Lupus Assessment Group Index (BILAG): 31], and that of SSc was also judged to be high because it was accompanied by interstitial pneumonia.\n\nRegarding her treatment, massive steroid therapy [methylprednisolone (mPSL) 36 mg iv] was introduced on the 1st hospital day without using antibiotics. To treat pulmonary hypertension, the administration of macitentan at 10 mg and tadalafil at 20 mg was initiated. Her general malaise tended to improve after treatment initiation, and improvement of the renal function (serum Cr: 0.97 mg/dL) was noted on blood tests. The blood pressure decreased during the course, and tadalafil was withdrawn on the 14th hospital day. Regarding the cardiac function, her LVEF was 35-40%, and her estimated systolic pulmonary arterial pressure was 46 mmHg on echocardiography on the 15th hospital day, showing improvement. On CT after treatment, the findings of pericarditis and acalculous cholecystitis had disappeared. The disease activity also decreased (SLEDAI: 9, BILAG: 5), showing a favorable course.\n\nOn the 20th hospital day, her β-D glucan level increased to 11.2 pg/mL and her galactomannan antigen was 1.6 C.I., being positive, but no nodules suggesting Aspergillus infection were present on chest CT.\n\nOn the 23rd hospital day, convulsive attack of the right side of the body suddenly developed, and hemorrhaging in the left frontal lobe was detected on CT (Fig. 1A). On magnetic resonance imaging (MRI), hemangioma and a tumorous lesion were suspected as the cause of the cerebral hemorrhaging, but surgical treatment could not be performed because of the patient's poor general condition, and conservative treatment was selected. No expansion of the hematoma was observed thereafter, but the cerebral edematous findings became aggravated, and the patient fell into a coma on the 42nd hospital day. Approximately 1,000 mL of fresh bloody bowel discharge occurred on the 48th hospital day, which was treated with blood transfusion and hemostatics, but the response to the treatment was poor. Respiratory arrest occurred on the same day followed by cardiac arrest, and death was confirmed.\n\nFigure 1. CT and autopsy images of cerebral hemorrhaging. (A) Hemorrhaging in the left frontal lobe on CT. (B) The 5-cm hematoma in the left frontal lobe.\n\nWhen a pathological autopsy was performed, a protruding mass and hemorrhaging were noted in the sigmoid colon, with the fecal bulk retained on the oral side, and this was deemed to have been the cause of fresh bloody bowel discharge. The histological diagnosis of the protruding mass was highly atypical tubulovillous adenoma. As the cause of the comatose state, left ventricular perforation and subarachnoid hemorrhaging were considered in addition to the 5-cm hematoma detected in the left frontal lobe and edema (Fig. 1B). On a histological examination, hyphae and infiltrating neutrophils were present in the arterial wall, showing necrotizing vasculitis accompanied by the most suspecting hypha of Aspergillus (Fig. 2A, B). Although it could not be confirmed by chest CT, a 4-mm abscess was found to have formed in S1+2 of the left lung on a histological examination, and it contained clumps of Aspergillus (Fig. 2C, D). Based on these findings, Aspergillus hyphae was suspected to have invaded the blood vessels and hematogenously disseminated to the central nervous system. Cerebral hemorrhaging caused by disseminated aspergillosis with central nervous system lesions may have caused encephalocele and led to respiratory arrest and death.\n\nFigure 2. Histological findings of the brain and the lung. (A), (B): Histological findings of the brain [Hematoxylin and Eosin (H&E) staining]. (A) Necrotizing vasculitis was noted (magnification 40×). (B) Many neutrophils and Aspergillus hyphae were present around the blood vessels in the brain (magnification 100×). (C), (D): Histological findings of the lung [(C) H&E staining, (D) Grocott staining]. (C) An abscess of approximately 4-mm was present in S1+2 of the left lung (magnification 100×). (D) Many Aspergillus hyphae were present in the abscess (magnification 100×).\n\nRegarding other organs, fibrosis of the skin was observed and deemed a finding of scleroderma. In the lungs, the case had interstitial pneumonia with an unusual pattern. There were inflammatory findings with lymphocytic infiltration in the pericardium, pleura, and gallbladder, which suggested serositis of SLE. We also noted findings of lupus nephritis [International Society of Nephrology (ISN)/Renal Pathology Society (RPS) classification, class III (A/C)] in the kidney.\n\nDiscussion\nIn the present case, cerebral hemorrhaging occurred in the left frontal lobe during massive steroid therapy for overlap syndrome of SLE and SSc, and the patient died. Based on the findings of a pathological autopsy, it was concluded that disseminated aspergillosis was the cause of the cerebral hemorrhaging.\n\nAspergillus infects mainly through the airway and manifests three types of pathologies: pulmonary aspergilloma, allergic bronchopulmonary aspergillosis, and invasive aspergillosis. Invasive aspergillosis develops as an opportunistic infection in immunocompromised patients. The fungus may invade blood vessels via the source of the infection (the lung) and rapidly spread throughout the body, causing concomitant disseminated aspergillosis. It has been reported that central nervous system lesions are present in 10-20% of patients with disseminated aspergillosis (2). Aspergillus hyphae invade the central nervous system directly through sinusitis or via hematogenous dissemination from lung lesions. The fatality rate of patients with disseminated aspergillosis with central nervous system lesions is 88.1%, showing that the prognosis is very poor (1); this is because Aspergillus causes local necrosis in the arterial wall, forming a small aneurysm, and rupture of this aneurysm causes cerebral and subarachnoid hemorrhaging (3). Aspergillus-induced mycotic aneurysm was formed in the cerebral artery in 12 of 49 autopsied patients with disseminated aspergillosis in a study (4), showing that it is quite common.\n\nCentral nervous system lesions of disseminated aspergillosis cause fatal cerebral hemorrhaging and the prognosis is poor; as such, the early diagnosis and therapeutic intervention are important. However, disseminated aspergillosis complicated by central nervous system lesions was diagnosed before death in only about 56% of cases in a study (4), showing that its diagnosis is very difficult. The reasons for the difficulty in the diagnosis include the absence of mycosis-specific imaging findings and a low rate of positivity (about 30%) on cerebrospinal fluid culture (5). Therefore, a test that can be performed instead of culture is necessary in order to diagnose central nervous system lesions of disseminated aspergillosis more quickly. The usefulness of evaluating galactomannan antigen and the polymerase chain reaction (PCR) test of Aspergillus in cerebrospinal fluid as an alternative test has been reported (4-6), with promising findings obtained. Winterholler et al. reported that even though the serum Aspergillus galactomannan antigen was negative, the antigen was positive in the cerebrospinal fluid (5). Since the sensitivity of the cerebrospinal fluid fungal culture test is low even for disseminated aspergillosis with central nervous system lesions, it is important to make a diagnosis based on a combination of the cerebrospinal fluid galactomannan antigen test and the Aspergillus PCR test.\n\nRegarding the timing of therapeutic intervention for aspergillosis, previous studies have proposed initiating treatment when serum galactomannan antigen is positive and hyphae are confirmed on chest CT or by a biopsy (7). However, when the neutrophil count is maintained, imaging findings are often insufficent thus making it difficult to make an accurate diagnosis (8). In the present patient, serum Aspergillus antigen was positive, but β-D glucan was weakly positive, and pulmonary nodules were very small, showing no findings suggestive of Aspergillus infection on CT. As such, no therapeutic intervention was performed. A cerebrospinal fluid test could not be performed because of the risk of encephalocele after cerebral hemorrhaging, and a brain biopsy was also not possible because of the patient's poor general condition.\n\nThe present patient was receiving massive steroid therapy and was sensitive to infection, and the serum galactomannan antigen value was high (1.6 C.I.), strongly suggesting aspergillosis. In addition, the capillary vascular abnormality observed in the nail fold region on video microscopy suggested the presence of SSc-induced capillary vascular disorder as background angiopathy. It was also considered that collagen disease-induced angiopathy and steroid-induced vascular wall fragility led to invasion of the vascular wall and organs by Aspergillus hyphae. For the treatment of collagen disease, early therapeutic intervention with antifungal agents may be desirable when aspergillosis is suspected based on a comprehensive review of the test results.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nLin SJ , Schranz J , Teutsch SM \nAspergillus case-fatality rate: systemic review of the literature . Clin Infect Dis \n32 : 358 -366 , 2001 .11170942 \n2. \nDenning DW , Anderson MJ , Turner G , Latgé JP , Bennett JW \nSequencing the Aspergillus fumigatus genome . Lancet Infect Dis \n2 : 251 -253 , 2002 .11937425 \n3. \nNorlinah MI , Ngow HA , Hamidon BB \nAngioinvasive cerebral aspergillosis presenting as acute ischaemic stroke in a patient with diabetes mellitus . Singapore Med J \n48 : e1 -e4 , 2007 .17245496 \n4. \nAntinori S , Corbellino M , Meroni L , et al \nAspergillus meningitis: a rare clinical manifestation of central nervous system aspergillosis. case report and review of 92 cases . J Infect \n66 : 218 -238 , 2013 .23178421 \n5. \nWinterholler M , Coras R , Geißdörfer W , et al \nFatal mycotic aneurysm of the basilar artery caused by Aspergillus fumigatus in a patient with pituitary adenoma and meningitis . Frontiers in Medicine \n4 : 113 , 2017 .28770205 \n6. \nKami M , Ogawa S , Kanda Y , et al \nEarly diagnosis of central nervous system aspergillosis using polymerase chain reaction, latex agglutination test, and enzyme-linked immunosorbent assay . Br J Haematol \n106 : 536 -537 , 1999 .10460619 \n7. \nMennink-Kersten MASH , Donnelly JP , Verweij PE \nDetection of circulating galactomannan for the diagnosis and management of invasive aspergillosis . Lanset Infect Dis \n4 : 349 -357 , 2004 .\n8. \nLuis Ostrosky-Zeichner \nInvasive mycoses: diagnostic challenges . Am J Med \n125 (1 Suppl ): S14 -S24 , 2012 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(7)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "cerebral hemorrhage; disseminated aspergillosis; systemic lupus erythematosus; systemic sclerosis",
"medline_ta": "Intern Med",
"mesh_terms": "D001228:Aspergillosis; D001344:Autopsy; D002543:Cerebral Hemorrhage; D017809:Fatal Outcome; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D016867:Immunocompromised Host; D008180:Lupus Erythematosus, Systemic; D008875:Middle Aged; D012595:Scleroderma, Systemic",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1023-1027",
"pmc": null,
"pmid": "30568120",
"pubdate": "2019-04-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10460619;11170942;11937425;15172343;17245496;22196205;23178421;28770205",
"title": "An Autopsy Case with Cerebral Hemorrhaging due to disseminated Aspergillosis During Glucocorticoid Therapy for Overlap Syndrome of Systemic Lupus Erythematosus and Systemic Sclerosis.",
"title_normalized": "an autopsy case with cerebral hemorrhaging due to disseminated aspergillosis during glucocorticoid therapy for overlap syndrome of systemic lupus erythematosus and systemic sclerosis"
} | [
{
"companynumb": "JP-FRESENIUS KABI-FK201906694",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": ... |
{
"abstract": "BACKGROUND\nThe actual prescription pattern of immunosuppressive agents in kidney transplantation is unclear.\n\n\nMETHODS\nWe investigated the pattern and trend of immunosuppressive treatment for kidney transplant patients in South Korea. A total of 636 patients at nine transplant centers were enrolled and followed for one year. We reviewed medical records and evaluated induction therapy, as well as the changing pattern and cause of maintenance therapy.\n\n\nRESULTS\nMost patients (n = 621, 97.6%) received induction therapy often comprising basiliximab (n = 542, 85.2%). The triple therapy including calcineurin inhibitor, mycophenolic acid, and steroids was the major initial maintenance immunosuppression (n = 518, 81.4%), but its proportion decreased by 14% (81.4% to 67.5%) after 1 year. Almost 40% of patients changed immunosuppressive regimen during the 1-year follow-up, most often at an early period (60.2% within the first 4 months). The primary reason for the change was gastrointestinal discomfort (n = 113, 29.8%), followed by infection (112, 29.6%). The most common changing pattern was mycophenolic acid withdrawal (n = 155, 39.1%).\n\n\nCONCLUSIONS\nThe initial immunosuppressive regimen is prone to change within the first year of kidney transplantation. Further studies are needed to evaluate the benefits and risks in patients who changed immunosuppressants.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.;Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.;Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.;Transplantation Center, Seoul National University Hospital, Seoul, Republic of Korea.;Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.;Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea.;Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea.;Division of Nephrology, Department of Internal Medicine, Ulsan University Hospital, Ulsan, Republic of Korea.;Division of Nephrology, Department of Internal Medicine, Bong Seng Memorial Hospital, Busan, Republic of Korea.;Department of Surgery, Korea University Anam Hospital, Seoul, Republic of Korea.;Department of Surgery, Ajou University Hospital, Suwon, Republic of Korea.;Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.",
"authors": "Chang|Ji-Yeun|JY|;Yu|Jihyun|J|;Chung|Byung Ha|BH|;Yang|Jaeseok|J|;Kim|Sung-Joo|SJ|;Kim|Chan-Duck|CD|;Lee|Sang-Ho|SH|;Lee|Jong Soo|JS|;Kim|Joong Kyung|JK|;Jung|Cheol Woong|CW|;Oh|Chang Kwon|CK|;Yang|Chul Woo|CW|http://orcid.org/0000-0001-9796-636X",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0183826",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0183826PONE-D-16-49516Research ArticleMedicine and Health SciencesSurgical and Invasive Medical ProceduresTransplantationOrgan TransplantationRenal TransplantationMedicine and Health SciencesSurgical and Invasive Medical ProceduresUrinary System ProceduresRenal TransplantationMedicine and Health SciencesUrologyGenitourinary InfectionsBiology and Life SciencesImmunologyImmune SuppressionMedicine and Health SciencesImmunologyImmune SuppressionMedicine and Health SciencesDiagnostic MedicineSigns and SymptomsImmune SuppressionMedicine and Health SciencesPathology and Laboratory MedicineSigns and SymptomsImmune SuppressionMedicine and Health SciencesPharmaceuticsDrug TherapyReceptor Antagonist TherapyMedicine and Health SciencesPharmacologyDrugsImmunosuppressivesMedicine and Health SciencesEndocrinologyEndocrine DisordersDiabetes MellitusMedicine and Health SciencesMetabolic DisordersDiabetes MellitusMedicine and Health SciencesGastroenterology and HepatologyGastrointestinal InfectionsMedicine and Health SciencesNephrologyMedical DialysisImmunosuppressant prescription pattern and trend in kidney transplantation: A multicenter study in Korea Pattern and trend of immunosuppressant in KTChang Ji-Yeun Data curationFormal analysisValidationVisualizationWriting – original draftWriting – review & editing1Yu Jihyun Data curationValidation1Chung Byung Ha ConceptualizationInvestigationMethodologyProject administrationResourcesSupervision1Yang Jaeseok InvestigationResources2Kim Sung-Joo InvestigationResources3Kim Chan-Duck InvestigationResources4Lee Sang-Ho InvestigationResources5Lee Jong Soo InvestigationResources6Kim Joong Kyung InvestigationResources7Jung Cheol Woong InvestigationResources8Oh Chang Kwon InvestigationResources9http://orcid.org/0000-0001-9796-636XYang Chul Woo ConceptualizationFunding acquisitionInvestigationMethodologyProject administrationResourcesSupervisionWriting – review & editing1*1 \nDivision of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea2 \nTransplantation Center, Seoul National University Hospital, Seoul, Republic of Korea3 \nDepartment of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea4 \nDivision of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea5 \nDivision of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea6 \nDivision of Nephrology, Department of Internal Medicine, Ulsan University Hospital, Ulsan, Republic of Korea7 \nDivision of Nephrology, Department of Internal Medicine, Bong Seng Memorial Hospital, Busan, Republic of Korea8 \nDepartment of Surgery, Korea University Anam Hospital, Seoul, Republic of Korea9 \nDepartment of Surgery, Ajou University Hospital, Suwon, Republic of KoreaRemuzzi Giuseppe EditorIstituto Di Ricerche Farmacologiche Mario Negri, ITALYCompeting Interests: The authors received funding from Novartis Korea, Ltd., a commercial company, for this study. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.\n\n* E-mail: yangch@catholic.ac.kr28 8 2017 2017 12 8 e018382626 12 2016 11 8 2017 © 2017 Chang et al2017Chang et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background\nThe actual prescription pattern of immunosuppressive agents in kidney transplantation is unclear.\n\nMethods\nWe investigated the pattern and trend of immunosuppressive treatment for kidney transplant patients in South Korea. A total of 636 patients at nine transplant centers were enrolled and followed for one year. We reviewed medical records and evaluated induction therapy, as well as the changing pattern and cause of maintenance therapy.\n\nResults\nMost patients (n = 621, 97.6%) received induction therapy often comprising basiliximab (n = 542, 85.2%). The triple therapy including calcineurin inhibitor, mycophenolic acid, and steroids was the major initial maintenance immunosuppression (n = 518, 81.4%), but its proportion decreased by 14% (81.4% to 67.5%) after 1 year. Almost 40% of patients changed immunosuppressive regimen during the 1-year follow-up, most often at an early period (60.2% within the first 4 months). The primary reason for the change was gastrointestinal discomfort (n = 113, 29.8%), followed by infection (112, 29.6%). The most common changing pattern was mycophenolic acid withdrawal (n = 155, 39.1%).\n\nConclusion\nThe initial immunosuppressive regimen is prone to change within the first year of kidney transplantation. Further studies are needed to evaluate the benefits and risks in patients who changed immunosuppressants.\n\nNovartis Korea, Ltd.CERL080AKR10http://orcid.org/0000-0001-9796-636XYang Chul Woo I confirm that this study was funded by Novartis Korea, Ltd. and protocol number was CERL080AKR10 (https://www.novartis.co.kr/). The authors who received the funding were JY, SJK, CDK, SHL, JSL, JKK, CWJ, CKO, CWY. The funder had a role of proposing a multicenter research and making 9 centers participate in the study. The funder did not serve on the editorial board of the journal and did not act as an expert witness in relevant legal proceedings. And the funder did not sit on a committee for an organization benefit from publication of the paper. Data AvailabilityAll relevant data are within the Supporting Information files.Data Availability\nAll relevant data are within the Supporting Information files.\n==== Body\nIntroduction\nThe introduction of calcineurin inhibitors (CNIs) in clinical practice much improved the short-term graft survival rates, but its effects in long-term graft longevity were not significant in kidney transplantation (KT) recipients [1]. Therefore, diverse combination of protocols were developed to improve immunosuppression with minimizing side effect of CNIs., Among them, triple therapy consisting of low-dose tacrolimus (TAC), mycophenolic acid (MPA) and steroid is popular in current practice as a maintenance ISx treatment. However, it is not well known whether the initial immunosuppressive regimens are maintained during the post-transplant periods in real-world medical settings. Therefore, we investigated practices in ISx prescription via national survey and compared the results with those of previous reports.\n\nPatients and methods\nDesign\nWe conducted a multi-center retrospective, chart-review study in order to evaluate the ISx use patterns in patients who underwent KT in South Korea. Trained renal fellows or clinical research coordinators at each center collected the primary data based on identical data-selection criteria. All the investigators reviewed the dataset provided and reorganized the information for analysis according to the study purpose. The local Institutional Review Board (IRB) approved this study at each center and all clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki. Informed consents were waived off owing to the retrospective nature of this study. None of the transplant donors were from a vulnerable population and all donors or next of kin provided written informed consent that was freely given.\n\nIRB approval number: Seoul St. Mary’s Hospital, KC14RSME0215; Seoul National University Hospital, H-1403-127-572; Samsung Medical Center, 2014-04-047; Kyungpook National University Hospital, KNUH 2014-04-026; Kyung Hee University Hospital at Gangdong, KHNMC 2014-03-011; Ulsan University Hospital, UUH 2014-03-019; Korea University Anam Hospital, ED14049; Ajou University Hospital, AJIRB-MED-MDB-14-098; Bong Seng Memorial Hospital, BSIRB-2014-006.\n\nStudy population\nThe study group consisted of patients aged ≥ 18 years who received KT between January 1 and December 31, 2012, at nine transplant centers in South Korea. Patients who received a multi-organ transplant, as well as patients without medical records or laboratory data one year after the KT, were excluded. Of 641 patients, retrieval data were available for 636 transplants. The 5 excluded patients had main characteristics that were similar to the included patients.\n\nData collection\nThe primary data contained demographic information (age, gender, height, and weight), patient’s disease status information (primary renal disease, pre-transplant dialysis status, pre-transplant and post-transplant comorbidities), transplant-related immunological baseline characteristics (transplant number, donor type, T-cell/B-cell cross matching test results by both the complement-dependent cytotoxicity method and the flow cytometry method, percent panel reactive antibody test (PRA), ABO compatibility status, and HLA mismatching number based on three HLA loci (A, B, DR)), details of ISx prescription (induction therapy regimen, initial maintenance regimen type and dose, modifications of ISx with cause and date), and information on allograft function (graft failure, serum creatinine level and estimated glomerular filtration rate (eGFR) calculated using CKD-EPI formula). Serum creatinine level and eGFR were measured at discharge immediately following and one year after the KT.\n\nDefinitions\nClassification of maintenance immunosuppressants\nMaintenance immunosuppressive agents were grouped according to the combination of drugs: 1) CNI-based triple therapy consisting of CNI (CSA or TAC), MPA (mycophenolate mofetil [MMF] or enteric-coated mycophenolate sodium [EC-MPS]), and steroid, 2) steroid-sparing regimen consisting of CNI and MPA, 3) MPA-sparing regimen consisting of CNI and steroid, 4) SRL-based regimen, which is defined as SRL with any drugs, and 5) other regimens.\n\nImmunosuppressant change\nThe “ISx change” was defined as 1) withdrawal of a certain drug, 2) addition of a certain drug, and 3) switching drug “A” to drug “B” during the first year post-transplant. Modifications that were not considered as an ISx change included: 1) dose modification of the same drug, 2) re-administration of the same drug after a temporary stopping, and 3) change based on a typical protocol. All kinds of steroids were regarded as the same drug in this study. For example, if a patient stopped MPA due to infection and restarted after the infection treatments, we considered it as MPA withdrawal due to infection, but not MPA addition due to recovery. The temporary withdrawal of CNI or MPA during anti-thymocyte globulin (ATG) treatment was also not considered as ISx change because it was a routine ATG protocol.\n\nPeriods of time after the transplantation\nThe one year time period of this study period was evenly divided into three groups: 1–4 months, 5–8 months and 9–12 months. We defined these three divisions of the period as the first, second, and third tertile, respectively.\n\nAssessment of post-transplant complications\nAcute rejection included both acute T-cell mediated and acute antibody-mediated rejection which were diagnosed by the pathologist at each center based on the Banff classification scheme [2]. Infection was defined as an illness resulting from any disease-causing organism. Cytomegalovirus (CMV) disease was defined as organ involvement of CMV and BK virus (BKV) infection included BK viremia greater than 10,000 copies /mL or BKV-associated nephropathy proven by allograft biopsy. GI problems included both subjective symptoms, such as abdominal bloating, dyspepsia, and pain, as well as objective sign like diarrhea or constipation. Cardiovascular events included myocardial infarction and symptomatic heart failure (NYHA class II to IV). Diabetes mellitus (DM) complications included uncontrolled blood glucose, DM foot, DM retinopathy, diabetes ketoacidosis and hyperglycemic hyperosmolar nonketotic coma. Bone marrow suppression was defined as a state with neutropenia (white blood cell count < 4000 per microliter), and/or thrombocytopenia (platelet count < 150,000 per microliter). Anemia was not included due to the obscurity of onset. Nephrotoxicity was given a presumptive definition. When kidney function was a affected without evidence of rejection, clinicians considered the ISx having nephrotoxicity. Graft failure was defined as the re-establishment of long-term dialysis treatment.\n\nStatistical analyses\nDescriptive statistics were used in all analyses. We presented continuous data as means ± standard deviations (SD) or median with interquartile ratio, and categorical data as counts or frequencies. The Mann-Whitney U test was used to compare the nonparametric continuous data, while the Fisher’s exact test was used to compare the categorical data. All analyses were conducted by using the IBM SPSS Statistics 24 software (Armonk, NY: IBM Corp.).\n\nResults\nBaseline characteristics\nIncluded patients were in mid-40s with a 3-year-duration of dialysis, and 16.7% were preemptive KT. Glomerulonephritis was a leading cause of ESRD, followed by DM. Donor type was living-donor-basis (60.4%), and most patients were non-sensitized. However, a small number of ABO incompatible, HLA-sensitized and re-transplant patients were also included (Table 1).\n\n10.1371/journal.pone.0183826.t001Table 1 Baseline characteristics of kidney transplant recipients at registration.\nVariable\tValue\t\nRecipient age\t45.4±12.7\t\nRecipient, male, n (%)\t377 (59.3)\t\nDeceased donor, n (%)\t252 (39.6)\t\nRetransplantation, n (%)\t45 (7.1)\t\nDialysis modality, preemptive: HD: PD\t106: 442: 124\t\nDuration of dialysis, months\t36.0 (6.0–71.0)\t\nCauses of ESRD, n (%)\t\t\n\tGlomerulonephritis\t226 (35.5)\t\n\tUnknown\t149 (23.4)\t\n\tDiabetes mellitus\t112 (17.6)\t\n\tHypertension\t87 (13.7)\t\n\tPolycystic kidney disease\t37 (5.8)\t\n\tLupus nephritis\t8 (1.3)\t\n\tReflux nephropathy\t4 (0.6)\t\n\tOthers\t13 (2.0)\t\nTotal HLA mismatch number\t3.3±1.6\t\nPanel reactive antibody, n (%)\t\t\n\tClass I > 50%\t49 (7.7)\t\n\tClass II > 50%\t30 (4.7)\t\nCross matching test positivity, n (%)\t\t\n\tT-cell\t6 (0.9)\t\n\tB-cell\t18 (2.8)\t\nABO incompatibility\t85 (13.4)\t\nContinuous variables with normal distributions are presented with mean±S.D, whereas continuous variables with non-normal distributions are presented with median (interquartile range)\n\nAbbreviations: HD, hemodialysis; PD, peritoneal dialysis; ESRD, end stage renal disease; HLA, human leukocyte antigen\n\nInduction therapy\nTable 2 shows the characteristics and graft outcome of KT recipients with or without induction and as a type the induction regimen. Most of the patients (n = 621, 97.6%) all but 15 (2.4%) underwent induction ISx therapy. Basiliximab, an anti-CD25 antibody, was a more commonly used agent (n = 542, 85.2%) than ATG (n = 79, 12.4%). The use of ATG was greater in highly sensitized patients, deceased-donor transplants, re-transplants, and ABO incompatible transplants. ISx change was more frequent in patients with ATG induction than in patients without ATG induction (Table 2). The graft failure rate and graft function were not different with or without induction therapy, nor were they different between basiliximab or ATG induction.\n\n10.1371/journal.pone.0183826.t002Table 2 Characteristics according to induction therapy.\n\tTotal Study Population\tPatients with Induction Tx.\t\n\tInduction(-)\tInduction(+)\tp-value\tBasiliximab\tATG\tp-value\t\n\tn = 15\tn = 621\t\tn = 542\tn = 79\t\t\nAge\t42.8±13.0\t45.4±12.6\t0.191\t45.1±12.9\t47.6±10.7\t0.061\t\nMale, n (%)\t11 (73.3)\t366 (58.9)\t0.301\t321 (59.2)\t45 (57.0)\t0.715\t\nDDKT, n (%)\t0 (0.0)\t252 (40.6)\t0.001\t206 (38.0)\t46 (58.2)\t0.001\t\nRetransplant, n (%)\t0 (0.0)\t45 (7.2)\t0.616\t30 (5.5)\t15 (19.0)\t<0.001\t\nHighly sensitized, n (%)\t1 (6.7)\t77 (12.4)\t0.708\t53 (9.8)\t24 (30.4)\t<0.001\t\nABO incompatibility, n (%)\t2 (13.3)\t83 (13.5)\t1.000\t66 (12.3)\t17 (21.5)\t0.033\t\nISx Change, n (%)\t1 (6.7)\t250 (40.3)\t0.007\t204 (37.6)\t46 (58.2)\t0.001\t\nGraft Failure, n (%)\t0 (0.0)\t2 (0.3)\t1.000\t2 (0.4)\t0 (0.0)\t1.000\t\neGFR (mL/min/1.73m2)\t\t\t\t\t\t\t\n\tAt KT\t74.7±20.1\t72.2±25.1\t0.704\t72.6±24.7\t69.1±27.4\t0.250\t\n\t1-year after KT\t65.7±13.2\t63.9±21.1\t0.748\t64.4±21.1\t60.4±21.0\t0.115\t\n\t∆eGFR (1 year)\t-7.1 (28.2)\t-8.0 (23.2)\t0.960\t-7.6 (23.1)\t-10.2 (26.3)\t0.641\t\nContinuous variables with normal distributions are presented with mean±S.D.\n\nContinuous variables without normal distributions are presented with median (interquartile range).\n\n∆eGFR represented the slope of eGFR between the time of discharge and 1-year after the transplantation.\n\nAbbreviation: Tx., treatment; ATG, anti-thymocyte globulin; DDKT, deceased-donor kidney transplantation; ISx, immunosuppressant; eGFR, estimated glomerular filtration rate.\n\nInitial and one-year maintenance therapy\nThe majority of KT recipients (81.4%) started their maintenance ISx with TAC-based triple therapy. All patients initially used CNI, and the proportion of TAC and CSA was 87.7% and 12.3%, respectively. Of MPA, MMF was predominant as compared with EC-MPS at the time of the KT (53.1% vs. 40.1%). On average, patients received 1.4 g of MMF and 0.8 g of EC-MPS. The dose of both MPA was higher in patients receiving TAC than in patients receiving CSA (MMF, 1439.4 mg vs. 1433.0 mg, p-value = 0.940; EC-MPS, 875.9 mg vs. 598.6 mg, p-value <0.001).\n\nAt one year, CNI-based triple regimen was still the most common ISx, but its use had decreased by 14% compared to that at the time of KT (81.4 to 67.5%). On the contrary, the prescription rate of steroid-sparing (11.3 to 13.2%) and SRL-based regimens (0.3 to 7.5%) increased. The total MPA prescription rate had decreased compared with the initial rate (93.1 to 82.1%), but the absolute number of KT recipients with EC-MPS increased, thereby resulting in a reverse MMF to EC-MPS ratio (1.3 to 0.9) (Table 3, Fig 1).\n\n10.1371/journal.pone.0183826.g001Fig 1 Initial and one-year CNI and MPA prescription\nThe vertical bar graph illustrates the prescription frequency of CNI (A) and MPA (B) at discharge and one year after the transplant. In terms of CNI, TAC is far more prescribed than CSA is (At KT, 558 vs. 78; 1yr after KT, 531 vs. 91). In terms of MPA, the beginning stage prescription for MMF is more than that for EC-MPS, but after one year, EC-MPS prescription rate exceeds that of MMF (At KT, 337 vs. 255; 1yr after KT, 241 vs. 281). Abbreviation: TAC, tacrolimus; CSA, cyclosporine A; CNI, calcineurin inhibitor; KT, kidney transplantation; yr, year; MPA, mycophenolic acid; MMF, mycophenolic mofetil; EC-MPS, enteric-coated mycophenolate sodium.\n\n10.1371/journal.pone.0183826.t003Table 3 Maintenance immunosuppression regimen.\nGroup\tAt Discharge after the KT\tOne Year after the KT\t\n1: CNI + MPA + Corticosteroid\t518 (81.4)\t429 (67.5)\t\n2: CNI + MPA\t72 (11.3)\t84 (13.2)\t\n3: CNI + Corticosteroid\t40 (6.3)\t38 (6.0)\t\n4: srl-based\t2 (0.3)\t48 (7.5)\t\n5: others\t4 (0.6)\t37 (5.8)\t\nData account for the number (%) of the patient; total number = 636.\n\nAbbreviation: KT, kidney transplantation; CNI, calcineurin inhibitor, MPA, mycophenolic acid; SRL, sirolimus.\n\nTime and frequency of overall immunosuppressant changes\nAlmost half of all patients (39.5%) changed their maintenance ISx one or more times during the first year after the KT (1.51 per person per year). Within one year, a total of 379 ISx changing cases with 396 changing patterns existed; in 16 cases, 2 to 3 types of ISx changing patterns were applied simultaneously (eg. withdrawal of both MPA and steroid). A majority of them (60.2%) occurred in the first 4 months (Fig 2).\n\n10.1371/journal.pone.0183826.g002Fig 2 Immunosuppressive regimen change within one year.\nThe sunburst graph on the left side represents the proportion of immunosuppression regimen changes and the bar graph on the right side represents the number of immunosuppressant changes as a function of the post-transplant period. A 39.5% of transplant recipients changed their ISx within one year of the transplant. Abbreviation: ISx, immunosuppressant.\n\nCause of immunosuppressive regimen change\nOf the 379 ISx changes, the primary cause of the change was a GI problem (n = 113, 29.8%) followed by infection (n = 112, 29.6%), hematologic abnormality (n = 25, 6.6%), and simplification of the medication dose (n = 17, 4.5%). Acute rejection (n = 15, 4.0%), hair loss (n = 15, 4.0%) and nephrotoxicity (n = 9, 2.4%) also resulted in ISx changes (Fig 3). GI problems mostly developed in the first tertile after the KT, and were the leading cause of ISx changes during the early transplant period. On the other hand, infection occurred steadily during the first year of KT and became the most common cause of ISx change in the second and third tertile (Fig 4). Infection was reported 121 times in 87 recipients, with 112 (92.6%) of them causing the ISx change. Among the infectious complications, CMV infection was most common (n = 28, 25%), followed by BKV infection (n = 25, 22.3%).\n\n10.1371/journal.pone.0183826.g003Fig 3 Causes of immunosuppressive regimen change.\nThe horizontal bar graph represents the causes of ISx change in order of frequency. The total number of changing cases was 379. GI problems most commonly resulted in ISx changes (113 times, 29.8%), followed by infection (112 times, 29.6%). Abbreviation: GI, gastrointestinal; BM, bone marrow; DM, diabetes mellitus; ISx, immunosuppressant.\n\n10.1371/journal.pone.0183826.g004Fig 4 Three main reasons of immunosuppressant change according to post-transplant periods.\nThe grouped vertical bar graph represents the frequency of the 3 most common causes of ISx according to post-KT periods evenly divided in to three sections. Black bars represent GI problem-induced ISx change, gray bars represent infection-induced ISx change, and white bars represent ISx change due to bone marrow suppression. All of three causes of ISx change were common in the first tertile period. The GI problem was the most common in the first tertile period, while infection became the main cause of the ISx change in the second and third tertile periods. Abbreviation: KT, kidney transplantation; GI, gastrointestinal; ISx, immunosuppressant.\n\nChanging pattern of immunosuppression\nThe most common pattern of the ISx change was MPA withdrawal (n = 155), followed by MMF to EC-MPS conversion (n = 86). Table 4 shows the cause of the MPA withdrawal. The clinicians opted to discontinue MPA in their patients due to various complications including infection, GI problems and bone marrow suppression. However, for the patients who complained of GI discomfort, many clinicians recommended switching from MMF to EC-MPS first. The SRL conversion was the third most common ISx pattern, observed in 46 cases. Among these, the conversion for better adherence to treatment with a once daily dosing occurred in 34.8% of patients (Table 4, Fig 5).\n\n10.1371/journal.pone.0183826.g005Fig 5 The changing pattern of immunosuppressants.\nThe horizontal bar graph represents the changing pattern of ISx in order of the frequency. The total number of the changing cases was 379. MPA withdrawal was the most common changing pattern (155 occurrences, 40.9%), followed by the conversion from MMF to EC-MPS (86 occurrences, 22.7%). Abbreviation: MPA, mycophenolic acid; MMF, mycophenolate mofetil; EC-MPS, enteric-coated mycophenolate sodium; SRL, sirolimus; CNI, calcineurin inhibitor; TAC, tacrolimus; CSA, cyclosporine A; MIZ, mizoribine; ISx, immunosuppressant.\n\n10.1371/journal.pone.0183826.t004Table 4 Changing patterns of immunosuppression according to causes.\nCause of Change\tThe Most Common Pattern (n)\tThe 2nd Most Common Pattern (n)\t\nGastrointestinal adverse event\tMMF to EC-MPS (72)\tMPA withdrawal (29)\t\nInfection\tMPA withdrawal (83)\tSRL conversion (8)\t\nBone marrow suppression\tMPA withdrawal (22)\tSteroid withdrawal (4)\t\nDose of simplicity\tSRL conversion (16)\tCSA to TAC (1)\t\nAcute rejection\tSRL conversion (4)\tCSA to TAC (3)\t\nHair loss\tTAC to CSA (8)\tMMF to EC-MPS (7)\t\nnephrotoxicity\tSRL conversion (7)\tCSA to TAC (1)\t\nDM complications\tSteroid withdrawal (3)\tTAC to CSA (2)\t\nmalignancy\tSRL conversion (3)\tMPA withdrawal (1)\t\ncardiovascular toxicity\tMPA withdrawal (2)\tCNI withdrawal (1)\t\nothers\tMPA withdrawal (17)\tSteroid withdrawal (13)\t\nData account for the number (%) of immunosuppression changing pattern; total number = 396.\n\nAbbreviation: GI, gastrointestinal; MMF, mycophenolic mofetil; EC-MPS, enteric-coated mycophenolate sodium; MPA, mycophenolic acid; SRL, sirolimus; CNI, calcineurin inhibitor; CSA, cyclosporine A; TAC, tacrolimus.\n\nAllograft function according to immunosuppressants change\nThere were two cases of graft failure and both occurred in patients who changed their ISx therapy. The one-year graft function was worse in the deceased-donor transplants than in the living-donor transplants (eGFR: 60.3 mL/min vs. 66.4 mL/min, p-value < 0.001), in patients using CSA than in those using TAC (eGFR: 57.8 mL/min vs. 64.8 mL/min, p-value = 0.005), worse in patients receiving CNI-based triple therapy than in those receiving other regimens (eGFR: 62.5 mL/min vs. 70.4 mL/min, p-value < 0.001), and worse in the ISx change group (eGFR: 59.7 mL/min vs. 66.8 mL/min, p-value < 0.001) (Table 5).\n\n10.1371/journal.pone.0183826.t005Table 5 Characteristics according to immunosuppression change.\n\tISx Change\t\nYES\tNO\tp-value\t\n(n = 251)\t(n = 385)\t\t\nAge\t46.7 ± 12.4\t44.6 ± 12.7\t0.043\t\nMale, n (%)\t137 (54.6)\t240 (62.3)\t0.058\t\nDDKT, n (%)\t105 (41.8)\t147 (38.2)\t0.363\t\nRetransplantation, n (%)\t20 (8.0)\t25 (6.5)\t0.528\t\nHighly sensitized, n (%)\t38 (15.1)\t40 (10.4)\t0.084\t\nABO incompatibility\t38 (15.1)\t47 (12.3)\t0.341\t\nInduction with ATG, n (%)\t46 (18.4)\t33 (8.9)\t0.001\t\nAcute rejection, n (%)\t68 (27.1)\t67 (17.4)\t0.004\t\nGRAFT FAILURE, N (%)\t2 (0.8)\t0 (0.0)\t0.155\t\nEGFR (mL/min/1.73m2)\t\t\t\t\n\tAt discharge after KT\t70.0 ± 26.3\t73.7 ± 24.0\t0.066\t\n\tOne year after KT\t59.7 ± 23.2\t66.8 ± 18.9\t< 0.001\t\n\t∆ eGFR (1 year)\t- 10.1 (23.1)\t- 6.5 (22.6)\t0.021\t\nContinuous variables with normal distributions are presented with mean±S.D.\n\nContinuous variables without normal distributions are presented with median (interquartile range).\n\n∆eGFR represented the slope of eGFR between the time of discharge and 1-year after the transplantation.\n\nAbbreviation: ISx, immunosuppressant; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; KT, kidney transplantation.\n\nDiscussion\nSeveral studies on ISx prescription trends have been reported [3–7]. Compared to other studies, this study focused on the actual prescription pattern for ISx changes, and the specific reasons behind each change. The results of our study clearly demonstrate that a considerable number of patients (39.5%) changed their ISx and most of those changes occurred due to drug-related events or medical events during the early transplant period. These findings suggest that clinicians should consider benefits and risk of choosing ISx in KT recipients.\n\nInduction therapy was prescribed for most of the patients in this study (97.6%) with basiliximab in 85.2% of cases. This choice was appropriate according to the Kidney Disease: Improving Global Outcome (KDIGO) guideline in that an interleukin-2 receptor antagonist is recommended as the first-line induction therapy in all kidney transplant recipients [8]. The reason for preferential use of basiliximab, rather than ATG, may be based on its excellent efficacy and safety, as confirmed in large meta-analysis of randomized trials, as well as its lower risk of CMV infection and malignancy compared to that of ATG [8, 9]. On the other hand, the recent Scientific Registry of Transplant Recipients (SRTR) data in the USA showed a dominant position of ATG in the induction therapy [7]. The reason for the difference in proportion with the induction regimen between the two countries may be due to different donor types (proportion of deceased donor) and immunologic risk (proportion of sensitized patients).\n\nAn initial ISx therapy containing biologics induction plus low-dose TAC-based triple therapy has been broadly accepted based on the Symphony study [10, 11]. Most recipients in our study (81.4%) also received the initial maintenance therapy with a CNI-based triple regimen, and TAC was used seven times more frequently than CSA was (87.7% vs. 12.3%). Most centers favored the CNI-based triple therapy, but two centers initially chose either a steroid-free regimen (n = 72) or an MPA-free regimen (n = 40). These dual regimens comprised 17.6% of all patients; the immunological risk of patients receiving dual therapy was similar to the others. Taken together, most maintenance ISx therapies comprise a CNI-based triple regimen, but selection of ISx is also influenced by center practice.\n\nAfter one year, the proportion of CNI-based triple therapy decreased by 14% (81.4% to 67.5%). On the other hand, the proportion of SRL-based regimens increased by 7.4% (0.3 to 7.7%), and that of steroid-free regimens increased by 1.9% (11.3 to 13.2%). The proportion of SRL-based regimens steadily increased, eventually leading to a decrease in CNI-based triple therapy. Interestingly, one-third of SRL conversions occurred due to the simplicity of a once daily dose (34.8%), and other causes were BKV infection (17.4%), nephrotoxicity (15.2%), and post-transplant malignancy (6.5%). In general, SRL is considered a replacement for CNIs due to its lower nephrotoxicity and anti-oncogenic effects. However, the results of our study suggested that the dose of simplicity for adherence was also important in determining the maintenance regimen.\n\nImportant finding of this study was that the most common cause of ISx change was GI problem and MPA was the most easily changed ISx. Our study revealed that clinicians chose two options (MMF to EC-MPS conversion or MPA withdrawal) when patients complained of GI discomforts, and favored converting to EC-MPS rather than MPA withdrawal (63.7% vs. 22.3%). The reason for higher rate of EC-MPS conversion may be related to previous reports indicating that EC-MPS conversion in KT recipients improved the GI tolerability of MPA treatment with maintaining immunosuppression [12–14]. Considering MMF-related GI discomforts and conversion rate of EC-MPS, it is also considerable to choose EC-MPS as an initial ISx.\n\nInfection was the second most common cause of ISx change and common infectious causes were CMV disease (28 out of 112) and BKV infection (25 out of 112). For both virus infections, the most common pattern of ISx change was MPA withdrawal (71.4% for CMV and 44.0% for BKV). Compared to that for CMV disease, diverse options of ISx change exist with BKV infection including SRL conversion (28%), steroid withdrawal (12%) and conversion from TAC to CSA (8%). Treatment selection from these approaches may be dependent on the immunological risk of the recipients. However, a randomized control study is needed to identify the proper ISx change in BKV infection.\n\nWe also evaluated the time period of ISx change after the KT. In this study, more than half of the changes occurred during the first tertile period, and GI problem was common causes, while infection became the main cause of ISx change in the second and third tertile periods. Since ISx changes were mostly attributed to GI problems (97 out of 228) and CMV disease (21 out of 58 infectious causes) in the first tertile, both MPA withdrawal (92 out of 234) and MMF to EC-MPS conversion (80 out of 234) occurred with similar frequencies in patients during this period. In the second tertile, SRL conversion was the second most common pattern (24 out of 98) following MPA withdrawal, along with an increase in the prevalence of BKV infection (20% for the first tertile, 56% for the second tertile, 24% for the third tertile). MMF to EC-MPS conversion rarely occurred since second tertile. These findings suggest that ISx is changeable during early transplant period, and strategy for reducing risk factors (GI complication and BKV infection) is needed for maintaining initial ISx.\n\nBecause MPA was the most easily changed ISx, we further evaluated the MPA dose. Asian patients have a higher MPA exposure than do Caucasian or African American patients with a comparable MMF dose. For this reason, MMF dose in Asian transplant recipients may be reduced to 20% to 46% lower than in Caucasian or African American patients [15–18]. In this study, the average dose of both MMF and EC-MPS (1.4 g and 0.8 g, respectively) was lower than in Western countries. In this study, the mean dose of MMF was not statistically different between patients with side-effects and patients without side-effects (1382 mg vs. 1486 mg, p-value = 0.058). But the mean dose of EC-MPS was higher in patients with side-effects compared to patients without side-effects (925 mg vs. 788 mg, p-value = 0.002). The optimal dose of MMF or EC-MPS in Asian patients is still undetermined but the dose should be reduced considering the high prevalence of MPA-related complications in this study.\n\nThere was an unexpected finding of our study. CSA-using patients are generally expected to require a higher MPA dose than TAC-using patients due to a lower MPA exposure [19]. Here, the MPA dose in TAC-using patients was higher than in CSA-using patients. These opposite results may be explained by a higher immunological risk of patients using TAC than that of patients using CSA, and may suggest the need for a pharmacokinetic study in patients with complications, even in those with low-dose MPA.\n\nThere were some limitations in this study. Our study was conducted retrospectively for short-term duration of one year. Therefore, prospective and long-term follow-up study is needed to evaluate whether early change of ISx affects the long-term graft survival. In addition, we did not analyze the center effect. There is a report that the ISx choice was largely driven by center practice [4]. However, our study showed relatively uniform pattern of ISx protocol, and center effect was not strong to affect overall ISx prescription pattern. Taken together, our study provides a guidance regarding the ISx prescription to KT clinicians. Further researches including clinical trials and data analyses are necessary in order to achieve the better immunosuppressive therapy and allograft outcome.\n\nIn conclusion, current ISx with triple therapy is prone to be changed within one year in KT recipients. More detailed strategy for maintaining immunosuppression is needed in clinical practice.\n\nSupporting information\nS1 File The individual data of kidney transplant recipients.\n(XLSX)\n\nClick here for additional data file.\n\n We would like to thank HJ Kim (OR/RWE Manager, Novartis Korea, Ltd.) for data collection and preparation of manuscript and SO An (biostatician, Dream CIS) for statistical analysis of the raw data.\n==== Refs\nReferences\n1 Lamb KE , Lodhi S , Meier-Kriesche HU . Long-term renal allograft survival in the United States: a critical reappraisal . American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons . 2011 ;11 (3 ):450 –62 . Epub 2010/10/27. doi: 10.1111/j.1600-6143.2010.03283.x .20973913 \n2 Sis B , Mengel M , Haas M , Colvin RB , Halloran PF , Racusen LC , et al\nBanff '09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups . American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons . 2010 ;10 (3 ):464 –71 . Epub 2010/02/04. doi: 10.1111/j.1600-6143.2009.02987.x .20121738 \n3 Saemann MD , Sunder-Plassmann G . Maintenance immunosuppressive therapy in adult renal transplantation: a single center analysis . Transplant immunology . 2008 ;20 (1–2 ):14 –20 . Epub 2008/09/23. doi: 10.1016/j.trim.2008.08.012 .18804533 \n4 Axelrod DA , Naik AS , Schnitzler MA , Segev DL , Dharnidharka VR , Brennan DC , et al\nNational Variation in Use of Immunosuppression for Kidney Transplantation: A Call for Evidence-Based Regimen Selection . American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons . 2016 ;16 (8 ):2453 –62 . Epub 2016/02/24. doi: 10.1111/ajt.13758 .26901466 \n5 Ali AA , Al-Saedi AJ , Al-Mudhaffer AJ , Al-Taee KH . Five years renal transplantation data: Single-center experience from Iraq . Saudi journal of kidney diseases and transplantation: an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia . 2016 ;27 (2 ):341 –7 . Epub 2016/03/22. doi: 10.4103/1319-2442.178559 .26997389 \n6 Ponticelli C . Present and future of immunosuppressive therapy in kidney transplantation . Transplantation proceedings . 2011 ;43 (6 ):2439 –40 . Epub 2011/08/16. doi: 10.1016/j.transproceed.2011.06.025 .21839286 \n7 Hart A , Smith JM , Skeans MA , Gustafson SK , Stewart DE , Cherikh WS , et al\nKidney . American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons . 2016 ;16 \nSuppl 2 :11 –46 . Epub 2016/01/13. doi: 10.1111/ajt.13666 .26755262 \n8 Kasiske BL , Zeier MG , Chapman JR , Craig JC , Ekberg H , Garvey CA , et al\nKDIGO clinical practice guideline for the care of kidney transplant recipients: a summary . Kidney international . 2010 ;77 (4 ):299 –311 . Epub 2009/10/23. doi: 10.1038/ki.2009.377 .19847156 \n9 Webster AC , Playford EG , Higgins G , Chapman JR , Craig JC . Interleukin 2 receptor antagonists for renal transplant recipients: a meta-analysis of randomized trials . Transplantation . 2004 ;77 (2 ):166 –76 . Epub 2004/01/27. doi: 10.1097/01.TP.0000109643.32659.C4 .14742976 \n10 Ekberg H , Tedesco-Silva H , Demirbas A , Vitko S , Nashan B , Gurkan A , et al\nReduced exposure to calcineurin inhibitors in renal transplantation . The New England journal of medicine . 2007 ;357 (25 ):2562 –75 . Epub 2007/12/21. doi: 10.1056/NEJMoa067411 .18094377 \n11 Ekberg H , Bernasconi C , Tedesco-Silva H , Vitko S , Hugo C , Demirbas A , et al\nCalcineurin inhibitor minimization in the Symphony study: observational results 3 years after transplantation . American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons . 2009 ;9 (8 ):1876 –85 . Epub 2009/07/01. doi: 10.1111/j.1600-6143.2009.02726.x .19563339 \n12 Salvadori M , Holzer H , de Mattos A , Sollinger H , Arns W , Oppenheimer F , et al\nEnteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients . American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons . 2004 ;4 (2 ):231 –6 . Epub 2004/02/21. doi: 10.1046/j.1600-6143.2003.00337.x .14974944 \n13 Budde K , Curtis J , Knoll G , Chan L , Neumayer HH , Seifu Y , et al\nEnteric-coated mycophenolate sodium can be safely administered in maintenance renal transplant patients: results of a 1-year study . American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons . 2004 ;4 (2 ):237 –43 . Epub 2004/02/21. doi: 10.1046/j.1600-6143.2003.00321.x .14974945 \n14 Hwang HS , Hyoung BJ , Kim S , Oh HY , Kim YS , Kim JK , et al\nImproved gastrointestinal symptoms and quality of life after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in renal transplant patients receiving tacrolimus . Journal of Korean medical science . 2010 ;25 (12 ):1759 –65 . Epub 2010/12/18. doi: 10.3346/jkms.2010.25.12.1759 ; PubMed Central PMCID: PMCPMC2995230.21165291 \n15 Li P , Shuker N , Hesselink DA , van Schaik RH , Zhang X , van Gelder T . Do Asian renal transplant patients need another mycophenolate mofetil dose compared with Caucasian or African American patients? \nTransplant international: official journal of the European Society for Organ Transplantation . 2014 ;27 (10 ):994 –1004 . Epub 2014/06/26. doi: 10.1111/tri.12382 .24963914 \n16 Suhail SM , Vathsala A , Lou HX , Woo KT . Safety and efficacy of mycophenolate mofetil for prophylaxis in Asian renal transplant recipients . Transplantation proceedings . 2000 ;32 (7 ):1757 –8 . Epub 2000/12/20. .11119922 \n17 Tsang WK , Tong KL , Yeung S , Lee W , Chan HW . Efficacy and safety of mycophenolate mofetil in different dosages in Asian renal allograft recipients . Transplantation proceedings . 2000 ;32 (7 ):1755 –6 . Epub 2000/12/20. .11119921 \n18 Cho EK , Han DJ , Kim SC , Burckart GJ , Venkataramanan R , Oh JM . Pharmacokinetic study of mycophenolic acid in Korean kidney transplant patients . Journal of clinical pharmacology . 2004 ;44 (7 ):743 –50 . Epub 2004/06/17. doi: 10.1177/0091270004266634 .15199079 \n19 Grinyo JM , Ekberg H , Mamelok RD , Oppenheimer F , Sanchez-Plumed J , Gentil MA , et al\nThe pharmacokinetics of mycophenolate mofetil in renal transplant recipients receiving standard-dose or low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus: the Symphony pharmacokinetic substudy . Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association—European Renal Association . 2009 ;24 (7 ):2269 –76 . Epub 2009/04/10. doi: 10.1093/ndt/gfp162 .19357111\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "12(8)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D056910:Republic of Korea",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0183826",
"pmc": null,
"pmid": "28846737",
"pubdate": "2017",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "20121738;11119922;21839286;15199079;19847156;18804533;24963914;21165291;20973913;18094377;19357111;14974945;19563339;26901466;14742976;14974944;26997389;11119921;26755262",
"title": "Immunosuppressant prescription pattern and trend in kidney transplantation: A multicenter study in Korea.",
"title_normalized": "immunosuppressant prescription pattern and trend in kidney transplantation a multicenter study in korea"
} | [
{
"companynumb": "KR-ROCHE-2004190",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nEpoprostenol and treprostinil are prostacyclins indicated for the treatment of pulmonary arterial hypertension (PAH). Although there is literature describing the conversion of intravenous (IV) epoprostenol to IV treprostinil or IV treprostinil to oral treprostinil, there is little data on the direct conversion of IV epoprostenol to oral treprostinil. In this case, we describe the direct conversion of IV epoprostenol to oral treprostinil without an intermediary conversion to IV treprostinil.\n\n\nCONCLUSIONS\nA 39 year-old female with PAH was admitted for altered mental status and self-removal of her peripherally inserted central catheter (PICC) used for IV epoprostenol. Given the unplanned hospitalization, absence of a dedicated central line for IV prostacyclin therapy, and concern the patient may remove a future subcutaneous line, the patient was transitioned to oral treprostinil. Of note, despite triple PAH therapy, the patient was unable to reach a low risk group based on her prognostic risk assessment. A right heart catheterization four months prior found severe PAH with a pulmonary arterial pressure of 79/32 mmHg (mean, 49 mmHg) and pulmonary vascular resistance of 10.6 Wood units. To expedite the transition, the patient was directly converted from IV epoprostenol to oral treprostinil without an intermediary conversion to IV treprostinil. A target oral treprostinil dose of 5 mg TID was calculated based on 110% of the IV epoprostenol dose (19 ng/kg/min) utilizing the conversion recommended by the medication manufacturer. Every 8 hours, IV epoprostenol was decreased by 2 ng/kg/min and oral treprostinil was increased by 0.5 mg. The target oral treprostinil dose of 5 mg TID was reached 72 hours after conversion initiation. Three hours after the final titration, the patient was discharged home on room air.\n\n\nCONCLUSIONS\nIn this case, rapid transition from IV epoprostenol to oral treprostinil was achieved in 72 hours without reported adverse effects.",
"affiliations": "Department of Pharmacy, University of New Mexico Hospital, Albuquerque, NM, USA.;Department of Pharmacy, University of New Mexico Hospital, Albuquerque, NM, USA.",
"authors": "Sarangarm|Preeyaporn|P|;Elwood|Kirsten|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ajhp/zxab239",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": null,
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": "derivatives; dosage; epoprostenol/administration & epoprostenol/analogs & epoprostenol/therapeutic use; hypertension; pulmonary/drug therapy; pulmonary/therapy",
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": null,
"nlm_unique_id": "9503023",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34100906",
"pubdate": "2021-06-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Transition from IV epoprostenol to oral treprostinil in a patient with group 1 pulmonary arterial hypertension.",
"title_normalized": "transition from iv epoprostenol to oral treprostinil in a patient with group 1 pulmonary arterial hypertension"
} | [
{
"companynumb": "US-AUROBINDO-AUR-APL-2022-010323",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LORAZEPAM"
},
"drugadditional": "4",
... |
{
"abstract": "OBJECTIVE\nCertain patients with treatment-refractory schizophrenia may be rechallenged with clozapine following previous neutropenia. Evidence guiding patient selection and the effectiveness of lithium and granulocyte-colony stimulating factor (G-CSF) in rechallenge is limited, and factors associated with successful outcomes are unclear.\n\n\nMETHODS\nOutcomes were studied in patients rechallenged with clozapine at a tertiary referral center between January 2007 and December 2013, following 1 or more previous trials terminated due to neutropenia, defined as an absolute neutrophil count (ANC) < 1.5 × 10(9)/L. Demographic characteristics, details of each clozapine trial including ANC, and coprescribed medication were extracted, and factors associated with rechallenge outcomes were examined.\n\n\nRESULTS\nNineteen patients underwent clozapine rechallenge following previous neutropenia; 4 (21%) experienced further neutropenia, 2 of which developed agranulocytosis. Compared to successfully rechallenged patients, unsuccessfully rechallenged patients were significantly older (t = 2.10, P = .05), experienced onset of neutropenia sooner (W = 10.0, P = .03), and were more commonly coprescribed valproate. In addition to 5 patients with benign ethnic neutropenia (BEN), 8 patients not of an ethnicity associated with BEN also had idiopathic low neutrophil counts at baseline; lithium and G-CSF coprescription facilitated successful rechallenge in these patients.\n\n\nCONCLUSIONS\nIn this selected population, the initial neutropenia was unlikely to be related to clozapine in a substantial proportion of cases. This group was successfully rechallenged following careful consideration of the risks and benefits, and lithium and G-CSF contributed to allowing continued clozapine therapy. In addition to black patients, other ethnic groups can have persistently low ANC unrelated to clozapine.",
"affiliations": "Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, 16 De Crespigny Park, London SE5 8AF, UK nicholas.meyer@kcl.ac.uk.",
"authors": "Meyer|Nicholas|N|;Gee|Siobhan|S|;Whiskey|Eromona|E|;Taylor|David|D|;Mijovic|Aleksandar|A|;Gaughran|Fiona|F|;Shergill|Sukhi|S|;MacCabe|James H|JH|",
"chemical_list": "D018692:Antimanic Agents; D014150:Antipsychotic Agents; D018020:Lithium Compounds; D016179:Granulocyte Colony-Stimulating Factor; D014635:Valproic Acid; D003024:Clozapine",
"country": "United States",
"delete": false,
"doi": "10.4088/JCP.14m09326",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-6689",
"issue": "76(11)",
"journal": "The Journal of clinical psychiatry",
"keywords": null,
"medline_ta": "J Clin Psychiatry",
"mesh_terms": "D000328:Adult; D018692:Antimanic Agents; D014150:Antipsychotic Agents; D003024:Clozapine; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D007958:Leukocyte Count; D018020:Lithium Compounds; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D009504:Neutrophils; D017063:Outcome Assessment, Health Care; D012559:Schizophrenia; D014635:Valproic Acid; D055815:Young Adult",
"nlm_unique_id": "7801243",
"other_id": null,
"pages": "e1410-6",
"pmc": null,
"pmid": "26646037",
"pubdate": "2015-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Optimizing outcomes in clozapine rechallenge following neutropenia: a cohort analysis.",
"title_normalized": "optimizing outcomes in clozapine rechallenge following neutropenia a cohort analysis"
} | [
{
"companynumb": "GB-PFIZER INC-2016153620",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RAMIPRIL"
},
"drugadditional": null,
... |
{
"abstract": "Pharmacologic hypersensitivities commonly express cutaneous manifestations, and the highest mortality is found in Stevens Johnson's syndrome and toxic epidermal necrolysis, mostly associated with antibiotics and anticonvulsive drugs. Toxic epidermal necrolysis is related in 80% of cases to pharmacologic hypersensitivity and systemic consequences may be found; hepatic injury has been described, but the finding of liver abscesses has not been reported among common injuries. The case of a patient with a rapid development of multiple liver abscesses in the clinical setting of hypersensitivity due to lamotrigine and the discussion of probable etiologies and management is presented.",
"affiliations": "Servicio de Medicina Interna, Hospital Regional de Tlalnepantla, ISSEMyM, Edo. de México.;Servicio de Medicina Interna, Hospital Regional de Tlalnepantla, ISSEMyM, Edo. de México.;Servicio de Medicina Interna, Hospital Regional de Tlalnepantla, ISSEMyM, Edo. de México.;Servicio de Medicina Interna, Hospital Regional de Tlalnepantla, ISSEMyM, Edo. de México.;Servicio de Medicina Interna, Hospital Regional de Tlalnepantla, ISSEMyM, Edo. de México.",
"authors": "Domínguez-Borgúa|Andrés|A|;González|Itzel|I|;Morales|Lucero|L|;Martínez-Carrillo|Francisco Manuel|FM|;Palacios|Paul|P|",
"chemical_list": "D014227:Triazines; D000077213:Lamotrigine",
"country": "Mexico",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-3813",
"issue": "151(4)",
"journal": "Gaceta medica de Mexico",
"keywords": null,
"medline_ta": "Gac Med Mex",
"mesh_terms": "D005260:Female; D006801:Humans; D000077213:Lamotrigine; D008100:Liver Abscess; D008875:Middle Aged; D013262:Stevens-Johnson Syndrome; D014227:Triazines",
"nlm_unique_id": "0010333",
"other_id": null,
"pages": "512-8",
"pmc": null,
"pmid": "26290028",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Toxic epidermal necrolysis and development of liver abscesses.",
"title_normalized": "toxic epidermal necrolysis and development of liver abscesses"
} | [
{
"companynumb": "MX-ALKEM-001159",
"fulfillexpeditecriteria": "1",
"occurcountry": "MX",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": null,
"drug... |
{
"abstract": "Opinions vary on whether buprenorphine can cause impairment in drivers. Relatively little information on the observed effects of buprenorphine, outside a laboratory or a controlled driving course, exist in the literature. The Wisconsin State Laboratory of Hygiene monitored the detection of buprenorphine and its pharmacologically active metabolite, norbuprenorphine (NBUP), in Wisconsin drivers over a 2-year period. A total of 204 individuals (78 females and 126 males) were driving under the influence of buprenorphine and/or NBUP. Concentrations in whole blood (ng/mL) ranged (mean) from 0.6 to 14 (2.0) and 0.5 to 20 (2.1) for buprenorphine and NBUP, respectively. Poly-substance use is extremely prevalent in Wisconsin operating while intoxicated casework, so prevalent that only four of the previously described cases had buprenorphine and/or NBUP as the only drug(s) detected. This paper summarizes and highlights the case histories and observed impairments of those four cases. Law enforcement (LE) made contact with three of the four subjects due to either a crash or poor/reckless driving. Police reports and observations made by LE, including drug recognition expert (DRE) evaluations, were collected. Physical and behavioral observations made by LE varied and included a combination of narcotic analgesic, central nervous system depressant- and stimulant-like effects. Impaired balance and lack of coordination during the administration of the Standardized Field Sobriety Tests were documented by the arresting officers and/or the DRE. While the number of buprenorphine-only cases reported here is limited, the results demonstrate the complex paradigm associated with forensic interpretation of buprenorphine in driving under the influence of drugs casework and the frequency of poly-substance administration in Wisconsin drivers.",
"affiliations": "Wisconsin State Laboratory of Hygiene-Forensic Toxicology Section, University of Wisconsin Madison School of Medicine and Public Health, 2601 Agriculture Drive Madison, WI 53707.",
"authors": "Edwards|Lorrine D|LD|",
"chemical_list": "D000701:Analgesics, Opioid; D002047:Buprenorphine",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkz068",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "43(8)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000701:Analgesics, Opioid; D002047:Buprenorphine; D000066448:Driving Under the Influence; D005260:Female; D053593:Forensic Toxicology; D006801:Humans; D008297:Male; D015813:Substance Abuse Detection; D014922:Wisconsin",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "644-650",
"pmc": null,
"pmid": "31436286",
"pubdate": "2019-09-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Bupenorphine in Wisconsin Drivers: Concerns for Impairment?",
"title_normalized": "bupenorphine in wisconsin drivers concerns for impairment"
} | [
{
"companynumb": "US-MYLANLABS-2019M1113229",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nWe report a case of thyroid storm caused by consuming a Chinese herb contaminated with thyroid hormones.\n\n\nMETHODS\nA 70-year-old man presented to an emergency department after 2 days of nausea, vomiting, and weakness. Three days previously, he had started taking Cordyceps powder and \"Flower Man Sang Hung\" as recommended by his Chinese physician. Following admission, the patient deteriorated and was eventually diagnosed with thyroid storm complicated by rapid atrial fibrillation requiring cardioversion, intubation, and intensive care admission. The analysis of the Chinese herb \"Flower Man Sang Hung\" was positive for levothyroxine. The patient was extubated 11 days after admission and discharged to a rehabilitation centre after 17 days of hospitalization. The Chinese medicine physician was informed of the events.\n\n\nCONCLUSIONS\nHerbal products can be the source of illness, medication interactions, and contamination. Awareness should be raised among Chinese medicine physicians, allopathic physicians, and their patients. Clinicians should also have a low threshold of suspicion to seek laboratory analysis of suspect substances when the cause of the clinical presentation is unclear.",
"affiliations": "Department of Clinical Pharmacology and Toxicology, Fellow for the Ontario & Manitoba Poison Centre, University of Toronto, Intensivist Clinical Associate for the Department of Critical Care Medicine at the Sunnybrook Health Sciences Centre, Toronto, ON, Canada.;Department of Laboratory Medicine, St. Michael Hospital, Toronto, ON, Canada.;Ontario & Manitoba Poison Centre, Program Director of the Clinical Pharmacology and Toxicology program at the University of Toronto, University of Toronto, Toronto, ON, Canada.",
"authors": "St-Onge|Maude|M|;Vandenberghe|Hilde|H|;Thompson|Margaret|M|",
"chemical_list": "D004338:Drug Combinations; D004365:Drugs, Chinese Herbal; D013963:Thyroid Hormones; D013974:Thyroxine",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.892305",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-5923",
"issue": "16()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000368:Aged; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal; D006801:Humans; D008297:Male; D013958:Thyroid Crisis; D013963:Thyroid Hormones; D013974:Thyroxine",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "57-9",
"pmc": null,
"pmid": "25644333",
"pubdate": "2015-02-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24803889;14624907;24452064;23250039;23185404;18363120;21501549;23028841",
"title": "Thyroid storm caused by a chinese herb contaminated with thyroid hormones.",
"title_normalized": "thyroid storm caused by a chinese herb contaminated with thyroid hormones"
} | [
{
"companynumb": "CA-GENUS_LIFESCIENCES-USA-POI0580201700090",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MONTELUKAST SODIUM"
},
"dru... |
{
"abstract": "OBJECTIVE\nA case of systemic lidocaine exposure in a bone marrow transplant recipient with severe hepatic sinusoidal obstruction syndrome (SOS) receiving treatment with lidocaine patch 5% is reported.\n\n\nCONCLUSIONS\nA 35-year-old Caucasian man with a history of refractory acute lymphoblastic leukemia was admitted for a third allogeneic, mismatched, peripheral blood hematopoietic stem cell transplant from an unrelated donor, with a conditioning regimen that included busulfan and fludarabine. The patient was receiving treatment with lidocaine patch 5% (two patches daily, which was started five months before another hospital admission for the treatment of vincristine-related peripheral neuropathy. Baseline laboratory findings were within normal limits except for disease-related neutropenia and thrombocytopenia. Twenty days after hematopoietic stem cell transplantation (HSCT), the patient developed signs and symptoms of severe hepatic SOS. His serum alanine transaminase concentration rose from 65 IU/L at baseline to 370 IU/L, and his serum aspartate transaminase concentration rose from 32 IU/L at baseline to 871 IU/L. His total bilirubin increased to 2.8 mg/dL, and his body weight increased by 15%. An abdominal ultrasound noted ascites and hepatomegaly without reversal of blood flow. The lidocaine patch was discontinued, but the patient's condition continued to deteriorate. He died 38 days after HSCT from complications of severe hepatic SOS.\n\n\nCONCLUSIONS\nA 35-year-old man developed hepatic SOS 20 days after his third HSCT. As a result of his hepatic impairment, the patient, who had been receiving lidocaine patch 5% for the treatment of neuropathic pain, experienced increased systemic exposure to lidocaine, which led to discontinuation of the patch.",
"affiliations": "Karmanos Cancer Institute, Detroit, MI, USA.",
"authors": "Gabra|Bichoy H|BH|;Abidi|Muneer H|MH|;Al-Khadimi|Zaid|Z|;Edwards|David J|DJ|;Ibrahim|Rami B|RB|",
"chemical_list": "D000779:Anesthetics, Local; D008012:Lidocaine",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp100026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "68(2)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000287:Administration, Topical; D000328:Adult; D000779:Anesthetics, Local; D016026:Bone Marrow Transplantation; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D008012:Lidocaine; D008099:Liver; D008297:Male; D012720:Severity of Illness Index; D012869:Skin Absorption; D019172:Transplantation Conditioning; D016896:Treatment Outcome",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "135-7",
"pmc": null,
"pmid": "21200060",
"pubdate": "2011-01-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Systemic absorption of topical lidocaine in a bone marrow transplant recipient with hepatic sinusoidal obstruction syndrome.",
"title_normalized": "systemic absorption of topical lidocaine in a bone marrow transplant recipient with hepatic sinusoidal obstruction syndrome"
} | [
{
"companynumb": "US-TEIKOKU PHARMA USA-TPU2020-00028",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": nu... |
{
"abstract": "OBJECTIVE\nTo report integrated electrocardiogram (ECG) summary and exposure-QTc analyses for avelumab, a human immunoglobulin G1 monoclonal antibody that binds programmed cell death 1 ligand 1, to assess potential effects on cardiac repolarization.\n\n\nMETHODS\nData were pooled from three-phase 1/2 studies of patients with advanced solid tumors who received avelumab monotherapy (22,000 ECGs from 1818 patients). All analyses used 12-lead singlet ECGs taken using local ECG machines before and approximately 2 h after avelumab infusion on prespecified days. The exposure-QTc and outlier analyses used locally read ECGs; since larger variability is known to be associated with local reading, outlier ECGs were subsequently reevaluated by central read. QTc derived from Fridericia's formula (QTcF) and a project-specific formula (QTcP) were analyzed. Multivariable linear mixed-effects models were used to describe the relationship between serum concentration of avelumab and QTc absolute value or change from baseline (ΔQTc).\n\n\nRESULTS\nExposure-QTc models showed that the effect of avelumab on QTc or ΔQTc was minimal and not statistically significant for both QTcP and QTcF. In addition, models including avelumab concentration and diphenhydramine premedication use did not show a clinically meaningful effect on the QT interval. The frequency of QTc outliers in both short and long ranges was overestimated by local reads. Six patients (0.3%) were QTc outliers; all had either received concomitant medication known to cause QT prolongation or had a preexisting cardiac condition.\n\n\nCONCLUSIONS\nAvelumab does not have any clinically relevant effect on cardiac repolarization.",
"affiliations": "Clinical Pharmacology, EMD Serono Research and Development Institute, Inc, 45 Middlesex Turnpike, Billerica, MA, 01821, USA. yulia.vugmeyster@emdserono.com.;Global Clinical Development Immuno-Oncology, Merck KGaA, Darmstadt, Germany.;Global Clinical Development, EMD Serono Research and Development Institute, Inc, Billerica, MA, USA.;Global Biostatistics, Merck KGaA, Darmstadt, Germany.;Clinical Pharmacology, EMD Serono Research and Development Institute, Inc, 45 Middlesex Turnpike, Billerica, MA, 01821, USA.",
"authors": "Vugmeyster|Yulia|Y|;Güzel|Gülseren|G|;Hennessy|Meliessa|M|;Loos|Anja H|AH|;Dai|Haiqing|H|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C000609138:avelumab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-019-03925-z",
"fulltext": "\n==== Front\nCancer Chemother PharmacolCancer Chemother. PharmacolCancer Chemotherapy and Pharmacology0344-57041432-0843Springer Berlin Heidelberg Berlin/Heidelberg 392510.1007/s00280-019-03925-zOriginal ArticleEvaluation of the potential for QTc prolongation with avelumab Vugmeyster Yulia 9789449057yulia.vugmeyster@emdserono.com 1Güzel Gülseren 2Hennessy Meliessa 3Loos Anja H. 4Dai Haiqing 11 Clinical Pharmacology, EMD Serono Research and Development Institute, Inc, 45 Middlesex Turnpike, Billerica, MA 01821 USA 2 grid.39009.330000 0001 0672 7022Global Clinical Development Immuno-Oncology, Merck KGaA, Darmstadt, Germany 3 Global Clinical Development, EMD Serono Research and Development Institute, Inc, Billerica, MA USA 4 grid.39009.330000 0001 0672 7022Global Biostatistics, Merck KGaA, Darmstadt, Germany 3 9 2019 3 9 2019 2019 84 5 1017 1026 23 7 2019 7 8 2019 © The Author(s) 2019Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Purpose\nTo report integrated electrocardiogram (ECG) summary and exposure–QTc analyses for avelumab, a human immunoglobulin G1 monoclonal antibody that binds programmed cell death 1 ligand 1, to assess potential effects on cardiac repolarization.\n\nMethods\nData were pooled from three-phase 1/2 studies of patients with advanced solid tumors who received avelumab monotherapy (22,000 ECGs from 1818 patients). All analyses used 12-lead singlet ECGs taken using local ECG machines before and approximately 2 h after avelumab infusion on prespecified days. The exposure–QTc and outlier analyses used locally read ECGs; since larger variability is known to be associated with local reading, outlier ECGs were subsequently reevaluated by central read. QTc derived from Fridericia’s formula (QTcF) and a project-specific formula (QTcP) were analyzed. Multivariable linear mixed-effects models were used to describe the relationship between serum concentration of avelumab and QTc absolute value or change from baseline (ΔQTc).\n\nResults\nExposure–QTc models showed that the effect of avelumab on QTc or ΔQTc was minimal and not statistically significant for both QTcP and QTcF. In addition, models including avelumab concentration and diphenhydramine premedication use did not show a clinically meaningful effect on the QT interval. The frequency of QTc outliers in both short and long ranges was overestimated by local reads. Six patients (0.3%) were QTc outliers; all had either received concomitant medication known to cause QT prolongation or had a preexisting cardiac condition.\n\nConclusion\nAvelumab does not have any clinically relevant effect on cardiac repolarization.\n\nKeywords\nQT intervalQTcAvelumabPD-L1Solid tumorCancerhttp://dx.doi.org/10.13039/100009945Merck KGaAhttp://dx.doi.org/10.13039/100004319Pfizerhttp://dx.doi.org/10.13039/100004755EMD Seronoissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2019\n==== Body\nIntroduction\nTumor cells exploit immune checkpoint mechanisms, such as the interaction between programmed cell death 1 protein (PD-1) and its ligand programmed cell death 1 ligand (PD-L1), to evade immune responses [1]. Expression of PD-L1 on tumor cells, which binds to PD-1 expressed on CD8+ T cells, inhibits T-cell-mediated destruction of tumor cells [2]. In recent years, several antibodies that inhibit PD-1 or PD-L1 have been approved as anticancer therapeutics [3].\n\nAvelumab is a human immunoglobulin G1 monoclonal antibody that binds specifically to PD-L1, inhibiting the interaction with PD-1 and preventing T-cell exhaustion [2, 4]. Avelumab is approved in multiple countries worldwide for the treatment of metastatic Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma after disease progression with platinum-containing chemotherapy, and has recently been approved by the US Food and Drug Administration in combination with axitinib for the treatment of advanced renal cell carcinoma [5, 6]. Currently, numerous clinical trials of avelumab are ongoing in a range of tumor types [7–9].\n\nDuring a clinical trial program, it is critical to determine whether a drug causes any harmful cardiac effects, such as arrhythmia [10]. Furthermore, prolongation of the QT interval (due to delayed cardiac repolarization) is associated with potentially fatal arrhythmias, including torsades de pointes [10, 11]. Drug-induced QT prolongation has been associated with inhibition of the potassium ion channel encoded by the hERG gene; the proposed mechanisms for this inhibition include disruption of hERG plasma membrane protein trafficking or blockage of the ion-channel cavity [12, 13]. Monoclonal antibodies, such as avelumab, are considered unlikely to cause QT prolongation because they are too large to cross plasma membranes and, as such, are unable to block the inner cavity of the hERG channel [14]; however, some monoclonal antibodies have been found to prolong the QT interval, the mechanism of which is still unknown [15]. Furthermore, cases of immune checkpoint inhibitor-related cardiotoxicity have been reported, which may have been associated with QT prolongation [16], and animal studies have shown that deficiency of CTLA-4 and PD-1 can cause autoimmune myocarditis [17]. Several small-molecule anticancer drugs have also been found to induce QT prolongation, including tyrosine kinase inhibitors, histone deacetylase inhibitors, and BRAF inhibitors [18].\n\nFor all drugs in clinical development, a thorough QT/corrected QT (QTc) analysis of the potential effect on cardiac repolarization is recommended by the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use E14 [10]. In 2015, the ICH updated its guidance to recommend that a concentration–QTc-modeling approach, which uses a prespecified linear mixed-effects model, be used as a potentially alternative method to determine whether a drug has any clinically relevant effect on the QTc interval [19].\n\nThis manuscript presents integrated electrocardiogram (ECG) summary and exposure–QTc analyses, based on the concentration–QTc-modeling approach in accordance with the ICH, to assess the potential effect of avelumab on cardiac repolarization in patients with metastatic or locally advanced solid tumors who were enrolled in three separate clinical studies. In each study, patients received avelumab monotherapy. Premedication with acetaminophen and an antihistamine for the prophylaxis of infusion-related reactions was also required; therefore, many patients received diphenhydramine, and the effect of this premedication on QT prolongation was also included in the exposure–QTc modeling.\n\nMaterials and methods\nStudy design and treatment\nThis analysis pooled data from patients enrolled in three studies of avelumab monotherapy: JAVELIN Solid Tumor (NCT01772004), JAVELIN Solid Tumor JPN (NCT01943461), and JAVELIN Merkel 200 (NCT02155647).\n\nJAVELIN Solid Tumor is a phase 1 study performed in patients with metastatic or locally advanced solid tumors, which included an initial dose-escalation phase [patients (n = 53) received avelumab doses of 1, 3, 10, or 20 mg/kg every 2 weeks (Q2W)] followed by a dose-expansion phase [all patients (n = 1650, as of June 9, 2016) received avelumab 10 mg/kg Q2W] [4, 7, 20]. JAVELIN Solid Tumor JPN is a phase 1 study performed in Japanese patients, comprising a dose-escalation phase in patients with metastatic or locally advanced solid tumors [patients (n = 17) received avelumab doses of 3, 10, or 20 mg/kg Q2W] and a dose-expansion phase in patients with gastric or gastroesophageal junction cancer [all patients (n = 34) received avelumab 10 mg/kg Q2W] [21]. JAVELIN Merkel 200 is a phase 2 study of avelumab 10 mg/kg Q2W in patients with metastatic Merkel cell carcinoma; this analysis included a cohort of patients (n = 88) who had received prior chemotherapy [22, 23].\n\nFull eligibility criteria for each study have been reported previously [4, 7, 21, 22]. In all three studies, patients with clinically significant (i.e., active) cardiovascular disease, specifically cerebrovascular accident/stroke or myocardial infarction < 6 months prior to enrollment, unstable angina, congestive heart failure (New York Heart Association class ≥ II), or serious uncontrolled cardiac arrhythmia requiring medication, were excluded from enrollment. Patients received avelumab treatment until disease progression, unacceptable toxicity, or any protocol-specified criterion for withdrawal occurred. Prior to avelumab, most patients received premedication with an antihistamine, such as diphenhydramine (25–50 mg, modified per local standards), 30–60 min before each avelumab infusion (approximately 66–80% of all patients who received 10 mg/kg avelumab across the three studies also received diphenhydramine). All studies were conducted in accordance with the Good Clinical Practice guidelines as defined by the ICH and the Declaration of Helsinki, and all patients provided informed consent before starting treatment.\n\nQT analyses overview\nA total of 22,000 ECGs from 1818 patients from the three studies were analyzed in the integrated ECG summary analyses. To identify mean changes in QTc absolute values and changes from baseline (ΔQTc) over the treatment period, descriptive statistics were used to analyze locally read ECGs. These locally read ECGs were also analyzed for potentially clinically significant abnormalities to determine outliers in QTc data at both short and long ranges. ECGs that displayed any of the following criteria were classified as “outliers”: heart rate ≤ 50 bpm and decrease from baseline ≥ 20 bpm; heart rate ≥ 120 bpm and increase from baseline ≥ 20 bpm; PR interval ≥ 220 ms and increase from baseline ≥ 20 ms; QRS interval ≥ 120 ms; QTcF or QTcP absolute interval values > 450 to ≤ 480 ms, > 480 to ≤ 500 ms, or > 500 ms; or ΔQTcF or ΔQTcP increase > 30 to ≤ 60 ms or > 60 ms.\n\nSince it has been previously reported that larger variability is associated with local reading of ECGs compared with centralized reading [24], outlier ECGs were subsequently reevaluated by central read. In two further analyses, to compare the outliers from locally and centrally read ECGs, patients were re-sampled and their ECGs were reevaluated by central read; one analysis included a random sampling of patients with two available ECG measurements (one taken at baseline and one at an on-treatment timepoint thereafter) from JAVELIN Solid Tumor and JAVELIN Merkel 200 (n = 180 patients; 360 total ECGs were planned to be analyzed; however, only 264 were available for reevaluation by central read), while the second sample analysis included all patients in the dose-escalation cohorts of JAVELIN Solid Tumor (483 total ECGs taken at screening or baseline or during treatment were analyzed from 53 patients). For the ECG summary analyses, the data cutoff date for JAVELIN Solid Tumor and JAVELIN Merkel 200 was June 9, 2016; for JAVELIN Solid Tumor JPN, the cutoff was November 20, 2015.\n\nTo investigate any potential relationship between avelumab concentration and the QTc interval, all patients from the three studies with ≥ 1 matched pair of pharmacokinetic (PK) and ECG measurements prior to avelumab infusion and within 0–2 h after infusion (2119 paired observations from 670 patients from all three studies) were included in an exposure–QT analysis. For the exposure–QT analysis, the data cutoff date for JAVELIN Solid Tumor and JAVELIN Solid Tumor JPN was November 20, 2015; for JAVELIN Merkel 200, the cutoff was January 20, 2016, and March 3, 2016, for PK and ECG data, respectively.\n\nECG assessments and summary analyses\n12-Lead singlet ECG measurements were taken using a local ECG machine before each avelumab infusion and approximately 2 h after infusion Q2W until week 13 and then every 6 weeks (JAVELIN Solid Tumor and JAVELIN Merkel 200) or 4 weeks (JAVELIN Solid Tumor JPN) thereafter. Patients included in the ECG summary analyses had received ≥ 1 dose of avelumab and had undergone ≥ 1 ECG measurement during the on-treatment period (from day 1 of treatment until ≤ 30 days after last treatment or until subsequent treatment, whichever occurred first).\n\nThe QT interval was corrected to reduce the effect of heart rate using either Fridericiaʼs formula (QTcF=QTRR3; where RR = 60/heart rate) or a project-specific formula (QTcP=QT+b^∗1-RR; where RR = 60/heart rate and b^ is estimated from a linear regression QT=a+b^∗RR), which was derived using all pooled baseline QT and RR data available.\n\nMeasurement of change (Δ) in QTcF/QTcP from baseline required both an evaluable on-treatment and baseline ECG read. ECGs within the treatment period were analyzed for trends using descriptive statistics of absolute values [95% confidence intervals (CIs)] and changes from baseline (90% CIs) for scheduled visits and by study and by dose. In addition, all ECGs were analyzed for potentially clinically significant abnormalities in heart rate, PR interval, QRS interval, QTcF, QTcP, ΔQTcF, and ΔQTcP.\n\nAll evaluable local ECG data with clinically significant prolongation of the QTc interval (QTcP or QTcF ≥ 500 ms or ΔQTcP or ΔQTcF ≥ 60 ms) were reevaluated by certified cardiologists in a central laboratory. All ECG summary statistics were repeated for diphenhydramine premedication as a potential covariate in the analyses; patients had either received no premedication or ≥ 1 dose of diphenhydramine.\n\nIn addition, a random sample of patients enrolled in JAVELIN Solid Tumor and JAVELIN Merkel 200 with two available ECG measurements (including one at baseline) were randomly chosen to have their ECGs reevaluated by central read, irrespective of outlier status. All patients in the dose-escalation cohort of JAVELIN Solid Tumor also had their ECGs reevaluated by central read. These analyses were similar to those of a previous study that compared QTc measurements from digital ECG machines and a centralized core laboratory [24] and were performed to investigate the variability and quality of local reads compared with central reads.\n\nPK assessment and exposure–QTc analysis\nIn the JAVELIN Solid Tumor and JAVELIN Solid Tumor JPN dose-escalation cohorts, serial PK sampling was conducted, including sampling prior to and at the end of the first infusion and at 0.5, 1, 2, 4, 6, 12, 24, 36, and 48 h after infusion (24-, 36-, and 48-h samples were optional in JAVELIN Solid Tumor, and an additional sample was taken at 168 h after infusion in JAVELIN Solid Tumor JPN); in patients from the dose-escalation and dose-expansion cohorts, sparse PK sampling was conducted at trough and/or the end of infusion at multiple visits throughout the study. In JAVELIN Merkel 200, sparse PK sampling was conducted before infusion, at the end of infusion, and at 2 to 8 h after infusion at multiple visits throughout the study.\n\nTo assess the relationship between QTc data and avelumab, ECG time matched with avelumab concentrations was used. The exposure–QTc analysis included all patients who had ≥ 1 time-matched pair of PK and ECG measurements both before and within 2 h after infusion, and QTc data collected both in the presence and absence of diphenhydramine premedication were analyzed. For the exposure–QTc analysis, the following were assumed: more complex or advanced models beyond linear mixed-effects models were not needed to describe the data, any time difference ≤ 2 h between the observed QTc value and its paired avelumab serum concentration value did not affect results, parameters in the linear regression had a normal distribution for calculation of CIs, and the 3 studies had no differences that might affect the QT interval.\n\nFour multivariable linear mixed-effects models were used to describe the quantitative relationship between serum concentration of avelumab and QTc or ΔQTc. The models used were based on the following equation: Yijk=β0+β1Cijk+β2PMijk+α0i+α1iCijk+ϵijk, where Yijk denotes QTc or ΔQTc, i denotes patient, j denotes study day, k denotes nominal time (before infusion/2 h after infusion), β0 denotes intercept, β1 denotes slope of incidence of avelumab concentration (C), β2 denotes premedication (PM) influence, α0i denotes interpatient variability on the intercept, and α1iCijk denotes interpatient variability on the slope. Models 1 and 3 were full models, which contained parameters to determine the effects of both avelumab and diphenhydramine premedication on QTc and ΔQTc, respectively. Models 2 and 4 were reduced models, which did not contain any parameters to measure the effect of diphenhydramine and, as such, only determined the relationship between avelumab and QTc and ΔQTc, respectively. The final models for QTc and ΔQTc data were selected based on the Akaike information criterion (AIC) and Bayesian information criterion (BIC).\n\nResults\nECG summary analyses\nOverall, 22,000 ECGs from 1818 patients, comprising 1681 patients from JAVELIN Solid Tumor, 51 from JAVELIN Solid Tumor JPN, and 86 from JAVELIN Merkel 200, were analyzed. Most patients analyzed had received the 10 mg/kg dose of avelumab (n = 1769); other doses received were 1 mg/kg (n = 4), 3 mg/kg (n = 18), and 20 mg/kg (n = 27).\n\nDescriptive statistics of ECG parameters from patients in JAVELIN Solid Tumor who received the 10 mg/kg dose (n = 1643) were comparable to the parameters in the other studies and dose groups in this analysis. Up to week 49 of treatment in JAVELIN Solid Tumor (10 mg/kg avelumab), mean ΔQTcF and ΔQTcP were < 5 ms before infusion and approximately 5 ms at 2 h after infusion for all timepoints, which included ECGs from ≥ 100 patients, with a 90% CI upper bound of < 10 ms; ΔQTcF values were highly variable, with standard deviations (SDs) of approximately 20.0 ms (range 17.2–27.7 ms).\n\nNo clinically meaningful change in heart rate was observed at any dose level in the three studies (Table 1); no comparison between the three studies could be made due to the uncontrolled study settings. The use of diphenhydramine premedication did not have a clinically meaningful effect on the QT interval; QTcF > 500 ms was observed in 2.2% (30/1369 patients) with premedication and 3.1% (14/449 patients) without premedication.Table 1 Frequency of patients from all studies with potentially clinically significant abnormalities during avelumab treatment at different doses based on locally read ECGs\n\nParameter\tPatients n (%)\t\n1 mg/kg (n = 4)\t3 mg/kg (n = 18)\t10 mg/kg (n = 1769)\t20 mg/kg (n = 27)\tTotal (N = 1818)\t\nHeart rate (bpm)\t\t\t\t\t\t\n ≤ 50 and decrease from baseline ≥ 20\t0 (0.0)\t0 (0.0)\t24 (1.4)\t0 (0.0)\t24 (1.3)\t\n ≥ 120 and increase from baseline ≥ 20\t0 (0.0)\t1 (5.6)\t47 (2.7)\t0 (0.0)\t48 (2.6)\t\nQRS interval (ms)\t\t\t\t\t\t\n ≥ 120\t0 (0.0)\t1 (5.6)\t165 (9.3)\t4 (14.8)\t170 (9.4)\t\nPQ/PR interval (ms)\t\t\t\t\t\t\n ≥ 220 and increase from baseline ≥ 20\t0 (0.0)\t0 (0.0)\t109 (6.2)\t4 (14.8)\t113 (6.2)\t\nQTcF interval (ms)\t\t\t\t\t\t\n > 450 and ≤ 480\t0 (0.0)\t4 (22.2)\t312 (17.6)\t7 (25.9)\t323 (17.8)\t\n > 480 and ≤ 500\t0 (0.0)\t0 (0.0)\t63 (3.6)\t2 (7.4)\t65 (3.6)\t\n > 500\t0 (0.0)\t0 (0.0)\t44 (2.5)\t0 (0.0)\t44 (2.4)\t\nΔQTcF (ms)\t\t\t\t\t\t\n Increase from baseline > 30 and ≤ 60\t0 (0.0)\t7 (38.9)\t393 (22.2)\t6 (22.2)\t406 (22.3)\t\n Increase from baseline > 60\t0 (0.0)\t0 (0.0)\t79 (4.5)\t1 (3.7)\t80 (4.4)\t\nQTcP interval (ms)\t\t\t\t\t\t\n > 450 and ≤ 480\t1 (25.0)\t5 (27.8)\t383 (21.7)\t8 (29.6)\t397 (21.8)\t\n > 480 and ≤ 500\t0 (0.0)\t0 (0.0)\t71 (4.0)\t2 (7.4)\t73 (4.0)\t\n > 500\t0 (0.0)\t0 (0.0)\t41 (2.3)\t0 (0.0)\t41 (2.3)\t\nΔQTcP (ms)\t\t\t\t\t\t\n Increase from baseline > 30 and ≤ 60\t0 (0.0)\t5 (27.8)\t351 (19.8)\t5 (18.5)\t361 (19.9)\t\n Increase from baseline > 60\t0 (0.0)\t0 (0.0)\t65 (3.7)\t2 (7.4)\t67 (3.7)\t\nECG electrocardiogram, QTcF QTc derived from Fridericia’s formula, QTcP QTc derived from a project-specific formula\n\n\n\nBased on locally read ECGs, 103 patients had on-treatment QTcF or QTcP ≥ 500 ms, or ΔQTcF or ΔQTcP ≥ 60 ms (Table 2). A total of 49 of 103 patients were evaluable for central read; patients were unevaluable due to deteriorated ECG paper or failure to send the ECG to the central laboratory before data cutoff. After centralized read, only 1 of 18 patients with QTcF > 500 ms and 5 of 43 patients with ΔQTcF or ΔQTcP > 60 ms were confirmed as outliers. All six patients with confirmed outlier ECGs had preexisting cardiac conditions [atrioventricular block (n = 1), bradycardia (n = 1), coronary artery bypass (n = 2), coronary artery disease (n = 1), hypercholesterolemia (n = 1), hypertension (n = 6), ischemic cardiomyopathy (n = 1), myocardial infarction (n = 1), pacemaker insertion (n = 2), or type 2 diabetes mellitus (n = 2)] or had been concomitantly treated with medication that has been associated with QT interval prolongation [dexchlorpheniramine (n = 1), diphenhydramine (n = 5), escitalopram (n = 1), loratadine (n = 1), ondansetron (n = 3), or oxycodone (n = 1)] [25–29].Table 2 Overview of QTcF or QTcP outliers by local and central ECG read\n\nParameter\tPatients, n\t\nOn-treatment outlier ECGs by local read\tEvaluable ECGs for central read\tOn-treatment outlier ECGs confirmed by central re-read\t\nQTcF or QTcP interval ≥ 500 ms per local machine–read ECG\t45b\t18b\t1\t\nΔQTcF or ΔQTcP ≥ 60 ms per local machinea\t87a,b\t43b\t5\t\nEither condition fulfilled\t103\t49\t6\t\nECG electrocardiogram, QTcF QTc derived from Fridericia’s formula, QTcP QTc derived from a project-specific formula\n\naPatients had evaluable baseline and on-treatment ECGs\n\nbAll evaluable outlier ECGs were centrally re-read\n\n\n\nThe random sample of patients enrolled in JAVELIN Solid Tumor and JAVELIN Merkel 200 (n = 180) provided 360 locally read ECGs that were randomly selected for reevaluation; 264 (73.3%) were evaluable for central read. Overestimation in locally read ECGs with QTcF < 400 ms was negligible with a mean of 0.8 ms; for ECGs with QTcF ≥ 400 ms, the mean overestimation was 10.3 ms (SDs of 14.4 and 15.3 ms, respectively). In the dose-escalation sample analysis (n = 53), locally read ECGs with QTcF < 400 and ≥ 400 ms were found to be overestimated in both short and long ranges, with mean differences of − 7.3 and − 13.9 ms (SDs of 9.4 and 12.0 ms), respectively.\n\nExposure–QTc analysis\nTo assess the quantitative relationship between QTc and drug concentration, 2119 singlet locally read ECGs were analyzed from 670 patients across all three studies who had a baseline ECG measurement; ECGs were time matched with avelumab concentrations measured during PK assessments.\n\nCorrelations between baseline QT, QTcP, and QTcF with the baseline RR interval were calculated (Fig. 1). As expected, a strong correlation was found between QT and RR (r = 0.7916). A weak but statistically significant correlation was found between QTcF and RR (r = 0.1941), whereas no correlation was found between QTcP and RR (r = − 0.0049). Therefore, QTcP was selected as the primary analysis variable; however, all analyses were also performed for QTcF.Fig. 1 Regression of a baseline QT interval vs baseline RR interval (n = 1780, P < 0.0001a, r = 0.7912), b baseline QTcF interval vs baseline RR interval (n = 1780, P < 0.0001a, r = 0.1982), or c baseline QTcP interval vs baseline RR interval (n = 1780, P =0.9024a, r = − 0.0029). QTcF, QTc derived from Fridericia’s formula; QTcP, QTc derived from a project-specific formula. aRefers to test of r = 0\n\n\n\nSeveral multivariable linear mixed-effects models were developed for the exposure–QTc analysis, including full and reduced models that did or did not include a parameter to account for the effect of diphenhydramine (Table 3). For the analysis of QTcP and QTcF, the full model (Model 1) provided a better fit for the data per the AIC and BIC compared with the reduced model (Model 2); therefore, Model 1 was chosen as the final regression model. In Model 1, diphenhydramine induced a 3.9 ms increase in QTcP (90% CI, 2.4–5.5 ms; P < 0.001) and a 4.2 ms increase in QTcF (90% CI, 2.6–5.9 ms; P < 0.001). Avelumab concentration did not significantly affect QTcP or QTcF; when the diphenhydramine effect was accounted for, the serum concentration slope was 0.002 ms/(μg/mL) [90% CI, − 0.003–0.007 ms/(μg/mL); P = 0.512] for QTcP and 0.003 ms/(μg/mL) [90% CI, − 0.002–0.009 ms/(μg/mL); P = 0.310] for QTcF.Table 3 Comparison of regression models for QTc absolute values and ΔQTc vs avelumab concentration including (full model; Models 1 and 3) or not including (reduced model; Models 2 and 4) a parameter for diphenhydramine premedication\n\nParameter\tModel\tVariable\tCoefficient ± SE\tP value\t90% CI\t\nQTcP\t1\tSerum concentration slope, ms/(μg/mL)\t0.002 ± 0.003\t0.512\t− 0.003–0.007\t\nPremedication intercept (ms)\t3.935 ± 0.935\t< 0.001\t2.395–5.475\t\n2\tSerum concentration slope, ms/(μg/mL)\t0.011 ± 0.002\t< 0.001\t0.008–0.015\t\nQTcF\t1\tSerum concentration slope, ms/(μg/mL)\t0.003 ± 0.003\t0.310\t− 0.002–0.009\t\nPremedication intercept (ms)\t4.227 ± 0.993\t< 0.001\t2.592–5.861\t\n2\tSerum concentration slope, ms/(μg/mL)\t0.014 ± 0.002\t< 0.001\t0.010–0.018\t\nΔQTcP\t3\tSerum concentration slope, ms/(μg/mL)\t0.003 ± 0.003\t0.266\t− 0.002–0.009\t\nPremedication intercept (ms)\t3.363 ± 0.918\t< 0.001\t1.851–4.874\t\n4\tSerum concentration slope, ms/(μg/mL)\t0.012 ± 0.002\t< 0.001\t0.008–0.015\t\nΔQTcF\t3\tSerum concentration slope, ms/(μg/mL)\t0.005 ± 0.003\t0.123\t0.000–0.010\t\nPremedication intercept (ms)\t3.610 ± 0.968\t< 0.001\t2.017–5.204\t\n4\tSerum concentration slope, ms/(μg/mL)\t0.014 ± 0.002\t< 0.001\t0.010–0.018\t\nAIC Akaike information criterion, BIC Bayesian information criterion, QTcF QTc derived from Fridericia’s formula, QTcP QTc derived from a project-specific formula\n\nQTcP: AIC(full model) – AIC(reduced model) = − 19.2; ([BIC(full model) − BIC(reduced model)]/2) = − 9.6\n\nQTcF: AIC(full model) − AIC(reduced model) = − 19.8; ([BIC(full model) − BIC(reduced model)]/2) = – 9.9\n\nΔQTcP: AIC(full model) − AIC(reduced model) = − 14.8; ([BIC(full model) − BIC(reduced model)]/2) = − 7.4\n\nΔQTcF: AIC(full model) − AIC(reduced model) = − 15.5; ([BIC(full model) − BIC(reduced model)]/2) = − 7.7\n\n\n\nFor the analysis of ΔQTcP and ΔQTcF, the full model (Model 3) also described the data more adequately than the reduced model (Model 4). In Model 3, diphenhydramine induced a 3.4 ms increase in ΔQTcP (90% CI, 1.9–4.9 ms; P < 0.001) and a 3.6 ms increase in ΔQTcF (90% CI, 2.0–5.2 ms; P < 0.001). Avelumab concentration did not have a statistically significant effect on ΔQTcP or ΔQTcF; the serum concentration slope was 0.003 ms/(μg/mL) [90% CI, − 0.002–0.009 ms/(μg/mL); P = 0.266] for ΔQTcP and 0.005 ms/(μg/mL) [90% CI, 0.0–0.01 ms/(μg/mL); P = 0.123] for ΔQTcF.\n\nAcross scheduled visits in JAVELIN Solid Tumor, the largest geometric mean maximum concentration (Cmax) values at 10 mg/kg (the approved-regimen dose) and 20 mg/kg (the highest dose tested) were 307 and 505 μg/mL, respectively. For patients who received diphenhydramine, the full model (Model 3) predicted a small increase in both ΔQTcP (3.5 and 4.2 ms for avelumab 10 and 20 mg/kg, respectively) and ΔQTcF (3.7 and 4.7 ms for avelumab 10 and 20 mg/kg, respectively), with a 90% CI upper bound of < 7 ms for both the 10 and 20 mg/kg doses (Table 4). For patients who did not receive diphenhydramine, ΔQTc at Cmax would be even smaller.Table 4 Model-predicted ΔQTcP and ΔQTcF at avelumab Cmax in patients who received diphenhydramine in the 10 and 20 mg/kg dose cohorts of JAVELIN Solid Tumor\n\nParameter\tDose level\tObserved maximum geometric mean Cmax (μg/mL)a\tModel-estimated ΔQTc at Cmax (ms)\t90% CI\t\nΔQTcP\t10 mg/kg\t307\t3.492\t(2.141–4.842)\t\n20 mg/kg\t505\t4.172\t(2.066–6.279)\t\nΔQTcF\t10 mg/kg\t307\t3.650\t(2.214–5.087)\t\n20 mg/kg\t505\t4.650\t(2.423–6.877)\t\nCmax maximum serum concentration, QTcF QTc derived from Fridericia’s formula, QTcP QTc derived from a project-specific formula\n\naGeometric mean values are the largest observed concentrations at the end of infusion in JAVELIN Solid Tumor across all visits, where n > 3\n\n\n\nDiscussion\nThe results of these analyses, performed in > 1800 patients with advanced solid tumors pooled from three studies, show that avelumab does not have any clinically relevant effect on cardiac repolarization. These analyses also show that avelumab coadministered with diphenhydramine, which is commonly given prior to avelumab treatment as prophylaxis for infusion-related reactions, does not have a clinically meaningful effect on the QTc interval.\n\nIn this analysis, we analyzed QTc values based on both Fridericia’s formula (QTcF) and a project-specific formula (QTcP) because QTcF did not completely remove the influence of RR on QTc. QTcP was chosen as the primary study endpoint of the exposure–QTc analysis due to its lack of correlation with RR. QTcF was also analyzed because it is commonly used in QTc analyses and, as such, was chosen as the secondary endpoint of the exposure–QTc analysis. Overall, results from the exposure–QTcF and QTcP analyses were consistent. All ECG analyses were repeated to test the effect of diphenhydramine on QTc prolongation, and the exposure–QTc analysis used linear mixed-effects models that included diphenhydramine as a covariant.\n\nThere were limitations associated with this study, including the lack of a controlled setting in which ECG measurements were taken. In the ECG summary analyses, there was a large degree of variation observed across different sites and countries, which made evaluation of the data challenging. Variability in QTcF absolute values resulted in an SD of approximately 20 ms for most timepoints. This variability could have been caused by concomitant medicines (e.g., antiemetics), known effects of diphenhydramine premedication [25], or underlying cardiovascular conditions; however, the analysis of this variation was not possible due to the lack of a placebo or control arm. Despite the aspects of the study design being suboptimal for exposure–QTc and ECG outlier analyses, the analysis objectives were met in accordance with ICH recommendations [19]: data were pooled from multiple studies that used the same methods of ECG measurement and analysis, and covered a wide range of avelumab doses; the exposure–QTc analysis used a robust modeling approach that included diphenhydramine premedication as a covariate; and locally read ECG data were reevaluated in a central laboratory, and the results of which, in line with reports from the previous studies [24], highlight the benefits of centrally read ECGs compared with locally read ECGs.\n\nOnly 6 of the 49 patients with locally read outlier ECGs evaluable for central read had confirmed outlier ECGs after reevaluation by central read (QTcF > 500 ms in one patient and ΔQTcF or ΔQTcP > 60 ms in five patients). All six patients had a history of cardiovascular conditions or were taking concomitant medications known to prolong the QT interval, which could explain the QTc findings.\n\nTo investigate the variability and quality of local reads compared with central reads, two additional ECG analyses were carried out: a random sample analysis of patients from JAVELIN Solid Tumor and JAVELIN Merkel 200 and a sample analysis of patients in the dose-escalation cohorts of JAVELIN Solid Tumor. Results from the random and dose-escalation sample analyses showed that overall QTcF was overestimated by locally read ECGs by a mean of 7.2 and 12.4 ms, respectively. In the dose-escalation sample analysis, overestimation occurred in both short and long ranges; however, in the random sample analysis, the overestimation of outliers in the short range was negligible. Based on these data, it was concluded that the frequency of QTc outliers in both short and long ranges was likely overestimated by local ECG reads. This is in line with previous studies, which have also reported potential overestimation of abnormalities in locally read ECGs compared with centralized reading [24].\n\nIn accordance with the concentration–QTc modeling approach recommended by the ICH E14 [19], we conducted an exposure–QTc analysis to describe the quantitative relationship between QTc and avelumab concentration. Diphenhydramine premedication, which is given prior to most avelumab infusions to reduce infusion-related reactions or for prophylactic purposes, has been reported to be associated with increased QTc prolongation and was, therefore, tested as a covariate in the exposure–QTc analysis. Multivariable regression models showed that diphenhydramine induced a small but significant effect on ΔQTc (ΔQTcP, 3.4 ms; ΔQTcF, 3.6 ms), consistent with the literature-reported risk of QTc prolongation [25]. The slopes of avelumab exposure vs ΔQTcP and ΔQTcF were not statistically different from zero after accounting for the effect of diphenhydramine [ΔQTcP: 0.003 ms/(μg/mL); P = 0.266; ΔQTcF: 0.005 ms/(μg/mL); P = 0.123]; these results showed that avelumab concentration had no statistically significant effect on the QT interval. Previous population PK analyses have suggested that diphenhydramine does not increase serum avelumab concentration (data on file) and, as such, the effect of diphenhydramine observed in this analysis is unlikely to be due to an effect on avelumab concentration.\n\nFor patients coadministered diphenhydramine, the model predicted a small increase in ΔQTc at the avelumab Cmax for the 10 or 20 mg/kg dose, with a 90% CI upper bound of < 7 ms at both 10 and 20 mg/kg. This is below the threshold of concern (95% CI upper bound of 10 ms) [19] and, as such, these results suggest that avelumab coadministered with diphenhydramine does not cause QTc prolongation at the recommended therapeutic dose of 10 mg/kg or up to 20 mg/kg.\n\nThe absence of effect of avelumab on cardiac repolarization was anticipated because its large molecular size may prevent it from crossing plasma membranes and blocking hERG ion channels. Furthermore, the proposed mechanism of action of avelumab is not known to impact cardiac ion transport. These results are in line with QTc analyses of other immune checkpoint inhibitors, including nivolumab [30]. Furthermore, these findings are consistent with the nonclinical drug safety data for avelumab in cynomolgus monkeys, which showed that a high dose of avelumab (140 mg/kg administered every week for 13 weeks) did not cause any effect on cardiovascular function, proarrhythmic risk, or QT interval (data not shown). Finally, based on the data available at the time, an independent analysis carried out in 2016 by the US Food and Drug Administration also concluded that avelumab had no clinically relevant effect on QTc [31].\n\nIn conclusion, the clinical ECG analyses, including ECG summary and exposure–QTc analyses, presented here indicate that avelumab does not have any clinically relevant effect on cardiac repolarization.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors would like to thank the patients and their families, investigators, coinvestigators, and study teams at each of the participating centers and at Merck KGaA, Darmstadt, Germany.\n\nFunding\nThis study was sponsored by EMD Serono, Inc, Billerica, Massachusetts, USA (a business of Merck KGaA, Darmstadt, Germany). The clinical trials reported in this manuscript were sponsored by Merck KGaA, as part of an alliance between Merck KGaA and Pfizer Inc, New York, New York, USA. Biostatistical programming support was provided by Sanjeev Kommera, Global Biostatics, EMD Serono Research and Development Institute, Inc, Billerica, Massachusetts, USA. Medical writing support was provided by ClinicalThinking and funded by Merck KGaA and Pfizer.\n\nCompliance with ethical standards\nConflicts of interest\nY. Vugmeyster declares employment and patents with EMD Serono; H. Dai and M. Hennessy declare employment with EMD Serono; G. Güzel declares employment with Merck KGaA; A.H. Loos declares employment, patents, royalties, stock in, or other intellectual property with Merck KGaA.\n\nEthical approval\nAll studies were conducted in accordance with the Good Clinical Practice guidelines as defined by the International Conference on Harmonisation and Declaration of Helsinki.\n\nInformed consent\nAll patients provided informed consent before starting treatment.\n==== Refs\nReferences\n1. Alsaab HO Sau S Alzhrani R PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome Front Pharmacol 2017 8 561 10.3389/fphar.2017.00561 28878676 \n2. Barkdull S Brownell I PD-L1 blockade with avelumab: a new paradigm for treating Merkel cell carcinoma Cancer Biol Ther 2017 18 937 939 10.1080/15384047.2017.1394552 29172995 \n3. Liu B Song Y Liu D Recent development in clinical applications of PD-1 and PD-L1 antibodies for cancer immunotherapy J Hematol Oncol 2017 10 174 10.1186/s13045-017-0541-9 29195503 \n4. Heery CR O’Sullivan-Coyne G Madan RA Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial Lancet Oncol 2017 18 587 598 10.1016/S1470-2045(17)30239-5 28373007 \n5. Bavencio (avelumab) (2019) [package insert]. Rockland, MA: EMD Serono\n6. Bavencio (avelumab) (2019) [summary of product characteristics]. Darmstadt, Germany: Merck KGaA\n7. Gulley JL Rajan A Spigel DR Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial Lancet Oncol 2017 18 599 610 10.1016/S1470-2045(17)30240-1 28373005 \n8. Le Tourneau C Hoimes C Zarwan C Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the JAVELIN solid tumor trial J Immunother Cancer 2018 6 111 10.1186/s40425-018-0424-9 30348224 \n9. Keilholz U Mehnert JM Bauer S Avelumab in patients with previously treated metastatic melanoma: phase 1b results from the JAVELIN Solid Tumor trial J Immunother Cancer 2019 7 12 10.1186/s40425-018-0459-y 30651126 \n10. Abraham J Tietje C Brouder A The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Handbook of transnational economic governance regimes 2009 Leiden Martinus Nijhoff Publishers 1041 1053 \n11. Roden DM Cellular basis of drug-induced torsades de pointes Br J Pharmacol 2008 154 1502 1507 10.1038/bjp.2008.238 18552874 \n12. Pollard CE Abi Gerges N Bridgland-Taylor MH Easter A Hammond TG Valentin J-P An introduction to QT interval prolongation and non-clinical approaches to assessing and reducing risk Br J Pharmacol 2010 159 12 21 10.1111/j.1476-5381.2009.00207.x 20141516 \n13. Ponte ML Keller GA Di Girolamo G Mechanisms of drug induced QT interval prolongation Curr Drug Saf 2010 5 44 53 10.2174/157488610789869247 20210718 \n14. Vargas HM Bass AS Breidenbach A Scientific review and recommendations on preclinical cardiovascular safety evaluation of biologics J Pharmacol Toxicol Methods 2008 58 72 76 10.1016/j.vascn.2008.04.001 18508287 \n15. Duan J Tao J Zhai M Anticancer drugs-related QTc prolongation, torsade de pointes and sudden death: current evidence and future research perspectives Oncotarget 2018 9 25738 25749 10.18632/oncotarget.25008 29876021 \n16. Ganatra S Neilan TG Immune Checkpoint Inhibitor-Associated Myocarditis Oncologist 2018 23 879 886 10.1634/theoncologist.2018-0130 29802219 \n17. Varricchi G Galdiero MR Marone G Cardiotoxicity of immune checkpoint inhibitors ESMO Open 2017 2 e000247 10.1136/esmoopen-2017-000247 29104763 \n18. Porta-Sánchez A Gilbert C Spears D Incidence, diagnosis, and management of QT prolongation induced by cancer therapies: a systematic review J Am Heart Assoc 2017 6 e007724 10.1161/JAHA.117.007724 29217664 \n19. Garnett C Bonate PL Dang Q Scientific white paper on concentration-QTc modeling J Pharmacokinet Pharmacodyn 2018 45 383 397 10.1007/s10928-017-9558-5 29209907 \n20. Chin K Chand VK Nuyten DSA Avelumab: clinical trial innovation and collaboration to advance anti-PD-L1 immunotherapy Ann Oncol 2017 28 1658 1666 10.1093/annonc/mdx170 28407031 \n21. Doi T Iwasa S Muro K Phase 1 trial of avelumab (anti-PD-L1) in Japanese patients with advanced solid tumors, including dose expansion in patients with gastric or gastroesophageal junction cancer: the JAVELIN Solid Tumor JPN trial Gastric Cancer 2019 22 4 817 827 10.1007/s10120-018-0903-1 30515672 \n22. Kaufman HL Russell J Hamid O Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial Lancet Oncol 2016 17 1374 1385 10.1016/S1470-2045(16)30364-3 27592805 \n23. Kaufman HL Russell JS Hamid O Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥ 1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial J Immunother Cancer 2018 6 7 10.1186/s40425-017-0310-x 29347993 \n24. Kleiman R Litwin J Morganroth J Benefits of centralized ECG reading in clinical oncology studies Ther Innov Regul Sci 2016 50 123 129 10.1177/2168479015597729 30236011 \n25. Shah A Yousuf T Ziffra J Zaidi A Raghuvir R Diphenhydramine and QT prolongation – a rare cardiac side effect of a drug used in common practice J Cardiol Cases 2015 12 126 129 10.1016/j.jccase.2015.06.002 30546575 \n26. Li K Vo K Lee BK Addo N Coralic Z Effect of a single dose of i.v. ondansetron on QTc interval in emergency department patients Am J Health Syst Pharm 2018 75 276 282 10.2146/ajhp161070 29317399 \n27. Fanoe S Jensen GB Sjøgren P Korsgaard MPG Grunnel M Oxycodone is associated with dose-dependent QTc prolongation in patients and low-affinity inhibiting of hERG activity in vitro Br J Clin Pharmacol 2009 67 172 179 10.1111/j.1365-2125.2008.03327.x 19159406 \n28. Singh P Maldonado-Duran JM Drug-induced QT prolongation as a result of an escitalopram overdose in a patient with previously undiagnosed congenital long QT syndrome Case Rep Med 2014 2014 917846 10.1155/2014/917846 25101129 \n29. Poluzzi E Raschi E Godman B Pro-arrhythmic potential of oral antihistamines (H1): combining adverse event reports with drug utilization data across europe PLoS One 2015 10 3 e0119551 10.1371/journal.pone.0119551 25785934 \n30. Agrawal S Waxman I Lambert A Roy A Darbenzio R Evaluation of the potential for QTc prolongation in patients with solid tumors receiving nivolumab Cancer Chemother Pharmacol 2016 77 635 641 10.1007/s00280-016-2980-3 26861469 \n31. Leighton J, Rahman NA, Sridhara R, et al (2016) BLA multidisciplinary review and evaluation: BLA 761049 Bavencio (avelumab). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761049Orig1s000MultidisciplineR.pdf. Accessed May 20 2019\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0344-5704",
"issue": "84(5)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Avelumab; Cancer; PD-L1; QT interval; QTc; Solid tumor",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004562:Electrocardiography; D006801:Humans; D008133:Long QT Syndrome; D009369:Neoplasms",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "1017-1026",
"pmc": null,
"pmid": "31478078",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis",
"references": "30515672;30651126;26861469;25785934;29172995;20210718;29104763;29802219;30348224;29876021;28373007;27592805;30546575;18552874;29347993;28878676;20141516;29209907;29217664;19159406;18508287;30236011;28407031;28373005;29195503;25101129;29317399",
"title": "Evaluation of the potential for QTc prolongation with avelumab.",
"title_normalized": "evaluation of the potential for qtc prolongation with avelumab"
} | [
{
"companynumb": "US-JNJFOC-20191111024",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AVELUMAB"
},
"drugadditional": "3",
"dr... |
{
"abstract": "Diaphragm disease (DD) of the small bowel is a rarely reported complication of non-steroidal anti-inflammatory drug (NSAID) use, characterised by diaphragm-like strictures, most commonly in the ileum, causing varying degrees of obstruction. It typically presents in the elderly, over many years with non-specific symptoms. Diagnosis is challenging, the majority of cases relying on histopathology for confirmation. Treatment involves NSAID cessation and surgery through a combination of stricturoplasties and/or segmental resection. Very rarely DD presents as a surgical emergency. A case presenting as acute small bowel obstruction (SBO) is described, initially diagnosed as adhesions, later confirmed to be DD of the terminal ileum following histopathological examination. Given the widespread use of NSAIDs and an ageing population, it is likely the incidence of DD will increase. It is, therefore, important that surgeons are aware of this disease entity and consider it as a potential diagnosis in patients presenting with acute SBO.",
"affiliations": "Cambridge Oesophago-Gastric Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK stevebennett@doctors.org.uk.;Cambridge Oesophago-Gastric Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.;Histopathology Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.;Cambridge Oesophago-Gastric Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.",
"authors": "Bennett|Stephen|S|;Martin|Jack|J|;Mahler-Araujo|Betania|B|;Gourgiotis|Stavros|S|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D003287:Contrast Media",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-233537",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(2)",
"journal": "BMJ case reports",
"keywords": "drugs: gastrointestinal system; gastrointestinal surgery; rheumatoid arthritis; unwanted effects/adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003250:Constriction; D003287:Contrast Media; D005260:Female; D006801:Humans; D007415:Intestinal Obstruction; D007421:Intestine, Small; D000267:Tissue Adhesions; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32034000",
"pubdate": "2020-02-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diaphragm disease of the terminal ileum presenting as acute small bowel obstruction.",
"title_normalized": "diaphragm disease of the terminal ileum presenting as acute small bowel obstruction"
} | [
{
"companynumb": "GB-VISTAPHARM, INC.-VER202003-000666",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN\\HYDROCODONE"
},
"dr... |
{
"abstract": "We report a case of an acquired Bartter-like syndrome (BLS) after 3 days of treatment initiation and improved after discontinuation of colistin therapy in pediatric intensive care unit. A 2-month-old girl with spinal muscular atrophy type 1 who had respiratory distress received colistin therapy with a dose of 5 mg/kg/day for Acinetobacter baumannii complex isolation from endotracheal aspirate on the 12th day follow-up. Polyuria (6 mL/kg/hour) in the presence of normal blood pressure and hypokalemic metabolic alkalosis were developed on the 3rd day of colistin treatment. Colistin was stopped on the 4th day, and 2 days after discontinuation of colistin, polyuria improved dramatically. Her metabolic alkalosis and hypokalemia discontinued after 2 and 4 days, respectively. There are very few reports about colistin-induced BLS. The onset of polyuria, hypokalemia, and metabolic alkalosis during treatment with colistin and resolution after interruption suggest a causative relationship. How to cite this article: Yavas DP, Ekinci F, Horoz OO, Gundeslioglu OO, Atmis B, Yildizdas D. Acquired Bartter-like Syndrome Presenting with Polyuria and Reversible Hypokalemia Associated with Colistin Use in a Critically Ill Pediatric Patient. Indian J Crit Care Med 2021;25(7):822-824.",
"affiliations": "Department of Pediatric Intensive Care, Cukurova University, Faculty of Medicine, Adana, Turkey.;Department of Pediatric Intensive Care, Cukurova University, Faculty of Medicine, Adana, Turkey.;Department of Pediatric Intensive Care, Cukurova University, Faculty of Medicine, Adana, Turkey.;Department of Pediatric Infectious Disease, Cukurova University, Faculty of Medicine, Adana, Turkey.;Department of Pediatric Nephrology, Cukurova University, Faculty of Medicine, Adana, Turkey.;Department of Pediatric Intensive Care, Cukurova University, Faculty of Medicine, Adana, Turkey.",
"authors": "Yavas|Damla P|DP|https://orcid.org/0000-0002-0424-4155;Ekinci|Faruk|F|https://orcid.org/0000-0001-6675-3150;Horoz|Ozden O|OO|https://orcid.org/0000-0001-7590-650X;Gundeslioglu|Ozlem O|OO|https://orcid.org/0000-0003-2202-7645;Atmis|Bahriye|B|https://orcid.org/0000-0002-1133-4845;Yildizdas|Dincer|D|https://orcid.org/0000-0003-0739-5108",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.5005/jp-journals-10071-23898",
"fulltext": "\n==== Front\nIndian J Crit Care Med\nIndian J Crit Care Med\nIJCCM\nIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine\n0972-5229\n1998-359X\nJaypee Brothers Medical Publishers\n\n10.5005/jp-journals-10071-23898\nCase Report\nAcquired Bartter-like Syndrome Presenting with Polyuria and Reversible Hypokalemia Associated with Colistin Use in a Critically Ill Pediatric Patient\nYavas Damla P 1https://orcid.org/0000-0002-0424-4155\n\nEkinci Faruk 2https://orcid.org/0000-0001-6675-3150\n\nHoroz Ozden O 3https://orcid.org/0000-0001-7590-650X\n\nGundeslioglu Ozlem O 4https://orcid.org/0000-0003-2202-7645\n\nAtmis Bahriye 5https://orcid.org/0000-0002-1133-4845\n\nYildizdas Dincer 6https://orcid.org/0000-0003-0739-5108\n\n1–3,6 Department of Pediatric Intensive Care, Cukurova University, Faculty of Medicine, Adana, Turkey\n4 Department of Pediatric Infectious Disease, Cukurova University, Faculty of Medicine, Adana, Turkey\n5 Department of Pediatric Nephrology, Cukurova University, Faculty of Medicine, Adana, Turkey\nDamla P Yavas, Department of Pediatric Intensive Care, Cukurova University, Faculty of Medicine, Adana, Turkey, Phone: +90 322 458 68 68, e-mail: damlapinaryavas@gmail.com\n7 2021\n25 7 822824\nCopyright © 2021; Jaypee Brothers Medical Publishers (P) Ltd.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ © Jaypee Brothers Medical Publishers. 2021 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial 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.\nAbstract\n\nWe report a case of an acquired Bartter-like syndrome (BLS) after 3 days of treatment initiation and improved after discontinuation of colistin therapy in pediatric intensive care unit. A 2-month-old girl with spinal muscular atrophy type 1 who had respiratory distress received colistin therapy with a dose of 5 mg/kg/day for Acinetobacter baumannii complex isolation from endotracheal aspirate on the 12th day follow-up. Polyuria (6 mL/kg/hour) in the presence of normal blood pressure and hypokalemic metabolic alkalosis were developed on the 3rd day of colistin treatment. Colistin was stopped on the 4th day, and 2 days after discontinuation of colistin, polyuria improved dramatically. Her metabolic alkalosis and hypokalemia discontinued after 2 and 4 days, respectively.\n\nThere are very few reports about colistin-induced BLS. The onset of polyuria, hypokalemia, and metabolic alkalosis during treatment with colistin and resolution after interruption suggest a causative relationship.\n\nHow to cite this article: Yavas DP, Ekinci F, Horoz OO, Gundeslioglu OO, Atmis B, Yildizdas D. Acquired Bartter-like Syndrome Presenting with Polyuria and Reversible Hypokalemia Associated with Colistin Use in a Critically Ill Pediatric Patient. Indian J Crit Care Med 2021;25(7):822–824.\n\nKeywords\n\nBartter-like syndrome\nColistin\nHypokalemia\nPediatric\nPolyuria\n==== Body\nIntroduction\n\nColistin is a polypeptide antibiotic that belongs to the polymyxin class of cationic polypeptide antibiotics.1 The emergence of multidrug-resistant, gram-negative bacterial infections has resulted in a significant increase in the use of intravenous colistimethate sodium.2 Colistin has dose-dependent bactericidal effect and also postantibiotic effect against Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumonia.3,4 Although colistin-associated nephrotoxicity has been previously reported on a wide range in the literature, there are very few reports about colistin-induced Bartter-like syndrome (BLS). BLS develops during treatment with different classes of drugs and is presented with hypokalemic metabolic alkalosis, hypomagnesemia, hypocalcemia, and normal serum creatinine levels.5 Herein we report a 2-month-old infant of an acquired BLS after 3 days of treatment initiation and improved after discontinuation of colistin therapy in pediatric intensive care unit (ICU).\n\nCase Descriptions\n\nA 2-month-old girl with spinal muscular atrophy type 1, receiving high-flow nasal cannula (HFNC) due to respiratory distress, was transferred from another hospital to our pediatric ICU. On admission, she was slightly tachycardiac with a heart rate of 136/ minute, blood pressure was 111/63 mm Hg, SpO2 was 100%, and capillary refilling was 2 seconds. On physical examination, she had tachypnea and her intercostal retractions and auscultation of the lungs revealed bilateral secretory rales. Preliminary blood gas and complete blood count were as follows: pH: 7.38, pCO2: 55 mm Hg, pO2: 83 mm Hg, HCO3: 26, lactate: 1.3 mmol/L, Hb:9.4 g/dL, WBC: 8.9 × 103 µL, platelets: 403 × 103 µL, BUN: 1.2 mg/dL, creatinine: 0.06 mg/dL, albumin: 34 g/L, sodium: 136 mEq/L, potassium: 4 mg/dL, phosphate: 4.2 mg/dL, calcium: 9.8 mg/dL, magnesium: 2 mg/dL, and procalcitonin: 0.2 ng/mL (0–0.5 normal range). We continued HFNC oxygen therapy and cefotaxime treatment for her pneumonia that she was already receiving. On the 2nd day of intensive care hospitalization, she required noninvasive ventilation through bilevel positive airway pressure due to the recurrent apneic episodes. The patient developed progressively increasing respiratory distress, and her chest X-ray showed new-onset infiltrates in the lower lobe of the left lung. Lung ultrasound showed increased localized B-lines in the zone 1 of the right lung. Meropenem and amikacin were initiated to extend the antimicrobial spectrum, and cefotaxime was discontinued.\n\nOn the 10th day follow-up, due to the persistence of recurrent apnea and worsening of respiratory failure while in noninvasive ventilation, patient underwent tracheostomy. Two days after tracheostomy procedure, patient's ventilatory pressures needed to be increased and she developed worsening respiratory distress despite invasive mechanical ventilation. A. baumannii complex (105 colony) was isolated from endotracheal aspirate that is sensitive only to colistin. Intravenous colistin was initiated with a dose of 5 mg/kg/day and divided into two equal doses. The patient received amikacin with colistin, and meropenem therapy was discontinued.\n\nPolyuria (6 mL/kg/hour) in the presence of normal blood pressure and hypokalemic metabolic alkalosis developed on the 3rd day of colistin treatment. The patient did not have any diarrhea or vomiting. Serum sodium, magnesium, calcium, chloride, and serum creatinine concentrations were within the normal range. Her blood test revealed serum potassium 2.5 mg/dL, albumin 25 g/L, and serum bicarbonate 29 mEq/L that increased to 35 mEq/L on the 4th day of colistin therapy. Polyuria with urine output was around 6–8 mL/kg/hour. Urine studies showed urine spot potassium was 25 mEq/L and urine potassium creatinine ratio was 2:3 mEq/mg. Urine density was 1003. Renal ultrasonography was normal. Colistin was stopped on the 4th day; meropenem and tigecycline were initiated. Daily potassium supplementation was given. Daily intravenous fluid supplementation was increased by 30%.\n\nTwo days after discontinuation of colistin, polyuria improved dramatically. Her metabolic alkalosis and hypokalemia discontinued after 2 and 4 days, respectively. On the 23rd day of hospitalization, her pneumonia showed regression, tracheal aspirate cultures showed any bacterial growth, and she was discharged to the general ward. The daily urine output, serum potassium, bicarbonate and pH levels were shown in Figure 1.\n\nFig. 1 Graphical representation of serum potassium, serum bicarbonate, and 24-hour urinary output trend. Day 12: Colistin started; Day 15: Colistin stopped\n\nDiscussion\n\nPharmacological studies on nephrotoxicity mechanisms of colistin have been neglected because it was off the market for a long time.6 Renal damage due to colistin is considered a result of its detergent activity for many years, but it induces membrane permeability, increases intracellular cations, anions, and water, and results in cell lysis, which have been proposed to be due to colistin's nephrotoxicity mechanism. In animal studies, antioxidant therapies have shown promising results in protecting the kidney.7 Colistin nephrotoxicity is defined as an increase in serum creatinine to a level of >2 mg/dL, a 50% reduction in GFR, or a decline in renal function leading to a need for renal replacement therapy.8 It is usually reversible.\n\nBartter syndrome (BS) is an autosomal recessive disease characterized by hypokalemia, hypochloremia, metabolic alkalosis, and hypercalciuria. Renin and aldosterone levels are increased, but blood pressure is normal. Primary pathology in BS is in the thick ascending limb of the loop of Henle.9 As a result of the influence of Na/K/2Cl, apical K, and basal chloride channels in the membrane, renal wasting of Na, K, and Cl occurs. Volume depletion also develops. BLS develops during treatment with different classes of drugs, including tuberculostatics and aminoglycosides, and is characterized by hypokalemic metabolic alkalosis, hypomagnesemia, hypocalcemia, and normal serum creatinine levels. It is unclear how prolonged use of colistin can cause such tubulopathy.\n\nIn recent case reports, BLS due to colistin therapy has been reported in only one child case who is a preterm infant. Following the literature, a total of five cases who developed BLS after colistin therapy have been reported; however, only two cases reported having polyuria after a short time (3–4 days) of colistin therapy. The association of colistin with hypokalemia was reported previously.10 We know about aminoglycoside-induced BLS. Colistin may directly activate the calcium-sensing receptor in the thick ascending loop of Henle and the distal tubule similar to aminoglycosides and result in hypokalemia, metabolic alkalosis, hypocalcemia, hypomagnesemia, and hypercalciuria.7–11\n\nIn our case, BLS developed on the 3rd day of colistin treatment, and she had already received amikacin for 12 days; symptoms disappeared only after colistin was discontinued. Also, amikacin treatment was continued after colistin, making it a causative factor, and not taking any diuretics suggests that colistin is the causative drug. In recent case reports, the onset of BLS after starting colistin therapy was, respectively, 3 days, 4 days, 9 days, 2 weeks, and 4 weeks. Only hypokalemia was developed with polyuria in the patient, and other electrolytes and serum creatinine levels were normal. We did not continue colistin because of significant hypokalemia and polyuria, and the patient also showed a remarkable improvement in lung function and other markers of sepsis after changing the treatment.\n\nConclusion\n\nOur case received colistin 5 mg/kg/day in two doses, and there is not any literature about the dosage and frequency of colistin administration for tubulopathies beside serum creatinine levels. The onset of the metabolic alterations during treatment with colistin and resolution after interruption suggest a causative relationship. More pharmacological studies are needed about colistin's nephrotoxicity and tubulopathy in critically ill children.\n\nHighlights\n\nColistin should be considered as the causative agent for BLS. BLS due to colistin therapy has been reported in a total of five cases, and only one of them was a child, that is, a preterm infant.\n\nAuthors’ Contributions\n\nD.P.Y., F.E., O.O.H., O.O.G., B.A., and D.Y. treated the patient and were responsible for the concept, design, and acquisition of data. D.P.Y. wrote the first draft of the manuscript; F.E., O.O.H., and D.Y. revised and edited the manuscript. O.O.G. and B.A. collected the data and were responsible for the literature search. All authors read and approved the final version of the manuscript.\n\nConsent\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nEthical Standard\n\nWe confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. All authors approved the final article.\n\nOrcid\n\nDamla P Yavas https://orcid.org/0000-0002-0424-4155\n\nFaruk Ekinci https://orcid.org/0000-0001-6675-3150\n\nOzden O Horoz https://orcid.org/0000-0001-7590-650X\n\nOzlem O Gundeslioglu https://orcid.org/0000-0003-2202-7645\n\nBahriye Atmis https://orcid.org/0000-0002-1133-4845\n\nDincer Yildizdas https://orcid.org/0000-0003-0739-5108\n\nSource of support: Nil\n\nConflict of interest: None\n==== Refs\nReferences\n\n1. Li J Nation RI Turnidge JD Milne RW Coulthard K Rayner CR et al. Colistin: the re-emerging antibiotic for multidrug-resistant Gram negative bacterial infections. Lancet Infect Dis 2006 6 9 589 601 DOI: 10.1016/S1473-3099(06)70580-1 16931410\n2. Tabish M Mahendran M Ray A Vikram NK. Colistin-induced acquiredBartter-like syndrome: an unusual cause of meltdown. BMJ Case Rep 2020 13 e232630 DOI: 10.1136/bcr-2019-232630\n3. Poirel L Jayol A Nordmann P. Polymyxins: antibacterial activity, susceptibility testing, and resistance mechanisms encoded by plasmids or chromosomes. Clin Microbiol Rev 2017 30 2 557 596 DOI: 10.1128/CMR.00064-16 28275006\n4. Javan AO Shokouhi S Sahraei Z. A review on colistin nephrotoxicity. Eur J Clin Pharmacol 2015 71 7 801 810 DOI: 10.1007/s00228-015-1865-4 26008213\n5. Cakir U Alan S Zeybek C Erdeve O Atasay B Yalcinkaya F et al. Acquired bartter-like syndrome associated with colistin use in a preterm infant. Ren Fail 2013 35 3 411 413 DOI: 10.3109/0886022X.2012.761084 23342992\n6. Gai Z Samodelov SL Kullak-Ublick GA Visentin M. Molecular mechanisms of colistin-induced nephrotoxicity. Molecules 2019 24 3 653 DOI: 10.3390/molecules24030653\n7. Berg JR Spilker CM Lewis SA. Modulation of polymyxin B effects on mammalian urinary bladder. Am J Physiol 1998 275 2 F204 F215 DOI: 10.1152/ajprenal.1998.275.2 9691009\n8. Florescu DF Qiu F McCartan MA Mindru C Fey PD Kalil A. What is the efficacy and safety of colistin for the treatment of ventilator-associated pneumonia? A systematic review and meta regression. Clin Infect Dis 54 5 670 680 DOI: 10.1093/cid/cir934\n9. Lee BH Cho HY Lee H Han KH Kang HG Ha IS et al. Genetic basis of Bartter syndrome in Korea. Nephrol Dial Transplant 2012 27 4 1516 1521 DOI: 10.1093/ndt/gfr475 21865213\n10. Ben Salem C Hmouda H Bouraoui K. Drug-induced hypokalaemia. Curr Drug Saf 2009 4 1 55 61 DOI: 10.2174/157488609787354369 19149525\n11. Kwon J-A Lee JE Huh W Peck KR Kim Y-G Kim DJ et al. Predictors of acute kidney injury associated with intravenous colistin treatment. Int J Antimicrob Agents 2010 35 5 473 477 DOI: 10.1016/j.ijantimicag.2009.12.002 20089383\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0972-5229",
"issue": "25(7)",
"journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine",
"keywords": "Bartter-like syndrome; Colistin; Hypokalemia; Pediatric; Polyuria",
"medline_ta": "Indian J Crit Care Med",
"mesh_terms": null,
"nlm_unique_id": "101208863",
"other_id": null,
"pages": "822-824",
"pmc": null,
"pmid": "34316180",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": "22322268;32029515;23342992;20089383;28275006;21865213;26008213;30759858;19149525;16931410;9691009",
"title": "Acquired Bartter-like Syndrome Presenting with Polyuria and Reversible Hypokalemia Associated with Colistin Use in a Critically Ill Pediatric Patient.",
"title_normalized": "acquired bartter like syndrome presenting with polyuria and reversible hypokalemia associated with colistin use in a critically ill pediatric patient"
} | [
{
"companynumb": "TR-AXELLIA-003860",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMIKACIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Palbociclib is a highly selective, reversible, oral inhibitor of cyclin-dependent kinases 4 and 6 that is approved to treat hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. An open-label, single-arm, Japanese phase 2 study was conducted to investigate the efficacy and safety of palbociclib plus letrozole as first-line treatment in 42 postmenopausal patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. The probability of progression-free survival originally reported at 1 year was 75.0% (90% confidence interval, 61.3-84.4), but median progression-free survival was not attained at the primary analysis. In this report, updated efficacy and safety results with a longer follow-up period are presented. The median duration of treatment in the updated analysis was 33.0 months (range, 1.8-49.2). The probability of progression-free survival at 1 year was 75.6% (90% confidence interval, 62.4-84.7). Median progression-free survival was 35.7 months (95% confidence interval, 21.7-46.7). Objective response rate and disease control rate were 47.6% (95% confidence interval, 32.0-63.6) and 85.7% (95% confidence interval, 71.5-94.6), respectively. Common treatment-related adverse events (all grades; grade 3/4) were neutropenia (100%; 93%), leukopenia (83%; 60%), and stomatitis (76%; 0%). Treatment-related febrile neutropenia was reported in one patient. In general, no clinically meaningful deterioration in health-related quality of life was observed. Palbociclib plus letrozole remained effective and tolerable in Japanese postmenopausal patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in this updated analysis.",
"affiliations": "National Hospital Organization Hokkaido Cancer Center, Hokkaido, Japan.;National Hospital Organization Osaka National Hospital, Osaka, Japan.;Kumamoto Shinto General Hospital, Kumamoto, Japan.;Saitama Cancer Center, Saitama, Japan.;The Cancer Institute Hospital of JFCR, Tokyo, Japan.;Aichi Cancer Center Hospital, Aichi, Japan.;Pfizer R&D Japan, Tokyo, Japan.;Pfizer Japan Inc, Tokyo, Japan.;Pfizer R&D Japan, Tokyo, Japan.;Kyoto University Graduate School of Medicine, Kyoto, Japan.",
"authors": "Takahashi|Masato|M|;Masuda|Norikazu|N|0000-0002-7302-0278;Nishimura|Reiki|R|;Inoue|Kenichi|K|;Ohno|Shinji|S|;Iwata|Hiroji|H|;Hashigaki|Satoshi|S|;Muramatsu|Yasuaki|Y|;Umeyama|Yoshiko|Y|0000-0003-4967-0382;Toi|Masakazu|M|",
"chemical_list": "D000970:Antineoplastic Agents; D010879:Piperazines; D011725:Pyridines; D000077289:Letrozole; C500026:palbociclib",
"country": "United States",
"delete": false,
"doi": "10.1002/cam4.3091",
"fulltext": "\n==== Front\nCancer Med\nCancer Med\n10.1002/(ISSN)2045-7634\nCAM4\nCancer Medicine\n2045-7634 John Wiley and Sons Inc. Hoboken \n\n10.1002/cam4.3091\nCAM43091\nOriginal Research\nClinical Cancer Research\nOriginal Research\nPalbociclib‐letrozole as first‐line treatment for advanced breast cancer: Updated results from a Japanese phase 2 study\nTAKAHASHI et al.Takahashi Masato \n1\ntakahashi.masato.mz@mail.hosp.go.jp Masuda Norikazu https://orcid.org/0000-0002-7302-0278\n2\n Nishimura Reiki \n3\n Inoue Kenichi \n4\n Ohno Shinji \n5\n Iwata Hiroji \n6\n Hashigaki Satoshi \n7\n Muramatsu Yasuaki \n8\n Umeyama Yoshiko https://orcid.org/0000-0003-4967-0382\n7\n Toi Masakazu \n9\n \n1 \nNational Hospital Organization Hokkaido Cancer Center\nHokkaido\nJapan\n\n\n2 \nNational Hospital Organization Osaka National Hospital\nOsaka\nJapan\n\n\n3 \nKumamoto Shinto General Hospital\nKumamoto\nJapan\n\n\n4 \nSaitama Cancer Center\nSaitama\nJapan\n\n\n5 \nThe Cancer Institute Hospital of JFCR\nTokyo\nJapan\n\n\n6 \nAichi Cancer Center Hospital\nAichi\nJapan\n\n\n7 \nPfizer R&D Japan\nTokyo\nJapan\n\n\n8 \nPfizer Japan Inc\nTokyo\nJapan\n\n\n9 \nKyoto University Graduate School of Medicine\nKyoto\nJapan\n\n* Correspondence\n\nMasato Takahashi, National Hospital Organization Hokkaido Cancer Center, 2‐3‐54, 4 Jo, Kikusui, Shiroishi‐ku, Sapporo, Hokkaido 003‐0804, Japan.\n\nEmail: takahashi.masato.mz@mail.hosp.go.jp\n\n18 5 2020 \n7 2020 \n9 14 10.1002/cam4.v9.144929 4940\n16 11 2019 10 4 2020 11 4 2020 © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nPalbociclib is a highly selective, reversible, oral inhibitor of cyclin‐dependent kinases 4 and 6 that is approved to treat hormone receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer. An open‐label, single‐arm, Japanese phase 2 study was conducted to investigate the efficacy and safety of palbociclib plus letrozole as first‐line treatment in 42 postmenopausal patients with estrogen receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer. The probability of progression‐free survival originally reported at 1 year was 75.0% (90% confidence interval, 61.3‐84.4), but median progression‐free survival was not attained at the primary analysis. In this report, updated efficacy and safety results with a longer follow‐up period are presented. The median duration of treatment in the updated analysis was 33.0 months (range, 1.8‐49.2). The probability of progression‐free survival at 1 year was 75.6% (90% confidence interval, 62.4‐84.7). Median progression‐free survival was 35.7 months (95% confidence interval, 21.7‐46.7). Objective response rate and disease control rate were 47.6% (95% confidence interval, 32.0‐63.6) and 85.7% (95% confidence interval, 71.5‐94.6), respectively. Common treatment‐related adverse events (all grades; grade 3/4) were neutropenia (100%; 93%), leukopenia (83%; 60%), and stomatitis (76%; 0%). Treatment‐related febrile neutropenia was reported in one patient. In general, no clinically meaningful deterioration in health‐related quality of life was observed. Palbociclib plus letrozole remained effective and tolerable in Japanese postmenopausal patients with estrogen receptor‐positive, human epidermal growth factor receptor 2‐negative advanced breast cancer in this updated analysis.\n\nWith longer follow‐up of an open‐label, single‐arm, Japanese phase 2 study conducted to investigate the efficacy and safety of palbociclib plus letrozole as first‐line treatment in postmenopausal patients with estrogen receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer, median progression‐free survival was 35.7 months (95% CI, 21.7‐46.7). Palbociclib plus letrozole remained effective and tolerable in Japanese postmenopausal patients with estrogen receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer.\n\n\nadvanced breast cancercyclin‐dependent kinaseJapaneseletrozolepalbociclibPfizer 10.13039/100004319 source-schema-version-number2.0cover-dateJuly 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.5 mode:remove_FC converted:17.07.2020\n\n\nTakahashi \nM \n, \nMasuda \nN \n, \nNishimura \nR \n, et al. Palbociclib‐letrozole as first‐line treatment for advanced breast cancer: Updated results from a Japanese phase 2 study\n. Cancer Med . 2020 ;9 :4929 –4940\n. 10.1002/cam4.3091 \n\n\n\n\nFunding information\n\n\nThis study (Study A5481010, the phase 2 portion; NCT01684215) was sponsored by Pfizer Inc. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication.\n==== Body\n1 INTRODUCTION\nThe incidence of breast cancer has increased dramatically in Japanese women.\n1\n It is now the most common cancer and one of the top 5 causes of cancer‐related deaths among Japanese women.\n1\n Breast cancer survival rates are high when detected early, but 5‐year survival rates are much lower for Japanese women with advanced breast cancer (ABC).\n2\n Cyclin‐dependent kinase 4/6 (CDK4/6) inhibitor treatment in combination with an aromatase inhibitor (AI) has become the standard of care as first‐line treatment in postmenopausal women with hormone receptor‐positive (HR+)/human epidermal growth factor receptor 2‐negative (HER2–) ABC.\n3\n In September 2017, palbociclib, a highly selective, reversible, oral CDK4/6 inhibitor,\n4\n, \n5\n was approved in Japan for the treatment of unresectable or recurrent breast cancer.\n6\n\n\n\nThe results of an international, open‐label, phase 2 clinical trial (PALOMA‐1; NCT00721409) indicated that palbociclib plus letrozole prolonged progression‐free survival (PFS) vs letrozole alone (20.2 vs 10.2 months, respectively; hazard ratio, 0.49; 95% CI, 0.32‐0.75; one‐sided P = .0004) in postmenopausal women with estrogen receptor‐positive (ER+)/HER2– ABC; Japanese patients were not included in this study.\n7\n However, Japanese patients were included in a phase 3, randomized, placebo‐controlled clinical trial of palbociclib plus letrozole as first‐line treatment in postmenopausal women with ER+/HER2– ABC (PALOMA‐2; NCT01740427).\n8\n, \n9\n In the overall study population, median PFS was significantly longer with palbociclib plus letrozole vs placebo plus letrozole (27.6 vs 14.5 months; hazard ratio, 0.56; 95% CI, 0.46‐0.69; one‐sided P < .0001; data cutoff date, 31 May 2017).\n10\n Japanese patients were also included in a phase 3, randomized, placebo‐controlled trial of palbociclib plus fulvestrant vs placebo plus fulvestrant as treatment for patients with HR+/HER2– ABC who had disease progression on prior endocrine therapy (PALOMA‐3; NCT01942135).\n11\n, \n12\n In the overall study population, median PFS was also significantly longer with palbociclib plus fulvestrant vs placebo plus fulvestrant (11.2 vs 4.6 months, respectively; data cutoff date, 23 October 2015; hazard ratio, 0.50; 95% CI, 0.40‐0.62; one‐sided P < .0001).\n13\n The median overall survival (OS) with palbociclib plus fulvestrant vs placebo plus fulvestrant was 34.9 vs 28.0 months (absolute difference, 6.9 months; hazard ratio, 0.81; 95% CI, 0.64‐1.03; P = .09).\n14\n\n\n\nBecause Japanese women were not enrolled in the PALOMA‐1 trial and the PALOMA‐2 results were not yet available, an open‐label, single‐arm, Japanese phase 2 study was initiated to assess the efficacy and safety of palbociclib in combination with letrozole in the treatment of postmenopausal Japanese women with ER+/HER2– ABC.\n15\n The probability of PFS at 1 year was 75.0% (90% CI, 61.3‐84.4). However, median PFS was not attained at the primary analysis. After palbociclib was approved by the Ministry of Health, Labour and Welfare in Japan on 27 September 2017, the study continued as a postmarketing clinical study until a sufficient number of PFS events were obtained. In this report, updated efficacy and safety results with a longer follow‐up period are presented from the Japanese phase 2 trial, together with the subsequent therapy and health‐related quality of life (HRQoL) data—the first time these types of data have been reported for Japanese patients from this trial.\n\n2 PATIENTS AND METHODS\n2.1 Study design and patients\nThis phase 2, single‐arm, open‐label, multicenter study was conducted in Japan. Detailed methods have been previously published.\n15\n Patients were postmenopausal women with ER+/HER2– ABC who had received no prior systemic therapy for their advanced disease. Additional key inclusion criteria were age ≥20 years; measureable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or bone‐only disease; Eastern Cooperative Oncology Group performance status (ECOG PS) 0‐2; and adequate bone marrow, renal, and liver function. Key exclusion criteria were HER2+ disease; advanced, symptomatic visceral spread; prior (neo)adjuvant treatment with a nonsteroidal AI and disease recurrence during treatment or ≤12 months after completing treatment; and prior treatment with a CDK4/6 inhibitor. The study was approved by the Institutional Review Board of each participating center and conducted according to applicable local laws and regulatory requirements, the International Conference on Harmonisation Good Clinical Practice guidelines, and the Declaration of Helsinki. Written informed consent was obtained from each participant.\n\n2.2 Study treatment\nPatients received 125mg/d oral palbociclib on days 1‐21 of each 28‐day cycle, followed by 7days without palbociclib treatment. Patients also received 2.5mg/d letrozole administered continuously. Palbociclib dose interruptions/delays were permitted in response to protocol‐specified, treatment‐related adverse events (AEs) that included uncomplicated grade 3 neutropenia, grade 3 neutropenia with fever, grade 4 neutropenia, grade 4 thrombocytopenia, grade ≥3 nonhematologic toxicity, and grade 3 QTc prolongation (QTc ≥501 ms on≥ 2 separate electrocardiograms). If necessary, the first palbociclib dose reduction was from 125 to 100mg/d, and the second dose reduction was from 100 to 75mg/d. After the study transitioned to a postmarketing clinical study, the patients switched from the study drug to commercially available palbociclib.\n\n2.3 Outcomes\nThe primary outcome was 1‐year PFS. Secondary outcomes included PFS, objective response rate (ORR), disease control rate (DCR), duration of objective response (DOR), 1‐year survival, OS, safety, and patient‐reported HRQoL. Safety was recorded during treatment and for 28 days after treatment; severity of AEs was graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 and classified according to the Medical Dictionary for Regulatory Activities (MedDRA, v21.1). Patient‐reported HRQoL was measured using the Functional Assessment of Cancer Therapy‐General (FACT‐G)\n16\n and Functional Assessment of Cancer Therapy‐Breast (FACT‐B)\n17\n scales, and the Trial Outcome Index (TOI)\n18\n; questionnaires were completed at baseline, day 1 of cycles 2 and 3, and day 1 of every other following cycle.\n\n2.4 Statistical analysis\nAll efficacy analyses were performed using the full analysis set, which comprised all patients who received >1 dose of palbociclib. Efficacy was also assessed in the baseline disease characteristic subgroups of visceral or nonvisceral metastases; length of disease‐free interval (DFI) since completion of prior treatment (≤12months, >12months, or de novo metastatic disease); prior or no prior endocrine therapy; prior or no prior chemotherapy; age (<65years or ≥65 years); and Ki67 staining (≤20% or >20%). The 1‐year PFS probability and 90% CI were estimated using the Kaplan‐Meier method. Median PFS, OS, and associated 95% CIs were also estimated using the Kaplan‐Meier method. ORR was defined as the percentage of patients who had either complete response (CR) or partial response (PR) based on RECIST criteria. DCR was the percentage of patients with CR, PR, or stable disease lasting ≥24 weeks. DOR was analyzed in patients in the full analysis set with OR and defined as the time from first OR to first objective disease progression or death. Treatment duration of subsequent therapy was estimated using the Kaplan‐Meier method. Change from baseline in HRQoL scale scores was summarized by descriptive statistics (mean±SD). As a post hoc analysis, an examination of the time to definitive deterioration (TTD) in FACT‐B total score was conducted using the Kaplan‐Meier method. A meaningful change in QOL is defined as a change in baseline score equal to or greater than the established minimally important differences: for FACT‐B, this is 7‐8 points.\n19\n In this study, TTD was defined as the duration between baseline and first occurrence of a decrease of ≥7 points in FACT‐B score with no subsequent observation of a >7‐point decrease, which is the same definition as that used in PALOMA‐2.\n20\n\n\n\n3 RESULTS\n3.1 Patient population\nA total of 42 patients were enrolled in the study. Patient demographics and baseline disease characteristics have been previously published\n15\n; brief patient demographics and baseline disease characteristics are presented in Table 1. Median patient age was 62.5 years. Approximately half of the patients had visceral metastases (47.6%). Eight patients (19.0%) had a DFI ≤12 months.\n\nTable 1 Patient demographics and baseline disease characteristics\n\nCharacteristic\t\nPalbociclib + Letrozole\n\n\nN = 42\n\n\n\t\nAge, median (range), y\t62.5 (43‐84)\t\nWeight, median (range), kg\t50.4 (38.6‐74.5)\t\nECOG PS, n (%)\t\n0\t39 (92.9)\t\n1\t3 (7.1)\t\nDisease site, n (%)\t\nVisceral\t20 (47.6)\t\nNonvisceral\t22 (52.4)\t\nBone only\t6 (14.3)\t\nDFI, n (%)\t\n≤12 mo\t8 (19.0)\t\n>12 mo\t20 (47.6)\t\nDe novo metastatic\t14 (33.3)\t\nPrior (neo)adjuvant therapies, n (%)\t\nHormone therapy\t27 (64.3)\t\nChemotherapy\t20 (47.6)\t\nKi67‐positive expression, n (%)\t\n≤20%\t19 (45.2)\t\n>20%\t23 (54.8)\t\nAbbreviations: DFI, disease‐free interval; ECOG PS, Eastern Cooperative Oncology Group performance status.\n\nJohn Wiley & Sons, Ltd3.2 Drug exposure\nStudy drug exposure is summarized in Table2. At a data cutoff date of 25 October 2018, 13 patients (31.0%) were being treated with commercially available palbociclib plus letrozole or letrozole alone. The median duration of study treatment was 33.0months (range, 1.8‐49.2). Median relative palbociclib dose intensity was 70.7% (range, 38.0‐99.6). In total, 29 patients (69.0%) required ≥1 palbociclib dose reduction due to an AE: 16 were reduced to 100mg/d, and 12 were reduced to 75mg/d. In addition, 1 patient reduced to 100mg/d and mistakenly took 25mg×2 capsules (=50mg) instead of 25mg×4 capsules (=100mg) for 1day. Palbociclib dose interruption was experienced by 39 patients (92.9%). The mean (SD) number of interruptions per patient was 2.7 (2.0), and the mean (SD) duration of the dose interruptions was 4.6 (2.3) days. Thirty‐two patients (76.2%) required dose interruption due to an AE. Palbociclib cycle delay occurred in 40 patients (95.2%); the mean (SD) number of cycle delays per patient was 13.6 (11.9), and the mean (SD) duration of cycle delay was 9.3 (6.6) days. Thirty‐nine patients (92.9%) required cycle delay due to an AE.\n\nTable 2 Exposure to study drug\n\n\t\nPalbociclib + Letrozole\n\n\nN = 42\n\n\n\t\nDuration of treatment,\na\n median (range), months\t33.0 (1.8‐49.2)\t\nPalbociclib (N = 42)\t\nAverage daily dose, median (range), mg\t100.6 (75‐125)\t\nDose reductions,\nb\n n (%)\t29 (69.0)\t\nReduction to 100 mg\t16 (38.1)\t\nReduction to 75 mg\t12 (28.6)\t\nReduction to 50 mg\t1 (2.4)\nf\n\n\t\nTime to first dose reduction,\nc\n median (range), days\t66 (29‐1067)\t\nDose interruption,\nd\n n (%)\t39 (92.9)\t\nCycle delay,\ne\n n (%)\t40 (95.2)\t\nRelative dose intensity, median (range), %\t70.7 (38.0‐99.6)\t\nLetrozole (N = 42)\t\nDose interruption,\nd\n n (%)\t35 (83.3)\t\nCycle delay,\ne\n n (%)\t10 (23.8)\t\nRelative dose intensity, median (range), %\t99.7 (69.6‐100.0)\t\na Total number of days from first to and including last day of each study treatment.\n\nb Includes any dose reduction from the initial prescribed dose not including dose interruptions.\n\nc Timed from (start of first occurrence minus first dose date of cycle 1) + 1.\n\nd Interruptions include missed dose based on the case report form and dose administered = 0 mg.\n\ne Cycle delay is defined as any delay of the cycle start date.\n\nf One patient mistakenly took 25 mg × 2 capsules (=50 mg) instead of 25 mg × 4 capsules (=100 mg) for 1 d.\n\nJohn Wiley & Sons, Ltd3.3 Efficacy\nAt the data cutoff date, the 1‐year probability of PFS was 75.6% (90% CI, 62.4‐84.7). The Kaplan‐Meier estimated median PFS was 35.7months (95% CI, 21.7‐46.7; Figure1). PFS was also assessed in subgroups based on baseline characteristics (Figure2). Median PFS was >40 months for patients with nonvisceral metastatic disease, for patients without prior chemotherapy, for patients with age ≥65 years, and for patients with Ki67 ≤20%. Median PFS was not reached for patients with de novo metastatic disease and for patients without prior endocrine therapy. A landmark analysis was performed to assess PFS in patients who did and did not require dose reduction within the first 90days (Figure3); PFS was similar in both subgroups.\n\nFigure 1 Kaplan‐Meier estimated PFS probability in the full analysis set. CI, confidence interval; PFS, progression‐free survival\n\nFigure 2 Kaplan‐Meier estimated PFS probability by patient subgroup. A, Visceral and nonvisceral metastasis subgroups. B, DFI since prior (neo)adjuvant therapy subgroups. C, Prior and no prior endocrine therapy subgroups. D, Prior and no prior chemotherapy subgroups. E, Age <65 y and ≥65 y subgroups. F, Ki67 expression subgroups. CI, confidence interval; DFI, disease‐free interval; NE, not estimable; NR, not reached; PFS, progression‐free survival\n\nFigure 3 Kaplan‐Meier estimated PFS probability for patients with and without dose reduction during the first 90 d. Patients with PFS time within 90 d were excluded. CI, confidence interval; NE, not estimable; PFS, progression‐free survival\n\nIn the full analysis set, 20 patients had OR, and the median DOR was 41.4 months (95% CI, 19.0–not estimable [NE]). In the full analysis set, the ORR was 47.6% (95% CI, 32.0‐63.6) and the DCR was 85.7% (95% CI, 71.5‐94.6). In the response evaluable set (n = 36), the ORR and DCR were 55.6% (95% CI, 38.1‐72.1) and 83.3% (95% CI, 67.2‐93.6), respectively. OS data remain immature; median OS was not reached at the date of this data cutoff (Figure 4). Survival probability was 92.9% (95% CI, 79.5‐97.6) at 1 year, 90.3% (95% CI, 76.3‐96.3) at 2 years, and 82.7% (95% CI, 67.1‐91.4) at 3 years.\n\nFigure 4 Kaplan‐Meier estimated OS probability in the full analysis set. CI, confidence interval; NE, not estimable; NR, not reached; OS, overall survival\n\n3.4 Subsequent therapy\nOf the 42 patients enrolled in the study, 24 patients had PFS events at the data cutoff date. Four of 24 patients did not have a record of subsequent therapy. Three patients permanently discontinued the study treatment due to AEs and then received subsequent therapy. In total, 23 patients (54.8%) received subsequent systemic anticancer therapies (Figure 5).\n\nFigure 5 CONSORT diagram of subsequent therapy. aOne patient continued commercially available letrozole only. AE, adverse event\n\nAmong these 23 patients, 10 received 1 subsequent regimen, 2 received 2 subsequent regimens, 3 received 3 subsequent regimens, and 8 received >3 subsequent regimens at the data cutoff date. Of the 42 patients, 13 patients were being treated with commercially available palbociclib plus letrozole or letrozole alone, and these patients were not included in the analyses of subsequent therapy assessment.\n\nThe most common first subsequent therapy was endocrine therapy, followed by chemotherapy (20 patients [87.0%] and 3 patients [13.0%], respectively; Table 3). Fulvestrant alone or fulvestrant‐containing regimens were used in 14 patients (60.9%). Exemestane alone or exemestane‐containing regimens were used in 3 patients (13.0%); everolimus plus exemestane was used in 1 of these 3 patients. Paclitaxel alone or paclitaxel‐containing regimens were used in 3 patients (paclitaxel alone in 1 patient, and bevacizumab plus paclitaxel in 2 patients) (Table S1).\n\nTable 3 Summary of subsequent anticancer treatment regimens\n\nSystemic Anticancer Therapy, n (%)\t\nPalbociclib + Letrozole\n\n\nN = 23\na\n\n\n\n\n\t\nFirst subsequent therapy\t23 (100.0)\t\nEndocrine therapy\t20 (87.0)\t\nChemotherapy\t3 (13.0)\t\nVEGF inhibitor\t2 (8.7)\t\nCDK4/6 inhibitor\t2 (8.7)\t\nmTOR inhibitor\t1 (4.3)\t\nOther\t2 (8.7)\t\nSecond subsequent therapy\t13 (56.5)\t\nEndocrine therapy\t7 (30.4)\t\nChemotherapy\t5 (21.7)\t\nVEGF inhibitor\t0\t\nCDK4/6 inhibitor\t1 (4.3)\t\nmTOR inhibitor\t0\t\nOther\t2 (8.7)\t\nThird or greater subsequent therapy\t11 (47.8)\t\nEndocrine therapy\t9 (39.1)\t\nChemotherapy\t10 (43.5)\t\nVEGF inhibitor\t4 (17.4)\t\nCDK4/6 inhibitor\t1 (4.3)\t\nmTOR inhibitor\t4 (17.4)\t\nOther\t2 (8.7)\t\nAbbreviations: CDK4/6, cyclin‐dependent kinase 4/6; mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor.\n\na Total number of patients who received subsequent therapy.\n\nJohn Wiley & Sons, LtdMedian duration of first, second, and third or greater subsequent therapy was 8.3 (95% CI, 3.9‐12.2), 3.5 (95% CI, 2.3‐9.8), and 3.8 (95% CI, 2.8‐4.6) months, respectively. Five patients received an everolimus‐containing regimen (4 patients and 1 patient received everolimus plus exemestane and everolimus plus toremifene, respectively) as any line of subsequent therapy. Median duration of subsequent everolimus‐containing treatment was 4.1 months (95% CI, 2.1‐8.4). The median time to first use of subsequent chemotherapy was not yet reached (95% CI, 24.2 months—NE) at the data cutoff date (Figure S1). The time course of subsequent therapies in each patient is shown in Figure 6.\n\nFigure 6 Time course of subsequent therapies in each patient. *Patients who were being treated with commercially available palbociclib plus letrozole or letrozole alone at the data cutoff date. OS, overall survival\n\n3.5 Safety\nThe most commonly reported AEs were similar to those previously described (Table 4), and no new safety signals were observed with longer follow‐up. Neutropenia remained the most frequent AE; however, treatment‐related febrile neutropenia (grade 3) was only observed in 1 patient. Two patients received granulocyte‐colony stimulating factor (G‐CSF), 1 due to grade 4 neutropenia and the other due to grade 3 febrile neutropenia. After recovery, both patients resumed palbociclib at a lower dose level. Two treatment‐related serious AEs (SAEs) were previously reported in this study: 1 report of grade 3 febrile neutropenia and 1 report of grade 5 subarachnoid hemorrhage. For this patient, the last doses of palbociclib and letrozole were given 12 and 5 days, respectively, before death.\n15\n No new treatment‐related SAEs have been reported since the primary analysis. Seven of the 42 patients (16.7%) discontinued palbociclib treatment due to treatment‐related AEs (neutropenia in 4 patients; and malaise, alanine aminotransferase/aspartate aminotransferase increased and subarachnoid hemorrhage in 1 patient each).\n\nTable 4 Palbociclib treatment‐related AEs occurring in ≥10% of patients\n\nAE, n (%)\t\nPalbociclib + Letrozole\n\n\nN = 42\n\n\n\t\nAny Grade\tGrade 3/4\t\nAny AE\t42 (100.0)\t39 (92.9)\t\nHematologic AE\t\t\t\nNeutropenia\na\n\n\t42 (100.0)\t39 (92.9)\t\nLeukopenia\nb\n\n\t35 (83.3)\t25 (59.5)\t\nThrombocytopenia\nc\n\n\t11 (26.2)\t0\t\nAnemia\t9 (21.4)\t2 (4.8)\t\nNonhematologic AE\t\t\t\nStomatitis\nd\n\n\t32 (76.2)\t0\t\nInfection\ne\n\n\t11 (26.2)\t0\t\nRash\nf\n\n\t10 (23.8)\t0\t\nConstipation\t10 (23.8)\t0\t\nALT increased\t10 (23.8)\t4 (9.5)\t\nAST increased\t10 (23.8)\t1 (2.4)\t\nAlopecia\t8 (19.0)\t0\t\nMalaise\t7 (16.7)\t0\t\nHeadache\t6 (14.3)\t0\t\nDiarrhea\t5 (11.9)\t0\t\nEpistaxis\t5 (11.9)\t0\t\nNausea\t5 (11.9)\t0\t\nAbbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; MedDRA, Medical Dictionary for Regulatory Activities; PT, preferred term.\n\na Neutropenia was categorized according to the MedDRA PTs neutropenia and neutrophil count decreased.\n\nb Leukopenia was categorized according to the MedDRA PTs leukopenia and white blood cell count decreased.\n\nc Thrombocytopenia was categorized according to the MedDRA PTs thrombocytopenia and platelet count decreased.\n\nd Stomatitis was categorized according to the MedDRA PTs cheilitis, glossitis, mucosal inflammation, oropharyngeal pain, and stomatitis.\n\ne Infections were categorized according to the MedDRA PTs angular cheilitis, cellulitis, conjunctivitis, cystitis, genital candidiasis, gingivitis, laryngitis, lip infection, nasopharyngitis, oral herpes, otitis media, pharyngitis, and upper respiratory tract infection.\n\nf Rash was categorized according to the MedDRA PTs rash, rash maculopapular, dermatitis, and dermatitis acneiform.\n\nJohn Wiley & Sons, Ltd3.6 HRQoL\nOverall changes from baseline to end of study treatment in FACT‐B and TOI total scores remained consistent (Figure 7), indicating that HRQoL was maintained with palbociclib plus letrozole. Changes from baseline to the end of study treatment in FACT‐G total scores and FACT‐B subscale scores were also consistent over the course of the study (Figure S2). The Kaplan‐Meier estimated median TTD in FACT‐B score was 43.0 months (95% CI, 26.0‐46.5; Figure 8).\n\nFigure 7 Change from baseline in patient‐reported HRQoL scale scores. A, FACT‐B total score. B, TOI total score. Bars indicate standard deviations. FACT‐B, Functional Assessment of Cancer Therapy‐Breast; HRQoL, health‐related quality of life; TOI, Trial Outcome Index\n\nFigure 8 Kaplan‐Meier estimated TTD probability in FACT‐B score. CI, confidence interval; FACT‐B, Functional Assessment of Cancer Therapy‐Breast; TTD, time to definitive deterioration\n\n4 DISCUSSION\nWith extended follow‐up, palbociclib plus letrozole remains an effective and well‐tolerated therapy in postmenopausal Japanese women with ER+/HER2– ABC. In general, the data reported here are consistent with those of the PALOMA‐2 extended follow‐up results; with a median duration of follow‐up of 37.6 months (data cutoff date, 31 May 2017), median PFS in the palbociclib arm of PALOMA‐2 was 27.6 months (95% CI, 22.4‐30.3).\n10\n Patient baseline disease characteristics were similar between the 2 studies, although the proportion of patients with ECOG PS of 0 was higher in the Japanese phase 2 study than in PALOMA‐2 (92.9% and 57.9%, respectively).\n10\n Overall, palbociclib plus letrozole appears to be as effective in Japanese patients as in the overall population of PALOMA‐2.\n\nPalbociclib plus letrozole remained well tolerated in Japanese patients. No new safety signals were observed in Japanese patients with longer follow‐up. Hematologic AEs were the most frequently reported AEs with extended follow‐up in both this Japanese phase 2 study and in PALOMA‐2.\n10\n The rate of all‐grade neutropenia was higher in the Japanese phase 2 study and in the Japanese subgroup analysis of PALOMA‐2 than in the overall population in PALOMA‐2.\n9\n, \n10\n In this Japanese phase 2 study, neutropenia was reported in 100% of patients receiving palbociclib. However, Japanese patients in the phase 2 study reported similar rates of treatment‐related SAEs (4.8%) as did patients receiving palbociclib in PALOMA‐2 (6.5%).\n10\n In both the Japanese study and in PALOMA‐2, febrile neutropenia was rare, reported in 2.4% and 2.0% of patients, respectively. Palbociclib‐related toxicities were generally managed with dose modification in Japanese patients. It was reported that dose reduction of palbociclib did not appear to impact the efficacy at the primary analysis\n15\n; however, the data were immature and we could not fully evaluate the impact of dose reduction on efficacy. In this report, the landmark analysis with extended follow‐up showed that PFS was similar in Japanese patients regardless of whether they required a palbociclib dose reduction within the first 90 days of treatment. Importantly, palbociclib tolerability appears to be similar in Japanese patients and in patients of other ethnicities, and dose modifications to manage palbociclib toxicities are unlikely to affect the efficacy in Japanese patients.\n\nJapanese patients with nonvisceral metastases demonstrated greater benefit with palbociclib plus letrozole than did patients with visceral metastases; median PFS was approximately 2.5years longer in patients with nonvisceral metastases (46.7 and 16.7months). A similar PFS difference between patients with visceral and nonvisceral metastases was also observed in other clinical trials. The proportion of patients with nonvisceral metastases was comparable in the Japanese phase 2 study and PALOMA‐2 (52.4% and 51.8%, respectively). In PALOMA‐2, median PFS was >1year longer in patients with nonvisceral metastases compared with patients with visceral metastases (35.9 and 19.3months, respectively).\n10\n Similarly in PALOMA‐3, median PFS was approximately 3months longer in patients with nonvisceral vs visceral disease (11.2 and 8.0months, respectively).\n21\n Median PFS was also longer for Japanese patients with a DFI >12 months than for patients with a shorter DFI; the difference between the 2 groups was >1 year (37.1 vs 21.7months). Median PFS was not reached for the 14 patients with de novo metastatic disease. Kaplan‐Meier plots of PFS were similar between Japanese patients with or without prior endocrine therapy. In contrast, median PFS was longer in Japanese patients who did not have prior chemotherapy compared to those with prior chemotherapy. Median PFS was also longer in Japanese patients aged ≥65 years vs those <65 years of age. Of note, in PALOMA‐2, median PFS was prolonged with palbociclib compared with placebo in all patient subgroups examined, suggesting that all patient subpopulations derive benefit from the addition of palbociclib to letrozole, regardless of their baseline characteristics.\n10\n In Japanese patients, median PFS was longer for the patients with Ki67 expression ≤20% vs >20% (46.7 and 27.6months, respectively). In PALOMA‐2, Ki‐67 index values at a 15% or 20% cutoff did not reveal a patient group with a better or worse PFS with palbociclib plus letrozole compared with placebo plus letrozole.\n22\n These subgroup data support the efficacy of palbociclib plus letrozole across patient subgroups.\n\nMost Japanese patients (87%) received endocrine therapy as their first subsequent therapy after disease progression on palbociclib, and approximately 30% received endocrine therapy as their second subsequent therapy. Only 3 patients (13%) received chemotherapy as their first subsequent therapy. Single‐agent fulvestrant was the most common subsequent treatment. In PALOMA‐2, 60.8% and 36.6% of patients received endocrine therapy and chemotherapy, respectively, as the first subsequent treatment after discontinuation of palbociclib,\n10\n suggesting that patients enrolled in PALOMA‐2 may have had more aggressive disease than did the patients in the Japanese study. However, PALOMA‐2 was a large, multinational trial, and differences in approved drug and insurance/reimbursement systems among countries could influence the selection of subsequent treatments after the discontinuation of palbociclib. Importantly, the data from the Japanese phase 2 study suggest that endocrine therapy remains effective after palbociclib combination therapy in the majority of Japanese patients. Subsequent endocrine therapy is advantageous because it delays the use of chemotherapy treatment, which is associated with increased toxicity and reduced quality of life.\n\nGenerally, no clinically meaningful deterioration in FACT‐G, FACT‐B, and TOI total scores and FACT‐B subscale scores was observed in Japanese patients in this study. This finding is similar to that observed in the overall PALOMA‐2 study population with extended follow‐up, in which the FACT‐B total score was maintained over time with palbociclib plus letrozole, and changes from baseline did not significantly differ between the palbociclib and placebo arms.\n10\n In addition, median TTD was 43.0 months in this study. This is longer than the findings from PALOMA‐2 in which the same definition of TTD was used for the analysis (24.9 months in the placebo plus letrozole arm and 26.3 months in the palbociclib plus letrozole arm).\n20\n These results suggest that palbociclib treatment does not negatively impact QoL in Japanese patients.\n\nThis study is subject to certain limitations, including its single‐arm, open‐label design and small sample size, and therefore may be subject to biases. However, with extended follow‐up, treatment of Japanese patients with ER+/HER2– ABC with palbociclib in combination with letrozole yielded a median PFS of almost 3 years. Palbociclib plus letrozole was confirmed as safe and effective, without clinically meaningful deterioration in patient‐reported HRQoL, in postmenopausal Japanese patients with ER+/HER2– ABC. Furthermore, as the majority of patients received hormonal therapy as subsequent therapy after disease progression with palbociclib plus letrozole in this study, it will provide the opportunity for future analysis of the efficacy of subsequent therapies.\n\nAUTHOR CONTRIBUTIONS\nM. Takahashi, H. Iwata, S. Hashigaki, Y. Muramatsu, Y. Umeyama, and M. Toi made substantial contributions to the study conception and design. M. Takahashi, N. Masuda, R. Nishimura, K. Inoue, S. Ohno, H. Iwata, and M. Toi participated in data acquisition. S. Hashigaki performed data analysis. All authors made substantial contributions to the interpretation of data. All authors were involved in drafting the manuscript or revising it critically for important intellectual content. All authors read and approved the final version of the manuscript to be published; have participated sufficiently in the work to take public responsibility for appropriate portions of the content; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nCONFLICTS OF INTEREST\nAuthors SH and YU are employees of Pfizer R&D Japan. YU also owns stock in Pfizer Inc. YM is an employee of Pfizer Japan Inc. HI received honoraria from Chugai, Daiichi‐Sankyo, AstraZeneca, and Pfizer; manuscript fees from Eisai; and research funding from MSD, Chugai, Daiichi‐Sankyo, and Boehringer Ingelheim. KI’s institution received research funding from Parexel, Puma Biotechnology, Pfizer, Novartis, MSD, GSK, Chugai, and Daiichi‐Sankyo. NM received honoraria from Chugai, Pfizer, Eli Lilly, Eisai, Takeda, and AstraZeneca; is a board member of the Japan Breast Cancer Research Group Association; and his institution received research funding from Chugai, AstraZeneca, Kyowa‐Kirin, MSD, Novartis, Pfizer, Eli Lilly, Eisai, and Daiichi‐Sankyo. SO received honoraria from Chugai, AstraZeneca, Eisai, Pfizer, Taiho, Kyowa‐Kirin, Nippon Kayaku, and Novartis, and research funding from Taiho and Eisai. RN received honoraria from Pfizer, Novartis, and Chugai. MTa received honoraria from Pfizer, AstraZeneca, Eli Lilly, and Eisai; and research funding from Taiho, Kyowa‐Kirin, and Eisai. MTo received honoraria from AstraZeneca and Eli Lilly; research funding from Taiho, Kyowa‐Kirin, Shimadzu, AFF Technology, Bizcom Japan, C&C Research Laboratories, Astellas, AstraZeneca, and Chugai; scholarship endowments from Chugai, Eisai, and Pfizer; and is a member of the board (no salary) of the Japan Breast Cancer Research Group association, Kyoto Breast Cancer Research Network, and Organisation for Oncology and Translational Research.\n\nSupporting information\nSupplementary Material\n\nClick here for additional data file.\n\n ACKNOWLEDGMENTS\nWe thank Junichi Tanuma and Naoko Mizutani of Pfizer R&D Japan for data collection and Hiroko Godai and Taku Uryu of Pfizer R&D Japan for data analysis. This study was sponsored by Pfizer Inc. Editorial support was provided by Jennifer Fetting, PhD, of Complete Healthcare Communications, LLC (North Wales, PA, USA), a CHC Group company, and was funded by Pfizer Inc.\n\nDATA AVAILABILITY STATEMENT\nUpon request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical‐trials/trial‐data‐and‐results for more information), Pfizer will provide access to individual deidentified participant data from Pfizer‐sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (ie, development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The deidentified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer.\n==== Refs\nREFERENCES\n1 \n\nNakamura \nK \n, \nOkada \nE \n, \nUkawa \nS \n, et al. Characteristics and prognosis of Japanese female breast cancer patients: the BioBank Japan project\n. J Epidemiol . 2017 ;27 :S58 ‐S64\n.28223083 \n2 \n\nAnan \nK \n, \nFukui \nN \n, \nKinoshita \nT \n, et al. Comprehensive prognostic report of the Japanese Breast Cancer Society Registry in 2005\n. Breast Cancer . 2016 ;23 :50 ‐61\n.26464008 \n3 \n\nRugo \nHS \n, \nRumble \nRB \n, \nMacrae \nE \n, et al. Endocrine therapy for hormone receptor–positive metastatic breast cancer: American Society of Clinical Oncology guideline\n. J Clin Oncol . 2016 ;34 :3069 ‐3103\n.27217461 \n4 \n\nFinn \nRS \n, \nDering \nJ \n, \nConklin \nD \n, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor‐positive human breast cancer cell lines in vitro\n. Breast Cancer Res . 2009 ;11 :R77 .19874578 \n5 \n\nFry \nDW \n, \nHarvey \nPJ \n, \nKeller \nPR \n, et al. Specific inhibition of cyclin‐dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts\n. Mol Cancer Ther . 2004 ;3 :1427 ‐1438\n.15542782 \n6 \nPharmaceutical and Medical Devices Agency (PMDA) \n. New Drugs Approved in September 2017\n. 2017 [cited July 16, 2019.] Available from URL: https://www.pmda.go.jp/english/review‐services/reviews/approved‐information/drugs/0002.html.\n7 \n\nFinn \nRS \n, \nCrown \nJP \n, \nLang \nI \n, et al. The cyclin‐dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first‐line treatment of oestrogen receptor‐positive, HER2‐negative, advanced breast cancer (PALOMA‐1/TRIO‐18): a randomised phase 2 study\n. Lancet Oncol . 2015 ;16 :25 ‐35\n.25524798 \n8 \n\nFinn \nRS \n, \nMartin \nM \n, \nRugo \nHS \n, et al. Palbociclib and letrozole in advanced breast cancer\n. N Engl J Med . 2016 ;375 :1925 ‐1936\n.27959613 \n9 \n\nMukai \nH \n, \nShimizu \nC \n, \nMasuda \nN \n, et al. Palbociclib in combination with letrozole in patients with estrogen receptor‐positive, human epidermal growth factor receptor 2‐negative advanced breast cancer: PALOMA‐2 subgroup analysis of Japanese patients\n. Int J Clin Oncol . 2019 ;24 :274 ‐287\n.30515674 \n10 \n\nRugo \nHS \n, \nFinn \nRS \n, \nDiéras \nV \n, et al. Palbociclib plus letrozole as first‐line therapy in estrogen receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer with extended follow‐up\n. Breast Cancer Res Treat . 2019 ;174 :719 ‐729\n.30632023 \n11 \n\nTurner \nNC \n, \nRo \nJ \n, \nAndré \nF \n, et al. Palbociclib in hormone‐receptor‐positive advanced breast cancer\n. N Engl J Med . 2015 ;373 :209 ‐219\n.26030518 \n12 \n\nMasuda \nN \n, \nInoue \nK \n, \nNakamura \nR \n, et al. Palbociclib in combination with fulvestrant in patients with hormone receptor‐positive, human epidermal growth factor receptor 2‐negative advanced breast cancer: PALOMA‐3 subgroup analysis of Japanese patients\n. Int J Clin Oncol . 2019 ;24 :262 ‐273\n.30392115 \n13 \n\nCristofanilli \nM \n, \nDeMichele \nA \n, \nGiorgetti \nC \n, et al. Predictors of prolonged benefit from palbociclib plus fulvestrant in women with endocrine‐resistant hormone receptor‐positive/human epidermal growth factor receptor 2‐negative metastatic breast cancer in PALOMA‐3\n. Eur J Cancer . 2018 ;104 :21 ‐31\n.30308388 \n14 \n\nTurner \nNC \n, \nSlamon \nDJ \n, \nRo \nJ \n, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer\n. N Engl J Med . 2018 ;379 :1926 ‐1936\n.30345905 \n15 \n\nMasuda \nN \n, \nNishimura \nR \n, \nTakahashi \nM \n, et al. Palbociclib in combination with letrozole as first‐line treatment for advanced breast cancer: a Japanese phase II study\n. Cancer Sci . 2018 ;109 :803 ‐813\n.29345736 \n16 \n\nCella \nDF \n, \nTulsky \nDS \n, \nGray \nG \n, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure\n. J Clin Oncol . 1993 ;11 :570 ‐579\n.8445433 \n17 \n\nBrady \nMJ \n, \nCella \nDF \n, \nMo \nF \n, et al. Reliability and validity of the Functional Assessment of Cancer Therapy‐Breast quality‐of‐life instrument\n. J Clin Oncol . 1997 ;15 :974 ‐986\n.9060536 \n18 \n\nWebster \nK \n, \nCella \nD \n, \nYost \nK \n. The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System: properties, applications, and interpretation\n. Health Qual Life Outcomes . 2003 ;1 :79 .14678568 \n19 \n\nEton \nDT \n, \nCella \nD \n, \nYost \nKJ \n, et al. A combination of distribution‐ and anchor‐based approaches determined minimally important differences (MIDs) for four endpoints in a breast cancer scale\n. J Clin Epidemiol . 2004 ;57 :898 ‐910\n.15504633 \n20 \n\nRugo \nHS \n, \nDiéras \nV \n, \nGelmon \nKA \n, et al. Impact of palbociclib plus letrozole on patient‐reported health‐related quality of life: results from the PALOMA‐2 trial\n. Ann Oncol . 2018 ;29 :888 ‐894\n.29360932 \n21 \n\nCristofanilli \nM \n, \nTurner \nNC \n, \nBondarenko \nI \n, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone‐receptor‐positive, HER2‐negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA‐3): final analysis of the multicentre, double‐blind, phase 3 randomised controlled trial\n. Lancet Oncol . 2016 ;17 :425 ‐439\n.26947331 \n22 \n\nFinn \nRS \n, \nLiu \nY \n, \nZhu \nZ \n, et al. Biomarker analyses of response to cyclin dependent kinase 4/6 inhibition and endocrine therapy in women with treatment‐naive metastatic breast cancer\n. Clin Cancer Res . 2019 ;26 :110 –121\n.31527167\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-7634",
"issue": "9(14)",
"journal": "Cancer medicine",
"keywords": "Japanese; advanced breast cancer; cyclin-dependent kinase; letrozole; palbociclib",
"medline_ta": "Cancer Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D007564:Japan; D000077289:Letrozole; D008875:Middle Aged; D010879:Piperazines; D011725:Pyridines",
"nlm_unique_id": "101595310",
"other_id": null,
"pages": "4929-4940",
"pmc": null,
"pmid": "32420697",
"pubdate": "2020-07",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "30392115;30515674;30632023;27217461;26947331;26030518;30308388;32420697;29345736;31527167;19874578;30345905;25524798;9060536;27959613;15542782;8445433;14678568;28223083;15504633;26464008;29360932",
"title": "Palbociclib-letrozole as first-line treatment for advanced breast cancer: Updated results from a Japanese phase 2 study.",
"title_normalized": "palbociclib letrozole as first line treatment for advanced breast cancer updated results from a japanese phase 2 study"
} | [
{
"companynumb": "JP-PFIZER INC-2015096199",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drugadditional": nul... |
{
"abstract": "There is a consensus that elderly individuals are quite vulnerable to adverse drug reactions (ADRs), and headaches are one of the most frequent clinical presentations of central nervous system problems in the general population, which can be an ADR. The purpose of our work was to analyze reports of \"headache\" associated ADRs in the elderly sent to the Portuguese Pharmacovigilance System (PPS), and also which drugs were more frequently associated with this adverse reaction. A retrospective analysis of suspected ADR reports involving patients aged 65 years or older received by the PPS in the last 10 years was conducted. A search of all the terms associated with the High Level Term \"headache\" was performed. All duplicate reports were excluded from the analysis. A total of 155 ADRs reports were included, in which 15 reported isolated \"headache\" as suspected ADR, while the remaining 140 ADRs reports reported \"headache\" together with several other adverse reactions. Most reports of \"headache\" ADR occurred in women (74.8%; n = 116). About half (46.5%; n = 72) of the ADR reports were considered serious. Anti-viral medication, anti-depressants, anti-dyslipidemic agents and central nervous system-acting analgesics were the most frequent drugs associated with \"headache\" ADR reports in this population. In elderly patients, most ADR reports involving headaches occurred in women and a high percentage (46.5%) were considered serious. Thus, it is important that healthcare professionals pay more attention to headaches reported as ADRs in the elderly and drugs suspected to cause them, in order to increase knowledge about this type of reaction and contribute towards safely using drugs in this age group.",
"affiliations": "UFBI-Pharmacovigilance Unit of Beira Interior, Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilhã, Portugal.;Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilhã, Portugal.;UFBI-Pharmacovigilance Unit of Beira Interior, Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilhã, Portugal.",
"authors": "Monteiro|Cristina|C|0000-0002-5225-6222;Dias|Beatriz|B|;Vaz-Patto|Maria|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/ijerph18052674",
"fulltext": "\n==== Front\nInt J Environ Res Public Health\nInt J Environ Res Public Health\nijerph\nInternational Journal of Environmental Research and Public Health\n1661-7827\n1660-4601\nMDPI\n\n10.3390/ijerph18052674\nijerph-18-02674\nArticle\nHeadache as an Adverse Reaction to the Use of Medication in the Elderly: A Pharmacovigilance Study\nhttps://orcid.org/0000-0002-5225-6222\nMonteiro Cristina 12\nDias Beatriz 2\nVaz-Patto Maria 123*\nTchounwou Paul B. Academic Editor\n1 UFBI—Pharmacovigilance Unit of Beira Interior, Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilhã, Portugal; ufarmabi@fcsaude.ubi.pt\n2 Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilhã, Portugal; zirtaeb96@gmail.com\n3 CICS UBI—Health Sciences Research Centre-UBI, Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilhã, Portugal\n* Correspondence: mariavazpato@fcsaude.ubi.pt\n07 3 2021\n3 2021\n18 5 267431 1 2021\n02 3 2021\n© 2021 by the authors.\n2021\nLicensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).\nThere is a consensus that elderly individuals are quite vulnerable to adverse drug reactions (ADRs), and headaches are one of the most frequent clinical presentations of central nervous system problems in the general population, which can be an ADR. The purpose of our work was to analyze reports of “headache” associated ADRs in the elderly sent to the Portuguese Pharmacovigilance System (PPS), and also which drugs were more frequently associated with this adverse reaction. A retrospective analysis of suspected ADR reports involving patients aged 65 years or older received by the PPS in the last 10 years was conducted. A search of all the terms associated with the High Level Term “headache” was performed. All duplicate reports were excluded from the analysis. A total of 155 ADRs reports were included, in which 15 reported isolated “headache” as suspected ADR, while the remaining 140 ADRs reports reported “headache” together with several other adverse reactions. Most reports of “headache” ADR occurred in women (74.8%; n = 116). About half (46.5%; n = 72) of the ADR reports were considered serious. Anti-viral medication, anti-depressants, anti-dyslipidemic agents and central nervous system-acting analgesics were the most frequent drugs associated with “headache” ADR reports in this population. In elderly patients, most ADR reports involving headaches occurred in women and a high percentage (46.5%) were considered serious. Thus, it is important that healthcare professionals pay more attention to headaches reported as ADRs in the elderly and drugs suspected to cause them, in order to increase knowledge about this type of reaction and contribute towards safely using drugs in this age group.\n\nadverse drug reaction\nelderly\nheadache\npharmacovigilance\n==== Body\n1. Introduction\n\nThe prevalence of headaches decreases with age, and their characteristics in the elderly tend to be different from those in a younger population [1,2,3,4]. Some headaches are more common in the elderly, such as those associated with ischemic and hemorrhagic strokes, subdural hematomas, trauma, neoplasia, giant cell arteritis and medication overuse [2,3,4]. Primary headache disorders may also manifest in an atypical way in elderly individuals for several reasons. Firstly, elderly individuals may have more prominent migraine-associated visual or sensory phenomena when compared with younger individuals [3]. Secondly, certain headache types tend to be geriatric disorders, such as primary cough headache, hypnic headache, typical aura without headache, exploding head syndrome and giant cell arteritis [2,4]. Although most headaches in the elderly are primary disorders (66%) [5] with no prominent features, serious headaches are more common in this age group, comprising up to 15% of new-onset headaches in this population [5,6].\n\nElderly patients also have an increased number of comorbidities and, consequently, polypharmacy [7]. The definition of “polypharmacy” is controversial, as the precise number of multiple medications used to define it may vary, most frequently involving at least five or more appropriate drugs [8,9,10,11,12]. An increase in the number of drugs being taken is a risk factor for adverse drug reactions (ADR) and is also associated with increasing ADR-related hospitalizations [11,13]. In fact, ADRs in elderly individuals represent a major burden, causing significant morbidity, mortality and increased health care costs [14]. Elderly patients are particularly susceptible to ADRs not only due to multiple medications but also to comorbidities, cognitive and functional impairment and age-related changes in pharmacokinetics and pharmacodynamics [11,15]. Another frequently observed problem in this population has to do with the use of over-the-counter (OTC) medication that can also interfere with other drugs [16].\n\nThere are many drugs, used in acute or chronic treatment of various illnesses, which are associated with headache as an adverse reaction [17,18]. Commonly used drugs in elderly patients that can cause headache include antibiotics (trimethoprim-sulfamethoxazole, tetracycline), sedatives, stimulants, amantadine, levodopa, dipyridamole, β-blockers, calcium-channel blockers, antiarrhythmics, nonsteroidal anti-inflammatory drugs (NSAIDs), H2-blockers, bronchodilators, chemotherapeutics (e.g., tamoxifen, cyclophosphamide), hormones and erectogenic agents [2].\n\nMany clinical trials do not recruit elderly patients due to their comorbidities [19]. Thus, treatment recommendations for the elderly are usually based on extrapolation of evidence from trials conducted in healthy and younger populations [9]. Since headaches as a manifestation of ADRs have received limited attention from pharmacovigilance, and there is a well-documented under-representation of elderly in clinical trials [19], it is urgent to study this topic.\n\nOur study aimed to analyze all reports of headache-associated ADR in elderly patients, including serious ADRs, sent to the Portuguese Pharmacovigilance System (PPS), and also describe which drugs were more frequently associated with this reaction. According to the definition of Good Pharmacovigilance Practices, Module VI [20], a serious ADR is “any untoward medical occurrence that at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or a congenital anomaly/birth defect”. To the best of our knowledge, this type of study was not performed before, and it may be useful in order to avoid or reduce ADRs in elderly patients.\n\nOur main hypotheses were that headache as an ADR in elderly people increased in Portugal in the last 10 years, and also that sex distribution of this population would be equal, due to the nature of these headaches. Finally we hypothesize that some of these headaches were not innocent and would accompany severe reactions\n\n2. Materials and Methods\n\nAn observational and retrospective analysis of suspected ADR reports sent to the PPS between 1 January 2007, and 31 December 2017, was performed. This analysis involved only ADR reports of patients aged 65 years or older, using the High Level Term (HLT) “headache”. All duplicate reports were excluded from the analysis, and thus our final sample included 155 reports.\n\nThe HLT classification belongs to the Medical Dictionary for Regulatory Activities (MedDRA). This is a rich and highly specific standardized medical terminology developed by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) which is used by regulatory authorities to facilitate international sharing of regulatory information on medical products used by humans. It is used worldwide by regulatory authorities, global pharmaceutical companies, clinical research organizations and health care professionals to code ADRs [21].\n\nEach report corresponds to a single individual, but each report may correspond to more than one ADR and more than one suspected drug.\n\nIn Portugal, the reports are collected by the PPS, coordinated by INFARMED—National Authority of Medicines and Health Products, I.P. They are sent by healthcare professionals, patients/consumers or marketing authorization holders by paper, e-mail, telephone or online.\n\nPatient demographics were analyzed using the following age group distribution: 65–74, 75–84, 85 years or older [12], and gender. Reports were stratified according to their seriousness and source (type of reporter: physicians, pharmacists, nurses, other healthcare professionals, consumers or other non-healthcare professionals or marketing authorization holders). We analyzed all reports with a fatal outcome and the relationship between exposure and death by following the criteria adopted by the PPS and the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) system for standardized case causality assessment [22]. According to this method, which considers the clinical-pharmacological aspects of the report history and the quality of the documentation, ADRs were classified as certain, probable, possible, unlikely, conditional or unclassifiable [22]. The causality assessment was attributed by experts belonging to the PPS.\n\nUsing the obtained data, it was also possible to evaluate the polypharmacy rate in this population, considering polypharmacy as the use of five or more drugs per day [10]. It was also checked whether or not suspected ADRs in our study were described in the Summary of Product Characteristics (SmPC) of the respective drug. Drugs involved were categorized by therapeutic group in accordance with the WHO Anatomical Therapeutic Chemical (ATC) classification system [23].\n\nReports that reported other reactions simultaneously with headaches were also evaluated.\n\nData were analyzed by descriptive statistics, such as absolute frequency, relative frequency and percentages, using the Office® Excel® 365 software (Microsoft Corporation, Redmond, WA, USA).\n\n3. Results\n\nDuring the studied 10-year period, we obtained 155 reports in which the HLT term “headache” was an ADR in elderly individuals. In general, there was an increase in reporting over the years, particularly in the last three years, which was also observed in the number of serious ADRs, as can be seen in Figure 1.\n\n3.1. Demographic Data\n\nOf the 155 analyzed reports, most (74.8%; n = 116) involved women. The highest number of ADR reports was associated with the group of 65–74 year-old individuals (Table 1).\n\n3.2. Prevalence of Polypharmacy\n\nIn the majority of the reports (75.5%, n = 117) patients were taking one or more concomitant drugs, and in 43.9% of cases (n = 68) patients were taking a minimum of five drugs simultaneously. In 29 reports (18.7%), the number of concomitant drugs was unknown, since such information was lacking in the reports. In nine reports (5.8%), patients were not taking any concomitant drugs (Figure 2).\n\n3.3. Adverse Drug Reactions Seriousness and Causality\n\nMost of the reports were classified as non-serious (53.5%, n = 83). In 72 serious reports (46.5%), 3 had death as an outcome, in 5 reports the patient’s life was threatened, 18 patients were hospitalized or had a prolonged hospitalization and in 27 reports ADRs caused incapacity. Other reports were only considered clinically important.\n\nIn the majority of the ADR reports (72.9%), the causal relationship between the drug and “headache” was classified as “possible” or “probable”. In 16.8% of the reports, there was no information about the causality between the drug and ADR. There were only three reports in which ADR was classified as “unlikely” or “unrelated”. These suspected drugs were norfloxacin, nilotinib and Sabalis serrulatae fructus.\n\nMoreover, 9.6% of drugs were classified as having a definitive relationship with the ADR by the regulatory authority. In these reports, the involved drugs were alendronic acid and cholecalciferol, aliskiren, fenofibrate, fluoxetine, ginkgo folium, nitroglycerin, normal human immunoglobulin (two cases), propranolol, telmisartan, esomeprazole, tramadol, exemestane and docetaxel.\n\n3.4. Drugs Associated with Headache as an Adverse Drug Reaction\n\nCertain drugs were more frequently suspected as triggers of ADR-headache than others. Table 2 shows the most frequently involved drugs in serious and non-serious ADRs and the number of occurrences for each one.\n\nIn 155 reports, we found 177 involved drugs. In 15 reports, more than one drug was suspected as a cause of the ADR-headache. A thorough analysis of drugs involved in serious ADR-headaches was performed.\n\n3.5. Fatal Outcomes\n\nAmong the serious ADRs reported, there were three deaths associated with domperidone, enoxaparin and ledipasvir–sofosbuvir. However, after evaluating the reports according to the WHO system for standardized case causality assessment, as described in Methods, it was considered that the suspected drugs were not directly related to the outcome because there were other adverse reactions and complications in the patients’ health status that may have motivated this outcome. As an example, when we searched for details in a report involving enoxaparin, we found that the patient had also suffered a secondary brain hemorrhagic stroke. The cause of death was attributed to stroke, associated with sudden holocranial headache and altered state of consciousness.\n\nWith domperidone, the causality attributed between the drug and the ADRs was only possible. The other ADRs present were hematuria, hematemesis, generalized edema and drowsiness.\n\nIn the report associated with ledipasvir-sofosbuvir, in addition to headache, the patient suffered cardiorespiratory arrest, sepsis, ascites, nausea, vomiting, disorders of the urinary system and abdominal pain. The cause of death was attributed to sepsis and cardiorespiratory arrest, and was thus not drug-related. In conclusion, in these three reports, patients had various previously diagnosed diseases and a poor health status wherefore the expert concluded that the drug was not related to the outcome.\n\n3.6. Other Adverse Drug Reactions Concomitant with Headache-ADR\n\nMost described headaches were present simultaneously with multiple other ADRs, such as dizziness, nausea and vision disorders (Table 3). Only in 9.7% (n = 15) of the reports was “headache” the single adverse reaction notified.\n\nWhen associated with vision disorders, reports mostly involved blurred vision, and occasionally double vision, eye pain, ocular photosensitivity, loss of vision, amaurosis fugax and sensation of pressure in the eye. The suspected drugs in these reports were indomethacin and brinzolamide eye drops, two reports with a 35 µg/h transdermal system of buprenorphine, a rectal nitroglycerin ointment and oral glucosamine formulations of 1500 mg, pentoxifylline 400 mg, bisoprolol 2.5 mg, cholecalciferol 22,400 IU, Escherichia coli lysate, association of telmisartan and hydrochlorothiazide, acetylsalicylic acid 100 mg, diltiazem 120 mg, nimesulide 100 mg, donepezil 5 mg, levocetirizine 5 mg, aceclofenac 100 mg, celecoxib 100, pregabalin 50 mg and verapamil 120 mg.\n\nIn eight reports (5.2%), changes in the state of consciousness were described, namely syncope (four reports), presyncope (three reports), altered state of consciousness (one report) and coma (one report). The drugs involved in the coma were sodium picosulfate combinations and the association of cilazapril and hydrochlorothiazide, both of which are suspected of causing ADRs. For both drugs, the causal relationship was considered probable by the regulatory authority. There was also a case of a fall reported as ADR, which is a relevant event in this older population. This reaction, considered serious, was associated with nitroglycerin and was accompanied by other ADRs such as dizziness and amaurosis fugax.\n\nAnalysis of the SmPCs of the suspected drugs identified in the reports found that headache was not described as a possible ADR in 26 of these drugs. In the remaining drugs (154), this ADR was described with frequencies ranging from very rare to very common. There were also reports in which this adverse reaction was known but its frequency was not known.\n\n3.7. Source of Adverse Drug Reactions Reports\n\nPharmacists were the health professionals who submitted the highest number of notifications (49.0%, n = 76), followed by consumers or other non-healthcare professionals (21.3%, n = 33), physicians (15.5%, n = 24), marketing authorization holders (11.6%, n = 18), nurses (1.9%, n = 3) and other healthcare professionals (0.7%, n = 1).\n\n4. Discussion\n\nOur search involving cases reported to the PPS over a 10-year period retrieved 155 reports of headache as an ADR in elderly individuals under treatment. Most reports of “headache” ADR occurred in women and 46.5% were considered serious. Anti-viral medication, anti-depressants, anti-dyslipidemic agents and central nervous system-acting analgesics were the most frequent drugs associated with “headache” ADR reports in this population.\n\nThe population included in the study was mainly composed of female patients in the 65–74-year-old age group, who were polymedicated, which is expected according to data on the elderly population in Portugal that shows that there are more women than men [24]. In addition, studies suggest that women are more susceptible to suffering from headache. A study concerning self-reported headaches across the lifespan in a German sample evaluated headache bouts and analgesic use in old age concluded that elderly women suffer from more frequent episodes of headache than elderly men [25]. This gender issue may also explain findings in our population. Other studies concerning ADRs showed that women are affected twice as much as men due to a combination of pharmacokinetics and pharmacodynamics factors [11], and also because the female gender is associated with an increased risk of an ADR-related hospitalization (RR 1.05; 95% CI 1.03, 1.08) in comparison with males [13].\n\nAlthough the number of reports presented is our study is not too large, it represents the total number of reports sent to the PPS during the last decade in Portugal. In recent years there have been a number of European legislative changes aiming to promote an increase in reporting adverse reactions, whereby the number of notifications of such reactions has been increasing during the observed years. This could also be related to consumer and provider perceptions of how severe an event needs to be to warrant submission of the event report to the post-marketing spontaneous reporting surveillance system, an important tool for monitoring drug safety in a large population [26,27].\n\nOur study shows the importance of headache as an ADR in an older population that is mostly female and polymedicated which may be associated with some serious clinical features. Nair et al. (2016) summarized the available evidence on ADR-related hospital admission in elderly patients living in the community, with a particular focus on risk factors for ADRs leading to hospital admission, and concluded that some of the main risk factors or predictors of ADR-related admissions were advanced age, polypharmacy and comorbidity [11], which may also explain our results. Angamo et al. (2016) evaluated the prevalence and contributing factors to ADR-related hospitalizations in developed and developing countries and concluded that the proportion of severe ADRs in developed countries was twice as high as that in developing countries [15]. The same study concluded that these severe ADRs were associated with an increasingly larger number of older patients with more comorbidities and who were likely taking more medications due to both more advanced age and higher financial capacity to obtain a wider variety of medications [15]. Although the majority of reports in our study were not serious, the percentage of serious cases reported has also been increasing over the years covered by the study, thereby showing the importance of “headache” as a serious adverse reaction particularly in elderly patients [28].\n\nIn addition to headaches, several other adverse reactions have been identified. The most common are nausea, vomiting, dizziness and vision disorders. Photophobia, nausea, and vomiting are frequently associated with migraine [29] and occur in approximately one third of patients with the very rare condition of Cardiac Cephalalgia [6]. On the other hand, dizziness and nausea include a spectrum of balance-related adverse reactions with various underlying causes [30]. Even though these ADRs might not represent a direct threat to life, they can indirectly cause secondary damage such as falls and fractures in these elderly patients, and can have serious effects in terms of mobility, cognition and psychological consequences (fear of falling in the future) [31]. Falls can also be a consequence of orthostatic hypotension caused by different drugs in elderly patients [32] and are associated with increased morbidity and mortality in such a population [31,33,34,35]. Nausea and vomiting were also widely reported and, in this population, they carry the risk of dehydration and malnutrition [36]. Although many medications can cause headaches, this ADR can be accompanied by more serious ones, and thus it should not be devalued, particularly in elderly patients. These results are not in agreement with another study performed in this population using a Portuguese pharmacovigilance database, where the most frequently reported suspected ADRs fall within the categories of general disorders and administration site conditions, and skin and subcutaneous tissue complaints [37]. However, our study gives us a global perspective of the ADRs profile in elderly Portuguese patients. In our study, most of the reported ADRs were expected because they are described in SmPC. These results are in agreement with other studies that claim that most ADRs are preventable [38,39]. Organic nitrates were an example of headache-ADR suspected drugs and can produce this ADR because vasodilation is one of the mechanisms that causes headache. This effect is expected to occur when using these drugs; however, it is likely to disappear when treatment is continued because of the development of tolerance [40]. Vasodilatation is often dose-dependent, but may also appear within the therapeutic range. This ADR can occur, namely with cardiovascular drugs such as calcium-channel blockers and angiotensin-converting enzyme inhibitors [17]. Another example involves the use of several antidiabetic drugs which can be related to headaches because of the hypoglycemia that they may induce. This adverse effect results directly from the mechanism of action of the drug and exacerbation of the desired clinical effect (decreased blood glucose) [41]. There are other drug mechanisms that produce headache as an adverse reaction. Raised intracranial pressure is an ADR which is not predictable from the mechanism of action of the medication, such as headache related to drug-induced aseptic meningitis [17]. There are also headaches occurring with chronic medication which are related to raised intracranial pressure as well as headaches related to substance withdrawal [17].\n\nThe most frequently notified drugs in this study were antivirals, antidyslipidemic agents, antidepressants, narcotic analgesics, bisphosphonates, drugs used in urine retention, immunomodulators and aromatase inhibitors. Several studies showed that these drugs are responsible for headache as ADR, but some of them are also responsible for a high number of ADRs leading to hospital admission [2,11,17,28,34,37].\n\nMost ADRs were reported directly by healthcare professionals, pharmacists and physicians, as also described in other studies [28]. In our study, pharmacists were the main reporters, just as seen in another study that described the characteristics of voluntarily reported ADRs in a tertiary healthcare setting [41]. Another study of community pharmacists practicing in the West Midlands, UK observed an increasing trend of ADR reporting among community pharmacists [42]. In the same study, the authors concluded that there were three main reasons for under-reporting of ADRs by community pharmacists: consideration that an ADR was not serious enough to report; the perception that well-known ADRs did not need to be reported; and, finally, lack of time to carry out the report [42]. These results emphasize the important role that community pharmacists play in the field of medicinal drugs, namely in terms of drug safety, and also that the abovementioned barriers need to be adequately addressed.\n\nWe acknowledge some limitations in our study: ADRs in the PPS were spontaneously reported, and thus the true incidence of ADRs cannot be determined using these data; furthermore, under-reporting is a general problem in pharmacovigilance [26]. On the other hand, ADR reporting may be influenced by several external factors, such as the time that the drug is in the market, litigation and advertising or other media attention and these factors cannot be addressed in our analysis. In addition, it was not possible to classify the different headaches in terms of clinical classification due to the lack of information in the reports.\n\nIn spite of the limitations, to the best of our knowledge, our study is the first analysis of “headache” ADR in an elderly population based on data reported to a pharmacovigilance system. The increasing number of elderly individuals with polypharmacy in society and the serious health issues associated with ADR-headache are important factors to evaluate in this population. Our work contributes to shedding some light on this problem, and is also a call to action in order to improve the life of older patients. In addition, we also intend to raise the awareness of the authorities to the need for developing educational programs, either for the population, or for health care providers, with the aim of improving drug safety in elderly people.\n\n5. Conclusions\n\nHeadache is a serious problem as an adverse reaction to medication in older patients, particularly in women. Many of the events reported in our study were considered serious and were often associated with other serious adverse reactions. For some classes of drugs, a higher association with this kind of adverse effects is clear and such drugs should therefore be prescribed carefully in older populations. The evaluation of ADRs in elderly patients is an important method contributing to prevention of drug-related side effects and promotion of pharmacological safety of this population.\n\nAuthor Contributions\n\nC.M. supervised collection of data; B.D. collected the data and organized the results; C.M. and M.V.-P. supervised the analysis of data; C.M. and M.V.-P. wrote the final draft. All authors made substantial contributions, approved the final version of the manuscript and agreed to be accountable for all aspects of the work. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nEthics Approval and Consent to Participate\n\nNot applicable.\n\nInstitutional Review Board Statement\n\nNot applicable.\n\nInformed Consent Statement\n\nNot applicable.\n\nData Availability Statement\n\nThe raw data used in this research are available to the authors, depending on INFARMED’s authorization.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 All suspected adverse drug reactions (ADRs) reports versus the serious reports per year.\n\nFigure 2 Description of the prevalence of polypharmacy (Note: “unknown” means that it is unknown if the patients were taking concomitant medication or not).\n\nijerph-18-02674-t001_Table 1 Table 1 Characterization of the sample by gender and age.\n\n\tGender\t\nAge\tFemale\tMale\tUnknown\tTotal\t\n65–74\t66\t13\t2\t81\t\n75–84\t37\t15\t-\t52\t\n≥85\t4\t4\t-\t8\t\nUnknown\t9\t5\t-\t14\t\nTotal\t116\t37\t2\t155\t\n\nijerph-18-02674-t002_Table 2 Table 2 Anatomical Therapeutic Chemical Classification System code (ATC): drugs most frequently involved in adverse drug reactions (ADRs) and the number of occurrences for each one.\n\n\tSerious\tNon Serious\t\t\nATC Classification\tDrugs (Number of Occurrences)\tDrugs (Number of Occurrences)\tTotal\t\nAntivirals for systemic use\tribavirin (1), sofosbuvir and ledipasvir (2), sofosbuvir (2),\tribavirin (1), sofosbuvir and ledipasvir (4), sofosbuvir (1),\t9.0%\t\nLipid modifying agents\tatorvastatin (1), pitavastatin (1)\tatorvastatin (1), fenofibrate (1), fluvastatin (1), pravastatin (2), simvastatin (4), simvastatin and ezetimibe (2)\t8.4%\t\nAntidepressants\tescitalopram(2), mirtazapine (1)\tagomelatine (1), fluoxetine (2), mirtazapine (1), sertralina (1), venlafaxine (1), vortioxetine (1)\t6.4%\t\nAnalgesics\tbuprenorphine(2), hydromorphone(1), tramadol (1), tramadol and paracetamol (2)\tcodeine and paracetamol (1), tramadol (1), tramadol and paracetamol (1)\t5.8%\t\nDrugs for the treatment of bone diseases\talendronic acid and cholecalciferol (2), zoledronic acid (1)\talendronic acid and colecalcifero (1), alendronic acid (2), ibandronic acid (2)\t5.2%\t\nUrologicals\tSabalis serrulatae fructus (1), tamsulosin (1)\tSabalis serrulatae fructus (2), tamsulosin (1), tamsulosin and dutasteride (1)\t3.9%\t\nImmunosuppressants\t-\tadalimumab (1), etanercept (1), Imatinib (1), mycophenolic acid (1), tocilizumab (2)\t3.9%\t\nEndocrine therapy\texemestane (2), letrozole (1)\tanastrozole (1), exemestane (1), letrozole (1),\t3.9%\t\n\nijerph-18-02674-t003_Table 3 Table 3 Other adverse drug reactions (ADRs) concomitant with headache-ADR with relative frequency >2%.\n\nOther ADRs Concomitant with Headache\tN (%)\t\nDizziness\t29 (18.7%)\t\nNausea\t25 (16.1%)\t\nVision complaints\t24 (15.5%)\t\nMalaise\t20 (12.9%)\t\nVomiting\t18 (11.6%)\t\nMyalgia\t11 (7.1%)\t\nDiarrhea\t11 (7.1%)\t\nIncreased blood pressure\t11 (7.1%)\t\nFever\t8 (5.2%)\t\nAsthenia\t8 (5.2%)\t\nInsomnia\t7 (4.5%)\t\nTachycardia\t6 (3.9%)\t\nFatigue\t6 (3.9%)\t\nStomach ache\t6 (3.9%)\t\nAbdominal pain\t6 (3.9%)\t\nArthralgia\t5 (3.2%)\t\nCough\t5 (3.2%)\t\nSomnolence\t5 (3.2%)\t\nItching\t4 (2.6%)\t\nEar buzzing\t4 (2.6%)\t\nLoss of appetite\t4 (2.6%)\t\nHeaviness of head\t4 (2.6%)\t\nDyspnea\t4 (2.6%)\t\nChills\t4 (2.6%)\t\nSyncope\t4 (2.6%)\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. WHO Headache Disorders Available online: https://www.who.int/news-room/fact-sheets/detail/headache-disorders (accessed on 20 March 2020)\n2. Bamford C.C. Mays M. Tepper S.J. Unusual Headaches in the Elderly Curr. Pain Headache Rep. 2011 15 295 301 10.1007/s11916-011-0196-0 21455737\n3. Sharma T.L. Common Primary and Secondary Causes of Headache in the Elderly Headache 2018 58 479 484 10.1111/head.13252 29322494\n4. Starling A.J. Diagnosis and Management of Headache in Older Adults Mayo Clin. Proc. 2018 93 252 262 10.1016/j.mayocp.2017.12.002 29406202\n5. Solomon G.D. Kunkel R.S. Frame J. Demographics of Headache in Elderly Patients Headache 1990 30 273 276 10.1111/j.1526-4610.1990.hed3005273.x 2354949\n6. Bravo T.P. Headaches of the Elderly Curr. Neurol. Neurosci. Rep. 2015 15 1 9 10.1007/s11910-015-0552-2 25893722\n7. Salazar J.A. Poon I. Nair M. Clinical consequences of polypharmacy in elderly: Expect the unexpected, think the unthinkable Exp. Opin. Drug Saf. 2007 6 695 704 10.1517/14740338.6.6.695\n8. Alsuwaidan A. Almedlej N. Alsabti S. Daftardar O. Al Deaji F. Al Amri A. Alsuwaidan S. A Comprehensive Overview of Polypharmacy in Elderly Patients in Saudi Arabia Geriatrics 2019 4 36 10.3390/geriatrics4020036\n9. Hughes C.M. Cadogan C.A. Patton D. Ryan C.A. Pharmaceutical strategies towards optimising polypharmacy in older people Int. J. Pharm 2016 502 360 365 10.1016/j.ijpharm.2016.02.035\n10. Masnoon N. Shakib S. Kalisch-ellett L. Caughey G.E. What is polypharmacy? A systematic review of definitions BMC Geriatr. 2017 17 1 10 10.1186/s12877-017-0621-2 28049446\n11. Nair N.P. Chalmers L. Peterson G.M. Bereznicki B.J. Castelino R.L. Bereznicki L.R. Hospitalization in older patients due to adverse drug reactions–the need for a prediction tool Clin. Interv. Aging. 2016 11 497 505 10.2147/CIA.S99097 27194906\n12. Pedrós C. Formiga F. Corbella X. Arnau J.M. Adverse drug reactions leading to urgent hospital admission in an elderly population: Prevalence and main features Eur. J. Clin. Pharmacol. 2016 72 219 226 26546335\n13. Ruiter R. Visser L.E. Rodenburg E.M. Trifiro G. Ziere G. Stricker B.H. Adverse Drug Reaction-Related Hospitalizations in Persons Aged 55 Years and Over Drugs Aging. 2012 29 225 232 10.2165/11599430-000000000-00000 22372725\n14. Oscanoa T.J. Lizaraso F. Carvajal A. Hospital admissions due to adverse drug reactions in the elderly. A meta-analysis Eur. J. Clin. Pharmacol. 2017 73 759 770 10.1007/s00228-017-2225-3 28251277\n15. Angamo M.T. Chalmers L. Curtain C. Bereznicki L.R. Adverse-Drug-Reaction-Related Hospitalisations in Developed and Developing Countries: A Review of Prevalence and Contributing Factors Drug Saf. 2016 39 847 857 10.1007/s40264-016-0444-7 27449638\n16. Cybulski M. Cybulski L. Krajewska-Kulak E. Orzechowska M. Cwalina U. Preferences and attitudes of older adults of Bialystok, Poland toward the use of over-the- counter drugs Clin. Interv. Aging 2018 13 623 632 10.2147/CIA.S158501 29692605\n17. Ferrari A. Spaccapelo L. Gallesi D. Sternieri E. Focus on headache as an adverse reaction to drugs J. Headache Pain. 2009 10 235 239 10.1007/s10194-009-0127-1 19495934\n18. Iversen H. Olesen J. Nitroglycerin-induced headache is not dependent on histamine release: Support for a direct nociceptive action of nitric oxide Cephalalgia 1994 14 1 6 10.1046/j.1468-2982.1994.1406437.x\n19. Carroll C.B. Zajicek J.P. Designing clinical trials in older people Maturitas 2011 68 337 341 10.1016/j.maturitas.2011.02.002 21376485\n20. EMA Guideline on Good Pharmacovigilance Practices (GVP) Module VI–Collection, Management and Submission of Reports of Suspected Adverse Reactions to Medicinal Products (Rev 2) Available online: https://www.ema.europa.eu/documents/regulatory-procedural-guideli (accessed on 28 February 2020)\n21. Introductory Guide MedDRA Version 22.1, (September 2019) Available online: https://www.meddra.org/sites/default/files/guidance/file/000354_intguide_22.1.pdf (accessed on 28 February 2020)\n22. World Heath Organization The Uppsala Monitoring Centre, Uppsala Available online: https://www.who-umc.org/ (accessed on 4 March 2020)\n23. WHO Collaborating Centre for Drug Statistics Methodology ATC/DDD Index 2020 Available online: https://www.whocc.no/atc_ddd_index/ (accessed on 3 March 2020)\n24. National Institute of Statistics Available online: https://www.ine.pt/xportal/xmain?xpid=INE&xpgid=ine_indicadores&indOcorrCod=0001272&xlang=pt&contexto=bd&selTab=tab2 (accessed on 25 March 2020)\n25. Müller B. Dresler T. Gaul C. Glass Ä. Jürgens T.P. Kropp P. More Attacks and Analgesic Use in Old Age: Self-Reported Headache Across the Lifespan in a German Front. Neurol. 2019 10 1 10 10.3389/fneur.2019.01000 30761061\n26. Biagi C. Montanaro N. Buccellato E. Roberto G. Vaccheri A. Motola D. Underreporting in pharmacovigilance: An intervention for Italian GPs (Emilia–Romagna region) Eur. J. Clin. Pharmacol. 2013 69 237 244 10.1007/s00228-012-1321-7 22706618\n27. Alatawi Y.M. Hansen R.A. Empirical estimation of under-reporting in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) Exp. Opin. Drug. Saf. 2017 16 761 767 10.1080/14740338.2017.1323867\n28. Sonawane K.B. Cheng N. Hansen R.A. Serious Adverse Drug Events Reported to the FDA: Analysis of the FDA Adverse Event Reporting System 2006-2014 Database JMCP 2018 24 682 690 10.18553/jmcp.2018.24.7.682 29952714\n29. Martins K. Bordini C.A. Bigal M.E. Speciali J. Migraine in the Elderly: A Comparison With Migraine in Young Adults Headache 2006 46 312 316 10.1111/j.1526-4610.2006.00343.x 16492241\n30. Chimirri S. Aiello R. Mazzitello C. Mumoli L. Palleria C. Citraro R. Vertigo/dizziness as a Drugs ’ adverse reaction J. Pharmacol. Pharmacother. 2013 4 Suppl. 1 S104 S109 24347974\n31. Khow K.S.F. Visvanathan R. Falls in the Aging Population Clin. Geriatr. Med. 2017 33 357 368 10.1016/j.cger.2017.03.002 28689568\n32. Butt D.A. Harvey P.J. Benefits and risks of antihypertensive medications in the elderly J. Intern. Med. 2015 278 599 626 10.1111/joim.12446 26497967\n33. Klotz U. Pharmacokinetics and drug metabolism in the elderly Drug Metab. Rev. 2009 41 67 76 10.1080/03602530902722679 19514965\n34. Kongkaew C. Noyce P.R. Ashcroft D.M. Hospital Admissions Associated with Adverse Drug Reactions: A Systematic Review of Prospective Observational Studies Ann. Pharmacother. 2008 42 1017 1025 10.1345/aph.1L037 18594048\n35. Maher R.L. Hanlon J. Hajjar E.R. Clinical consequences of polypharmacy in elderly Expert Opin. Drug Safety. 2014 13 57 65 10.1517/14740338.2013.827660\n36. Bulgarelli K. Proposal for the testing of a tool for assessing the risk of dehydration in the elderly patient Acta Biomed. 2015 9 134 141\n37. Monteiro C. Duarte A.P. Alves G. Adverse drug reactions in elderly: A five-year review of spontaneous reports to the Portuguese pharmacovigilance system Exp. Opin. Drug Saf. 2021 20 109 118 10.1080/14740338.2020.1849137 33170742\n38. Geer M.I. Koul P.A. Tanki S.A. Shah M.Y. Frequency, types, severity, preventability and costs of Adverse Drug Reactions at a tertiary care hospital J. Pharmacol. Toxicol. Methods 2016 81 323 334 10.1016/j.vascn.2016.04.011 27109493\n39. Gurwitz J. Field T.S. Harrold L.R. Rothschild J. Debellis K. Seger A.C. Incidence and Preventability of in the Ambulatory Setting JAMA 2003 289 1107 1116 10.1001/jama.289.9.1107 12622580\n40. Gonzalez A. Hyde E. Sangwan N. Gilbert J.A. Viirre E. Knight R. Migraines Are Correlated with Higher Levels of Nitrate-, Nitrite-, and Nitric Oxide-Reducing Oral Microbes in the American Gut Project Cohort mSystems 2016 1 3 6 10.1128/mSystems.00105-16\n41. Aung A.K. Tang M.J. Adler N.R. Adverse Drug Reactions Reported by Healthcare Professionals: Reaction Characteristics and Time to Reporting J. Clin. Pharmacol. 2018 58 1332 1339 10.1002/jcph.1148 29733431\n42. Cheema E. Haseeb A. Khan T.M. Sutcliffe P. Singer D.R. Barriers to reporting of adverse drugs reactions: A cross sectional study among community pharmacists in United Kingdom Pharm. Pract. 2017 15 931 10.18549/PharmPract.2017.03.931\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1660-4601",
"issue": "18(5)",
"journal": "International journal of environmental research and public health",
"keywords": "adverse drug reaction; elderly; headache; pharmacovigilance",
"medline_ta": "Int J Environ Res Public Health",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006261:Headache; D006801:Humans; D060735:Pharmacovigilance; D012189:Retrospective Studies",
"nlm_unique_id": "101238455",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33799926",
"pubdate": "2021-03-07",
"publication_types": "D016428:Journal Article",
"references": "28689568;27449638;29952714;24073682;27822557;25893722;26546335;29017448;31096616;31749752;28447485;21455737;19514965;26497967;24347974;33170742;16492241;22706618;27194906;27109493;28251277;18594048;22372725;7535192;26629668;19495934;29692605;29322494;28943977;12622580;2354949;26921516;29406202;29733431;21376485;17967158",
"title": "Headache as an Adverse Reaction to the Use of Medication in the Elderly: A Pharmacovigilance Study.",
"title_normalized": "headache as an adverse reaction to the use of medication in the elderly a pharmacovigilance study"
} | [
{
"companynumb": "2022A226215",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ANASTROZOLE"
},
"drugadditional": "4",
"drugadmin... |
{
"abstract": "Ulcerative colitis can be associated with numerous extraintestinal organ manifestations. Pulmonary disease in inflammatory bowel disease (IBD) is supposed to be a rare entity and has to be distinguished from infectious complications and side-effects of medications used in the treatment of IBD. We present the case of a 20-year-old male patient with ulcerative colitis and a 4-week history of respiratory symptoms, malaise, fever and respiratory insufficiency under a medication with mesalazine. Computed tomography showed bilateral subpleural consolidations, bronchoscopy revealed signs of acute bronchitis. The diagnostic work-up ruled out an infectious cause. Under the tentative diagnosis of a mesalazine-induced bronchiolitis obliterans with organizing pneumonia (BOOP) the medication with mesalazine was withdrawn and the patient received a corticosteroid trial. The symptoms quickly improved and prednisone was tapered and stopped after 6 months. Unexpectedly, lung function after complete resolution of respiratory symptoms revealed a residual obstructive ventilatory defect that might be due to an asymptomatic pulmonary manifestation of ulcerative colitis. A review of the literature shows that pulmonary manifestations in IBD as well as pulmonary toxicity of mesalazine might not be as rare as expected and should be included as differential diagnoses in the work-up of respiratory symptoms in patients with IBD. A pragmatic therapeutic approach is reasonable in critically ill patients as it is not always easy to distinguish both entities.",
"affiliations": "Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.;Center for Infectious Diseases and Infection Control, Jena University Hospital, Jena, Germany.;Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.;Clinic of Internal Medicine I, Department of Pneumology and Allergy/Immunology, Jena University Hospital, Jena, Germany.;Clinic of Internal Medicine IV, Jena University Hospital, Jena, Germany.",
"authors": "Moeser|A|A|;Pletz|M W|MW|;Hagel|S|S|;Kroegel|C|C|;Stallmach|A|A|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D019804:Mesalamine",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0041-103377",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0044-2771",
"issue": "53(9)",
"journal": "Zeitschrift fur Gastroenterologie",
"keywords": null,
"medline_ta": "Z Gastroenterol",
"mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003093:Colitis, Ulcerative; D018549:Cryptogenic Organizing Pneumonia; D006801:Humans; D015212:Inflammatory Bowel Diseases; D008297:Male; D019804:Mesalamine",
"nlm_unique_id": "0033370",
"other_id": null,
"pages": "1091-8",
"pmc": null,
"pmid": "26367026",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Lung disease and ulcerative colitis--mesalazine-induced bronchiolitis obliterans with organizing pneumonia or pulmonary manifestation of inflammatory bowel disease?",
"title_normalized": "lung disease and ulcerative colitis mesalazine induced bronchiolitis obliterans with organizing pneumonia or pulmonary manifestation of inflammatory bowel disease"
} | [
{
"companynumb": "DE-ALLERGAN-1647139",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "1",
"dr... |
{
"abstract": "BACKGROUND\nTo analyze cardiovascular risk factors and comorbidity of acute unilateral visual loss due to combined central retinal vein occlusion (CRVO) and cilioretinal artery occlusion (CLRAO).\nAmong patients with retinal vein or artery occlusion hospitalized at the Department of Ophthalmology between January 2011 and August 2017, subjects with combined CRVO/CLRAO were selected. All of them underwent ophthalmologic and cardiologic examination, including fluorescein angiography, optical coherence tomography, 12-lead electrocardiogram, transthoracic and transesophageal echocardiography, carotid Doppler sonography, cerebral magnetic resonance imaging, and a panel of laboratory tests.\nFour subjects with coexisting CRVO and CLRAO were found among 146 patients with retinal vein or artery occlusion. There were no other types of concomitance of CRVO and retinal artery occlusion.\n\n\nMETHODS\nAll patients were treated with low molecular heparin in a full dose for 2 weeks, then with 1 mg/kg once daily for the next 2 weeks, followed by acetylsalicylic acid 75 mg/kg/d. Other medication included long-term statins, angiotensin-converting-enzyme inhibitor in 3 patients and beta-blocker in one patient.\n\n\nRESULTS\nAll patients with CRVO/CLRAO presented multiple cardiovascular risk factors, including hypertension, obesity, hyperlipidemia, chronic nicotine addiction, and a positive family history of coronary artery disease or stroke. In all of them, echocardiography revealed left ventricular hypertrophy and atherosclerotic lesions in the descending aorta; in addition, 3 patients had insignificant atherosclerotic plaques in the carotid artery. Also, in 3 subjects, focal ischemic cerebral changes were diagnosed.\n\n\nCONCLUSIONS\nPatients with combined CRVO and CLRAO present numerous cardiovascular risk factors and abnormalities on imaging examinations, which should be routinely evaluated and treated.",
"affiliations": "Department of Ophthalmology, Poznań City Hospital, Poznań University of Warmia and Mazury, Olsztyn Department of Internal Diseases, Poznań City Hospital, Poznań, Poland.",
"authors": "Grzybowski|Andrzej|A|;Elikowski|Waldemar|W|;Gaca-Wysocka|Magdalena|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000009255",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29505511MD-D-17-0093110.1097/MD.0000000000009255092555800Research ArticleClinical Case ReportCardiovascular risk factors in patients with combined central retinal vein occlusion and cilioretinal artery occlusion Case reportGrzybowski Andrzej MD, PhDab∗Elikowski Waldemar MD, PhDcGaca-Wysocka Magdalena MD, PhDaZhang. Yao-Jun a Department of Ophthalmology, Poznań City Hospital, Poznańb University of Warmia and Mazury, Olsztync Department of Internal Diseases, Poznań City Hospital, Poznań, Poland.∗ Correspondence: Andrzej Grzybowski, Department of Ophthalmology, Poznan City Hospital, Szwajcarska 3, 60-285, Poznan, Poland (e-mail: ae.grzybowski@gmail.com).1 2018 05 1 2018 97 1 e925522 2 2017 20 11 2017 22 11 2017 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. http://creativecommons.org/licenses/by-nd/4.0Abstract\nRationale:\nTo analyze cardiovascular risk factors and comorbidity of acute unilateral visual loss due to combined central retinal vein occlusion (CRVO) and cilioretinal artery occlusion (CLRAO).\n\nPatient concerns:\nAmong patients with retinal vein or artery occlusion hospitalized at the Department of Ophthalmology between January 2011 and August 2017, subjects with combined CRVO/CLRAO were selected. All of them underwent ophthalmologic and cardiologic examination, including fluorescein angiography, optical coherence tomography, 12-lead electrocardiogram, transthoracic and transesophageal echocardiography, carotid Doppler sonography, cerebral magnetic resonance imaging, and a panel of laboratory tests.\n\nDiagnoses:\nFour subjects with coexisting CRVO and CLRAO were found among 146 patients with retinal vein or artery occlusion. There were no other types of concomitance of CRVO and retinal artery occlusion.\n\nInterventions:\nAll patients were treated with low molecular heparin in a full dose for 2 weeks, then with 1 mg/kg once daily for the next 2 weeks, followed by acetylsalicylic acid 75 mg/kg/d. Other medication included long-term statins, angiotensin-converting-enzyme inhibitor in 3 patients and beta-blocker in one patient.\n\nOutcomes:\nAll patients with CRVO/CLRAO presented multiple cardiovascular risk factors, including hypertension, obesity, hyperlipidemia, chronic nicotine addiction, and a positive family history of coronary artery disease or stroke. In all of them, echocardiography revealed left ventricular hypertrophy and atherosclerotic lesions in the descending aorta; in addition, 3 patients had insignificant atherosclerotic plaques in the carotid artery. Also, in 3 subjects, focal ischemic cerebral changes were diagnosed.\n\nLessons:\nPatients with combined CRVO and CLRAO present numerous cardiovascular risk factors and abnormalities on imaging examinations, which should be routinely evaluated and treated.\n\nKeywords\ncardiovascular risk factorscentral retinal vein occlusioncilioretinal artery occlusionOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nCombined central retinal vein occlusion (CRVO) and cilioretinal artery occlusion (CLRAO) is an uncommon variant of retinal vascular disease, which causes sudden unilateral visual acuity loss.[1] It was first described by Oosterhuis in 1968[2] and later by other authors.[3–7] The cilioretinal artery is a branch of the posterior ciliary artery, arising either directly from the posterior ciliary artery or from the choroid.[1] It is usually suggested that CLRAO occurs secondary to the raised capillary pressure caused by CRVO.[8,9] CRVO/CLRAO results in a significant increase in intraluminal pressure in the capillary bed, so CLRAO should be interpreted as a hemodynamic block.[1,10] Another hypothesis assumes that primary reduction in perfusion pressure of the cilioretinal and retinal arteries may lead to decreased retinal circulation[5,9,11,12] and subsequent venous stasis and thrombosis.[3] It is well known that the most important risk factors for CRVO are the same as those for atherosclerosis, including advanced age, hypertension, hyperlipidemia, diabetes, cigarette smoking, positive family history.[13,14] Other systemic predisposing factors include inherited and acquired thrombophilia, high blood viscosity, systemic vasculitis, and autoimmune disease.[10,14] The mechanism of action of the systemic factors may relate to the damage of the adjacent artery.[15] It is not well established whether the profile of the risk factors in patients with combined CRVO/CLRAO is similar to that observed in isolated CRVO or CRVO coexisting with central or branch retinal artery occlusion. Some authors have distinguished a subgroup of patients with CRVO or combined CRVO/CLARO, usually at a younger age, without obvious systemic disease.[1,9,13] Such a view, however, may, in part, be the result of incomplete assessment of the risk factors or even of rejected norm values of some investigated parameters.\n\nThe aim of the paper is to present the clinical picture and the cardiovascular risk factors of combined CRVO and CLRAO including transthoracic and transesophageal echocardiography, carotid Doppler sonography, cerebral magnetic resonance imaging (MRI), and a panel of laboratory tests, including thrombophilia screening.\n\n2 Material and methods\nAbout 146 patients with retinal vein or artery occlusion were hospitalized at the Department of Ophthalmology between January 2011 and August 2017. They underwent ophthalmologic and cardiovascular examination as well as a panel of laboratory tests, inter alia thrombophilia screening. Ophthalmologic assessment included measurements of the best-corrected visual acuity (BCVA) and intraocular pressure (IOP) by Goldmann applanation tonometry, slit lamp evaluation of the anterior eye segment performed after pupil dilation with 1% tropicamide, indirect ophthalmoscopy, intravenous fluorescein angiography (IVFA) after 5 mL of 10% sodium fluorescein solution bolus administration using a Zeiss fundus camera and optical coherence tomography (OCT) with the Topcon Triton Medical System. Cardiovascular assessment included electrocardiogram, transthoracic and transesophageal echocardiography (TEE), carotid Doppler sonography, cerebral MRI. Echocardiographic assessment comprised left ventricular hypertrophy, left ventricular contractile disturbances, valvular abnormalities, presence of a persistent foramen ovale, looking for thromboembolic material. The examination was performed using Vivid 7 dimension with sector, 3-dimensional and transesophageal probes. The quantification of the chambers and their function, evaluation of the valves and of a cardiac source of embolism were based on appropriate guidelines.[16–18] In detail, the atherosclerotic lesions of the descending aorta were graded according to the modified scoring system originally proposed by Fazio et al[19]: grade 0—no sign of atherosclerosis; grade 1—intimal thickening; grade 2—plaque <5 mm; grade 3—plaque >5 mm and/or “complex” plaque with ulcerated or mobile parts. Carotid artery Doppler sonography was done in accordance with the appropriate standards.[20] All examinations performed were routinely done, a written consent was given by patients for all examinations on admission and, additionally, before TEE and MRI. An analysis of the data was performed retrospectively. The patients’ consent for every examination and for using their data in the publication was obtained. The study was conducted in consistence with the Declaration of Helsinki and the regulations of local IRB.\n\n3 Results\nFour subjects with coexisting CRVO and CLRAO were found. There were no other types of concomitance of CRVO and retinal artery occlusion. Ophthalmologic data of these patients are shown in Table 1. All patients presented as sudden painless deterioration of vision with a dark spot in the affected eye and were admitted to the Department of Ophthalmology with a 6 to 36-hour delay from the onset of symptoms. Fundus examination, IVFA and OCT in cases 1 and 2 represent a spectrum of the severity of the disease with mild to advanced retina edema and hemorrhage. (Fig. 1) Cardiologic information is collected in Table 2. All 4 patients presented multiple cardiovascular risk factors, including hypertension, obesity, chronic nicotine addiction, and a positive family history of coronary artery disease or stroke. In all of them, echocardiography revealed left ventricular hypertrophy and atherosclerotic lesions in the descending aorta (Fig. 2); in addition, 3 patients had insignificant atherosclerotic plaques in the carotid artery. Also, in 3 subjects, focal ischemic cerebral changes were diagnosed (Fig. 3). All patients were treated with low molecular weight heparin (LMWH) in a full dose for 2 weeks, then with 1 mg/kg once daily, followed by acetylsalicylic acid (ASA) 75 mg/d. Other medications included long-term statins (rosuvastatin, atorvastatin for the next 2 weeks, or simvastatin), angiotensin-converting-enzyme inhibitor (ramipril) in 3 patients, and beta-blocker (carvedilol) in patient number 3. During a 2 to 60-month follow-up period, the oldest patient developed unstable angina.\n\nTable 1 Ophthalmologic data of patients with combined central retinal vein occlusion and cilioretinal artery occlusion.\n\nFigure 1 Fundus picture and optical coherence tomography of patients No 1, 2, and 4 (see Table 1).\n\nTable 2 Cardiovascular assessment of patients with combined central retinal vein occlusion and cilioretinal artery occlusion.\n\nFigure 2 Atherosclerotic lesions of the descending aorta on transesophageal echocardiography (arrows) in patients No 1 to 3.\n\nFigure 3 Ischemic foci on magnetic resonance imaging (arrows) in patients No 1 to 3.\n\n4 Discussion\nThere are 3 different types of combined retinal vein and artery occlusions: CRVO with central retinal artery occlusion (CRAO), CRVO with branch retinal artery occlusion (BRAO) and CRVO with CLRAO.[10] While the most frequent cause of isolated CRAO or BRAO is of embolic etiology, in CRAO or BRAO coexisting with CRVO emboli are rarely or never found.[10] At the same time, Schmidt suggests that the profile of the factors predisposing to combined CRVO/CRAO or CRVO/BRAO differs from that observed in isolated CRVO with the prevalence of immunological diseases, malignancies, and other causes of coagulopathies.[10]\n\nApart from CLRAO associated with CRVO, 2 other etiologically distinct types of CLRAO have been reported: nonarteritic CLRAO alone and arteritic CLRAO associated with giant cell arteritis or with ischemic optic neuropathy.[21–23] Combined CRVO and CLRAO represents 27%[23] to 62%[1] of all CLRAOs. In 1 retrospective study, 33 eyes with CLRAO over a 10-year period were diagnosed, including 9 cases of CLRAO combined with CRVO.[23] The largest group based on 38 eyes with CRVO/CLRAO was reported by Hayreh et al.[1]\n\nMost publications focus on the interpretation of the pathomechanism of combined CRVO/CLRAO, which still remains unclear.[6,7,11] Observation of the clinical course of the particular cases gives arguments for the initiating role of CRVO, after which an evolution of arterial occlusion is observed.[24] The probability of CLRAO should grow with the increasing severity of CRVO.[25] It is also possible that the incidence of combined CRVO and CLRAO is grossly underestimated.[26] On the other hand, the 1st occurrence of CLRAO seems to confirm the hypothesis concerning primary arterial affection.[27] In evidence of arterial vasospasm, related to an increased contractility of the retinal arteries, initial retinal blanching along the cilioretinal artery followed by signs of venous stasis can be observed.[9,28] Brazitikos et al[9] distinguish 2 types of combined CRVO/CLRAO in relation to cilioretinal artery filling pattern in IVFA. Patients with delayed filling were older and had systemic risk factors, while in subjects with normal cilioretinal filling systemic disease was not revealed. Recovery of visual acuity in this group was expected. Contrary to this observation, Keyser et al[12] suggest that otherwise healthy patients often presented prolonged retinal artery inflow and, after an initial improvement of vision, recurrent episodes of visual loss may occur.\n\nThe most important risk factors for CRVO (and combined CRVO/CLRAO), widespread among the population, are the same as those for atherosclerosis: advanced age, hypertension, hyperlipidemia, diabetes, cigarette smoking, a positive family history.[1,14] In some studies, including the highest number of patients with CRVO or CRVO/CLRAO, hyperlipidemia was diagnosed in an unexpectedly low percentage.[1,13] However, it should be pointed out that norm values may evolve with time. Systemic predisposing factors can also include inherited and acquired thrombophilia, systemic vasculitis, and autoimmune disease and other illnesses or clinical situations (Table 3).\n\nTable 3 Risk factors for central retinal vein occlusion (including combined central retinal vein occlusion and cilioretinal artery occlusion).\n\nRarely is combined CRVO/CLRAO reported in otherwise healthy subjects,[1,9,12] although at least some of these patients did not undergo full diagnostics panel including TEE, cerebral MRI or thrombophilia screening ,or had atypical burdens such as intensive sport practice. It is important to consider uncommon (e.g., Flammer syndrome) or common but so far unrecognized risk factors (e.g., hypertension). Fluctuation of the blood pressure is probably an unacknowledged risk factor for CRVO/CLRAO occurrence.\n\nThere are some controversies as to antithrombotic therapy for CRVO.[15,29] Hayreh et al[29] suggest no benefit from treatment with antiplatelets or anticoagulants; they have even observed a significantly greater severity of retinal hemorrhages among aspirin users than among nonusers. According to the latest guidance for the management of venous thrombosis in unusual site, LMWH may be considered for acute phase treatment of RVO in selected patients; further long-term treatment with ASA should be based on individual indications for primary or secondary prevention of cardiovascular disease.[15]\n\n5 Conclusion\nPatients with combined CRVO and CLRAO present numerous cardiovascular risk factors and abnormalities on imaging examinations, which should be routinely evaluated and treated. Combined CRVO and CLRAO require combined ophthalmologic and cardiovascular care.\n\nAbbreviations: ASA = acetylsalicylic acid, BCVA = best-corrected visual acuity, CLRAO = cilioretinal artery occlusion, CRVO = central retinal vein occlusion, ECG = electrocardiogram, HELLP = hemolysis, elevated liver enzymes, a low platelet count, IOP = intraocular pressure, IVFA = intravenous fluorescein angiography, LMWH = low molecular weight heparin, MRI = magnetic resonance imaging, OCT = optical coherence tomography, TEE = transesophageal echocardiography, TTE = transthoracic echocardiography.\n\nAbstract of the article has been presented previously at Euretina in Copenhagen, Denmark August 9, 2016 to August 11, 2016.\n\nThe authors report no conflicts of interest.\n==== Refs\nReferences\n[1] Hayreh SS Fraterrigo L Jonas J \nCentral retinal vein occlusion associated with cilioretinal artery occlusion . Retina \n2008 ;28 :581 –94 .18398361 \n[2] Oosterhuis JA \nHenkes HE \nFluorescein fundus angiography in retinal vein occlusion . Perspectives in Ophthalmology . Amsterdam : Excerpta Medica Foundation ; 1968 \n29 –47 .\n[3] Hayreh SS \nPathogenesis of occlusion of the central retinal vessels . Am J Ophthalmol \n1971 ;72 :998 –1011 .5315812 \n[4] McLeod D \nCilio-retinal arterial circulation in central retinal vein occlusion . Br J Ophthalmol \n1975 ;59 :486 –92 .1203235 \n[5] McLeod D Ring CP \nCilio-retinal infarction after retinal vein occlusion . Br J Ophthalmol \n1976 ;60 :419 –27 .25233547 \n[6] Lefrançois A Sterkers-Renault C d’Esperey-Fougères R \nOcclusion de la veine centrale de la rétine avec infarctus d’une artère cilio-rétinienne . Bull Soc Ophtalmol Fr \n1980 ;80 :67 –72 .7226374 \n[7] Turut P Castier P Beve C \nInfarctus cilio-rétinien et occlusion veineuse rétinienne . J Fr Ophtalmol \n1987 ;10 :355 –63 .3693805 \n[8] Schatz H Fong AC McDonald HR \nCilioretinal artery occlusion in young adults with central retinal vein occlusion . Ophthalmology \n1991 ;98 :594 –601 .2062490 \n[9] Brazitikos PD Pournarus CJ Othenin-Girard P \nPathogenic mechanisms in combined cilioretinal artery and retinal vein occlusion: a reappraisal . Int Ophthalmol \n1993 ;17 :235 –42 .8132400 \n[10] Schmidt D \nComorbidities in combined retinal artery and vein occlusions . Eur J Med Res \n2013 ;18 :27 .23947749 \n[11] Glacet-Bernard A Gaudric A Touboul C \nOcclusion de la veine centrale de la rétine avec occlusion d’une artère cilio-rétinienne: à propos de 7 cas . J Fr Ophtalmol \n1987 ;10 :269 –77 .3624794 \n[12] Keyser BJ Duker JS Brown GC \nCombined central retinal vein occlusion and cilioretinal artery occlusion associated with prolonged retinal arterial filling . Am J Ophthalmol \n1994 ;117 :308 –13 .8129002 \n[13] Hayreh SS Zimmerman B McCarthy MJ \nSystemic diseases associated with various types of retinal vein occlusion . Am J Ophthalmol \n2001 ;131 :61 –77 .11162981 \n[14] Kolar P \nRisk factors for central and branch retinal vein occlusion: a meta-analysis of published clinical data . J Ophthalmol \n2014 ;2014 :724 –80 .\n[15] Ageno W Beyer-Westendorf J Garcia DA \nGuidance for the management of venous thrombosis in unusual sites . J Thromb Thrombolysis \n2016 ;41 :129 –43 .26780742 \n[16] Lang RM Badano LP Mor-Avi V \nRecommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging . Eur Heart J Cardiovasc Imaging \n2015 ;16 :233 –70 .25712077 \n[17] Vahanian A Alfieri O Andreotti F \nGuidelines on the management of valvular heart disease (version 2012): Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS) . Eur Heart J \n2012 ;33 :2451 –96 .22922415 \n[18] Saric M Armour AC Arnaout MS \nGuidelines for the Use of Echocardiography in the Evaluation of a Cardiac Source of Embolism . J Am Soc Echocardiogr \n2016 ;29 :1 –42 .26765302 \n[19] Fazio GP Redberg RF Winslow T \nTransesophageal echocardiographically detected atherosclerotic aortic plaque is a marker for coronary artery disease . J Am Coll Cardiol \n1993 ;21 :144 –50 .8417055 \n[20] Brott TG Halperin JL Abbara S \n2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery . Circulation \n2011 ;124 :489 –532 .21282505 \n[21] Brown GC Duker JS Lehman R \nCombined central retinal artery-central vein obstruction . Int Ophthalmol \n1993 ;17 :9 –17 .7686140 \n[22] Hayreh SS \nOcular vascular occlusive disorders: natural history of visual outcome . Prog Retin Eye Res \n2014 ;41 :1 –25 .24769221 \n[23] Stoffelns BM Laspas P \nCilioretinal artery occlusion . Klin Monbl Augenheilkd \n2015 ;232 :519 –24 .25902112 \n[24] Murray DC Christopoulou D Hero M \nCombined central retinal vein occlusion and cilioretinal artery occlusion in a patient on hormone replacement therapy . Br J Ophthalmol \n2000 ;84 :549 –50 .\n[25] McLeod D \nCentral retinal vein occlusion with cilioretinal infarction from branch flow exclusion and choroidal arterial steal . Retina \n2009 ;29 :1381 –95 .19898176 \n[26] Messner LV Newman TL Bartlett M \nCilioretinal artery occlusion with central retinal vein occlusion . Optom Vis Sci \n1999 ;76 :741 –6 .10566858 \n[27] Kim IT Lee WY Choi YJ \nCentral retinal vein occlusion combined with cilioretinal artery occlusion . Korean J Ophthalmol \n1999 ;13 :110 –4 .10761407 \n[28] Bottós JM Aggio FB Dib E \nImpending central retinal vein occlusion associated with cilioretinal artery obstruction . Clin Ophthalmol \n2008 ;2 :665 –8 .19668772 \n[29] Hayreh SS \nAcute retinal arterial occlusive disorders . Prog Retin Eye Res \n2011 ;30 :359 –94 .21620994\n\n",
"fulltext_license": "CC BY-ND",
"issn_linking": "0025-7974",
"issue": "97(1)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D000369:Aged, 80 and over; D002339:Carotid Arteries; D002675:Child, Preschool; D017548:Echocardiography, Transesophageal; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D015356:Retinal Artery Occlusion; D012170:Retinal Vein Occlusion; D012307:Risk Factors; D014786:Vision Disorders",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e9255",
"pmc": null,
"pmid": "29505511",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7686140;10566858;19668772;8132400;26780742;8129002;1203235;10847711;19898176;7226374;18398361;21620994;5315812;24769221;25902112;3693805;8417055;25233547;21282505;2062490;25712077;23947749;26765302;10761407;22922415;25009743;11162981;3624794",
"title": "Cardiovascular risk factors in patients with combined central retinal vein occlusion and cilioretinal artery occlusion: Case report.",
"title_normalized": "cardiovascular risk factors in patients with combined central retinal vein occlusion and cilioretinal artery occlusion case report"
} | [
{
"companynumb": "PL-MYLANLABS-2018M1035395",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARVEDILOL"
},
"drugadditional": "3",
... |
{
"abstract": "Intrathecal baclofen pumps are commonly used in pediatric patients with spastic cerebral palsy. Baclofen binds to γ-aminobutyric acid receptors to inhibit both monosynaptic and polysynaptic reflexes at the spinal cord level. The blockade stops the release of excitatory transmitters and thereby decreases muscle contraction. It is commonly used for lower limb spasticity and has been shown to improve postural ability and functional status. The US Food and Drug Administration has approved baclofen for the treatment of spasticity of cerebral or spinal origin in adult and pediatric patients 4 years or older. Various complications of baclofen pumps are described in the literature. Immediately after surgery, problems from infection can arise and range from superficial skin infections to meningitis and bacteremia. Another early complication includes cerebrospinal fluid leak that can be observed by notable swelling beneath the lumbar incision. Additional problems that arise later are usually from the mechanics of the pump and catheter. Pump-related complications include failure, migration, and flipping. Catheter-related complications include disconnection, occlusion, fracture, or kink. Most of these complications typically lead to baclofen withdrawal, although there are a few case reports of overdose due to mechanical causes. Here we describe 2 cases of individuals experiencing complications of excessive baclofen exposure after significant changes in the atmospheric pressure due to travel involving ambient altitude change. These cases reflect the need to discuss this potential complication with families and patients with baclofen pumps before travel to high elevations.",
"affiliations": "Division of Pediatric Emergency Medicine, sydney.ryan@hsc.utah.edu.;Division of Pediatric Emergency Medicine.;Department of Pediatrics, Primary Children's Hospital, University of Utah, Salt Lake City, Utah; and.;Division of Pediatric Emergency Medicine.;Department of Pediatric Emergency Medicine, Rady Children's Hospital, San Diego, California.",
"authors": "Ryan|Sydney|S|;Dudley|Nanette|N|;Green|Michael|M|;Pruitt|Charles|C|;Jackman|Geoffrey|G|",
"chemical_list": "D009125:Muscle Relaxants, Central; D001418:Baclofen",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2017-3973",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "142(2)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000293:Adolescent; D000531:Altitude; D001274:Atmospheric Pressure; D001418:Baclofen; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D009125:Muscle Relaxants, Central; D000077260:Sleepiness; D013850:Thinking",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29976571",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Altered Mental Status at High Altitude.",
"title_normalized": "altered mental status at high altitude"
} | [
{
"companynumb": "US-LANNETT COMPANY, INC.-US-2018LAN001142",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "BACLOFEN"
},
"drugadditional"... |
{
"abstract": "Acute kidney injury is a reversible medical condition commonly caused by nephrotoxic agents. The infrequency that a nebulized medication elicits a renal insult presents a rare diagnostic challenge. Within this case, we report a 57-year-old cystic fibrosis patient with chronic kidney disease (CKD) Stage G3b (baseline 1.5-1.6 mg/dL) who developed an acute kidney injury (AKI) with a serum creatinine elevation to 4.08 mg/dL and associated worsening vestibular dysfunction related to twice-daily nebulized tobramycin inhalation solution (TIS). The patient was found to have a tobramycin serum level of 4.2 μg/mL 2.5 h after TIS dosing, with elevation remaining present at 1.1 μg/mL 24 h after discontinuation of therapy. Laboratory values at one month continued to show elevated creatinine levels at 2.1 mg/dL, suggesting progression of his baseline CKD. This case supports the benefit of obtaining tobramycin serum levels and vestibular/audiology function testing when evaluating patients on chronic nebulized TIS who present with acute or chronic renal dysfunction. From these serum levels, adjustments to daily dosing, regular monitoring of tobramycin serum levels, or discontinuation of treatment should be made to prevent permanent renal damage in patients with CKD. Calculated Naranjo ADR Probability Scale: 9; Definite.",
"affiliations": "Department of Medicine, West Virginia University, Morgantown, WV 26506, USA.;Department of Pediatrics and Medicine, West Virginia University, Morgantown, WV 26506, USA.;Department of Pharmaceutical Services, West Virginia University, Morgantown, WV 26506, USA.;Section of General Internal Medicine, Department of Medicine, West Virginia University, Morgantown, WV 26506, USA.;Section of Nephrology, Department of Medicine, West Virginia University, Morgantown, WV 26506, USA.",
"authors": "Miller|Tyler|T|0000-0003-0415-9476;Pastuch|Cristina|C|;Garavaglia|Lisa|L|;Gannon|Kelley|K|0000-0002-0463-1307;Parravani|Anthony|A|0000-0001-8232-9245",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/antibiotics10040424",
"fulltext": "\n==== Front\nAntibiotics (Basel)\nAntibiotics (Basel)\nantibiotics\nAntibiotics\n2079-6382\nMDPI\n\n10.3390/antibiotics10040424\nantibiotics-10-00424\nCase Report\nUnknown Renal Impairment: A Rare Case of Inhaled Tobramycin Induced Acute Kidney Injury in a Cystic Fibrosis Patient\nhttps://orcid.org/0000-0003-0415-9476\nMiller Tyler 1*\nPastuch Cristina 23\nGaravaglia Lisa 4\nhttps://orcid.org/0000-0002-0463-1307\nGannon Kelley 5\nParravani Anthony 6\nBeringer Paul M. Academic Editor\n1 Department of Medicine, West Virginia University, Morgantown, WV 26506, USA\n2 Department of Pediatrics and Medicine, West Virginia University, Morgantown, WV 26506, USA; cpastuch@hsc.wvu.edu\n3 Adult Cystic Fibrosis, Mountain State Cystic Fibrosis Center, West Virginia University, Morgantown, WV 26506, USA\n4 Department of Pharmaceutical Services, West Virginia University, Morgantown, WV 26506, USA; biondol@wvumedicine.org\n5 Section of General Internal Medicine, Department of Medicine, West Virginia University, Morgantown, WV 26506, USA; kgannon@hsc.wvu.edu\n6 Section of Nephrology, Department of Medicine, West Virginia University, Morgantown, WV 26506, USA; aparravani@hsc.wvu.edu\n* Correspondence: tcmiller@hsc.wvu.edu\n12 4 2021\n4 2021\n10 4 42403 3 2021\n10 4 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nAcute kidney injury is a reversible medical condition commonly caused by nephrotoxic agents. The infrequency that a nebulized medication elicits a renal insult presents a rare diagnostic challenge. Within this case, we report a 57-year-old cystic fibrosis patient with chronic kidney disease (CKD) Stage G3b (baseline 1.5–1.6 mg/dL) who developed an acute kidney injury (AKI) with a serum creatinine elevation to 4.08 mg/dL and associated worsening vestibular dysfunction related to twice-daily nebulized tobramycin inhalation solution (TIS). The patient was found to have a tobramycin serum level of 4.2 μg/mL 2.5 h after TIS dosing, with elevation remaining present at 1.1 μg/mL 24 h after discontinuation of therapy. Laboratory values at one month continued to show elevated creatinine levels at 2.1 mg/dL, suggesting progression of his baseline CKD. This case supports the benefit of obtaining tobramycin serum levels and vestibular/audiology function testing when evaluating patients on chronic nebulized TIS who present with acute or chronic renal dysfunction. From these serum levels, adjustments to daily dosing, regular monitoring of tobramycin serum levels, or discontinuation of treatment should be made to prevent permanent renal damage in patients with CKD. Calculated Naranjo ADR Probability Scale: 9; Definite.\n\ncystic fibrosis (CF)\ntobramycin inhalation solution (TIS)\ntobramycin serum levels\nacute kidney injury (AKI)\nchronic kidney disease (CKD)\n==== Body\n1. Introduction\n\nAcute kidney injury (AKI) is a reversible medical condition leading to an increase in serum creatinine and reduction in urinary output commonly caused by pre-renal (reduced blood flow secondary to hypotension, dehydration, or hemorrhage), renal (intrinsic insults such as glomerulonephritis, acute tubular necrosis, or nephrotoxic medications), or post-renal (renal calculi or lower urinary tract obstructions) causes. The presence of comorbid risk factors such as chronic kidney disease (CKD), congestive heart failure, diabetes, older age, sepsis, hypotension, or chronic medication use (non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, proton pump inhibitors, antibiotics, or chemotherapy agents) can place a patient at an increased risk for developing an AKI [1]. Traditional evaluation includes a thorough history, basic metabolic panel, urine electrolytes, urine analysis, and renal ultrasound. The goals of treatment are to identify and remove the insulting factor and treat with intravenous (IV) fluids to restore renal perfusion and prevent permanent damage [2]. If the diagnosis is delayed, progression to chronic kidney disease (CKD) can occur, which may necessitate long-term hemodialysis or renal transplant [3].\n\nThe prevalence of AKI and subsequent progression to CKD may be increased in patients with cystic fibrosis (CF). Cystic fibrosis is a genetic disease that affects more than 70,000 people worldwide by causing mutations within the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This mutation effects chloride channels’ production of mucus and sweat, leading to thickened secretions. This increased mucus commonly leads to trapping of bacteria with associated colonization and long-term respiratory infections and inflammation. The disease also causes pancreatic insufficiency with associated poor growth, nutritional deficiencies, malabsorption, and often male infertility [4]. Risk factors for progression to CKD within a CF patient include older age, cystic fibrosis-related diabetes (CFRD), intermittent frequent IV aminoglycoside usage, and prolonged use of immunosuppressant therapy (tacrolimus, cyclosporine, azathioprine, and glucocorticoids) following solid organ transplantation [5,6]. The use of IV aminoglycosides with a second beta-lactam anti-pseudomonal antibiotic is commonly part of the standard treatment of a CF-pulmonary exacerbation. It has been shown that the number of pulmonary exacerbations and required hospitalizations a CF patient experiences increases with age and decline in FEV1 [7]. Over a lifetime, the cumulative doses of IV aminoglycosides may be substantial for an adult with CF and can potentiate the risk for CKD progression.\n\nProtocols for CF aminoglycoside dosing is higher than standard protocols for the non-CF patient due to increased renal clearance [8]. This combination of higher dosing and frequent IV aminoglycoside usage places patients with CF at increased risk for CKD over their lifetime. Aminoglycoside antibiotics exhibit concentration-dependent bactericidal activity against susceptible organisms. Thus, the higher the serum concentration that is achieved, the more rapid the bactericidal activity. To maximize efficacy and minimize toxicity such as AKI, once-daily dosing (ODD) of IV aminoglycoside antibiotics has been determined a standard of care [9]. Current prophylactic strategies using tobramycin inhalation solution (TIS) for suppressive therapy has been shown to have greater airway penetration and higher antibiotic sputum levels than traditional IV routes [10,11]. TIS has been a critical advancement within CF treatment as it has been shown to reduce chronic infections, prevent exacerbations, improves lung function, and patient quality of life; it currently serves as a common first-line treatment for Pseudomonas aeruginosa [12]. Studies report sputum concentration of the drug is at least 25 times the minimal inhibitory concentration, with a ratio of median serum concentration to median sputum concentration of 0.01, making it an ideal method of administration [11].\n\nNebulized TIS common side effects include cough, shortness of breath, dizziness, and changes in voice. Limited research exists comparing the systemic involvement of nebulized TIS on acute and long-term renal impairment and vestibular dysfunction [9,13,14]. The infrequency that a nebulized medication can elicit a renal insult and present with detectable antibiotic serum levels presents a rare diagnostic challenge; reported cases are few and measurement of tobramycin levels are not standard practice. Within this case, we report a 57-year-old cystic fibrosis patient who developed an acute kidney injury on chronic kidney disease with associated worsening vestibular dysfunction related to twice-daily nebulized TIS.\n\n2. Case Presentation\n\nA 57-year-old male with cystic fibrosis (CF) with mutations F508del/c.3718-3T>G was admitted with fever, back pain, mild balance instability, hearing reduction, and loss of visual focus during movement. A concern for acute kidney injury on chronic kidney disease (Stage G3b) was noted after a review of routine annual laboratory evaluation. During the five days before admission, he also described progressive dynamic visual stabilization deficits with vestibular dysfunction.\n\nHis past medical history was significant for pancreatic insufficiency, chronic Pseudomonas aeruginosa pulmonary infection, CKD Stage G3b (serum creatinine 1.5–1.6 mg/dL), internal hemorrhoids, iron deficiency anemia, and previous neuronitis. The patient had no history of previous multidrug resistant pulmonary infections but had grown methicillin sensitive Staphylococcus aureus (MSSA) in prior sputum cultures, with last exacerbation in 2018. Medications included nebulized albuterol with hypertonic saline, dornase-alpha, azithromycin, pancreatic enzyme replacement therapy (PERT), anti-Pseudomonal suppressive inhalation continuous alternating therapy (CAT) with aztreonam inhalation solution (AIS) and tobramycin inhalation solution (TIS), and elexacaftor/tezacaftor/ivacaftor (Elexa/Tez/Iva) highly effective modulator therapy. He was currently on day 25 of 28 days of TIS.\n\nOn admission, the patient denied changes in urinary output, dysuria, hematuria, cough, shortness-of-breath, or sputum production. He felt “overall well and his lung health has improved since starting Elexa/Tez/Iva one year ago” with improved overall endurance. He denied any recent or chronic NSAID use, IV antibiotics, dehydration, or recent changes to daily medications.\n\nFamily history revealed cystic fibrosis and CHD post double lung transplant in a cousin and colon cancer in his father. The patient denied any tobacco, alcohol, or drug usage. Physical examination was normal except for bright red blood per rectum; he had clear lung fields, no edema or anasarca, and non-tender abdominal and flank examination. See Table 1 for laboratory values on admission.\n\nUrine electrolytes were obtained to calculate FENa (fractional excretion sodium) and FEUrea (fractional excretion urea) in order to classify AKI. Results showed intrinsic renal cause suggesting glomerulonephritis, acute tubular necrosis, or nephrotoxic medications as the source for insult. Renal ultrasound showed a benign 8 mm non-obstructive right renal lower pole calculus without hydronephrosis present, a normal left kidney without calculus or hydronephrosis, an enlarged prostate, and a normal-sized bladder without debris or focal wall thickening.\n\nThe patient was continued on all medications including the TIS 300 mg twice a day, with the addition of intravenous (IV) hydration. On hospital day 3, a tobramycin level obtained 2.5 h after the nebulized dose was 4.2 μg/mL; 5.5 h later the level was 3.6 μg/mL. The TIS and Elexa/Tez/Iva were discontinued. A tobramycin level drawn 24 h after the last inhaled dose was 1.1 μg/mL.\n\nDespite IV hydration and discontinuation of the TIS, the serum creatinine and potassium remained elevated. IV fluids were later discontinued and sodium-zirkonium cyclosilicate, sevelamer carbonate, sodium bicarbonate, and a low potassium diet were initiated. Urine sodium, urine osmolality, and serum osmolality were obtained after discontinuation of IV fluids suggesting continued intrinsic insult. Repeat FENa and FEUrea was not recalculated after IV fluid completion on day 7. His kidney function did not completely return to his chronic baseline. The patient was discharged on day 11 once serum creatinine stabilized. The patient did not require hemodialysis or renal biopsy due to plateau of serum creatinine. See Table 1 for all the laboratory values. Laboratory values at 1 month (day 41) continued to show elevated creatinine levels, noting possible CKD progression. Elexa/Tez/Iva and inhaled aztreonam were resumed at his cystic fibrosis follow-up appointment. The nebulized TIS was never resumed.\n\n3. Discussion\n\nThis case presented a rare diagnostic challenge of acute kidney injury on chronic kidney disease (Stage G3b) in a patient with cystic fibrosis denying recent changes in medication, dosing, hydration, or new urinary retention. The patient additionally denied recent pulmonary exacerbations requiring IV antibiotics or steroids. His last noted exacerbation was in 2018, making an acute exacerbation a less likely influencing factor to his AKI on CKD. Most recent sputum culture prior to admission grew Pseudomonas aeruginosa. Per chart review, patient had a baseline creatinine of 1.5–1.6 mg/dL with a GFR of 44–45 mL/min from previous labs. Decline in renal function occurred two years prior to presentation due to significant dehydration; he previously had a creatinine around 1 mg/dL. At that time, the patient was advised to increase fluid intake and follow with nephrology; he never attended this appointment.\n\nAfter a minimal improvement in renal function with traditional IV fluids, elevated tobramycin serum levels revealed an inability to adequately clear the aminoglycoside, leading to kidney injury. Once the nebulized tobramycin was discontinued, the renal function slowly improved. Within cystic fibrosis literature, recurrent systemic use of aminoglycosides is commonly associated with long term renal damage and worsening creatinine clearance. The systemic absorption of nebulized tobramycin can be mildly detectable but not high enough to cause changes in creatinine or BUN when administered via a nebulizer [15,16,17]. Limited studies exist documenting the systemic effects that nebulized tobramycin can have on the renal system. A 2010 placebo-controlled, double-blind, randomized study of 300 mg nebulized tobramycin dosing found the typical serum levels 30 to 60 min after drug administration ranged from 0.54 μg/mL to 2.64 μg/mL (with a lower limit of detection at 0.18 μg/mL) [18]. A study comparing median serum levels following a single 600 mg once daily dosing of nebulized tobramycin, instead of the standard 300 mg twice daily dosing, were 3.44 μg/mL and 2.84 μg/mL with the AKITA and PARI-LC nebulizer machines, respectively. These serum levels were obtained immediately after administration (0.44 and 0.40 h) [19]. Our case presents a unique sustained elevation in tobramycin serum levels that are higher than previously published levels.\n\nAdvancement in research and medications has increased the life expectancy within patients with cystic fibrosis. As patients live longer, the risk for secondary complications to the disease such as AKI or CKD may increase in documented frequency. Presentations such as the one described in this case may become more common and may require clinicians to be more clinically aware of potential adverse side effects to these new novel agents within older cystic fibrosis patients such as our patient. Several case reports document systemic side effects from nebulized tobramycin. In a case from 2002, a 20-year-old patient with CF, receiving TIS for P. aeruginosa, developed an AKI; serum creatinine was 9.0 mg/dL (baseline of 0.6 mg/dL) with concomitant serum tobramycin level of 2.8 μg/mL. Acute tubular necrosis (ATN) was confirmed by renal biopsy; renal function was restored (1.6 mg/dL) after TIS was held [20]. This episode is the most recent documented case of renal damage related to nebulized tobramycin in a cystic fibrosis patient. Only one other case has been reported in the past eighteen years on this rare side effect within this population group. Including our case of AKI, there have been four other reported cases of kidney injury related to TIS: one in a patient with CF and three others (post heart transplant, complicated pneumonia, and COPD). In one report, a heart transplant patient receiving TIS via positive pressure ventilation for pneumonia had tobramycin serum levels of >2.0 μg/mL. The elevated level was postulated to be due to recent transplant graft failure complicated by cardiac and renal failure [21]. Our case had limited predisposing conditions despite baseline CKD (creatinine baseline of 1.5–1.6 mg/dL) and our patient received no immunosuppressant therapy. In another report, a woman undergoing imipenem-cilastatin, vancomycin, and inhaled nebulized tobramycin antibiotic treatment for sepsis secondary to pneumonia was reported to develop nephrotoxicity and worsening serum creatinine greater than her baseline of 2 mg/dL. Tobramycin trough levels were found to be 0.7 μg/mL with a worsening serum creatinine of 4.5 mg/dL. The patient ultimately required hemodialysis without return of renal function after resolution of her pneumonia [22]. The nephrotoxic effects reported in this case may have been the result of the combination of vancomycin and imipenem, and not TIS. The third case described a 73-year-old woman with COPD and newly acquired positive sputum culture for Pseudomonas aeruginosa. After four days of therapy, GFR decreased to 50mL/min and tobramycin level was 5.6 µg/mL; dialysis was initiated [23].\n\nIn regard to our patient’s progressive vestibular dysfunction (mild balance problems, hearing reduction, and loss of visual focus during movement), it was first thought to be related to a prior episode of neuronitis diagnosed one year ago. However, due to his acute worsening of symptoms five days before admission, it was concluded that our patient’s symptoms were most likely in response to elevated tobramycin levels. Similar acute vestibular side effects from TIS have been reported in prior case reports, with most formal research focusing on IV aminoglycosides effects [14]. Limited research has been performed documenting the prevalence of vestibular dysfunction in TIS. In a case report from 2004, it was documented that a female with chronic renal failure (creatinine 9.2 mg/dL) on hemodialysis with a chronic Pseudomonas aeruginosa infection who was receiving TIS was reported to develop reversible vestibular toxicity with associated dizziness, ataxia, and oscillopsia. Her documented tobramycin level was 19.2 μg/mL, which trended down to 9.8 μg/mL two days later withholding of TIS [24]. Our case presents similar findings as this report, and it helps to suggest our patient’s vestibular symptoms were connected to his AKI and elevated tobramycin levels. These findings go against previously supported conclusions that nebulized tobramycin does not cause ototoxic or vestibular injury [25]. The presence of new or worsening vestibular symptoms in the setting of TIS usage can be potentially used as a screening measure to assess for medication toxicity.\n\nThe information presented in our case documents important and relevant information on potential rare side effects for nebulized tobramycin that have only been anecdotally reported previously. Our case presents a unique account of tobramycin toxicity in a patient who is not acutely ill and has tolerated TIS for over two years without previous systemic side effects. Based on the WHO-UMC and Naranjo Probability Scale, our reported adverse drug reaction (ADR) receives a score of “9” with an associated causality as “Definite” [26]. This scoring suggests our ADR (elevation in creatinine) has a plausible time relationship with the nebulization of tobramycin. Additionally, reported withdrawal of the medication showed a plausible improvement in serum creatinine levels, concluding this event was a definitive pharmacologic phenomenon. These findings are critical to report to help aid clinicians when evaluating and treating similarly presenting patients with cystic fibrosis.\n\n4. Conclusions\n\nThis case illustrates the potential for TIS to cause acute kidney injury and raises clinical awareness of the importance of monitoring nebulized antibiotic treatments in the face of advancing age and potential renal toxicity in a patient with baseline CKD. This case supports the benefit of obtaining tobramycin serum levels when evaluating patients on chronic daily suppressive nebulized tobramycin treatments, especially when presenting with acute or chronic renal dysfunction, elevated creatinine, and reduced GFR. Adjustments to daily dosing, regular monitoring of tobramycin serum levels, or discontinuation of treatment should be made to prevent permanent renal damage.\n\nAcknowledgments\n\nKathryn Moffett-Bradford, Lesley Cottrell, and Kyle Chapman assisted in reviewing and editing for the case report. Thank you for your assistance.\n\nAuthor Contributions\n\nT.M., C.P., L.G. wrote the first draft of the case report; T.M., C.P., L.G., K.G., and A.P. reviewed literature, supervised editing, and manuscript review. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis case report received no external funding.\n\nInstitutional Review Board Statement\n\nNot applicable.\n\nInformed Consent Statement\n\nInformed consent was obtained from the patient involved in this case report.\n\nData Availability Statement\n\nThe data presented in this study is available on request from the corresponding author and approval by the consented patient involved in this report. The data is not publicly available to protect patient privacy and identity.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nantibiotics-10-00424-t001_Table 1 Table 1 Laboratory Values. The table shows pertinent laboratory value trends one-year preadmission, during hospitalization (day 0 to day 9), at discharge (day 11), and after follow-up (day 41) for our patient.\n\nLaboratory Test\tNormal Range\tRange One Year\nPreadmission\tDay 0\tDay 3\tDay 4\tDay 7\tDay 9\tDay 11\tDay 41\t\nCreatinine (mg/dL)\t0.62–1.27\t1.5–1.6\t2.50\t3.06\t3.27\t3.74\t4.08\t3.86\t2.1\t\nGFR 1 (ml/min)\t>60\t44–45\t27\t22\t20\t17\t15\t16\t33\t\nPotassium\n(mmol/L)\t3.5–5.5\t4–5\t5.7\t5.2\t4.8\t4.8\t4.4\t4.8\t5.4\t\nHemoglobin (g/dL)\t13.4–17.5\t8–10\t8.2\t8.7\t8.5\t8.6\t8.6\t8.5\t\t\nTobramycin Level after TIS 2 with Timing\n(μg/mL)\t\t\t\t4.2 (2.5 h)\n3.6 (8 h)\t1.1 (24 h)\t\t\t\t\t\nUrinalysis\t\t\tNormal\t\t\tNormal\t\t\t\t\nOther\t\tRespiratory Culture: 1 + Rare\nPseudomonas aeruginosa\tFENa 3 3.8% (intrinsic), FEUrea 4 59.3% (intrinsic),\nBicarbonate 17 mEq/L\t\t\tUNa 5 72 mM,\nUOsm 6 277 mOsm/kg,\nSOsm 7 308 mOsm/kg H2O,\nUpH 8 5\t\t\t\t\n1 GFR = glomerular filtration rate, 2 TIS = tobramycin inhalation solution, 3 FENa = fractional excretion sodium, 4 FEUrea = fractional excretion urea, 5 UNa = urine sodium, 6 UOsm = urine osmolality, 7 SOsm = serum osmolality, 8 UpH = urine pH.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Naughton C.A. Drug-induced nephrotoxicity Am. Fam. Physician 2008 78 743 750 18819242\n2. Harty J. Prevention and management of acute kidney injury Ulster Med. J. 2014 83 149 157 25484464\n3. Chawla L.S. Amdur R.L. Amodeo S. Kimmel P.L. Palant C.E. The severity of acute kidney injury predicts progression to chronic kidney disease Kidney Int. 2011 79 1361 1369 10.1038/ki.2011.42 21430640\n4. Kelly J. Environmental scan of cystic fibrosis research worldwide J. Cyst. Fibros. 2017 16 67 370 10.1016/j.jcf.2016.11.002\n5. Berg K.H. Ryom L. Faurholt-Jepsen D. Pressler T. Katzenstein T.L. Prevalence and characteristics of chronic kidney disease among Danish adults with cystic fibrosis J. Cyst. Fibros. 2018 17 478 483 10.1016/j.jcf.2017.11.001 29187303\n6. Knoop C. Thiry P. Saint-Marcoux F. Rousseau A. Marquet P. Estenne M. Tacrolimus pharmacokinetics and dose monitoring after lung transplantation for cystic fibrosis and other conditions Am. J. Transplant. 2005 5 1477 1482 10.1111/j.1600-6143.2005.00870.x 15888057\n7. Goss C.H. Burns J.L. Exacerbations in cystic fibrosis 1: Epidemiology and pathogenesis Thorax 2007 62 360 367 10.1136/thx.2006.060889 17387214\n8. Vandenbussche H.L. Homnick D.N. Evaluation of serum concentrations achieved with an empiric once-daily tobramycin dosage regimen in children and adults with cystic fibrosis J. Pediatr. Pharmacol. Ther. 2012 17 67 77 23118659\n9. Nazareth D. Walshaw M. A review of renal disease in cystic fibrosis J. Cyst. Fibros. 2013 12 309 317 10.1016/j.jcf.2013.03.005 23618617\n10. Geller D.E. Pitlick W.H. Nardella P.A. Tracewell W.G. Ramsey B.W. Pharmacokinetics and bioavailability of aerosolized tobramycin in cystic fibrosis Chest 2002 122 219 226 10.1378/chest.122.1.219 12114362\n11. Young D. Zoebell J. Stockmann C. Waters C.D. Ampofo K. Sherwin C.M. Spigarelli M.G. Optimization of Anti-Pseudomonal Antibiotics for Cystic Fibrosis Pulmonary Exacerbations: V. Aminoglycosides Pediatric Pulmonol. 2013 48 1047 1061 10.1002/ppul.22813 24000183\n12. Shteinberg M. Elborn J.S. Use of inhaled tobramycin in cystic fibrosis Adv. Ther. 2015 32 1 9 10.1007/s12325-015-0179-3 25620537\n13. Scheinberg P. Shore E. A pilot study of the safety and efficacy of tobramycin solution for inhalation in patients with severe bronchiectasis Chest 2005 127 1420 1426 10.1378/chest.127.4.1420 15821224\n14. Prayle A. Watson A. Fortnum H. Smyth A. Side effects of aminoglycosides on the kidney, ear, and balance in cystic fibrosis Thorax 2010 65 654 658 10.1136/thx.2009.131532 20627927\n15. Florescu M.C. Lyden E. Murphy P.J. Florescu D.F. Fillaus J. Long-term effect of chronic intravenous and inhaled nephrotoxic antibiotic treatment on the renal function of patients with cystic fibrosis Hemodial. Int. 2012 16 414 419 10.1111/j.1542-4758.2012.00675.x 22469183\n16. Ramsey B.W. Pepe M.S. Quan J.M. Otto K.L. Montgomery A.B. Wiilliams-Warren J. Vasilijev K.M. Borowitz D. Bowman C.M. Marshal B.C. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group N. Engl. J. Med. 1999 340 23 30 10.1056/NEJM199901073400104 9878641\n17. Al-Aloul M. Miller H. Alapati S. Stockton P.A. Ledson M.J. Walshaw M.J. Renal impairment in cystic fibrosis patients due to repeated intravenous aminoglycoside use Pediatr. Pulmonol. 2005 39 15 20 10.1002/ppul.20138 15521084\n18. Baker A.F. Couch L. Fiel S.B. Gotfried M.H. Ilowite J. Meyer K.C. O’Donnell A. Sahn S.A. Smith L.J. Stewart J.O. Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis Am. J. Respir. Crit. Care Med. 2000 162 481 485 10.1164/ajrccm.162.2.9910086 10934074\n19. van Velzen A.J. Bos A.C. Touw D.J. Tiddens H.A. Heijerman H.G. Janssens H.M. Pharmacokinetics and Tolerability of Once Daily Double Dose Tobramycin Inhalation in Cystic Fibrosis Using Controlled and Conventional Nebulization J. Aerosol. Med. Pulm. Drug Deliv. 2016 29 273 280 10.1089/jamp.2015.1259 26716357\n20. Hoffmann I.M. Rubin B.K. Iskandar S.S. Schechter M.S. Nagaraj S.K. Bitzan M.M. Acute renal failure in cystic fibrosis: Association with inhaled tobramycin therapy Pediatr. Pulmonol. 2002 34 375 377 10.1002/ppul.10185 12357482\n21. Kahler D.A. Schowengerdt K.O. Fricker F.J. Mansfield M. Vinser G.A. Faro A. Toxic serum trough concentrations after administration of nebulized tobramycin Pharmacotherapy 2003 4 543 545 10.1592/phco.23.4.543.32122\n22. Cannella C.A. Wilkinson S.T. Acute renal failure associated with inhaled tobramycin Am. J. Health Syst. Pharm. 2006 63 1858 1861 10.2146/ajhp060196 16990632\n23. Izquierdo M.J. Gomez-Alamillo C. Ortiz F. Calabia E. Ruiz J. de Francisco A. Arias M. Acute Renal Failure associated with use of inhaled tobramycin for treatment of chronic airway colonization with pseudomonas aeruginosa Clin. Nephrol. 2006 66 464 467 10.5414/CNP66464 17176920\n24. Edson R.S. Brey R.H. McDonald T.J. Terrell E. Ruiz C.L. McCarthy J.T. Thibert J.M. Vestibular toxicity due to inhaled tobramycin in a patient with renal insufficiency Mayo Clin. Proc. 2004 79 1185 1191 10.1016/S0025-6196(11)62603-7 15357042\n25. Chuchalin A. Amelina E. Bianco F. Tobramycin for inhalation in cystic fibrosis: Beyond respiratory improvements Pulm. Pharmacol. Ther. 2009 22 526 532 10.1016/j.pupt.2009.06.001 19616111\n26. Zaki S.A. Adverse drug reaction and causality assessment scales Lung India 2011 28 152 153 10.4103/0970-2113.80343 21712934\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2079-6382",
"issue": "10(4)",
"journal": "Antibiotics (Basel, Switzerland)",
"keywords": "acute kidney injury (AKI); chronic kidney disease (CKD); cystic fibrosis (CF); tobramycin inhalation solution (TIS); tobramycin serum levels",
"medline_ta": "Antibiotics (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101637404",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33921466",
"pubdate": "2021-04-12",
"publication_types": "D002363:Case Reports",
"references": "16990632;17387214;15357042;24000183;10934074;15521084;20627927;12357482;26716357;19616111;12680485;15888057;18819242;23118659;29187303;23618617;22469183;12114362;27916551;25620537;15821224;21712934;21430640;17176920;9878641;25484464",
"title": "Unknown Renal Impairment: A Rare Case of Inhaled Tobramycin Induced Acute Kidney Injury in a Cystic Fibrosis Patient.",
"title_normalized": "unknown renal impairment a rare case of inhaled tobramycin induced acute kidney injury in a cystic fibrosis patient"
} | [
{
"companynumb": "US-CHIESI-2021CHF02306",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZTREONAM"
},
"drugadditional": "1",
"... |
{
"abstract": "To systematically review contemporary data on the safety of clopidogrel and newer antiplatelet agents in pregnant women, with particular attention to maternal and neonatal complications.\n\n\n\nThe review protocol was published via PROSPERO (ID 42020165235) and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Databases were searched using MeSH and free text terms encompassing the included antiplatelets, relevant indications, and pregnancy. Included studies reported the drug dose, the stage of pregnancy at which it was administered, and at least one primary or secondary outcome relating to pregnancy. The primary outcome was reporting of complications associated with antiplatelet use in pregnancy.\n\n\n\nThe search yielded 5271 results. 39 publications were included, incorporating 42 live births. The mean age of women was 34.6 years. Seven different antiplatelet agents were described, clopidogrel being most frequent (n = 37). 14 women received antiplatelet therapy in the first trimester. 14 women had regional anaesthesia (12 while taking clopidogrel), all without complication. Two women developed bleeding post caesarean section. There were no recorded neonatal delivery complications. Two neonates had congenital anomalies not felt to be related to maternal antiplatelet use.\n\n\n\nThis systematic review describes outcomes for both mothers and neonates when exposed to clopidogrel at varying durations throughout gestation, and does not suggest higher than acceptable risk, with a congenital anomaly rate comparable to background risk. Evidence for other antiplatelet agents remains limited. Regional anaesthesia should be offered, with recommendation to stop prior to delivery in line with national guidance and in the context of individualised decision making.",
"affiliations": "Department of Obstetric Medicine, Guy's and St. Thomas' NHS Foundation Trust and Imperial Healthcare NHS Trust, London, United Kingdom. Electronic address: Melanie.Nana@gstt.nhs.uk.;School of Cardiovascular Medicine and Sciences, King's College London, London, United Kingdom.;Department of General Internal Medicine, Wrexham Maelor Hospital, Betsi Cadwaladr University Health Board, Wrexham, United Kingdom.;Department of General Internal Medicine, Wrexham Maelor Hospital, Betsi Cadwaladr University Health Board, Wrexham, United Kingdom.;Department of General Internal Medicine, Wrexham Maelor Hospital, Betsi Cadwaladr University Health Board, Wrexham, United Kingdom.;Department of Obstetric Medicine, Guy's and St. Thomas' NHS Foundation Trust and Imperial Healthcare NHS Trust, London, United Kingdom.",
"authors": "Nana|Melanie|M|;Morgan|Holly|H|;Moore|Sacha|S|;Lee|Zong Xuan|ZX|;Ang|Eshen|E|;Nelson-Piercy|Catherine|C|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.phrs.2021.105547",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1043-6618",
"issue": "168()",
"journal": "Pharmacological research",
"keywords": "Antiplatelet therapy; Clopidogrel; Pregnancy; Regional anaesthesia; Systematic review",
"medline_ta": "Pharmacol Res",
"mesh_terms": null,
"nlm_unique_id": "8907422",
"other_id": null,
"pages": "105547",
"pmc": null,
"pmid": "33716166",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Antiplatelet therapy in pregnancy: A systematic review.",
"title_normalized": "antiplatelet therapy in pregnancy a systematic review"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2021-03736",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugaddi... |
{
"abstract": "OBJECTIVE\nTo evaluate the cumulative recurrence rates of ovarian endometrioma among patients using a levonorgestrel-releasing intrauterine system (LNG-IUS) after conservative laparoscopic surgery.\n\n\nMETHODS\nA retrospective review was conducted of premenopausal women who underwent conservative laparoscopic surgery for ovarian endometrioma and subsequent treatment with LNG-IUS at two gynecologic surgery centers in South Korea between January 1, 2007, and September 30, 2014. Eligible patients had no residual ovarian lesions before LNG-IUS insertion, underwent insertion within 12 months of primary surgery, and were followed up for at least 6 months afterwards. Recurrence was defined as a cystic mass (≥2 cm in diameter) detected by transvaginal ultrasonography.\n\n\nRESULTS\nOverall, 61 patients were included. The mean duration of follow-up was 42.9 ± 22.0 months (range 8-98). Recurrence of ovarian endometrioma was detected among 7 (11%) of the patients. On Kaplan-Meier analysis, the cumulative recurrence rates were 4.0%, 6.3%, and 25.5% at 24, 36, and 60 months after surgery, respectively. In multivariate analysis, nulliparity at surgery was the only risk factor for recurrence (hazard ratio 5.892, 95% confidence interval 1.139-30.484; P=0.034).\n\n\nCONCLUSIONS\nLong-term maintenance therapy with LNG-IUS after conservative surgery might be a treatment option to consider to prevent ovarian endometrioma recurrence among premenopausal women.",
"affiliations": "Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, South Korea.;Department of Obstetrics and Gynecology, Dong-A University Medical Center, College of Medicine, Dong-A University, Busan, South Korea.;Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, South Korea.;Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, South Korea.;Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, South Korea.;Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, South Korea. Electronic address: sjseongcheil@naver.com.",
"authors": "Kim|Mi-La|ML|;Cho|Yeon Jean|YJ|;Kim|Mi Kyoung|MK|;Jung|Yong Wook|YW|;Yun|Bo Seong|BS|;Seong|Seok Ju|SJ|",
"chemical_list": "D003277:Contraceptives, Oral, Combined; D016912:Levonorgestrel",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-7292",
"issue": "134(3)",
"journal": "International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics",
"keywords": "Conservative surgery; Endometriosis; Levonorgestrel-releasing intrauterine system; Ovarian endometrioma; Recurrence rate",
"medline_ta": "Int J Gynaecol Obstet",
"mesh_terms": "D000328:Adult; D003131:Combined Modality Therapy; D003277:Contraceptives, Oral, Combined; D004334:Drug Administration Schedule; D004715:Endometriosis; D005260:Female; D006801:Humans; D016912:Levonorgestrel; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms; D056910:Republic of Korea; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0210174",
"other_id": null,
"pages": "256-9",
"pmc": null,
"pmid": "27346551",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "The efficacy of long-term maintenance therapy with a levonorgestrel-releasing intrauterine system for prevention of ovarian endometrioma recurrence.",
"title_normalized": "the efficacy of long term maintenance therapy with a levonorgestrel releasing intrauterine system for prevention of ovarian endometrioma recurrence"
} | [
{
"companynumb": "KR-ALLERGAN-1834347US",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVONORGESTREL"
},
"drugadditional": null,
... |
{
"abstract": "This study aimed to evaluate the clinical characteristics of levetiracetam (LEV)-induced cutaneous adverse drug reactions (cADRs) and to explore its possible genetic association with the human leukocyte antigen (HLA) genes.\n\n\n\nNine cases with LEV-induced cADRs were recruited. Demographic and clinical information of these cases was summarized. Additionally, cases were matched with LEV-tolerant controls (1:4). High-resolution HLA class I and class II genotyping was performed for each participant. The allele frequencies between the cases and controls were compared.\n\n\n\nAll LEV-induced cADRs were mild skin rashes which occurred within 28 days of LEV exposure. The mean latency from LEV exposure to skin rash was (15.67±5.41) days (ranging 6-27). The carrier rates of the two alleles, HLA-DRB1*0405 and HLA-DQB1*0401, were higher in cases compared with controls (the same P=0.036, OR=13.875, 95% CI: 1.273-151.230). The association between the HLA-C*0304 allele and LEV-induced cADRs was boundary (P=0.05, OR=5.2, 95% CI: 1.086-24.897). However, the above-mentioned HLA alleles didn't reach statistical significance after multiple comparisons.\n\n\n\nSafety monitoring was necessary within four weeks after the initiation of LEV treatment, although it has been regarded as a safe antiepileptic drug. Our study failed to show any potential link between HLA alleles and LEV-induced cADRs in Han Chinese. Further studies are needed to clarify the genetic and immunological mechanisms of LEV-induced cADRs.",
"affiliations": "Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.;Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.;Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.;Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.;Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.;Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China. Electronic address: zhoudong66@yahoo.de.",
"authors": "Hu|Fa-Yun|FY|;Wang|Wei|W|;Ren|Jie-Chuan|JC|;An|Dong-Mei|DM|;Chen|Jia-Ni|JN|;Zhou|Dong|D|",
"chemical_list": "D000927:Anticonvulsants; D006680:HLA Antigens; D000077287:Levetiracetam; D010889:Piracetam",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0920-1211",
"issue": "124()",
"journal": "Epilepsy research",
"keywords": "Cutaneous adverse drug reactions; Epilepsy; Human leukocyte antigen; Levetiracetam; Rash",
"medline_ta": "Epilepsy Res",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D044466:Asians; D002648:Child; D002681:China; D004827:Epilepsy; D005076:Exanthema; D005260:Female; D005787:Gene Frequency; D060005:Genotyping Techniques; D006680:HLA Antigens; D006579:Heterozygote; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D010889:Piracetam",
"nlm_unique_id": "8703089",
"other_id": null,
"pages": "12-5",
"pmc": null,
"pmid": "27162008",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Levetiracetam-induced cutaneous adverse drug reactions were not associated with HLA genes in a small sample of Chinese patients with epilepsy.",
"title_normalized": "levetiracetam induced cutaneous adverse drug reactions were not associated with hla genes in a small sample of chinese patients with epilepsy"
} | [
{
"companynumb": "CN-LUPIN PHARMACEUTICALS INC.-2016-02105",
"fulfillexpeditecriteria": "2",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditio... |
{
"abstract": "The study of neonatal acute kidney injury (AKI) has transitioned from small, single-center studies to the development of a large, multicenter cohort. The scope of research has expanded from assessment of incidence and mortality to analysis of more specific risk factors, novel urinary biomarkers, interplay between AKI and other organ systems, impact of fluid overload, and quality improvement efforts. The intensification has occurred through collaboration between the neonatology and nephrology communities. This review discusses 2 case scenarios to illustrate the clinical presentation of neonatal AKI, important risk factors, and approaches to minimize AKI events and adverse long-term outcomes.",
"affiliations": "Stead Family Department of Pediatrics, University of Iowa, 200 Hawkins Drive, 2015-26 BT, Iowa City, IA 52241, USA.;Division of Pediatric Nephrology, Dialysis, and Transplantation, Stead Family Department of Pediatrics, University of Iowa, 200 Hawkins Drive, 2029 BT, Iowa City, IA 52241, USA. Electronic address: Jennifer-jetton@uiowa.edu.;Division of Neonatology, Golisano Children's Hospital, University of Rochester School of Medicine, 601 Elmwood Avenue, Box 651, Rochester, NY 14642, USA; College of Health and Medicine, Australian National University, Canberra, Australian Capital Territory 2601, Australia. Electronic address: https://twitter.com/Aussiekidney.",
"authors": "Kavanaugh|Keegan J|KJ|;Jetton|Jennifer G|JG|;Kent|Alison L|AL|",
"chemical_list": "D015415:Biomarkers",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ccc.2020.11.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-0704",
"issue": "37(2)",
"journal": "Critical care clinics",
"keywords": "Acute kidney injury; Biomarkers; Neonate; Outcomes; Prematurity",
"medline_ta": "Crit Care Clin",
"mesh_terms": "D058186:Acute Kidney Injury; D015415:Biomarkers; D006801:Humans; D015994:Incidence; D007231:Infant, Newborn; D015337:Multicenter Studies as Topic; D012307:Risk Factors; D014883:Water-Electrolyte Imbalance",
"nlm_unique_id": "8507720",
"other_id": null,
"pages": "349-363",
"pmc": null,
"pmid": "33752860",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Neonatal Acute Kidney Injury: Understanding of the Impact on the Smallest Patients.",
"title_normalized": "neonatal acute kidney injury understanding of the impact on the smallest patients"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-336052",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLDOPA"
},
"drug... |
{
"abstract": "A trial of the antifungal triazole fluconazole was conducted in cancer patients with presumed or proven mold infection. Groups of patients received fluconazole at four dosages (800, 1200, 1600, or 2000 mg/day). Adverse events, plasma levels, and clinical response were examined. Thirty-nine patients were enrolled. The 28 evaluable patients had presumed (13 patients) or proven (15) mold infection with Aspergillus (4) and Fusarium (3) species, Zygomycetes organisms (1), or nonspeciated mold (7). Adverse effects included elevated liver function test results (8 patients), nausea and vomiting (2), and erythema multiforme (1). Neurologic toxicity occurred in 3 patients receiving 2000 mg/day. Average steady-state peak plasma concentrations were 51.8, 74.4, and 91.8 mg/L for dosages 1200, 1600, and 2000 mg/day, respectively. Seven of 28 evaluable patients responded. Response did not appear to be related to dose. Fluconazole is well tolerated at total daily doses up to 1600 mg. The data suggest a linear plasma concentration-dose relationship. The activity of fluconazole in refractory mold infections seems to be limited.",
"affiliations": "Department of Medical Specialties, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.",
"authors": "Anaissie|E J|EJ|;Kontoyiannis|D P|DP|;Huls|C|C|;Vartivarian|S E|SE|;Karl|C|C|;Prince|R A|RA|;Bosso|J|J|;Bodey|G P|GP|",
"chemical_list": "D015725:Fluconazole",
"country": "United States",
"delete": false,
"doi": "10.1093/infdis/172.2.599",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1899",
"issue": "172(2)",
"journal": "The Journal of infectious diseases",
"keywords": null,
"medline_ta": "J Infect Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D001230:Aspergillus; D004305:Dose-Response Relationship, Drug; D005260:Female; D015725:Fluconazole; D005670:Fusarium; D006801:Humans; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged; D009090:Mucorales; D009181:Mycoses; D009369:Neoplasms; D009894:Opportunistic Infections",
"nlm_unique_id": "0413675",
"other_id": null,
"pages": "599-602",
"pmc": null,
"pmid": "7622915",
"pubdate": "1995-08",
"publication_types": "D016430:Clinical Trial; D018848:Controlled Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Safety, plasma concentrations, and efficacy of high-dose fluconazole in invasive mold infections.",
"title_normalized": "safety plasma concentrations and efficacy of high dose fluconazole in invasive mold infections"
} | [
{
"companynumb": "US-PFIZER INC-2020164366",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "In 2008, the World Health Organization proposed a new entity of childhood myelodysplastic syndrome (MDS), which was referred to as refractory cytopenia of childhood (RCC). However, whether this morphological classification reflects clinical outcomes remains unclear. We performed a prospective evaluation of bone marrow morphology in 252 children with acquired bone marrow failure between 2009 and 2013. Of 252 patients, 63 were diagnosed with aplastic anaemia (AA), 131 with RCC without multilineage dysplasia (RCC-w/o-MLD) and 58 with RCC with MLD (RCC-MLD). One patient with AA, three with RCC-w/o-MLD and nine with RCC-MLD presented with chromosomal abnormalities at diagnosis (P = 0·001). The response rates to immunosuppressive therapy (IST) at 6 months and the cumulative incidence of clonal evolution at 5 years did not significantly differ among the three groups. A multivariate analysis revealed that the morphological classification of RCC-MLD was a significant risk factor for secondary graft failure after haematopoietic cell transplantation (HCT) (P = 0·003). In view of these findings, RCC could be divided into two categories, RCC-w/o-MLD and RCC-MLD, because children with this condition exhibited a distinct morphology, frequent chromosomal abnormalities at diagnosis and a high frequency of secondary graft failure after HCT.",
"affiliations": "Department of Paediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Paediatrics, St. Luke's International Hospital, Tokyo, Japan.;Department of Paediatrics, St. Luke's International Hospital, Tokyo, Japan.;Department of Laboratory Medicine, St. Luke's International Hospital, Tokyo, Japan.;Department of Paediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Paediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Haematology/Oncology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan.;Department of Paediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.;Department of Haematology/Oncology, Saitama Children's Medical Centre, Saitama, Japan.;Department of Paediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Haematology and Oncology, Shizuoka Children's Hospital, Shizuoka, Japan.;Department of Paediatrics, Toho University School of Medicine, Tokyo, Japan.;Department of Pathology, Japanese Red Cross Aichi Medical Centre Nagoya First Hospital, Nagoya, Japan.;Department of Paediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.",
"authors": "Hama|Asahito|A|https://orcid.org/0000-0002-7582-0201;Hasegawa|Daisuke|D|https://orcid.org/0000-0002-9446-9568;Manabe|Atsushi|A|;Nozawa|Kazue|K|;Narita|Atsushi|A|https://orcid.org/0000-0001-6518-4726;Muramatsu|Hideki|H|;Kosaka|Yoshiyuki|Y|;Kobayashi|Masao|M|;Koh|Katsuyoshi|K|;Takahashi|Yoshiyuki|Y|;Watanabe|Kenichiro|K|;Ohara|Akira|A|;Ito|Masafumi|M|;Kojima|Seiji|S|https://orcid.org/0000-0003-4125-5467",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bjh.17921",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": null,
"journal": "British journal of haematology",
"keywords": "acquired bone marrow failure; aplastic anaemia; children; myelodysplastic syndrome with multilineage dysplasia; refractory cytopenia of childhood",
"medline_ta": "Br J Haematol",
"mesh_terms": null,
"nlm_unique_id": "0372544",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34729770",
"pubdate": "2021-11-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Prospective validation of the provisional entity of refractory cytopenia of childhood, proposed by the World Health Organization.",
"title_normalized": "prospective validation of the provisional entity of refractory cytopenia of childhood proposed by the world health organization"
} | [
{
"companynumb": "JP-NOVARTISPH-NVSC2022JP033739",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "4",
... |
{
"abstract": "BACKGROUND\nToxoplasma gondii is a zoonotic parasite that has arisen as an important opportunistic infection that causes morbidity and mortality especially in HIV positive patients. This study was carried out to determine the sero-prevalence of T. gondii (IgG and IgM) and the associated risk factors among HIV positive and negative patients in Northern South Africa.\n\n\nMETHODS\nThe study was conducted in the Vhembe District in Limpopo province from April 2012 to January 2013. A well-structured questionnaire was used to collect socio-demographic information and possible risk factor information on toxoplasmosis from participants. A total of 161 blood samples of both HIV positive and negative patients visiting the local clinics in the Vhembe district were collected. Serum samples were tested for IgG and IgM against T. gondii using commercially available ELISA protocol.\n\n\nRESULTS\nThe prevalence of T. gondii IgG was 31.7% while that of T. gondii IgM was 4.9%. The prevalence of T. gondii IgG was higher in HIV positive patients (38%) compared to 16.7% among HIV negative patients (p=0.001). Toxoplasma gondii IgG antibodies were more common in patients who were not taking ARV's (46.2%) compared to those who were taking ARV's (35.2%) (P<0.001).\n\n\nCONCLUSIONS\nThe present study has shown a high prevalence of T. gondii (IgG) among patients attending different HIV clinics in the Vhembe district with no current infections among pregnant women. In addition to the sero-positive status of the patient to HIV, other significant risk factors for toxoplasmosis included high viral load, non-adherence to ARV therapy and age (>25 years).",
"affiliations": "Molecular Parasitology and Opportunistic Infections Program, Department of Microbiology, School of Mathematical and Natural Sciences, University of Venda, South Africa.;Molecular Parasitology and Opportunistic Infections Program, Department of Microbiology, School of Mathematical and Natural Sciences, University of Venda, South Africa.",
"authors": "Ngobeni|Renay|R|;Samie|Amidou|A|",
"chemical_list": null,
"country": "Nigeria",
"delete": false,
"doi": "10.21010/ajid.v11i2.1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2006-0165",
"issue": "11(2)",
"journal": "African journal of infectious diseases",
"keywords": "ELISA; HIV; Opportunistic infections; Sero-prevalence; Toxoplasma gondii",
"medline_ta": "Afr J Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101578779",
"other_id": null,
"pages": "1-9",
"pmc": null,
"pmid": "28670634",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": "25548409;26108015;26951986;27092763;21771468;18337350;17686219;27139453;26924348;27083153;22360636;20691951;19374326;24064557;20214142;23216887;26762861;16621694;26952970;27155133",
"title": "PREVALENCE OF TOXOPLASMA GONDII IGG AND IGM AND ASSOCIATED RISK FACTORS AMONG HIV-POSITIVE AND HIV-NEGATIVE PATIENTS IN VHEMBE DISTRICT OF SOUTH AFRICA.",
"title_normalized": "prevalence of toxoplasma gondii igg and igm and associated risk factors among hiv positive and hiv negative patients in vhembe district of south africa"
} | [
{
"companynumb": "ZA-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-036783",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
},
"... |
{
"abstract": "Antithyroid drugs as thionamides are largely used in the treatment of the thyrotoxicosis. Side effects were reported in less than 10% of the cases, especially hematological, hepatic or skin allergies. One of the most severe manifestations is agranulocytosis, probably based on an immune mechanism that is exacerbated by the presence of the thyroid autoimmune disease itself. If the presence of the severe leucopenia is actually an epiphenomenon of a preexisting hematological disturbance as multiple myeloma is debated. The myeloma may also be correlated with an autoimmune predisposition. We present the case of a 56 years old female patient diagnosed with Graves' disease, who developed agranulocytosis after 8 months of therapy with thiamazole. Two months after antithyroid drug's withdrawal, the granulocytes number increased and she received therapy with radioiodine. Two years later she came back for diffuse bone pain that turned out to be caused by a multiple myeloma, confirmed by bone marrow biopsy. It might be a connection between the severe form of leucopenia that the patient developed and the medullar malignancy.",
"affiliations": "\"Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania.",
"authors": "Dănciulescu Miulescu|R|R|;Carşote|M|M|;Trifănescu|R|R|;Ferechide|D|D|;Poiană|C|C|",
"chemical_list": "D013956:Antithyroid Agents",
"country": "Romania",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nJ Med LifeJ Med LifeJMedLifeJournal of Medicine and Life1844-122X1844-3117Carol Davila University Press Romania JMedLife-06-327Case PresentationAntithyroid drugs induced agranulocytosis and multiple myeloma:\ncase report and general considerations Dănciulescu Miulescu R *Carșote M *Trifănescu R ***Ferechide D *Poiană C **** “Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania** “C.I. Parhon\" National Institute of Endocrinology, Bucharest, RomaniaCorrespondence to:Raluca Trifănescu, MD,\nDepartment of Endocrinology, “Carol Davila\" University of Medicine and Pharmacy,\n“C. I. Parhon\" National Institute of Endocrinology,\n34–36 Aviatorilor Avenue, 011863 Bucharest, Romania,\nPhone +40745048692, E-mail: ralucatrifanescu@yahoo.com\n15 9 2013 25 9 2013 6 3 327 331 01 3 2013 19 6 2013 ©Carol Davila University Press\n2012This is\nan open-access article distributed under the terms of the Creative\nCommons Attribution License, which permits unrestricted use,\ndistribution, and reproduction in any medium, provided the original work\nis properly cited.Antithyroid drugs as thionamides are largely used in the treatment of the thyrotoxicosis. Side effects were reported in less than 10% of the cases, especially hematological, hepatic or skin allergies. One of the most severe manifestations is agranulocytosis, probably based on an immune mechanism that is exacerbated by the presence of the thyroid autoimmune disease itself. If the presence of the severe leucopenia is actually an epiphenomenon of a preexisting hematological disturbance as multiple myeloma is debated. The myeloma may also be correlated with an autoimmune predisposition. We present the case of a 56 years old female patient diagnosed with Graves’ disease, who developed agranulocytosis after 8 months of therapy with thiamazole. Two months after antithyroid drug’s withdrawal, the granulocytes number increased and she received therapy with radioiodine. Two years later she came back for diffuse bone pain that turned out to be caused by a multiple myeloma, confirmed by bone marrow biopsy. It might be a connection between the severe form of leucopenia that the patient developed and the medullar malignancy.\n\nthiamazoleGraves’ diseaseagranulocytosismultiple myeloma\n==== Body\nIntroduction\nThiamazole is an antithyroid drug, largely used in the treatment of Graves’s disease. One side effect is granulocytopenia up to agranulocytosis, that makes necessary a periodic blood count and withdrawal of medication once it was discovered. The pathological profile of those cases with hematological disturbances is still unclear. It seems that autoimmunity, high doses of thiamazole increases the risk. Age is not a risk factor. If the chance is higher in those patients who are at risk of hematological malignancy is still debated.\n\nCase presentation \nA 56-year-old female patient was admitted to our hospital for 20 kg weight loss, fatigability, peripheral tremor, intolerance to heat; symptoms were presented for the last 3 months. The clinical exam revealed homogenous goiter associated with signs of hyperthyroidism (tachycardia; soft, wet skin; tremor). \n\n The blood count and biochemical panel were normal. The hormonal profile confirmed the hyperthyroidism: suppressed thyroid-stimulating hormone (TSH), high triiodothyronine (T3)–436 ng/mL (normal range between 80 and 200 ng/dL), and high thyroxine (T4)–20.3 μg/mL (normal range between 4.5 and 13 μg/dL). Autoimmune etiology of thyrotoxicosis was suggested by elevated TPO antibodies-439 UI/mL (normal range: <36 IU/mL). The 131I scintigraphy revealed large, homogenous goiter; radioiodine uptake was high at 2 hours (29%, normal range: 12+5%) and 12% at 24 hours (normal range: 30+5%) (Fig. 1). Thyroid ultrasound confirmed the homogenous, hypoechoic pattern. Symptoms or signs of Graves’ ophthalmopathy were absent.\n\n\nFigure 1 The I131 scintigraphy showing a large, homogenous thyroid gland\n\nThyrotoxicosis due to Graves’s disease was diagnosed, and treatment with antithyroid drugs, thiamazole, 40 mg per day, p.o., was started. The dose was progressively decreased to 20 mg per day. No acute adverse reaction was registered. The disease was slowly equilibrating for the next 8 months, when marked leucopenia (leucocytes–1200/mm3), but normal platelets and red cells count were found. Thiamazole was stopped and glucocorticoids (Dexamethasone) were initiated. There was persistence of thyrotoxicosis (TSH<0.03 mIU/L), requiring lithium treatment for the reducing of thyroid hormones levels. \n\nTwo months later, the complete blood count was normal (leucocytes–5100/mm3) and lithium was stopped. Radical ablative therapy with radioiodine (5 mCi 131I) was administered; hypothyroidism was noted 2 months later, and levothyroxine 50 μg per day was recommended. The blood count showed mild anemia (hemoglobin–9.9 g/dL) and increased erythrocyte sedimentation rate (ESR) – 36 mm at 1 hour, (normal range between 1 and 25 mm at 1 hour). \n\n Two years later, the patient was admitted for diffuse bone pain, fatigability and medium efforts dyspnea. The blood count showed an aggravated anemia (hemoglobin–7.9 g/dL) and markedly increased erythrocyte sedimentation rate (ESR – 120 mm at 1 hour). The serum protein levels were increased (total serum protein–11.6 g/dL; normal range: 6.6-8.3 g/dL). The serum protein electrophoresis showed monoclonal hyper gamma-globulinemia. The thoracic-abdominal computed tomography scan revealed osteolytic lesions of 2.17/1.9 cm with broken cortical, at the level of the thoracic vertebral bodies, of 4.09/2.38 cm at the right ribs and sternum (Fig. 2). \n\nFigure 2 Computed tomography exam showing osteolytic lesions with broken cortical, at the level of the thoracic vertebral bodies, the right ribs and the sternum\n\n The skull X-Ray exam showed disseminated osteolytic lesions, with a diameter varying from a few millimeters to 2 cm (Fig. 3). \n\nFigure 3 Skull X-Ray exam showing disseminated osteolytic lesions\n\nThe bone marrow examination revealed a highly cellular marrow, with 57-60% large plasma cells, having round nuclei, abundant, intense basophile cytoplasm. The other series, granulocytes (23%), eritroblastic (13%) and megakaryocytic lines were abnormally low, with arrested maturation. Based on these, diagnosis of multiple myeloma was established (stage II according to clinical stages of Durie and Salmon). Treatment with alkylation agent Melphalan and bisphosphonate Clodronate was started, but unfortunately the patient died 2 months later. \n\nGeneral considerations \n\n\nAntithyroid drugs\n\n The antithyroid drugs are derived from amides as thioamide (or thionamide) or derived from thiourrhea as propylthiouracil (PTU). In the first category the most known drug is thiamazole (or methimazole) and also carbimazole that is converted in vivo into the first one. Thioamides inhibit the enzyme thyroid peroxidase in the thyroid, reducing the synthesis of triiodothyronine (T3) and thyroxine (T4), and blocking the uptake of iodotyrosines from the thyroid colloid. PTU also acts by inhibiting the tetraiodothyronine 5' deiodinase that converts T4 into T3. Maximum effects occur only after a month since hormone depletion is caused by reduced synthesis, which is a slow process. Side effects of antithyroid drugs are seen in 1 up to 10% of the patients as skin eruptions as macula or papula, dermatitis, urticaria, artralgia, hepatitis, jaundice, muscle pain, thrombocytopenia, abnormal hair loss, vomiting, loss of taste. Life threatening agranulocytosis developed in 0.03% of all patients. \n\nAgranulocytosis\n\n\n Agranulocytosis is a severe type of leucopenia particularly of the neutrophils. Generally the granulocytes (a class that includes neutrophils, basophiles and eosinophils) decrease below 500 cells/mm³ of blood or less than one-sixth of the reference value of 3-10 x 103 cells/mm³. The terms of agranulocytosis, granulocytopenia and neutropenia are often used interchangeably, but agranulocytosis is the most severe form. Precisely, neutropenia describes absolute neutrophile counts less than 500 per microlitre, whereas agranulocytosis means less than 100 per microlitre. Granulocytopenia is defined by a decrease below 1500 cells per microlitre. \n\n Agranulocytosis has been reported in about 0.35% up to 1.75 % of the patients treated with methimazole [1,2]. Granulocytopenia appears in about 2.5 % of cases [3]. The risk of agranulocytosis is increased when high thiamazole doses are used. In a retrospective study, agranulocytosis was observed in 4.1% of patients treated with at least 20 mg per day of methimazole, compared with only 0.31% from the patients with smaller doses [4]. According to the same authors, age does not seem to be a risk factor [5] but former studies did not reach to the same conclusion [6]. \n\n Usually, the reaction develops after 2 up to 12 weeks of treatment; however, in our case, leucopenia developed after 8 months treatment, despite periodic complete blood counts. It frequently has acute onset, but cases have been described in which it followed after granulocytopenia [7]. In our case there was an asymptomatic form. Agranulocytosis was found even in patients who previously tolerated the antithyroid drugs, after several exposures. Multiple exposures may represent a risk factor for developing hematological disturbances [2,3]. Cross reactions between the different thioamides may appear, so replacing one drug with another is not recommended [8]. \n\n The most common manifestation of leukopenia refers to febrile infections, frequently upper respiratory tract infections as angina and gingivitis [3,9].The most severe form is sepsis [1]. In such cases, the bone marrow biopsy usually shows decrease in the numbers of granulocytes and their precursors, or cellular hyperplasia. Maturation arrest in the myeloid line is common and sometimes it is the only finding [3,10]. The cost effectiveness of serial blood count in order to detect the granulocytes abnormalities is still a matter of debate. Although not widely recommended, it has the advantage of identifying patients before the clinical manifestations occur, like in our case [1]. Another still open question is the usefulness of the therapy with granulocyte - colony stimulating factor (G-CSF), which is generally recommended for patients with drug-induced granulocytopenia. A Japanese study on 109 patients with thiamazole induced granulocytopenia did not found benefits in treating symptomatic patients with very low granulocyte counts, although in less severe cases the recovery time was shortened. Prolonged treatment in unresponsive patients is not effective [11]. There has been suggested that measuring the granulocytes 4 hours after the injection with G-CSF may detect the patients in which this treatment is effective [12]. The effect of treatment with Dexamethasone has not been certainly proved [1]. \n\n Older studies showed a mortality of up to 18% for agranulocytosis [9], but, during the last years, because of better treatment of infections and maybe due to the use of G-CSF, the fatal outcome appears in less than 5% of cases [13]. \n\nAplastic anemia is a rare life threatening complication of the antithyroid medication that develops only in association with agranulocytosis. It usually appears soon after the beginning of the treatment and resolves after drug’s withdrawal [14]. Bone marrow is hypocellular, in some cases with plasmacytosis, suggesting an immunogenic cause [15]. The treatment is supportive, but cases responding favorably to G-CSF have been described [8]. \n\nThe agranulocytosis and autoimmunity \n\n The etiopathogeny of agranulocytosis is still unclear. Immunologic mechanism has been incriminated, because anti-granulocyte antibodies have been identified in certain cases, but other mechanisms are probably involved [1,2]. Methimazole does not cause a decrease in the levels of natural G-CSF [10]. \n\n Methimazole has also other autoimmune side effects. In a small prospective study, 3 out of 33 patients on thiamazole developed antineutrophil cytoplasmic antibody (ANCA) and other 2 had ANCA-positive vasculitis, with renal involvement [16]. One case of central nervous system vasculitis has also been described [17]. These autoimmune syndromes seem to disappear after the discontinuation of the drug [16,17]. Methimazole has been involved in the development of insulin antibodies [18]. Other rare complications, possible with similar mechanism including pancreatitis and parotiditis have been described [19]. \n\n\nMultiple myeloma and autoimmunity\n\n\n Multiple myeloma is a malignancy of plasma cells, which can range from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. It represents about 15% of all lymphatic hematopoietic neoplasia, with a higher incidence in black men [20]. The incidence increases with age. \n\n The disease is characterized by an over-production of monoclonal paraproteins, leading to hyper viscosity, amyloidosis, renal failure and disrupting the normal immune response. Because of proliferation of plasma cells in the bone marrow, patients develop osteolytic lesions and hypercalcemia. Our patient had bone lesions, but no hypercalcemia. Even if new therapy protocols, including autologous stem-cell transplantation have been developed and are effective, the disease has a median survival period after the diagnosis of about 3 years (higher in younger patients) [2]. \n\n The etiology of multiple myeloma in unknown, but an association with chronic stimulation of the immune system, like in autoimmune diseases has been described [21]. The data concerning multiple myeloma and thyroid pathology is somewhat controversial. In a retrospective study on 73 cases of patients with multiple myeloma compared with gender and age controls showed a higher incidence of autoimmune thyroid disease. The authors conclude that patients with thyroid pathology have an odds ratio of 2.41 for developing multiple myeloma, compared with healthy controls [20]. Also, a familial history of thyroid disease is associated with increased risk of multiple myeloma. This finding was not confirmed by a case-control study performed on 179 female patients with multiple myeloma which did not found any correlation between thyroid medication and the hematological disease [22]. Also, a large Swedish population based study (on over 8000 patients with multiple myeloma) did not show a strong correlation with personal or familial autoimmune diseases [23]. \n\nConclusions\nWe present this case as an argument for the periodical check up of the blood count during the treatment with antithyroid drugs in order to detect anomalies as leukopenia and even worse agranulocytosis. It is difficult to express any certain correlation between the autoimmune thyroid disease as Graves’s disease and the risk of hematological disturbances. It is possible that the patients who develop agranulocytosis actually have more severe marrow diseases as malignancy and the drop of granulocytes is in fact the exposed part of an iceberg. Further serial investigations should be performed.\n==== Refs\n1 Cooper DS Drug Therapy. Antithyroid Drugs N Engl J Med 2005 352 905 917 15745981 \n2 Kyle RA Rajkumar SV Multiple Myeloma N Engl J Med 2004 351 1860 1873 15509819 \n3 Rosove MH Agranulocytosis and antithyroid drugs West J Med 1977 126 339 343 867981 \n4 Tsuboi K Ueshiba H The relation of initial methimazole dose to the incidence of methimazole-induced agranulocytosis in patients with Graves' disease Endocr J 2007 54 39 43 17053291 \n5 Dai WX Zhang JD Retrospective analysis of 18 cases of antithyroid drug (ATD)-induced agranulocytosis Endocr J 2002 49 29 33 12008747 \n6 Cooper DS Goldminz D Agranulocytosis associated with antithyroid drugs. Effects of patient age and drug dose Ann Intern Med 1983 98 26 29 6687345 \n7 Schut NH Wiersinga WM Methimazole-induced agranulocytosis preceded by transient granulocytopenia. A case report Neth J Med 1993 43 71 73 8232698 \n8 Mezquita P Luna V Methimazole-induced aplastic anemia in third exposure: successful treatment with recombinant human granulocyte colony-stimulating factor Thyroid 1998 8 791 794 9777751 \n9 Murakami Y Sasaki I Serum concentrations of granulocyte colony-stimulating factor (G-CSF) in antithyroid drug-induced agranulocytosis. Endocr J. 2004 51 579 585 15644577 \n10 Tajiri J Noguchi S Antithyroid drug-induced agranulocytosis: how has granulocyte colony-stimulating factor changed therapy? Thyroid 2005 15 292 297 15785251 \n11 Tajiri J Noguchi S Usefulness of granulocyte count measurement four hours after injection of granulocyte colony-stimulating factor for detecting recovery from antithyroid drug-induced granulocytopenia Thyroid 1997 7 575 578 9292945 \n12 Federici L Weitten T Idiosyncratic drug-induced agranulocytosis. Presse Med 2008 37 1327 1333 18644319 \n13 Thomas D Moisidis A Antithyroid drug-induced aplastic anemia Thyroid 2008 18 1043 1048 18816182 \n14 Yamamoto A Katayama Y Methimazole-induced aplastic anemia caused by hypocellular bone marrow with plasmacytosis Thyroid 2004 14 231 235 15072706 \n15 Chen LQ Zhang XL Relationship between methimazole and antineutrophil cy toplasmic antibody-positive vasculitis Zhonghua Er Ke Za Zhi 2008 46 446 449 19099784 \n16 Tripodi PF Ruggeri RM Central nervous system vasculitis after starting methimazole in a woman with Graves' disease Thyroid 2008 18 1011 1013 18788922 \n17 Uchigata Y Kuwata S Patients with Graves' disease who developed insulin autoimmune syndrome (Hirata disease) possess HLA-Bw62/Cw4/DR4 carrying DRB1*0406. J Clin Endocrinol Metab 1993 77 249 254 8325948 \n18 Taguchi M Yokota M Acute pancreatitis and parotitis induced by methimazole in a patient with Graves' disease Clin Endocrinol (Oxf) 1999 51 667 670 10594530 \n19 Alexander DD Mink PJ Multiple myeloma: a review of the epidemiologic literature Int J Cancer. 2007 12 40 61 17405120 \n20 Söderberg KC Jonsson F Autoimmune diseases, asthma and risk of haematological malignancies: a nationwide case-control study in Sweden Eur J Cancer 2006 42 3028 3033 16945522 \n21 Dalamaga M Karmaniolas K Association of thyroid disease and thyroid autoimmunity with multiple myeloma risk: a case-control study Leuk Lymphoma 2008 49 1545 1552 18766968 \n22 Landgren O Zhang Y Risk of multiple myeloma following medication use and medical conditions: a case-control study in Connecticut women Cancer Epidemiol Biomarkers Prev 2006 15 2342 2347 17132770 \n23 Landgren O Linet MS Familial characteristics of autoimmune and hematologic disorders in 8,406 multiple myeloma patients: a population-based case-control study Int J Cancer 2006 118 3095 3098 16395700\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1844-122X",
"issue": "6(3)",
"journal": "Journal of medicine and life",
"keywords": "Graves’ disease; agranulocytosis; multiple myeloma; thiamazole",
"medline_ta": "J Med Life",
"mesh_terms": "D000380:Agranulocytosis; D013956:Antithyroid Agents; D015551:Autoimmunity; D005260:Female; D006801:Humans; D008875:Middle Aged; D009101:Multiple Myeloma; D010014:Osteolysis; D011877:Radionuclide Imaging; D013961:Thyroid Gland; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101477617",
"other_id": null,
"pages": "327-31",
"pmc": null,
"pmid": "24155785",
"pubdate": "2013-09-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "867981;17132770;15509819;18816182;17405120;18788922;6687345;9292945;16395700;19099784;8325948;15745981;9777751;18766968;16945522;8232698;10594530;15785251;12008747;15072706;17053291;18644319;15644577",
"title": "Antithyroid drugs induced agranulocytosis and multiple myeloma: case report and general considerations.",
"title_normalized": "antithyroid drugs induced agranulocytosis and multiple myeloma case report and general considerations"
} | [
{
"companynumb": "PHHY2014RO078742",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHIMAZOLE"
},
"drugadditional": null,
"dru... |
{
"abstract": "There is no head-to-head trial comparing ustekinumab and vedolizumab in patients with Crohn's disease (CD) refractory to anti-tumour necrosis factor (anti-TNF).\n\n\n\nTo compare the effectiveness and safety of ustekinumab and vedolizumab in patients with CD refractory to anti-TNF in a multicentre retrospective observational cohort.\n\n\n\nAll consecutive patients with CD refractory or intolerant to anti-TNF who initiated either vedolizumab or ustekinumab were included between May 2014 and August 2018. Clinical remission, steroid-free clinical remission (SFCR) and treatment persistence were assessed at week 48 with intention-to-treat analysis and propensity scores weighted comparison.\n\n\n\nA total of 239 patients were included, 107 received ustekinumab and 132 received vedolizumab. At week 48, ustekinumab was associated with a higher clinical remission rate (54.4% vs 38.3%; odds ratios, OR = 1.92, 95% CI [1.09-3.39]) and treatment persistence (71.5% vs 49.7%; OR = 2.54, 95% CI [1.40-4.62]) than vedolizumab. The rate of SFCR did not differ significantly between ustekinumab and vedolizumab (44.7% vs 34.0%; OR = 1.57, 95% CI [0.88-2.79]). Subgroup analyses showed that ustekinumab was associated with a higher clinical remission rates at week 48 in patients with ileal location (OR = 3.49, 95% CI [1.33-9.17) and penetrating behaviour (OR = 6.58, 95% CI [1.91-22.68]). Regardless of the treatment group, combination therapy at initiation was associated with a higher clinical remission rate at week 48 (OR = 1.93, 95% CI [1.09-3.43]).\n\n\n\nThis study suggests that ustekinumab is associated with a higher rate of clinical remission and treatment persistence than vedolizumab after 48 weeks of follow-up, in patients with CD refractory or intolerant to anti-TNF. The rate of SFCR was not significantly different.",
"affiliations": "Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Université Paris Saclay, Le Kremlin Bicêtre, France.;Assitance-Publique-Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Université Paris Est Créteil, Créteil, France.;Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Sorbonne Université, Paris, France.;Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, Université de Paris, Clichy, France.;Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Université de Paris, Paris, France.;Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, Université de Paris, Clichy, France.;Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Sorbonne Université, Paris, France.;Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Université Paris Saclay, Le Kremlin Bicêtre, France.;Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Université Paris Saclay, Le Kremlin Bicêtre, France.",
"authors": "Alric|Hadrien|H|0000-0002-0343-4440;Amiot|Aurélien|A|;Kirchgesner|Julien|J|;Tréton|Xavier|X|0000-0001-8123-9213;Allez|Matthieu|M|;Bouhnik|Yoram|Y|;Beaugerie|Laurent|L|;Carbonnel|Franck|F|;Meyer|Antoine|A|0000-0003-1156-9289",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D014409:Tumor Necrosis Factor-alpha; C543529:vedolizumab; D000069549:Ustekinumab",
"country": "England",
"delete": false,
"doi": "10.1111/apt.15706",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-2813",
"issue": "51(10)",
"journal": "Alimentary pharmacology & therapeutics",
"keywords": null,
"medline_ta": "Aliment Pharmacol Ther",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D015331:Cohort Studies; D003424:Crohn Disease; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha; D000069549:Ustekinumab",
"nlm_unique_id": "8707234",
"other_id": null,
"pages": "948-957",
"pmc": null,
"pmid": "32249966",
"pubdate": "2020-05",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "The effectiveness of either ustekinumab or vedolizumab in 239 patients with Crohn's disease refractory to anti-tumour necrosis factor.",
"title_normalized": "the effectiveness of either ustekinumab or vedolizumab in 239 patients with crohn s disease refractory to anti tumour necrosis factor"
} | [
{
"companynumb": "FR-JNJFOC-20200414129",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "USTEKINUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Botulinum toxin type A (BoNT-A) is generally considered safe and is widely used to treat a variety of clinical conditions involving muscle hyperactivity and for cosmetic purposes. However, the effects of BoNT-A poisoning (botulism) on brain function are poorly understood.\n\n\n\nHerein, we investigated brain functions in 9 patients who received illegal cosmetic injections of botulinum and 18 matched controls by combining the analysis methods of regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) based on resting-state fMRI. Compared with the controls, the patients with botulism exhibited significantly reduced ReHo values in the left posterior lobe of the cerebellum extending to the right anterior lobe of the cerebellum, as well as in the right anterior lobe of the cerebellum extending to the parahippocampal gyrus and right posterior lobe of the cerebellum. The patients with botulism also showed weakened ALFF values in the right anterior lobe of the cerebellum extending to the left anterior lobe of the cerebellum and right posterior lobe of the cerebellum, as well as in the right anterior lobe of the cerebellum.\n\n\n\nThe results indicate that BoNT-A may modulate cerebral activation in specific areas, which may play roles in both the adverse effects of botulism and the mechanism underlying clinical treatment with BoNT-A.",
"affiliations": "Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Shanghai Key Laboratory of Magnetic Resonance and Department of Physics, School of Physics and Materials Science, East China Normal University, Shanghai, China.;Shanghai Key Laboratory of Magnetic Resonance and Department of Physics, School of Physics and Materials Science, East China Normal University, Shanghai, China.;Shanghai Key Laboratory of Magnetic Resonance and Department of Physics, School of Physics and Materials Science, East China Normal University, Shanghai, China.;Shanghai Key Laboratory of Magnetic Resonance and Department of Physics, School of Physics and Materials Science, East China Normal University, Shanghai, China.;Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Shanghai Key Laboratory of Magnetic Resonance and Department of Physics, School of Physics and Materials Science, East China Normal University, Shanghai, China.",
"authors": "Li|Ge-Fei|GF|;Ban|Shiyu|S|;Wang|Mengxing|M|;Zhang|Jilei|J|;Lu|Haifeng|H|;Shi|Yan-Hui|YH|;He|Xin-Wei|XW|;Wu|Yi-Lan|YL|;Peng|Peng|P|;Liu|Yi-Sheng|YS|;Zhuang|Mei-Ting|MT|;Zhao|Rong|R|;Shen|Xiao-Lei|XL|;Li|Qiang|Q|;Liu|Jian-Ren|JR|;Du|Xiaoxia|X|0000-0001-8470-7852",
"chemical_list": "D019274:Botulinum Toxins, Type A",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0207448",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0207448PONE-D-17-42407Research ArticleMedicine and Health SciencesInfectious DiseasesBacterial DiseasesBotulismBiology and Life SciencesAnatomyBrainCerebral CortexCerebellumMedicine and Health SciencesAnatomyBrainCerebral CortexCerebellumBiology and Life SciencesNeuroscienceBrain MappingFunctional Magnetic Resonance ImagingMedicine and Health SciencesDiagnostic MedicineDiagnostic RadiologyMagnetic Resonance ImagingFunctional Magnetic Resonance ImagingResearch and Analysis MethodsImaging TechniquesDiagnostic RadiologyMagnetic Resonance ImagingFunctional Magnetic Resonance ImagingMedicine and Health SciencesRadiology and ImagingDiagnostic RadiologyMagnetic Resonance ImagingFunctional Magnetic Resonance ImagingResearch and Analysis MethodsImaging TechniquesNeuroimagingFunctional Magnetic Resonance ImagingBiology and Life SciencesNeuroscienceNeuroimagingFunctional Magnetic Resonance ImagingBiology and Life SciencesToxicologyToxic AgentsToxinsBacterial ToxinsBotulinum ToxinMedicine and Health SciencesPathology and Laboratory MedicineToxicologyToxic AgentsToxinsBacterial ToxinsBotulinum ToxinBiology and Life SciencesAnatomyMusculoskeletal SystemMusclesGastrocnemius MusclesMedicine and Health SciencesAnatomyMusculoskeletal SystemMusclesGastrocnemius MusclesMedicine and Health SciencesDiagnostic MedicineSigns and SymptomsPoisoningMedicine and Health SciencesPathology and Laboratory MedicineSigns and SymptomsPoisoningResearch and Analysis MethodsResearch DesignClinical Research DesignAdverse EventsBiology and Life SciencesAnatomyNervous SystemCentral Nervous SystemMedicine and Health SciencesAnatomyNervous SystemCentral Nervous SystemBrain functional changes in patients with botulism after illegal cosmetic injections of botulinum toxin: A resting-state fMRI study Brain functional changes in patients with botulismLi Ge-Fei Data curationInvestigation12Ban Shiyu Data curationFormal analysisInvestigation3Wang Mengxing Data curationMethodology3Zhang Jilei Formal analysisInvestigation3Lu Haifeng Data curation3Shi Yan-Hui Data curationInvestigation12He Xin-Wei Data curationInvestigation12Wu Yi-Lan Data curationInvestigation12Peng Peng Data curationInvestigation1Liu Yi-Sheng Investigation1Zhuang Mei-Ting Data curationInvestigation1Zhao Rong Data curationInvestigation12Shen Xiao-Lei Data curationInvestigation1Li Qiang ConceptualizationSupervisionWriting – original draft1*Liu Jian-Ren Funding acquisitionProject administrationWriting – review & editing12*http://orcid.org/0000-0001-8470-7852Du Xiaoxia Funding acquisitionProject administrationSupervisionWriting – original draftWriting – review & editing3*1 \nDepartment of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China2 \nClinical Research Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China3 \nShanghai Key Laboratory of Magnetic Resonance and Department of Physics, School of Physics and Materials Science, East China Normal University, Shanghai, ChinaChen Kewei EditorBanner Alzheimer's Institute, UNITED STATESCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: xxdu@phy.ecnu.edu.cn (XD); lqsmmu@126.com (QL); liujr021@sjtu.edu.cn (JRL)28 11 2018 2018 13 11 e02074488 12 2017 31 10 2018 © 2018 Li et al2018Li et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background\nBotulinum toxin type A (BoNT-A) is generally considered safe and is widely used to treat a variety of clinical conditions involving muscle hyperactivity and for cosmetic purposes. However, the effects of BoNT-A poisoning (botulism) on brain function are poorly understood.\n\nMethodology/Principal findings\nHerein, we investigated brain functions in 9 patients who received illegal cosmetic injections of botulinum and 18 matched controls by combining the analysis methods of regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) based on resting-state fMRI. Compared with the controls, the patients with botulism exhibited significantly reduced ReHo values in the left posterior lobe of the cerebellum extending to the right anterior lobe of the cerebellum, as well as in the right anterior lobe of the cerebellum extending to the parahippocampal gyrus and right posterior lobe of the cerebellum. The patients with botulism also showed weakened ALFF values in the right anterior lobe of the cerebellum extending to the left anterior lobe of the cerebellum and right posterior lobe of the cerebellum, as well as in the right anterior lobe of the cerebellum.\n\nConclusions/Significance\nThe results indicate that BoNT-A may modulate cerebral activation in specific areas, which may play roles in both the adverse effects of botulism and the mechanism underlying clinical treatment with BoNT-A.\n\nthe National Natural Science Foundation of China81571658http://orcid.org/0000-0001-8470-7852Du Xiaoxia http://dx.doi.org/10.13039/501100001809National Natural Science Foundation of China81271302Liu Jian-Ren research innovation project from Shanghai Municipal Science and Technology Commission14JC1404300Liu Jian-Ren \"Prevention and Control of Chronic Diseases Project\" of Shanghai Hospital Development CenterSHDC12015310Liu Jian-Ren project from SHSMU-ION Research Center for Brain Disorders2015NKX006Liu Jian-Ren project from Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support20161422Liu Jian-Ren Clinical Research Project from Shanghai Jiao Tong University School of MedicineDLY201614Liu Jian-Ren Biomedicine Key program from Shanghai Municipal Science and Technology Commission16411953100Liu Jian-Ren This research was supported by grants from the National Natural Science Foundation of China (nos. 81571658 to X.X. Du), the National Natural Science Foundation of China (no. 81271302 to J.R. Liu), the Project of Shanghai Municipal Science and Technology Commission research innovation project (no. 14JC1404300, to J.R. Liu), the \"Prevention and Control of Chronic Diseases Project\" of Shanghai Hospital Development Center (no. SHDC12015310, to J.R. Liu), the SHSMU-ION Research Center for Brain Disorders project (no. 2015NKX006, to J.R. Liu), the Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support project (no. 20161422 to J.R. Liu), the Clinical Research Project from Shanghai Jiao Tong University School of Medicine (no. DLY201614 to J.R. Liu), and the Biomedicine Key program of Shanghai Municipal Science and Technology Commission (no. 16411953100 to J.R. Liu). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityAll relevant data are within the paper.Data Availability\nAll relevant data are within the paper.\n==== Body\nIntroduction\nBotulinum toxin type A (BoNT-A) is widely used to treat a variety of clinical conditions characterized by excessive muscle contraction, including dystonia and spasticity [1, 2]. BoNT-A is also used as a treatment for other medical conditions, such as neuropathic pain, axillary hyperhidrosis, neurogenic detrusor overactivity and sialorrhea [1, 3–6]. In addition, BoNT-A, alone or in combination with other agents, is exploited in a variety of cosmetic treatments. BoNT-A acts at neuromuscular junctions to inhibit the release of the neurotransmitter acetylcholine, thus weakening the contraction of muscle fibers responsible for excessive involuntary movements [1]. Both basic and clinical research has thoroughly addressed the toxin’s peripheral actions, and its mechanism of action on muscle spindles is well described [7, 8]. BoNT-A also acts on central nervous system (CNS) structures. BoNT-A may exert effects via supraspinal mechanisms that alter the balance between afferent input and motor output, thereby altering cortical excitability [9]. Furthermore, BoNT-A injected into facial muscles induces changes in the central motor organization of this body region that are independent of altered sensory input; this pattern of clinical activity is probably derived from summated peripheral and central actions [10]. Previous rodent experimental studies have shown that botulinum toxin receptors exist in the CNS and that a small amount of botulinum toxin can pass through the blood-brain barrier [10, 11].\n\nIncreasing evidence supported by neuroimaging studies in patients indicates that central reorganization occurs following BoNT-A treatment. In previous fMRI studies in patients with focal spasticity, cortical changes occurred after BoNT-A injections, and brain (such as sensorimotor and cerebellar) activity was modulated by BoNT-A [12–16]. Most previous fMRI studies in patients have investigated and described changes in cortical activity based on tasks. However, cortical changes in the resting state are unclear, and the influence of BoNT-A on brain function in healthy individuals is not yet known. We suspected that BoNT-A induces changes in brain activities not only in the task state but also in the resting state; we further postulated that the brain’s spontaneous activity would be altered by peripheral BoNT-A injection in healthy individuals.\n\nAlthough BoNT-A is generally considered safe, it may cause serious adverse events after both therapeutic and cosmetic uses [17]. Adverse events associated with BoNT-A include dysarthria, dysphonia, dysphagia, respiratory compromise, generalized muscle weakness, marked bilateral ptosis, pain, bowel/bladder-related changes, blood circulation-related changes, gait-related changes, and neurological problems [17, 18]. A subject who experiences a serious adverse event after BoNT-A injection of a dose substantially exceeding that commonly used in the clinic provides an unusual opportunity to investigate the pharmacological and toxicological mechanisms of BoNT-A, especially the effect of BoNT-A on brain function. These observations could contribute to a better understanding of the therapeutic effects of BoNT-A on dystonia [1, 19], spasticity [1, 19], depression [20, 21], and pain [22, 23], among others. Moreover, a better understanding of the mechanisms underlying BoNT-A poisoning could also improve the guidelines for BoNT-A administration, as well as the outcomes, and minimize adverse events. This study aimed to investigate resting-state neural function in 9 subjects with botulism after cosmetic use of BoNT-A; we focused on the activation of motor control brain regions (such as sensorimotor and cerebellar areas), which plays an important role in BoNT-A treatment.\n\nHerein, we analyzed resting-state fMRI data to evaluate brain function in patients with botulism and controls by applying the regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) analysis methods. The ReHo method tests for local correlations in blood oxygen level-dependent (BOLD) time series using Kendall’s coefficient of concordance (KCC) to measure regional synchronizations of temporal changes in BOLD activity [24]. ALFF changes in signals are thought to be associated with local neuronal activity, and ALFF analysis is effective at detecting fluctuations in spontaneous low-frequency oscillations. In this study, we detected changes in spontaneous brain activity by comparing ALFF and ReHo values between botulism patients and healthy controls.\n\nMaterials and methods\nThe study was approved by the Independent Ethics Committee of Shanghai Ninth People’s Hospital (No. 2016-44-T1). All patients and healthy controls provided written informed consent using forms approved by the committee. All the investigations were conducted according to principles expressed in the Declaration of Helsinki.\n\nSubjects\nNine female patients with BoNT-A poisoning (botulism) were recruited from the Department of Neurology at Shanghai Ninth People’s Hospital of the Shanghai Jiao Tong University School of Medicine from October 2016 to December 2016. An attending neurologist diagnosed these patients as having botulism after cosmetic BoNT-A injection based on their medical history, clinical manifestations, and various supplementary examinations. Patient demographic and clinical data are shown in Table 1. The average age of the patients was 29.4±5.5 years, the average time from injection to onset of botulism symptoms was 5.4±4.1 days, the average time from onset to significant symptom relief was 35.6±11.2 days, the average time from onset to total recovery was 59.4±13.2 days, and the average time from fMRI scan to botulism onset was 39.4±14.6 days.\n\n10.1371/journal.pone.0207448.t001Table 1 Clinical data of patients with botulinum toxin type A poisoning.\nPatient ID\tAge\n(years)\tClinical manifestation\tInjection site\tBottles*\tTime from injection to symptom onset (days)\tTime from onset to significant symptom relief (days)\tTime from onset to total recovery (days)\tTime from injection to fMRI scan (days)\t\n1\t29\tDizziness, dysphagia, fatigue, and dyspnea\tBilateral gastrocnemius muscle\t1\t7\t28\t70\t57\t\n2\t43\tBlurred vision and diplopia\tForehead, bilateral ocular area\t2\t14\t30\t60\t64\t\n3\t33\tBlurred vision, diplopia, salivation, dysarthria, dysphagia, and dyspnea\tBilateral gastrocnemius muscle\t2\t3\t60\t90\t53\t\n4\t26\tDysphagia, tongue stiffness, and drooping eyelids\tBilateral gastrocnemius muscle\t3\t7\t30\t50\t37\t\n5\t25\tDiarrhea, blurred vision, numbness of limbs, and dyspnea\tBilateral gastrocnemius muscle\t3\t0.5\t30\t60\t37.5\t\n6\t31\tDizziness, dysphagia, blurred vision, diplopia, and photophobia\tForehead, bilateral ocular area\t2\t5\t30\t55\t21\t\n7\t28\tDizziness, chest tightness, fatigue, blurred vision, dysarthria and dysphagia\tBilateral masseter muscle\t3\t3\t45\t60\t46\t\n8\t25\tFatigue, weakness of the neck, dysphagia, blurred vision, and dry eyes\tBilateral gastrocnemius muscle\t2\t7\t30\t50\t23\t\n9\t28\tDizziness, fatigue, and drooping eyelids\tBilateral gastrocnemius muscle\t1\t3.5\t30\t50\t33.5\t\n* The number of bottles of botulinum toxin injected according to the patient’s recollection.\n\nAll patients had botulism following cosmetic injections with an unlicensed, highly concentrated botulinum preparation. The patients received the BoNT-A injections in beauty shops. Eight patients were from Shanghai city, and one was from Nanjing city. Six subjects received BoNT-A in the bilateral gastrocnemius muscle for lean legs, 2 subjects received BoNT-A in the bilateral ocular region for facial wrinkles, and one subject received BoNT-A in the bilateral masseter muscle for bilateral masseter hypertrophy treatment. The toxin was purchased through illegal channels (such as smuggling) without a license. The concentrations of unlicensed BoNT-A preparations can be 9 times higher than that normally used in the clinic according to one test report of a similar case from a local health inspection office. However, all patients had normal blood oxygen saturation levels. Although some subjects had dyspnea, their blood gas analysis results were within the normal range, even in the most severe stage. The patients underwent MRI exams after significant relief of all their symptoms (severe systemic muscle paralysis), and they had no dyspnea, anxiety, depressive symptoms, or other discomfort during the MRI scans. Patient details are provided in Table 1.\n\nThe healthy controls were recruited from the Shanghai population, and they were age- and gender-matched (1:2) to the botulism patients. Subjects who had experienced any neurological disorders or received a BoNT-A injection within the past five years were excluded. The healthy controls had a mean age of 29.4±5.5 years (same as the patient group). All subjects were right-handed and had no history of substance abuse. All neurological and psychiatric diseases were excluded based on a clinical examination and structured interviews.\n\nMRI acquisition\nFunctional and structural MRI data were acquired using a 3.0 Tesla Siemens Trio Tim system (Siemens Healthcare, Erlangen, Germany) with a 12-channel head coil. All subjects’ head movements were minimized with custom-fit foam pads. We obtained the whole-brain anatomical volume using a high-resolution, T1-weighted, 3-dimensional, magnetization-prepared, rapid-acquisition, gradient-echo pulse sequence. The parameters were as follows: repetition time = 2530 ms, echo time = 2.34 ms, inversion time = 1100 ms, flip angle = 7°, number of slices = 192, sagittal orientation, field of view = 256×256 mm2, matrix size = 256×256, and slice thickness = 1 mm, with a 50% gap. Resting-state fMRI images were acquired using a T2*-weighted, gradient-echo, echo-planar imaging pulse sequence with the following parameters: repetition time = 2000 ms, echo time = 30 ms, flip angle = 90°, number of slices = 33, transverse orientation, field of view = 220 × 220 mm2, matrix size = 64 × 64, slice thickness = 3.5 mm, 25% distance factor, with 210 volumes in total. During the fMRI scan, the subjects were instructed to relax, remain still and close their eyes.\n\nResting-state fMRI data preprocessing\nResting-state fMRI data preprocessing was conducted with statistical parametric mapping software (SPM12; http://www.fil.ion.ucl.ac.uk/spm/software/spm12) and MATLAB software (MathWorks, Natick, MA) on a personal computer. For each participant, the first 10 volumes were discarded to avoid scanner instability and to allow the participants to adapt to the scanner noise. The remaining volumes were corrected for the intravolume acquisition time delay using slice-timing correction and were realigned to the first volume using a six-parameter (rigid body) spatial transformation. After these corrections, we coregistered the high-resolution, T1-weighted image to the mean functional image. The T1 images were then segmented into gray matter, white matter and deformation field images. Next, the images were spatially normalized to the standard Montreal Neurological Institute (MNI) stereotaxic space and resampled to 3 × 3 × 3 mm3. Spurious signals, including the time series of six head motion parameters and signals from the white matter and cerebrospinal fluid, were regressed out using a general linear model, and linear trends were removed from the fMRI data. Finally, spatial smoothing was performed on the functional images using a Gaussian filter (6 mm full width at half-maximum, FWHM).\n\nThe head motion parameters of all participants were calculated in the translational and rotational directions (i.e., x, y, z, roll, pitch, and yaw). Participants were excluded if their maximum translation was > 2 mm or if their rotation was > 2° in any direction; no patients or controls exhibited excessive movement.\n\nData analysis\nReHo analysis\nWe used Data Processing and Analysis of Brain Imaging (DPABI) v2.0 to conduct ReHo analysis based on unsmoothed data [25]. A temporal bandpass filter (0.01 < f < 0.1 Hz) was applied to reduce the influences of low-frequency drift and high-frequency respiratory and cardiac noise.\n\nAn individual ReHo map was generated by calculating the concordance of the KCC of the time series of a given voxel with those of its 26 nearest neighbors [24]. To eliminate the effect of individual diversification, the ReHo value of each voxel was converted into a z-score by subtracting the mean ReHo value and dividing the standard deviation of the whole-brain ReHo map [26]. Finally, standardized ReHo maps were spatially smoothed with a 6-mm FWHM Gaussian kernel.\n\nALFF analysis\nALFF analysis was conducted on the basis of preprocessed data. For a given voxel, the time series was transformed to the frequency domain using fast Fourier transforms, and the square root of the power spectrum was calculated and averaged across 0.01–0.1 Hz. This averaged square root was referred to as the ALFF. Finally, the ALFF value of each voxel was converted into a standardized z-score by subtracting the mean ALFF value and dividing the standard deviation of the whole-brain ALFF map such that the maps could be compared across subjects [26, 27].\n\nStatistical analysis\nThe ReHo and ALFF maps for each group were obtained by one-sample t-tests within a brain mask. To assess the ReHo and ALFF differences across the groups, significant differences in the ReHo and ALFF maps of the 9 patients with botulism and 18 controls were compared using voxelwise two-sample t-tests within a brain mask. Clusterwise familywise error (FWE) corrections were applied to control for multiple comparisons of ReHo and ALFF maps, with a voxelwise uncorrected threshold of p < 0.001 and a clusterwise corrected threshold of p < 0.02 [28]. The surviving clusters were reported.\n\nResults\nDemographic and clinical data of botulism patients and healthy controls\nThe demographic and clinical data of the patients with botulism are presented in Table 1. Age was matched between the botulism patients and the controls (p = 1).\n\nReHo and ALFF\nThe ReHo and ALFF maps for the 9 botulism patients and 18 controls had similar distributions within groups as indicated by a one-sample t-test. The difference between groups was revealed by a two-sample t-test (Figs 1 and 2). Compared with the controls, the patients with botulism exhibited significantly decreased ReHo values in the left posterior lobe of the cerebellum extending to the right anterior lobe of the cerebellum, right anterior lobe of the cerebellum extending to the right parahippocampal gyrus and right posterior lobe of the cerebellum (Table 2 and Fig 1). Compared with the controls, the patients with botulism also showed decreased ALFF values in the right anterior lobe of the cerebellum extending to the left anterior lobe of the cerebellum and right posterior lobe of the cerebellum and right anterior lobe of the cerebellums (Table 2 and Fig 2).\n\n10.1371/journal.pone.0207448.g001Fig 1 Regional homogeneity (ReHo) maps showing significant differences between the botulism patients and the healthy controls.\nA) ReHo maps of each group were obtained using one-sample t-tests (p < 0.001 and FWE-corrected to p < 0.02 at the cluster level). The dots that the arrows point to correspond to the peak positions of the clusters for the differences between two-sample t-tests. B) When compared with the controls, the patients exhibited significantly decreased ReHo values in the cerebellum and parahippocampal gyrus and significantly increased ReHo values in the right anterior and middle cingulate gyri. The mean ReHo z-scores within significantly altered brain areas (cluster 1 and cluster 2 in Table 2) were extracted from each subject’s data.\n\n10.1371/journal.pone.0207448.g002Fig 2 Amplitude of low-frequency fluctuation (ALFF) maps showing significant differences between the botulism patients and the healthy controls.\na) ALFF maps of each group were obtained using one-sample t-tests (p < 0.001 and FWE-corrected to p < 0.02 at the cluster level). The dots that the arrows point to correspond to the peak positions of the clusters for the differences between two-sample t-tests. b) Compared with the controls, the patients exhibited significantly decreased ALFF values in the bilateral anterior lobe of the cerebellums. The mean ALFF z-scores within significantly altered brain areas (cluster 1 and cluster 2 in Table 2) were extracted from each subject’s data.\n\n10.1371/journal.pone.0207448.t002Table 2 Significant intergroup differences in ReHo and ALFF values between patients with BoNT-A poisoning and controls.\nCluster\nnumber\tPredominant regions in cluster\tCluster\nsize\tPeak t-value\tMNI coordinates\tCluster level\t\nx\ty\tz\tPFWE-corrected\t\nReHo reduction in patients with botulism\t\nCluster 1\tLeft posterior lobe of the cerebellum extending to the right anterior lobe of the cerebellum\t258\t-6.04\t-6\t-63\t-51\t<0.001\t\nCluster 2\tRight anterior lobe of the cerebellum extending to the right parahippocampal gyrus and right posterior lobe of the cerebellum\t345\t-5.29\t21\t-45\t-39\t<0.001\t\nALFF reduction in patients with botulism\t\nCluster 1\tRight anterior lobe of the cerebellum extending to left anterior lobe of the cerebellum and right posterior lobe of the cerebellum\t87\t-5.52\t6\t-48\t-33\t< 0.001\t\nCluster 2\tRight anterior lobe of the cerebellum\t36\t-5.16\t24\t-45\t-36\t= 0.011\t\nThe surviving clusters were assigned thresholds at p < 0.001 and FWE-corrected to p < 0.02 at the cluster level. ReHo: regional homogeneity; ALFF: amplitude of low-frequency fluctuation; BoNT-A: botulinum toxin type A.\n\nDiscussion\nIn this study, we evaluated alterations in spontaneous brain activity in patients with botulism using two different types of data-driven analyses, ReHo and ALFF. The results of the ReHo and ALFF analysis were consistent. In the patients with botulism, the ReHo and ALFF values in the cerebellar anterior and posterior lobes were decreased. In addition, the patients with botulism showed reduced ReHo values in the parahippocampal gyrus. Thus, central reorganization occurred following BoNT-A injection. The patients with botulism also showed abnormal fALFF (fractional amplitude of low-frequency fluctuation) values in the cerebellar anterior and posterior lobes and in the parahippocampal gyrus, and these findings were consistent with the ALFF and ReHo results. The details of the fALFF method and results are presented in the S1 Table.\n\nIn humans, the cerebellum is involved in processing sensorimotor, affective and cognitive information [29–31]. In addition, the anterior lobe of the cerebellum may be involved in sensorimotor function, and the posterior lobe of the cerebellum may be involved in cognitive/emotional function [29–31]. Cerebellar damage impairs both sensory and motor function [32] and produces disorders in fine movement, equilibrium, posture, and motor learning in humans [32]. The abnormal spontaneous brain activity in the cerebellum after BoNT-A injection in our study indicates that BoNT-A can modulate cerebellar (such as the anterior lobe) activity and affect both sensory and motor function. Functional MRI has been used to uncover modulation in the central reorganization associated with BoNT-A therapy for clinical conditions characterized by excessive muscle contraction. Using resting-state fMRI, Delnooz et al. revealed that BoNT-A treatment resulted in partial restoration of connectivity abnormalities in the sensorimotor and primary visual networks in cervical dystonia patients [33]. These findings suggest that BoNT-A directly acts on the peripheral local injection site as well as on the CNS and that BoNT-A treatment is derived from summated peripheral and central actions.\n\nIn this study, the patients with botulism showed abnormal activation in the cerebellum, consistent with previous clinical research. For example, cerebellar activation was altered after BoNT-A treatment for upper-limb spasticity [13, 16]. In one study, task fMRI was used to measure changes in cerebellar activation before and after upper-limb BoNT-A injection; cerebellar activation increased bilaterally during gripping with the paretic hand and during rest after the BoNT-A injection, suggesting that reducing spasticity with BoNT-A injection may increase cerebellar activation [16]. Veverka et al. investigated localized brain activation changes in stroke patients treated with BoNT-A for upper-limb spasticity using fMRI and found that BoNT-A transiently lowered modified Ashworth scale scores, and additional clusters transiently emerged bilaterally in the cerebellum, contralesional sensorimotor cortex, and contralesional occipital cortex at 4 weeks after BoNT-A injection [13]. Our results indicated that abnormal cerebellar activation may be involved in the adverse effects of BoNT-A poisoning. Conversely, our results showed that BoNT-A can modulate cerebellar (especially anterior lobe) activation, which may play an important role in the treatment of movement disorders.\n\nWe also found abnormal spontaneous brain activity in the parahippocampal gyrus after BoNT-A poisoning. How BoNT-A affects the parahippocampal gyrus remains unclear. In chronic stroke patients suffering from severe hand paralysis with arm spasticity, task-related fMRI prior to BoNT-A treatment showed extensive activation of the bilateral frontoparietal sensorimotor cortical areas, anterior cingulate gyrus, pallidum, thalamus and cerebellum [12]. The parahippocampal gyrus is part of the limbic area, and the limbic lobe and cerebellum are involved in emotion processing [29–31], which plays an important role in depression [34, 35]. Recently, published studies have shown a reduction in depressive symptoms after BoNT-A injection into the glabellar region [20, 21, 36, 37]. In our study, BoNT-A injection induced abnormal spontaneous brain activity in the cerebellum (especially the posterior lobe) and parahippocampal gyrus in patients with botulism, suggesting that BoNT-A could modulate the activity of these brain areas. These areas are involved in emotion processing and are associated with the pathophysiology of depression. Thus, further clinical studies in patients with depression are necessary to investigate the mechanism and efficacy of BoNT-A injections for the treatment of depressive disorders.\n\nThe fMRI scan was performed when the patients’ symptoms of muscle weakness had nearly disappeared; they participated in normal activities of daily living and did not have anxiety or depression because their symptoms had been significantly relieved and they knew that their symptoms were completely reversible. Therefore, we believe that mild residual muscle weakness would not have a significant impact on the fMRI results. Ultimately, we found that BoNT-A had an influence on spontaneous brain function in the subacute stage (21–64 days after injection of BoNT-A). It could be speculated that the brain function of patients would be more significantly affected in the earlier stage after injection of BoNT-A. Central effects of BoNT-A reported previously were obtained in patients with focal spasticity, and that kind of central effect could not be a direct effect of BoNT-A on the brain and must be secondary to the therapeutic effect on focal spasticity. However, we found a central effect of BoNT-A in previously healthy individuals, and our study supported the idea that BoNT-A could have a direct impact on brain function.\n\nOur research revealed abnormal spontaneous brain activity in patients with botulism who were previously healthy, but the study had several limitations. First, the sample size of patients with botulism was small, although patients come to our hospital (the largest plastic surgery medical center in China) from all over the country. Second, this study was not a strictly designed experiment, and there were individual differences among the subjects, such as the injection position and the time from injection to fMRI scanning. However, in our study, all patients with botulism were young and previously healthy when they unexpectedly received a high dose of BoNT-A; thus, these patients offered a unique opportunity to investigate the direct effects of BoNT-A on brain function in healthy individuals. Although we demonstrated that the botulism patients showed abnormal spontaneous brain activity in the CNS, the central mechanism underlying this result was unclear. Because this study was preliminary, the results need further pharmacological and clinical validation.\n\nConclusion\nIn this study, we determined that patients with botulism showed not only serious adverse effects on the peripheral neuromuscular junction but also abnormal spontaneous brain activity in the cerebellum and parahippocampal gyrus. Our results indicated that BoNT-A may directly modulate cerebral activation, which may be involved in both the adverse effects and the therapeutic mechanisms of BoNT-A. The findings have potential implications for the therapeutic use of botulinum toxin in complex indications in which clinical improvement cannot be explained by local muscle relaxation alone. This possibility especially applies to the emerging use of botulinum toxin in the treatment of mental disorders, such as depression.\n\nSupporting information\nS1 Checklist Strobe checklist.\n(DOCX)\n\nClick here for additional data file.\n\n S1 Table Significant inter-group differences in fALFF values between patients with BoNT-A poisoning and controls.\n(DOCX)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Orsini M , Leite MA , Chung TM , Bocca W , de Souza JA , de Souza OG , et al\nBotulinum Neurotoxin Type A in Neurology: Update . Neurology international . 2015 ;7 (2 ):5886 \n10.4081/ni.2015.5886 ; PubMed Central PMCID: PMC4591494.26487928 \n2 Monheit GD , Pickett A . AbobotulinumtoxinA: A 25-Year History . Aesthetic surgery journal . 2017 ;37 (suppl_1 ):S4 –S11 . 10.1093/asj/sjw284 ; PubMed Central PMCID: PMC5434488.28388718 \n3 Karmarkar R , Khullar V . Emerging drugs for overactive bladder . Expert opinion on emerging drugs . 2015 ;20 (4 ):613 –24 . 10.1517/14728214.2015.1086995 .26359223 \n4 Oh HM , Chung ME . Botulinum Toxin for Neuropathic Pain: A Review of the Literature . Toxins . 2015 ;7 (8 ):3127 –54 . 10.3390/toxins7083127 ; PubMed Central PMCID: PMC4549742.26287242 \n5 de Almeida AR , Montagner S . Botulinum toxin for axillary hyperhidrosis . Dermatologic clinics . 2014 ;32 (4 ):495 –504 . 10.1016/j.det.2014.06.013 .25152343 \n6 Petracca M , Guidubaldi A , Ricciardi L , Ialongo T , Del Grande A , Mulas D , et al\nBotulinum Toxin A and B in sialorrhea: Long-term data and literature overview . Toxicon: official journal of the International Society on Toxinology . 2015 ;107 (Pt A ):129 –40 . 10.1016/j.toxicon.2015.08.014 .26327120 \n7 Dressler D , Saberi FA , Barbosa ER . Botulinum toxin: mechanisms of action . Arquivos de neuro-psiquiatria . 2005 ;63 (1 ):180 –5 . doi: /S0004-282X2005000100035 .15830090 \n8 Rosales RL , Dressler D . On muscle spindles, dystonia and botulinum toxin . European journal of neurology . 2010 ;17 \nSuppl 1 :71 –80 . 10.1111/j.1468-1331.2010.03056.x .20590812 \n9 Curra A , Trompetto C , Abbruzzese G , Berardelli A . Central effects of botulinum toxin type A: evidence and supposition . Movement disorders: official journal of the Movement Disorder Society . 2004 ;19 \nSuppl 8 :S60-4. 10.1002/mds.20011 .15027056 \n10 Curra A , Berardelli A . Do the unintended actions of botulinum toxin at distant sites have clinical implications? \nNeurology . 2009 ;72 (12 ):1095 –9 . 10.1212/01.wnl.0000345010.98495.fc .19307544 \n11 Herreros J , Marti E , Ruiz-Montasell B , Casanova A , Niemann H , Blasi J . Localization of putative receptors for tetanus toxin and botulinum neurotoxin type A in rat central nervous system . The European journal of neuroscience . 1997 ;9 (12 ):2677 –86 . .9517473 \n12 Veverka T , Hlustik P , Tomasova Z , Hok P , Otruba P , Kral M , et al\nBoNT-A related changes of cortical activity in patients suffering from severe hand paralysis with arm spasticity following ischemic stroke . Journal of the neurological sciences . 2012 ;319 (1–2 ):89 –95 . 10.1016/j.jns.2012.05.008 .22687958 \n13 Veverka T , Hlustik P , Hok P , Otruba P , Zapletalova J , Tudos Z , et al\nSensorimotor modulation by botulinum toxin A in post-stroke arm spasticity: Passive hand movement . Journal of the neurological sciences . 2016 ;362 :14 –20 . 10.1016/j.jns.2015.12.049 .26944111 \n14 Senkarova Z , Hlustik P , Otruba P , Herzig R , Kanovsky P . Modulation of cortical activity in patients suffering from upper arm spasticity following stroke and treated with botulinum toxin A: an fMRI study . Journal of neuroimaging: official journal of the American Society of Neuroimaging . 2010 ;20 (1 ):9 –15 . 10.1111/j.1552-6569.2009.00375.x .19453837 \n15 Santamato A , Panza F , Filoni S , Ranieri M , Solfrizzi V , Frisardi V , et al\nEffect of botulinum toxin type A, motor imagery and motor observation on motor function of hemiparetic upper limb after stroke . Brain injury . 2010 ;24 (9 ):1108 –12 . 10.3109/02699052.2010.494591 .20569045 \n16 Chang CL , Weber DJ , Munin MC . Changes in Cerebellar Activation After Onabotulinumtoxin A Injections for Spasticity After Chronic Stroke: A Pilot Functional Magnetic Resonance Imaging Study . Archives of physical medicine and rehabilitation . 2015 ;96 (11 ):2007 –16 . 10.1016/j.apmr.2015.07.007 ; PubMed Central PMCID: PMC4628596.26239302 \n17 Yiannakopoulou E . Serious and long-term adverse events associated with the therapeutic and cosmetic use of botulinum toxin . Pharmacology . 2015 ;95 (1–2 ):65 –9 . 10.1159/000370245 .25613637 \n18 Phadke CP , Balasubramanian CK , Holz A , Davidson C , Ismail F , Boulias C . Adverse Clinical Effects of Botulinum Toxin Intramuscular Injections for Spasticity . The Canadian journal of neurological sciences Le journal canadien des sciences neurologiques . 2016 ;43 (2 ):298 –310 . 10.1017/cjn.2015.314 .26597813 \n19 Grigoriu AI , Dinomais M , Remy-Neris O , Brochard S . Impact of Injection-Guiding Techniques on the Effectiveness of Botulinum Toxin for the Treatment of Focal Spasticity and Dystonia: A Systematic Review . Archives of physical medicine and rehabilitation . 2015 ;96 (11 ):2067 –78 e1. 10.1016/j.apmr.2015.05.002 .25982240 \n20 Kruger TH , Wollmer MA . Depression—An emerging indication for botulinum toxin treatment . Toxicon: official journal of the International Society on Toxinology . 2015 ;107 (Pt A ):154 –7 . 10.1016/j.toxicon.2015.09.035 .26415901 \n21 Parsaik AK , Mascarenhas SS , Hashmi A , Prokop LJ , John V , Okusaga O , et al\nRole of Botulinum Toxin in Depression . Journal of psychiatric practice . 2016 ;22 (2 ):99 –110 . 10.1097/PRA.0000000000000136 .27138078 \n22 Matak I , Lackovic Z . Botulinum toxin A, brain and pain . Progress in neurobiology . 2014 ;119–120 :39 –59 . 10.1016/j.pneurobio.2014.06.001 .24915026 \n23 Sandrini G , De Icco R , Tassorelli C , Smania N , Tamburin S . Botulinum neurotoxin type A for the treatment of pain: not just in migraine and trigeminal neuralgia . The journal of headache and pain . 2017 ;18 (1 ):38 \n10.1186/s10194-017-0744-z ; PubMed Central PMCID: PMC5360746.28324318 \n24 Zang Y , Jiang T , Lu Y , He Y , Tian L . Regional homogeneity approach to fMRI data analysis . NeuroImage . 2004 ;22 (1 ):394 –400 . 10.1016/j.neuroimage.2003.12.030 .15110032 \n25 Yan CG , Wang XD , Zuo XN , Zang YF . DPABI: Data Processing & Analysis for (Resting-State) Brain Imaging . Neuroinformatics . 2016 ;14 (3 ):339 –51 . 10.1007/s12021-016-9299-4 .27075850 \n26 Yan CG , Craddock RC , Zuo XN , Zang YF , Milham MP . Standardizing the intrinsic brain: towards robust measurement of inter-individual variation in 1000 functional connectomes . NeuroImage . 2013 ;80 :246 –62 . 10.1016/j.neuroimage.2013.04.081 ; PubMed Central PMCID: PMC4074397.23631983 \n27 Chao-Gan Y , Yu-Feng Z . DPARSF: A MATLAB Toolbox for \"Pipeline\" Data Analysis of Resting-State fMRI . Frontiers in systems neuroscience . 2010 ;4 :13 \n10.3389/fnsys.2010.00013 ; PubMed Central PMCID: PMC2889691.20577591 \n28 Cremers HR , Wager TD , Yarkoni T . The relation between statistical power and inference in fMRI . PloS one . 2017 ;12 (11 ):e0184923 \n10.1371/journal.pone.0184923 ; PubMed Central PMCID: PMC5695788.29155843 \n29 Timmann D , Drepper J , Frings M , Maschke M , Richter S , Gerwig M , et al\nThe human cerebellum contributes to motor, emotional and cognitive associative learning . A review. Cortex . 2010 ;46 (7 ):845 –57 . Epub 2009/08/12. 10.1016/j.cortex.2009.06.009 .19665115 \n30 Stoodley CJ , Schmahmann JD . Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing . Cortex . 2010 ;46 (7 ):831 –44 . Epub 2010/02/16. 10.1016/j.cortex.2009.11.008 ; PubMed Central PMCID: PMC2873095.20152963 \n31 Stoodley CJ , Schmahmann JD . Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies . NeuroImage . 2009 ;44 (2 ):489 –501 . Epub 2008/10/07. 10.1016/j.neuroimage.2008.08.039 .18835452 \n32 Therrien AS , Bastian AJ . Cerebellar damage impairs internal predictions for sensory and motor function . Current opinion in neurobiology . 2015 ;33 :127 –33 . 10.1016/j.conb.2015.03.013 ; PubMed Central PMCID: PMC4786071.25863011 \n33 Delnooz CC , Pasman JW , Beckmann CF , van de Warrenburg BP . Task-free functional MRI in cervical dystonia reveals multi-network changes that partially normalize with botulinum toxin . PloS one . 2013 ;8 (5 ):e62877 \n10.1371/journal.pone.0062877 ; PubMed Central PMCID: PMC3641096.23650536 \n34 Fusar-Poli P , Placentino A , Carletti F , Landi P , Allen P , Surguladze S , et al\nFunctional atlas of emotional faces processing: a voxel-based meta-analysis of 105 functional magnetic resonance imaging studies . Journal of psychiatry & neuroscience: JPN . 2009 ;34 (6 ):418 –32 . ; PubMed Central PMCID: PMC2783433.19949718 \n35 Wessa M , Lois G . Brain Functional Effects of Psychopharmacological Treatment in Major Depression: a Focus on Neural Circuitry of Affective Processing . Current neuropharmacology . 2015 ;13 (4 ):466 –79 . 10.2174/1570159X13666150416224801 ; PubMed Central PMCID: PMC4790403.26412066 \n36 Hawlik AE , Freudenmann RW , Pinkhardt EH , Schonfeldt-Lecuona CJ , Gahr M . [Botulinum toxin for the treatment of major depressive disorder ]. Fortschritte der Neurologie-Psychiatrie . 2014 ;82 (2 ):93 –9 . 10.1055/s-0033-1356093 .24519192 \n37 Magid M , Reichenberg JS , Poth PE , Robertson HT , LaViolette AK , Kruger TH , et al\nTreatment of major depressive disorder using botulinum toxin A: a 24-week randomized, double-blind, placebo-controlled study . The Journal of clinical psychiatry . 2014 ;75 (8 ):837 –44 . 10.4088/JCP.13m08845 .24910934\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "13(11)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000328:Adult; D019274:Botulinum Toxins, Type A; D001906:Botulism; D003357:Cosmetic Techniques; D005260:Female; D005625:Frontal Lobe; D006801:Humans; D008279:Magnetic Resonance Imaging",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0207448",
"pmc": null,
"pmid": "30485326",
"pubdate": "2018",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "20590812;15830090;29155843;20152963;26327120;26287242;26359223;23650536;20577591;24519192;19949718;24915026;25152343;26597813;28388718;25982240;15027056;19307544;27138078;26415901;15110032;19453837;27075850;9517473;26944111;26239302;20569045;25613637;23631983;25863011;19665115;24910934;26487928;22687958;18835452;26412066;28324318",
"title": "Brain functional changes in patients with botulism after illegal cosmetic injections of botulinum toxin: A resting-state fMRI study.",
"title_normalized": "brain functional changes in patients with botulism after illegal cosmetic injections of botulinum toxin a resting state fmri study"
} | [
{
"companynumb": "CN-IPSEN BIOPHARMACEUTICALS, INC.-2018-19038",
"fulfillexpeditecriteria": "2",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BOTULINUM TOXIN TYPE A"
},
... |
{
"abstract": "Biliary disease is common in the older population, and gallbladder dysfunction and increased bile lithogenicity predispose to calculi formation. This case demonstrates an unusual presentation of gallbladder empyema. A 90-year-old male with metastatic prostate cancer presented with hypoactive delirium. With no localising features, normal liver function tests but persistently raised inflammatory markers, he was initially managed as a urinary tract infection. Chest wall discomfort and swelling over the right costal margin later developed. Abdominal imaging demonstrated a massive gallbladder empyema invaginating through the lower right rib cage, causing the superficial swelling. Pre-morbid status prevented cholecystectomy and he was managed conservatively with percutaneous cholecystostomy and antibiotics. He was discharged to 24-h care 2 weeks after diagnosis with a long-term drain.",
"affiliations": "Internal Medicine Trainees, Department of Geriatric Medicine, Doncaster Royal Infirmary, Doncaster DN2 5LT, UK.;Internal Medicine Trainees, Department of Geriatric Medicine, Doncaster Royal Infirmary, Doncaster DN2 5LT, UK.;Internal Medicine Trainees, Department of Geriatric Medicine, Doncaster Royal Infirmary, Doncaster DN2 5LT, UK.;Consultant in Geriatric Medicine, Department of Geriatric Medicine, Doncaster Royal Infirmary, Doncaster DN2 5LT, UK.",
"authors": "Hosty|Jennifer|J|;Narramore|Ruth|R|;Boothroyd|Matthew|M|;Ramanath|Rekha|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ageing/afab123",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-0729",
"issue": "50(5)",
"journal": "Age and ageing",
"keywords": "biliary; comorbidity; empyema; frailty; older people; sepsis",
"medline_ta": "Age Ageing",
"mesh_terms": "D000369:Aged, 80 and over; D002763:Cholecystectomy; D002767:Cholecystostomy; D004322:Drainage; D006801:Humans; D008297:Male",
"nlm_unique_id": "0375655",
"other_id": null,
"pages": "1859-1860",
"pmc": null,
"pmid": "34146392",
"pubdate": "2021-09-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diagnostic complexity in the older patient: an unusual presentation of advanced biliary disease.",
"title_normalized": "diagnostic complexity in the older patient an unusual presentation of advanced biliary disease"
} | [
{
"companynumb": "GB-BAUSCH-BL-2022-003856",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAA is an acquired dermatosis distributed universally, with multifactorial etiology. It affects the hair follicle with or without nail involvement, resulting in an acute nonscarring alopecia with a relapsing course.1 Being a relatively common skin disease, LPP (lichen planopilaris) is initiated by a chronic lymphocytic inflammation that selectively destructs the hair follicles and eventually leads to scarring alopecia. Also, even though there is enough literature available for the co-existence of AA and LPP with each other and their association with other autoimmune conditions, there are only very few reports on the anatomical concomitance of both disorders.3 AIMS: Although the incidence of not only one but two autoimmune diseases in an immunosuppressed individual is very unusual, we hereby report a case of co-localization of AA and LPP in a patient receiving immunosuppression due to a previous history of SLE (Systemic lupus erythematosus).\n\n\nMETHODS\nA 37-year-old woman, housewife, presented to our office with general alopecia on the scalp since about two years ago (Figure 1), particularly on the vertex which was accompanied by mild itching and trichodynia. She had a history of hypothyroidism and lupus erythematosus arthritis. She had been receiving long-term treatment with prednisolone, hydroxychloroquine, azathioprine, and levothyroxine but had not been treated for hair loss. Despite being on all of the above-mentioned immunosuppressants, the patient developed AA and LPP which are both immune-mediated diseases.\n\n\nRESULTS\nIn addition to continuing her oral immunosuppressants, the patient was treated with Minoxidil 5% and Clobetasol solution as well as a higher dose of Azathioprine than she was receiving beforehand. Approximately, 3 months into the treatment, the follicular hyperkeratosis and scalp erythema resolved. Also, hair growth could be seen on AA spots.\n\n\nCONCLUSIONS\nOur case report is indicating the possibly mutual immunopathogenesis of these two T cell-mediated disorders. Furthermore, we want to bring attention to the probability of new autoimmune diseases occurring even during treatment with immunosuppressive medications.",
"affiliations": "Department of Dermatology, Faculty of Medicine, Islamic Azad University of Medical Sciences, Sari, Iran.;Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran.;Student Research Committee, Islamic Azad University of Medical Sciences, Sari, Iran.;Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.",
"authors": "Mofarrah|Ramin|R|https://orcid.org/0000-0002-5145-792X;Mofarrah|Ramina|R|;Jahani Amiri|Kousar|K|https://orcid.org/0000-0002-3723-2521;Ghasemi|Maryam|M|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": "10.1111/jocd.13600",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1473-2130",
"issue": "20(3)",
"journal": "Journal of cosmetic dermatology",
"keywords": "alopecia areata; co-localization; immunosuppressive treatment; lichen planopilaris",
"medline_ta": "J Cosmet Dermatol",
"mesh_terms": "D000328:Adult; D000505:Alopecia; D000506:Alopecia Areata; D005260:Female; D018859:Hair Follicle; D006801:Humans; D007166:Immunosuppressive Agents; D008010:Lichen Planus; D012535:Scalp",
"nlm_unique_id": "101130964",
"other_id": null,
"pages": "976-979",
"pmc": null,
"pmid": "33167077",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Co-localization of alopecia areata and lichen planopilaris in a patient receiving immunosuppressants: A rare case.",
"title_normalized": "co localization of alopecia areata and lichen planopilaris in a patient receiving immunosuppressants a rare case"
} | [
{
"companynumb": "IR-ALKEM LABORATORIES LIMITED-IR-ALKEM-2021-01379",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"dru... |
{
"abstract": "At present, little is known regarding Listeria monocytogenes-associated biliary tract infection, a rare form of listeriosis.In this article, we will study 12 culture-proven cases reported to the French National Reference Center for Listeria from 1996 to 2013 and review the 8 previously published cases.Twenty cases were studied: 17 cholecystitis, 2 cholangitis, and 1 biliary cyst infection. Half were men with a median age of 69 years (32-85). Comorbidities were present in 80%, including cirrhosis, rheumatoid arthritis, and diabetes. Five patients received immunosuppressive therapy, including corticosteroids and anti-tumor necrosis factor biotherapies. Half were afebrile. Blood cultures were positive in 60% (3/5). Gallbladder histological lesions were analyzed in 3 patients and evidenced acute, chronic, or necrotic exacerbation of chronic infection. Genoserogroup of the 12 available strains were IVb (n=6), IIb (n=5), and IIa (n=1). Their survival in the bile was not enhanced when compared with isolates from other listeriosis cases. Adverse outcome was reported in 33% (5/15): 3 deaths, 1 recurrence; 75% of the patients with adverse outcome received inadequate antimicrobial therapy (P=0.033).Biliary tract listeriosis is a severe infection associated with high mortality in patients not treated with appropriate therapy. This study provides medical relevance to in vitro and animal studies that had shown Listeria monocytogenes ability to survive in bile and induce overt biliary infections.",
"affiliations": "Institut Pasteur, Biology of Infection Unit (CC, CF, LT, ML); Institut Pasteur French National Reference Center and WHO Collaborating Center for Listeria (CC, BC, HBD, AL, ML); Inserm U1117 (CC, CF, LT, ML); Université Paris Descartes, Sorbonne Paris Cité, Centre d'Infectiologie Necker-Pasteur, Hôpital Necker-Enfants Malades, Institut Imagine (CC, ML); Service de Chirurgie viscérale, Centre Hospitalier Universitaire de Nantes (JP); Service de Chirurgie viscérale et digestive, Centre Hospitalier de Roubaix (DA, LG); Service d'Anatomopathologie et Cytologie, Centre Hospitalier Universitaire de Nantes (CB); Service d'Anatomopathologie et Cytologie, Centre Hospitalier de Roubaix (FC); and Service d'Anatomopathologie et Cytologie, Centre Hospitalier de Pau (VC).",
"authors": "Charlier|Caroline|C|;Fevre|Cindy|C|;Travier|Laetitia|L|;Cazenave|Benoît|B|;Bracq-Dieye|Hélène|H|;Podevin|Juliette|J|;Assomany|Daher|D|;Guilbert|Lydie|L|;Bossard|Céline|C|;Carpentier|Françoise|F|;Cales|Valérie|V|;Leclercq|Alexandre|A|;Lecuit|Marc|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D010406:Penicillins",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000000105",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2531943910.1097/MD.0000000000000105001054900ArticleObservational StudyListeria monocytogenes-Associated Biliary Tract Infections A Study of 12 Consecutive Cases and ReviewCharlier Caroline MD, PhDFevre Cindy PhDTravier Laetitia PhDCazenave Benoît MDBracq-Dieye Hélène Podevin Juliette MDAssomany Daher MDGuilbert Lydie MDBossard Céline MDCarpentier Françoise MDCales Valérie MDLeclercq Alexandre MScLecuit Marc MD, PhDFeghaly Rana El Institut Pasteur, Biology of Infection Unit (CC, CF, LT, ML); Institut Pasteur French National Reference Center and WHO Collaborating Center for Listeria (CC, BC, HBD, AL, ML); Inserm U1117 (CC, CF, LT, ML); Université Paris Descartes, Sorbonne Paris Cité, Centre d’Infectiologie Necker-Pasteur, Hôpital Necker-Enfants Malades, Institut Imagine (CC, ML); Service de Chirurgie viscérale, Centre Hospitalier Universitaire de Nantes (JP); Service de Chirurgie viscérale et digestive, Centre Hospitalier de Roubaix (DA, LG); Service d’Anatomopathologie et Cytologie, Centre Hospitalier Universitaire de Nantes (CB); Service d’Anatomopathologie et Cytologie, Centre Hospitalier de Roubaix (FC); and Service d’Anatomopathologie et Cytologie, Centre Hospitalier de Pau (VC).Correspondence: Caroline Charlier, Unité de Biologie des Infections, Institut Pasteur, 28 rue du Dr Roux, Paris 75015, France (e-mail: caroline.charlier@pasteur.fr).10 2014 10 10 2014 93 18 e1055 6 2014 7 8 2014 10 8 2014 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins2014This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nAt present, little is known regarding Listeria monocytogenes-associated biliary tract infection, a rare form of listeriosis.\n\nIn this article, we will study 12 culture-proven cases reported to the French National Reference Center for Listeria from 1996 to 2013 and review the 8 previously published cases.\n\nTwenty cases were studied: 17 cholecystitis, 2 cholangitis, and 1 biliary cyst infection. Half were men with a median age of 69 years (32–85). Comorbidities were present in 80%, including cirrhosis, rheumatoid arthritis, and diabetes. Five patients received immunosuppressive therapy, including corticosteroids and anti-tumor necrosis factor biotherapies. Half were afebrile. Blood cultures were positive in 60% (3/5). Gallbladder histological lesions were analyzed in 3 patients and evidenced acute, chronic, or necrotic exacerbation of chronic infection. Genoserogroup of the 12 available strains were IVb (n = 6), IIb (n = 5), and IIa (n = 1). Their survival in the bile was not enhanced when compared with isolates from other listeriosis cases. Adverse outcome was reported in 33% (5/15): 3 deaths, 1 recurrence; 75% of the patients with adverse outcome received inadequate antimicrobial therapy (P = 0.033).\n\nBiliary tract listeriosis is a severe infection associated with high mortality in patients not treated with appropriate therapy. This study provides medical relevance to in vitro and animal studies that had shown Listeria monocytogenes ability to survive in bile and induce overt biliary infections.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nA severe foodborne infection that mostly occurs in immune-compromised patients is Listeria monocytogenes (Lm) that is a facultative intracellular Gram-positive bacterium responsible for listeriosis. Three main forms are described: septicemia (S), central nervous system (CNS), and maternal–neonatal (MN) infections. Aside from these typical presentations, localized infections are also reported, mostly as a consequence of a subclinical bacterial systemic dissemination. They include endocarditis, osteoarticular, and cutaneous infections1–3 as well as biliary tract infections, which have only been reported as isolated case reports, although Lm is well known to colonize the gut and survive in the bile.4–6\n\nWe undertook a comprehensive retrospective survey over a 17-year period to review all the cases referred to the national surveillance system of listeriosis in France since it has been established. Twelve cases were identified and analyzed. In addition, the 8 previously published case reports were reviewed. This study reveals that among biliary tract infections, those associated with Lm tend to exhibit specific features, with a higher frequency of comorbidities, of concomitant bacteremia and of adverse outcome, which are reported in 80%, 60%, and 33% of cases, respectively.7\nLm-associated biliary tract infections should be considered in the occurrence of biliary tract infection in immunocompromised patients. Their diagnosis requires a clinical and microbiological workup, and treatment is based on a specific amoxicillin-based antibiotic regimen to which Lm is sensitive, and which is, otherwise, not recommended as a first-line therapy for biliary tract infections.\n\nPATIENTS AND METHODS\nData Collection\nSurveillance of human listeriosis in France is based on both mandatory reporting of cases to the Institut de Veille Sanitaire, France, since 1999 and voluntary submission of Lm strains to the National Reference Center for Listeria (NRCL).8 The exhaustiveness of this reporting is estimated above 87%.9 We studied all listeriosis cases declared between January 1999 and March 2013 with mention of “cholecystitis,” “cholangitis,” “liver,” or “bile duct.” In addition, all patients with similar clinical data and for whom isolates were sent to the NRCL between 1996 and 1999, before the mandatory reporting era, were also included. Clinicians and microbiologists were contacted, and medical charts were directly analyzed according to a preestablished checklist. An appropriate local ethical committee (Comité de Protection des Personnes Ile de France 8) considered the study as observational and hence exempted to the Institutional Review Board approval, according to the French legislation.\n\nReview of the Literature\nWe searched the PubMed database for reports published between January 1966 and June 2013, using the terms “Listeria,” “listeriosis,” “cholecystitis,” “cholangitis,” “liver,” and “bile” without language restriction.\n\nCase Definition\nA case was defined as a person from whom Lm was isolated from the biliary tract. Infections were classified as cholecystitis, cholangitis, or biliary tract cyst infection. Liver abscesses without bile tract infection were excluded. Diagnosis of concurrent septicemia was based on a positive blood culture.\n\nL monocytogenes Typing\nListeria isolates referred to the NRCL were identified with API Listeria (BioMérieux, Marcy l’Etoile, France), serotyped until January 2005,10 and then typed by multiplex polymerase chain reaction (PCR) genoserogrouping.11 PCR serogroups correspond to the 4 major serovars that cause human disease.11 Isolates were characterized by multilocus sequence typing (MLST) similar to the 745 other strains received in the NRCL, as previously described.12–14\n\nBile Resistance Assays\nForty-two isolates were tested: 10 from biliary tract infection referred to the NRCL, the EGD bile susceptible, the LO28 bile-resistant reference strains,6 and 30 clinical isolates randomly selected among those received by the NRCL in 2012 (10 for each form: S, CNS, and MN). All were grown to log phase in brain heart infusion (BHI) broth (Becton Dickinson, Le Pont de Claix, France) at 37°C overnight, and then were inoculated by a A400 Multipoint Inoculator (Denley, West Sursex, UK) yielding 104 cells per spot on pork bile agar plates containing BHI base medium and 0%–10%, 15%, 20%, 25%, and 30% pork bile (Sigma Chemical Co, St Louis, MO) (pH = 7). The plates were incubated at 37°C in anaerobic condition for 24 hours and the minimal inhibitory concentration (MIC) of bile, defined as the lowest concentration totally inhibiting the growth of spots, was determined for each isolate. Mann–Whitney test was used to compare MICs.\n\nIndirect Immunofluorescence Assay of InlA Surface Expression\nBacteria were grown overnight in liquid BHI at 37°C, rinsed, incubated with I4.4/L7.7 monoclonal antibodies against InlA (1:1000)15 for 1 hour, and then with a secondary goat anti-mouse Alexa Fluor 488 antibody (Life technologies, Carlfbad, CA) (1:500). Preparations were analyzed by epifluorescence microscopy (AxioObserver Z1 inverted microscope, Zeiss) and analyzed with the AxioVision software (Zeiss). Lm EGD that expresses surface InlA was used as positive control and Lm L028 that expresses a secreted truncated InlA was used as negative control. In case of absence of InlA surface expression, InlA truncation was confirmed by inlA sequencing.12\n\nBiofilm Assays\nForty-four isolates were tested: 12 bile tract infection isolates referred to the NRCL, the EGD, the LO28 Lm reference strains,6 and the 30 clinical isolates described above. Cultures were performed in BHI broth at 37°C upon shaking. Aliquot of BHI overnight liquid cultures (1:20) was added to fresh BHI medium. Exponential cultures were diluted in BHI medium, BHI with pork bile, at pH 5 and 7, to an optical density (OD600 nm) of 0.06 in 100 μL 96-well poly (vinyl chloride) microtiter plates (Falcon; Becton Dickinson Labware, Oxnard, CA). Biofilms were allowed to grow for 24 hours at 37°C. Unbound cells were removed by microplate inversion and tapping on absorbent paper. Microplates were washed in water and adherent cells were stained with crystal violet for 20 minutes. Excess stain was removed by 3 washes in water. Quantification of bound cells was performed by adding acetone–ethanol (20:80) and dissolved crystal violet was measured at OD595 nm. Each biomass was standardized relative to EGD reference strain, and Mann–Whitney test was used to compare each group.\n\nHistopathological Analyses\nEight-micrometer-thick sections of paraffin-embedded tissue specimens were stained with hematoxylin eosin. Lm was labeled by immunohistochemistry using a polyclonal rabbit antiserum that detects Lm serotype 4b (Listeria O V/VI antiserum Seiken kit; Denka Seiken Co, Tokyo, Japan) and a goat anti-rabbit antibody coupled to peroxidase (EnVision+, Dako, Glosturp, Denmark), followed by hematoxylin counterstaining. Images were captured on a AxioImager A2 microscope (Zeiss) equipped with an AxioCam ICc 1 digital camera (Zeiss) and the AxioVision 4.8 software (Zeiss).\n\nRESULTS\nClinical Cohort\nA retrospective analysis of all cases declared to the NRCL was performed as described in the “Patients and Methods” section. Among the 3231 human cases for which a clinical Lm strain was collected between January 1996 and March 2013, 12 involved patients with biliary tract infections (hereafter named the French cohort), representing 0.37% of the infections reported during the study period. They included 9 cholecystitis (75%), 2 cholangitis (17%), and 1 biliary cyst infection (8%) that is listed in Table 1 .16–22 Eight additional cases were identified in the literature; all were cholecystitis and are also listed in Table 1 . The patients from the French cohort and those previously reported were analyzed together to identify the main characteristics of Lm-associated biliary tract infections.\n\nTABLE 1 Characteristics of 20 Patients With Lm-Associated Biliary Tract Infections\n\nTABLE 1 (Continued) Characteristics of 20 Patients With Lm-Associated Biliary Tract Infections\n\nTABLE 1 (Continued) Characteristics of 20 Patients With Lm-Associated Biliary Tract Infections\n\nEpidemiology\nTen patients were men (50%) and their median age was 69 years (range 32–85). Comorbidities are detailed in Table 1 : 16 patients (80%) had 1 to 4 associated comorbidities (16/20), which included cirrhosis, hypertension, and rheumatoid arthritis (n = 4, each), diabetes (n = 3), aortic patch tube (n = 2), obesity, end-stage renal insufficiency, liver transplantation, chronic adrenal insufficiency, myocardial infarction, dementia, hypothyroidism, chronic obstructive pulmonary disease, chronic lymphoid leukemia, and breast cancer (n = 1, each). Five patients were receiving immunosuppressive drugs at the time of Lm-associated biliary tract infections, namely, corticosteroids (n = 4), infliximab plus methotrexate (2/17, 12%, one of them with additional ciclosporin), etanercept, tacrolimus, and fludarabin (n = 1, each). Cholecystolithiasis was reported in 88% of the patients with cholecystitis (14/16).\n\nClinical Features\nMedian time from first symptom to hospitalization was 2 days (range 0–60, n = 12) with all but 2 patients hospitalized within the first week of symptoms. Median duration of hospitalization was 11 days (range 1–96, n = 18). Fever was reported in 50% of the cases (10/20, range 38–40°C). Abdominal pain was reported in 88% of cases (15/17). Previous or concomitant diarrhea and vomiting were observed in 11% (2/18). Gastric ulcer was concomitantly diagnosed in 2 other patients (2/18, 11%). Jaundice was noted in only 1 case with cirrhosis (1/18, 6%). None of these cases arose in the context of neurolisteriosis or pregnancy-associated listeriosis.\n\nLaboratory Characteristics\nTransaminases blood levels ranged from <1N to 6N (n = 15), and median aspartate amino transferase and alanine amino transferase were 73 and 49 UI/mL, respectively. Total bilirubin blood level was normal in 93% of cases (13/14). Median leukocytosis was 8100/mm3 (range 4200–17,500, n = 17), with only 2 patients with leukocytosis above 12,000/mm3. Median lymphocyte count was 1221/mm3 (range 432–3690, n = 10), including 3 patients below 1000/mm3. Median hemoglobin blood level was 14 g/dL (n = 15), and median platelet count was 189,500/mm3 (n = 14) including 3 patients below 100,000/mm3. Median C-reactive protein blood level was 125 mg/L (range 11–300, n = 8).\n\nMicrobiological Features\nDiagnosis was confirmed by bile or gallbladder swab culture in all the cases. Lm was never suspected before culture results and was the only recovered pathogen in all cases. Blood cultures were performed in only 5/18 patients, 4 of them had temperature >38°C; they were positive in 3 (60%). Further microbiological analyses were performed on the 12 French isolates. Antimicrobial sensitivity was unremarkable when compared with a large panel of more than 4000 clinical strains.23\n\nGenoserogrouping\nFrench strains were collected from patients originating from various geographical origins, at various times (1996, 1997, 1998, twice in 1999, 2000, 2003, 2008, 2009, twice in 2010, and 2013). They belonged to 3 major genoserogroups: IVb (n = 6/12), IIb (n = 5/112), and IIa (n = 1/12), and matched the overall distribution of human clinical isolates in France during the same period (data not shown).\n\nMLST\nTh strains were identified as belonging to 9 distinct clonal complexes (CCs), without any CC associated with biliary tract strains (Figure 1).\n\nFIGURE 1 Multilocus sequence typing-based minimum spanning tree of 745 Listeria\nmonocytogenes isolates of lineages I and II. Each circle denotes a single type (ST) and the diameter reflects the number of isolates in that ST. Red sectors denote biliary-tract infections isolates; white sectors correspond to other isolates. Bold lines between circles correspond to links with a single allelic mismatch; plain lines correspond to those with 2 allelic mismatches. Links corresponding to more than 2 allelic mismatches are not represented, as several equally likely alternative links exist; therefore, the relative positions of clonal complexes (CCs) or single STs should not be taken as evidence of phylogenetic proximity. Values inside circles indicate the ST numbers of the central STs of numerically important CCs. Left panel represents lineage I whereas right panel represents lineage II. The arrow denotes 2 isolates from the same patient (Patient 2) who presented with a documented recurrence of infection. All data are available at http://www.pasteur.fr/mlst.\n\nInlA Surface Expression\nAmong the 12 strains of the French cohort, 1 exhibited a truncated form of InlA, confirmed by sequencing (data not shown).\n\nBile Survival Assays\nMICs were similar for Lm biliary tract isolates and from S and CNS (20%, P > 0.05) (Figure 2).\n\nFIGURE 2 Bile resistance in 10 French isolates and in 30 strains selected at random among isolates received in 2012 from the National Reference Center for Listeria from patients with septicemia (S), central nervous system (CNS), and maternal–neonatal (MN) infections. The minimal inhibitory concentration of bile for a strain was interpreted as the lowest concentration totally inhibiting the growth of spots. P values were determined as compared to S, CNS, and MN isolates (Mann–Whitney test). BTI = bile tract infections.\n\nBiofilm Assays\nNo difference in biofilm ability among strains was observed with or without pork bile at pH 7 reflecting the gallbladder conditions. In the presence of pork bile, at pH 5 reflecting duodenal conditions, bile tract isolates had significantly lower biofilm ability than those from S, CNS, and MN infections (P = 0.001) (Figure 3).\n\nFIGURE 3 Biofilm formation in 12 French isolates and in 30 strains selected at random among isolates received in 2012 from the National Reference Center for Listeria from patients with septicemia (S), central nervous system (CNS), and maternal–neonatal (MN) infections. P values were determined as compared to S, CNS, and MN isolates (Mann–Whitney test). BHI = brain heart infusion, BTI = bile tract infections.\n\nHistology\nGall bladder histopathology was analyzed and anti-Lm immunoenzymatic labeling was performed in 3 patients for whom gallbladder samples were available (Table 1 ). Cholecystitis with cholecystolithiasis was confirmed in all the cases (Figure 4). Patient 1 had acute cholecystitis with edematous congestive transmural inflammation (Figure 4A), polymorphonuclear cells infiltrate (Figure 4B), and focal mucosal ulceration. Patient 2 had necrotic exacerbation of chronic cholecystitis (Figure 4D), with necrosis of the mucosa and muscularis (Figure 4D and E), necrotic luminal tissue debris, and inflammatory fibrosis in the serosal coat. An aspect evocative of chronic cholecystitis was observed in Patient 3, with a diffuse mucosal-based infiltrate of mononucleate cells (Figure 4G and H). Such patterns of acute, chronic, and necrotic exacerbations of chronic infection mirror those reported in classical cholecystitises. The presence of Lm was confirmed in 3 cases (Figure 4C, F, and I). Bacteria were located in the gallbladder lumen, sometimes as aggregates (Figure 4C and I), or within tissue fragments in necrotic cholecystitis (Figure 4F).\n\nFIGURE 4 (A–C) Gallbladder sections from 3 patients with acute cholecystitis (Patient 1), (D–F) necrotic exacerbation of chronic cholecystitis (Patient 2), and (G–I) chronic cholecystitis (Patient 3). Lm was genoserotyped as IVb in the 3 cases. In acute cholecystitis, HE staining revealed edematous congestive transmural inflammation (A; arrow), polymorphonuclear cells infiltrate (B; arrow), and focal mucosal ulceration (B; arrowhead). Lm was seen in the lumen as aggregates and individual bacteria (C). In the necrotic exacerbation of chronic infection, necrosis involved the mucosa and the muscularis (D, E), with necrotic luminal tissue debris and inflammatory fibrosis in the serosal coat. Lm was located in the lumen and in necrotic tissues lining the lumen (F). In chronic cholecystitis, diffuse mucosal-based infiltrate of mononucleate cells was observed (G, H; arrow). Lm was observed inside the lumen (I). Scale bars: HE staining, 100 µm; IHC staining, 2 µm. HE = hematoxylin–eosin, IHC = immunohistochemistry, L = lumen, P = peritoneal cavity.\n\nTreatment and Outcome\nSurgical and medical treatments are detailed in Table 1 . All patients with cholecystitis underwent cholecystectomy, and all those with cholangitis or collection had drainage of infected bile. Sixty-five percent of patients (13/20) had penicillin-based regimens with various dosages and durations. Three of them received aminoglycosides. Inadequate therapy with cephalosporin (n = 2) or no antibiotic (n = 5) was reported in 35% (7/20). Five patients were lost for follow-up. Adverse outcome was reported in 33% (5/15), namely, 3 early deaths, 1 microbiologically proven recurrence (see case report and Table 1 ), and 1 concomitant cerebellous stroke unrelated to Lm (Table 1 ). Of the 4 patients who died or experienced microbiological failure, 3 (75%) did not receive any antibiotic (n = 1) or were treated by inappropriate cephalosporin-based regimens ineffective against Lm (n = 2). Inadequate treatment (ineffective or lack of thereof) was significantly associated with the occurrence of death or microbiological failure, defined as a microbiologically proven recurrence (P = 0.033, Fisher exact test).\n\nDISCUSSION\nHere, we have studied the detailed features of Lm-associated biliary tract infections in a cohort of 20 cases, that includes 12 new consecutive cases declared in France over the last 17 years and 8 previously published reports. Important conclusions can be drawn from this study. First, Lm-associated biliary tract infection is a genuine clinical entity. It mostly involves older patients with comorbidities and is associated with a much higher mortality rate than other biliary tract infections (15% vs 3%, P < 0.03).24 The nonprescription of amoxicillin/ampicillin or other effective antibiotics such as ampicillin/sulbactam, piperacillin/tazobactam, or carbapenems might be associated with poor outcome: death or recurrence of infection (P = 0.03). These conclusions have important implications for clinicians: the identification of Lm in a bile sample should lead to the swift prescription of amoxicillin/ampicillin, which should be maintained beyond the perioperative period, in contrast to current guidelines for the management of community-acquired biliary tract infections that recommend discontinuation of antibiotics within 24 hours after cholecystectomy in the absence of infection outside the gallbladder wall.25 Among the first-line drugs recommended in uncomplicated community-acquired cholecystitis, third-generation cephalosporins should not be used because of their intrinsic lack of activity, whereas carbapenems and piperacillin/tazobactam both display bactericidal activity toward Lm. Peroperative bacteriological sampling is not systematically recommended and the absence of fever reported in most cases does not lead to the prescription of blood cultures: this likely leads to an underestimation of the actual burden of biliary tract infections associated with Lm. The main limitation of the study is its retrospective nature, because of the rarity of the disease.\n\nLm is known to colonize the gut and Lm asymptomatic fecal carriage has been documented in 1% to 12% of healthy individuals.26–28 Bile exhibits antimicrobial activities, given its ability to interact with membrane lipids and damage bacterial membranes.29\nLm, as many other enteric pathogens, has evolved to survive in the bile and in the proximal region of the small intestine where bile is released.30 The occurrence of biliary tract infections associated with Lm is therefore not surprising. Indeed, all Lm strains express a bile salt hydrolase encoded by bsh that detoxifies bile by deconjugating glycine/taurine from bile salts.6\nLm is also able to accumulate solutes such as betaine and carnitine, thereby enhancing its resistance to stress conditions,31 and the osmolyte transporters OpuC, BetL, and Gbu involved in their uptake play a major role in Lm tolerance to the bile.4,5 An active bile exclusion system called BilE is also implicated in Lm survival in bile.5 All these systems are transcriptionally regulated by PrfA, Lm master virulence gene regulator, and are functionally active at the low pH of the proximal small intestine. Other genes and metabolic pathways implicated in amino acid synthesis, purine metabolism, and biotin uptake have been more recently identified in Lm and may be involved in resistance to bile stress in gallbladder neutral pH conditions.32\n\nConsistent with these in vitro data, Lm is able to colonize the gall bladder after both oral and intravenous challenge in a mouse model of infection.30 It can survive and multiply extracellularly in the mouse gallbladder lumen, be released via the biliary tract in the intestinal lumen, and induce overt cholecystitis.30,33,34 These experimental findings match those observed in the present cohort of patients with Lm-associated biliary tract infection (Figure 4) and are therefore relevant to the human situation. Indeed, as observed in the mouse, Lm was consistently found extracellularly in the gallbladder of the patients (Figure 4). Moreover, 1 of the clinical strains expresses a truncated and, therefore, nonfunctional form of InlA unable to mediate Lm internalization, further illustrating that Lm-associated biliary tract infection does not result from epithelial invasion, a finding that is also de facto observed in the mouse model of biliary tract infection, InlA being not functional in the mouse.30,35\n\nSurvival in bile in vivo and the ability to induce biliary tract infection is likely a general property of Lm for several reasons. First, the isolates responsible for Lm-associated biliary tract infection do not belong to specific clonal complexes but reflect the diversity of the strains isolated from patients with listeriosis. Second, biliary tract infection isolates do not have increased survival in bile-containing medium. They do not either exhibit enhanced biofilm-producing ability, including in a bile-rich environment.\n\nThe ability of Lm to survive in bile has several clinical consequences. First, asymptomatic Lm bile colonization could be nonpathogenic per se, but serve as a reservoir reinoculating the proximal small intestine where Lm crosses the intestinal barrier.36,37 It could also constitute the reservoir that feeds long-term fecal shedding, reported in up to 12% of patients. This would facilitate dissemination and have major public health implications, as described for Salmonella enterica serovar Typhi.38 Although not formally demonstrated in humans, this sequence of events has been observed in mice, where bioluminescence studies have shown the release of viable Lm in the bile during gallbladder contractions and their expulsion in the digestive tract. From the gut, they could reinfect the host and disseminate into the environment.39 Finally, obstructing lithiasis in the context of preexisting Lm bile colonization is the most probable trigger of overt Lm cholangitis/cholecystitis, as described in other typical biliary tract infections.7\n\nThe lower positivity rate of blood cultures compared with the bile cultures mirrored previously published data on bile tract infections.40\n\nMicrobiological examination of the bile/gallbladder and blood cultures are far from being routinely performed in cholecystectomized patient with cholecystitis, and Lm-associated biliary tract infection, although certainly rare, therefore likely remains largely undetected in the clinical practice. Furthermore, piperacillin/tazobactam is routinely used in the United States to treat patients with biliary infections and may explain the rare isolation of Listeria. In a review compiling 211 cases of cholecystectomy (including 34 urgent and 177 elective surgeries), diphteroid-like rods compatible with Lm were evidenced in at least 3 cases,41 yet no further characterization was performed. As culture-based pathogens detection could be lowered by preoperative prophylaxis (http://www.sages.org/publication/id/06/), more recent studies using PCR tools have also been performed to identify pathogens involved in cholecystitis. Neither Lemos et al,42 in a Brazilian study involving 84 patients who had not receive preoperative antibioprophylaxis, nor Lee et al,43 in a Korean study performed on bile tract samples from 156 patients, evidenced any Lm.\n\nLm biliary tract infection should be considered as a genuine although rare cause of cholecystitis. In contrast, the occurrence of transient and asymptomatic Lm bile colonization could be frequent although this remains to be established in the context of prospective studies.\n\nIn conclusion, the results from this study validate in human the experimental data that had been obtained in the mouse and provide strong evidence that the presence of Lm in the bile should be taken into account by clinicians. Lm-associated biliary tract infection requires a specific treatment based on surgery and the prescription of amoxicillin. Lm survival in the bile and chronic colonization in the biliary tract is not only a cause of morbidity and mortality. The biliary tract also likely constitutes a reservoir that favors Lm long-term fecal carriage and transmission.\n\nAbbreviations: BHI = brain heart infusion, CNS = central nervous system, Lm = Listeria monocytogenes, MIC = minimal inhibitory concentration, MLST = multilocus sequence typing, MN = maternal–neonatal, NRCL = National Reference Center for Listeria, S = septicemia.\n\nCF and LT equally contributed in writing of this article.\n\nThis study received financial support form Institut Pasteur, Inserm, Fondation BNP Paribas, Ville de Paris, Fondation pour la Recherche Médicale and Institut de Veille Sanitaire.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n1 Allerberger F Wagner M \nListeriosis: a resurgent foodborne infection . Clin Microbiol Infect . 2010 ;16 :16 –23 .20002687 \n2 Godshall CE Suh G Lorber B \nCutaneous Listeriosis . J Clin Microbiol . 2013 ;51 :3591 –3597 .23966491 \n3 Charlier C Leclercq A Cazenave B \nListeria monocytogenes-associated joint and bone infections: a study of 43 consecutive cases . Clin Infect Dis . 2012 ;54 :240 –248 .22100574 \n4 Watson D Sleator RD Casey PG \nSpecific osmolyte transporters mediate bile tolerance in Listeria monocytogenes . Infect Immun . 2009 ;77 :4895 –4904 .19737907 \n5 Sleator RD Wemekamp-Kamphuis HH Gahan CG \nA PrfA-regulated bile exclusion system (BilE) is a novel virulence factor in Listeria monocytogenes . Mol Microbiol . 2005 ;55 :1183 –1195 .15686563 \n6 Dussurget O Cabanes D Dehoux P \nListeria monocytogenes bile salt hydrolase is a PrfA-regulated virulence factor involved in the intestinal and hepatic phases of listeriosis . Mol Microbiol . 2002 ;45 :1095 –1106 .12180927 \n7 Sarmiento RV \nEmphysematous cholecystitis: report of four cases and review of the literature . Arch Surg . 1966 ;93 :1009 –1014 .5954322 \n8 Goulet V Jacquet C Martin P \nSurveillance of human listeriosis in France, 2001-2003 . Euro Surveill . 2006 ;11 :79 –81 .16801697 \n9 Goulet V de Valk H Pierre O \nEffect of prevention measures on incidence of human listeriosis, France, 1987-1997 . Emerg Infect Dis . 2001 ;7 :983 –989 .11747725 \n10 Seeliger HPR Hohne K \nSerotyping of Listeria monocytogenes and related species . In: Bergan T Norris JR ed. Methods in Microbiology . New York : Academic Press ; 1979 :31 –48 .\n11 Doumith M Buchrieser C Glaser P \nDifferentiation of the major Listeria monocytogenes serovars by multiplex PCR . J Clin Microbiol . 2004 ;42 :3819 –3822 .15297538 \n12 Ragon M Wirth T Hollandt F \nA new perspective on Listeria monocytogenes evolution . PLoS Pathog . 2008 ;4 :e1000146 .18773117 \n13 Chenal-Francisque V Diancourt L Cantinelli T \nOptimized Multilocus variable-number tandem-repeat analysis assay and its complementarity with pulsed-field gel electrophoresis and multilocus sequence typing for Listeria monocytogenes clone identification and surveillance . J Clin Microbiol . 2013 ;51 :1868 –1880 .23576539 \n14 Chenal-Francisque V Lopez J Cantinelli T \nWorldwide distribution of major clones of Listeria monocytogenes . Emerg Infect Dis . 2011 ;17 :1110 –1112 .21749783 \n15 Mengaud J Lecuit M Lebrun M \nAntibodies to the leucine-rich repeat region of internalin block entry of Listeria monocytogenes into cells expressing E-cadherin . Infect Immun . 1996 ;64 :5430 –5433 .8945603 \n16 Medoff G Kunz LJ Weinberg AN \nListeriosis in humans: an evaluation . J Infect Dis . 1971 ;123 :247 –250 .5000073 \n17 Gordon S Singer C \nListeria monocytogenes cholecystitis . J Infect Dis . 1986 ;154 :918 –919 .3095439 \n18 Allerberger F Langer B Hirsch O \nListeria monocytogenes cholecystitis . Z Gastroenterol . 1989 ;27 :145 –147 .2497593 \n19 Gluck T Linde HJ Scholmerich J \nAnti-tumor necrosis factor therapy and Listeria monocytogenes infection: report of two cases . Arthritis Rheum . 2002 ;46 :2255 –2257 .12209538 \n20 Wagner M Allerberger F \nCharacterization of Listeria monocytogenes recovered from 41 cases of sporadic listeriosis in Austria by serotyping and pulsed-field gel electrophoresis . FEMS Immunol Med Microbiol . 2003 ;35 :227 –234 .12648841 \n21 Descy J De Mol P Hayette MP \nAcute cholecystitis with Listeria monocytogenes . Acta Clin Belg . 2012 ;67 :295 –297 .23019807 \n22 Bruminhent J Lynch TK Gefen J Santoro J \nListeria monocytogenes cholecystitis: a possible new syndrome . Am J Med Sci . 2013 ;345 :414 –417 .23221515 \n23 Morvan A Moubareck C Leclercq A \nAntimicrobial resistance of Listeria monocytogenes strains isolated from humans in France . Antimicrob Agents Chemoth . 2010 ;54 :2728 –2731 .\n24 Houghton PW Jenkinson LR Donaldson LA \nCholecystectomy in the elderly: a prospective study . Brit J Surg . 1985 ;72 :220 –222 .3978383 \n25 Solomkin JS Mazuski JE Bradley JS \nDiagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America . Clin Infect Dis . 2010 ;50 :133 –164 .20034345 \n26 Kampelmacher EH Huysinga WT van Noorle Jansen LM \nThe presence of Listeria monocytogenes in feces of pregnant women and neonates . Zentralbl Bakteriol Orig A . 1972 ;22 :258 –262 .4144801 \n27 Lamont RJ Postlethwaite R \nCarriage of Listeria monocytogenes and related species in pregnant and non-pregnant women in Aberdeen, Scotland . J Infect . 1986 ;13 :187 –193 .3093591 \n28 Grif K Patscheider G Dierich MP Allerberger F \nIncidence of fecal carriage of Listeria monocytogenes in three healthy volunteers: a one-year prospective stool survey . Eur J Clin Microbiol Infect Dis . 2003 ;22 :16 –20 .12582739 \n29 Begley M Gahan CG Hill C \nThe interaction between bacteria and bile . FEMS Microbiol Rev . 2005 ;29 :625 –651 .16102595 \n30 Hardy J Francis KP DeBoer M \nExtracellular replication of Listeria monocytogenes in the murine gall bladder . Science . 2004 ;303 :851 –853 .14764883 \n31 Sleator RD Hill C \nCompatible solutes: a listerial passe-partout ? Gut Microbes . 2010 ;1 :77 –79 .21326913 \n32 Dowd GC Joyce SA Hill C Gahan CG \nInvestigation of the mechanisms by which Listeria monocytogenes grows in porcine gallbladder bile . Infect Immun . 2011 ;79 :369 –379 .20937762 \n33 Briones V Blanco MM Marco A \nBiliary excretion as possible origin of Listeria monocytogenes in fecal carriers . Am J Vet Res . 1992 ;53 :191 –193 .1575382 \n34 Lopez S Prats N Marco AJ \nExpression of E-selectin, P-selectin, and intercellular adhesion molecule-1 during experimental murine listeriosis . Am J Pathol . 1999 ;155 :1391 –1397 .10514421 \n35 Lecuit M Dramsi S Gottardi C \nA single amino acid in E-cadherin responsible for host specificity towards the human pathogen Listeria monocytogenes . Embo J . 1999 ;18 :3956 –3963 .10406800 \n36 Lecuit M Vandormael-Pournin S Lefort J \nA transgenic model for listeriosis: role of internalin in crossing the intestinal barrier . Science . 2001 ;292 :1722 –1725 .11387478 \n37 Nikitas G Deschamps C Disson O \nTranscytosis of Listeria monocytogenes across the intestinal barrier upon specific targeting of goblet cell accessible E-cadherin . J Exp Med . 2011 ;208 :2263 –2277 .21967767 \n38 Lai CW Chan RC Cheng AF \nCommon bile duct stones: a cause of chronic salmonellosis . Am J Gastroenterol . 1992 ;87 :1198 –1199 .1519582 \n39 Hardy J Margolis JJ Contag CH \nInduced biliary excretion of Listeria monocytogenes . Infect Immun . 2006 ;74 :1819 –1827 .16495556 \n40 Kuo CH Changchien CS Chen JJ \nSeptic acute cholecystitis . Scand J Gastroenterol . 1995 ;30 :272 –275 .7770718 \n41 Truedson H Elmros T Holm S \nThe incidence of bacteria in gallbladder bile at acute and elective cholecystectomy . Acta Chir Scand . 1983 ;149 :307 –313 .6613468 \n42 Lemos R Franca PH Ferreira LE \nDetection of bacterial DNA in acute and chronic cholecystitis . Brit J Surg . 2010 ;97 :532 –536 .20169571 \n43 Lee JW Lee DH Lee JI \nIdentification of Helicobacter pylori in gallstone, bile, and other hepatobiliary tissues of patients with cholecystitis . Gut Liver . 2010 ;4 :60 –67 .20479914\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "93(18)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D015746:Abdominal Pain; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D001660:Biliary Tract Diseases; D002761:Cholangitis; D002763:Cholecystectomy; D002764:Cholecystitis; D041761:Cholecystolithiasis; D015897:Comorbidity; D003560:Cysts; D024881:Drug Resistance, Bacterial; D005260:Female; D005334:Fever; D005602:France; D005705:Gallbladder Diseases; D006801:Humans; D007166:Immunosuppressive Agents; D008089:Listeria monocytogenes; D008088:Listeriosis; D008297:Male; D008508:Medication Errors; D008875:Middle Aged; D009336:Necrosis; D010406:Penicillins; D011159:Population Surveillance; D012189:Retrospective Studies",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e105",
"pmc": null,
"pmid": "25319439",
"pubdate": "2014-10",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "20937762;12209538;1519582;16801697;14764883;16102595;4144801;20479914;15686563;3093591;3095439;21967767;20002687;11387478;18773117;8945603;10514421;23966491;19737907;21749783;12648841;16495556;11747725;7770718;12582739;20034345;20169571;20385859;12180927;2497593;10406800;1575382;5000073;22100574;15297538;21326913;23221515;23576539;6613468;5954322;3978383;23019807",
"title": "Listeria monocytogenes-associated biliary tract infections: a study of 12 consecutive cases and review.",
"title_normalized": "listeria monocytogenes associated biliary tract infections a study of 12 consecutive cases and review"
} | [
{
"companynumb": "FR-ROXANE LABORATORIES, INC.-2015-RO-01117RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugaddi... |
{
"abstract": "This case report describes the first survivor with chronic stroke who was treated with percutaneous, intramuscular neuromuscular electrical stimulation (NMES) for shoulder subluxation and pain. The patient developed shoulder subluxation and pain within 2 mo of his stroke. After discharge from acute inpatient rehabilitation, he developed shoulder and hand pain, which was treated with subacromial bursa steroid injection and ibuprofen with eventual resolution. The patient remained clinically stable until approximately 15 mo after his stroke-when he developed severe shoulder pain associated with shoulder abduction, external rotation, and downward traction. The patient could not tolerate transcutaneous NMES because of the pain of stimulation. At approximately 17 mo post-stroke, the patient's posterior deltoid, middle deltoid, and supraspinatus muscles were percutaneously implanted with intramuscular electrodes. After 6 wk of percutaneous, intramuscular NMES treatment, marked improvements in shoulder subluxation and pain, and modest improvements in activities of daily living and motor function were noted. One year after the onset of treatment, the patient remained pain free, but subluxation had recurred. However, the patient was able to volitionally reduce the subluxation by abducting his shoulder. The patient remained pain free for up to 40 mo after the initiation of percutaneous, intramuscular NMES treatment. This case report demonstrates the feasibility of using percutaneous, intramuscular NMES for treating shoulder subluxation and pain in hemiplegia.",
"affiliations": "Department of Physical Medicine and Rehabilitation, MetroHealth Medical Center, Cleveland, OH 44109, USA.",
"authors": "Chae|J|J|;Yu|D|D|;Walker|M|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/00002060-200104000-00014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0894-9115",
"issue": "80(4)",
"journal": "American journal of physical medicine & rehabilitation",
"keywords": null,
"medline_ta": "Am J Phys Med Rehabil",
"mesh_terms": "D004599:Electric Stimulation Therapy; D004567:Electrodes, Implanted; D006429:Hemiplegia; D006801:Humans; D008297:Male; D008875:Middle Aged; D012783:Shoulder Dislocation; D020069:Shoulder Pain; D004561:Transcutaneous Electric Nerve Stimulation; D016896:Treatment Outcome",
"nlm_unique_id": "8803677",
"other_id": null,
"pages": "296-301",
"pmc": null,
"pmid": "11277137",
"pubdate": "2001-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Percutaneous, intramuscular neuromuscular electrical stimulation for the treatment of shoulder subluxation and pain in chronic hemiplegia: a case report.",
"title_normalized": "percutaneous intramuscular neuromuscular electrical stimulation for the treatment of shoulder subluxation and pain in chronic hemiplegia a case report"
} | [
{
"companynumb": "US-RANBAXY-2014US-91501",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nAfter the onset of HAART, some HIV-infected individuals under treatment present a exacerbated inflammation in response to a latent or a previously treated opportunistic pathogen termed immune reconstitution inflammatory syndrome (IRIS). Few reports of tegumentary leishmaniasis have been described in association with IRIS. Moreover, the immunopathogenesis of IRIS in association with Leishmania is unclear.\n\n\nMETHODS\nThe present study reports on a 29-year-old HIV-infected individual who developed mucocutaneous leishmaniasis associated with immune reconstitution inflammatory syndrome (IRIS) five months following highly active antiretroviral therapy (HAART). Severe lesions resulted in the partial destruction of the nasal septum, with improvement observed 15 days after treatment with Amphotericin B and corticosteroids. The immune response of this patient was evaluated before and after the lesions healed. IRIS was diagnosed in association with high levels of TNF-α and IL-6. Decreased production of IFN-γ and a low IFN-γ/IL-10 ratio were also observed in response to Leishmania antigens. After receiving anti-leishmanial treatment, the individual's specific Th1 immune response was restored.\n\n\nCONCLUSIONS\nThe results suggest that the production of inflammatory cytokines by unstimulated T-lymphocytes could contribute to occurrence of leishmaniasis associated with IRIS.",
"affiliations": "Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia, Brazil. lualeandro1@hotmail.com.;Hospital Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Bahia, Brazil. rbadaro884@gmail.com.;Department of Medicine, University of California, San Diego, USA. rschooley@ucsd.edu.;Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia, Brazil. grassi@bahia.fiocruz.br.",
"authors": "Gois|Luana|L|;Badaró|Roberto|R|;Schooley|Robert|R|;Grassi|Maria Fernanda Rios|MF|",
"chemical_list": "D000953:Antigens, Protozoan",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-015-0774-6",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 2564533077410.1186/s12879-015-0774-6Case ReportImmune response to Leishmania antigens in an AIDS patient with mucocutaneous leishmaniasis as a manifestation of immune reconstitution inflammatory syndrome (IRIS): a case report Gois Luana lualeandro1@hotmail.com Badaró Roberto rbadaro884@gmail.com Schooley Robert rschooley@ucsd.edu Grassi Maria Fernanda Rios grassi@bahia.fiocruz.br Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia Brazil Hospital Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Bahia Brazil Department of Medicine, University of California, San Diego, USA 3 2 2015 3 2 2015 2015 15 3818 9 2014 20 1 2015 © Gois et al.; licensee BioMed Central. 2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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\nAfter the onset of HAART, some HIV-infected individuals under treatment present a exacerbated inflammation in response to a latent or a previously treated opportunistic pathogen termed immune reconstitution inflammatory syndrome (IRIS). Few reports of tegumentary leishmaniasis have been described in association with IRIS. Moreover, the immunopathogenesis of IRIS in association with Leishmania is unclear.\n\nCase presentation\nThe present study reports on a 29-year-old HIV-infected individual who developed mucocutaneous leishmaniasis associated with immune reconstitution inflammatory syndrome (IRIS) five months following highly active antiretroviral therapy (HAART). Severe lesions resulted in the partial destruction of the nasal septum, with improvement observed 15 days after treatment with Amphotericin B and corticosteroids. The immune response of this patient was evaluated before and after the lesions healed. IRIS was diagnosed in association with high levels of TNF-α and IL-6. Decreased production of IFN-γ and a low IFN-γ/IL-10 ratio were also observed in response to Leishmania antigens. After receiving anti-leishmanial treatment, the individual’s specific Th1 immune response was restored.\n\nConclusion\nThe results suggest that the production of inflammatory cytokines by unstimulated T-lymphocytes could contribute to occurrence of leishmaniasis associated with IRIS.\n\nKeywords\nHIVLeishmaniaIRISCytokinesImmune responseissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nHighly active antiretroviral therapy (HAART) has significantly benefited the majority of HIV-infected individuals. HAART results in a decrease in the plasma HIV-viral load and a partial recovery of CD4 + T-lymphocytes [1]. As a consequence, a sharp decrease is observed in morbidity and mortality rates [2]. However, some individuals under treatment experience clinical deterioration as a result of unregulated and rapid restoration of the immune response; i.e., the immune reconstitution inflammatory syndrome (IRIS). In these cases, an exacerbated inflammatory immune response against subclinical pathogens or residual antigens is observed [3].\n\nMost cases of IRIS are associated with the Mycobacterium avium complex, Mycobacterium tuberculosis, cytomegalovirus or herpes zoster [4,5]. Few cases of tegumentary leishmaniasis as a manifestation of IRIS in patients with AIDS have been reported to date [6-8]. Furthermore, the underlying immunological mechanisms of IRIS in association with this co-infection remain unclear. The present report describes a case of severe mucocutaneous leishmaniasis as a manifestation of IRIS in an HIV-infected patient from Brazil, and evaluates his cellular immune responses to Leishmania antigens.\n\nMaterials and methods\nA case of mucocutaneous leishmaniasis in association with IRIS in an HIV-infected individual was recorded in 2009 at the Professor Edgar Santos University Hospital (HUPES), located in Salvador, Bahia–Brazil. The HUPES Institutional Research Review Board approved the present case report and informed written consent was obtained from the patient. Blood samples for immunological assessments were collected prior to and immediately after (the following day) the course of Amphotericin B and corticosteroid treatment. Peripheral blood mononuclear cells (PBMCs) were isolated by passage over a Ficoll-Hypaque gradient (Amersham Biosciences, Piscataway, NJ, USA). PBMCs were labeled with 1.5 μM of carboxyfluorescein succinimidyl ester dye (CFSE, Molecular Probes, Eugene-OR) and cultured for five days in the presence of either 10 μg/mL of soluble Leishmania antigen (SLA),[9] 5 μg/mL of phytohaemagglutinin (PHA) or culture medium,.[10] Next, PBMCs were stained with CD4+ and CD8+ monoclonal antibodies conjugated with phycoerythrin (PE) and allophycocyanin (APC). Cell acquisition was performed using a FACSAria Flow-Cytometer (Becton Dickinson, CA, USA) and subsequently analyzed by Flowjo™ software (v7.6, Tree Star, Inc. 1997–2009). The cell division index (DI) was used to quantify the proliferation intensity of T-cell subsets (DI = 0.06 for CD4+ and 0.09 for CD8+ T-cells.) The frequencies of CD4+ and CD8+ T-cells producing intracellular cytokines were quantified using flow cytometry. PBMCs were cultured in the presence of SLA, PHA or culture medium for 18 h. Heat-inactivated human AB serum, brefeldin A and monensin were added to all cultures in the final four hours. Next, PBMCs were stained with anti-CD4-fluorescein isothiocyanate (FITC) and anti-CD8-APC, then permeabilized with PBS-BSA-Saponin 0.2% and incubated with anti-INF-γ-PE, anti-TNF-α-PE, and anti-IL-10-PE (Becton Dickinson, CA, USA). Plasma cytokine levels were quantified using the BD Cytometric Bead Array (CBA) Human Th1/Th2 Cytokine Kit II (San Jose, CA, USA).\n\nCase presentation\nThe patient, a 29-year-old HIV-1-infected male, reported being treated for pulmonary tuberculosis in 2006. In 2007, the patient’s serology for HIV tested positive. Eight months later, the patient reported an ulcerative lesion in his lower right limb, which was diagnosed as tegumentary leishmaniasis. He subsequently received pentavalent antimony therapy, resulting in the healing of this lesion. In December 2008, the patient began HAART therapy (zidovudine, lamivudine, and efavirenz). At this time, his CD4+ T-cell count was 160 cells/mm3 and viral load was 92,479 copies/mL. In May 2009, he presented with ulcerative lesions on his face in association with nasal obstruction. At this point, his CD4+ T-cell count was 516 cells/mm3 with an undetectable HIV viral load. The lesions subsequently progressed, resulting in severe inflammation characterized by a pronounced swelling of the lips, nasal and mentum regions. He was admitted to Hospital Professor Edgard Santos (HUPES) in August 2009 (Figure 1). The lesions were crusty in appearance and a partial destruction of the patient’s upper lip and nose was observed (Figure 2A and B). In addition, myiasis was observed in his necrotic lesions. Destruction of the nasal septum was confirmed by computerized tomography of the paranasal sinus cavities (Figure 2C).Figure 1 \nA time line of clinical manifestation of a patient with mucocutaneous leishmaniasis as a manifestation of immune reconstitution inflammatory syndrome.\n\n\nFigure 2 \nAn HIV-infected patient with mucocutaneous leishmaniasis as a manifestation of immune reconstitution inflammatory syndrome (IRIS). In May 2009, five months after the initiation of HAART therapy, he presented with ulcerative lesions on his face in association with nasal obstruction. A and B: By August 2009, the lesions progressed and severe inflammation with pronounced swelling of the lips, nasal and mentum regions are pictured. C: Computerized tomography of the paranasal sinus cavities shows partial destruction of the nasal septum (white arrow) (August, 2009). D: Healing of lesions observed following treatment with Prednisolone and Amphotericin B (September 2009).\n\n\n\nA skin biopsy revealed the presence of granulomatous lesions. Caseous necrosis was identified by a cervical lymph node biopsy. Amastigote forms of Leishmania spp. were found in both skin and lymph node biopsies. The skin test for Leishmania was positive (15 mm) and indirect ELISA for soluble L. brasiliensis antigens was positive, while ELISA for rK39 was negative. IgG anti-L. braziliensis levels were measured using indirect ELISA for soluble L. braziliensis antigens. The specie determination was further confirmed using a serial real-time quantitative PCR assay system, as described by Weirather, JL, 2011 [11].\n\nThe patient was then diagnosed with mucocutaneous leishmaniasis as a manifestation of IRIS and HAART was discontinued. He was subsequently treated with 80 mg/day of Prednisolone and 1 mg/Kg/day of Amphotericin B from August to September 2009. After 15 days of treatment, improvement in the mucocutaneous lesions and in the patient’s cervical lymphadenopathy was observed (Figure 2D). After two months of hospitalization, the lesions had completely healed and the patient was discharged. HAART therapy was subsequently reintroduced.\n\nImmune response to Leishmania antigens during and after IRIS\nPrior to treatment with Amphotericin B, the patient’s proliferative response to SLA was undetectable in both CD4+ and CD8+ T-cell subsets (Figure 3 – white bars). In the absence of SLA stimulus, the production of cytokines (IFN-γ, TNF-α and IL-10) by both CD4+ and CD8+ T-cells were similar under both conditions. In addition, IL-10 production was undetectable following SLA stimulation in the CD4+ T-cell subset (Figure 4A). Following leishmanial treatment, a proliferative response to SLA was observed in both CD4+ (DI: 0.3) and CD8+ T-cell subsets (DI: 0.2) (Figure 3 – black bars). In the absence of SLA stimulus, IFN-γ, TNF-α and IL-10 production by CD4+ T-cells was undetectable, and few CD8+ T-cells were observed producing these cytokines. By contrast, in response to SLA stimulation, a high proportion of CD4+ and CD8+ T-cells producing TNF-α and IL-10 was detected (Figure 4B). Production of IFN-γ was markedly higher in CD8+ cells in comparison with that of CD4+ T-cells. Plasmatic levels of INF-γ, TNF-α, IL-2 and IL-10 were higher at the conclusion of treatment with Amphotericin B, while IL-6 decreased, and the IFN-γ/IL-10 ratio rose from 0.0 to 3.6 over the course of treatment (Table 1).Figure 3 \nEvaluation of CD4+ and CD8+ T-lymphocyte proliferation in response to soluble\nLeishmania\nantigens (SLA) in a patient with mucocutaneous leishmaniasis as manifestation of IRIS. Blood samples were collected before (August 2009) and one day following the conclusion of Amphotericin B and corticosteroid treatment (September 2009). The cell division index was calculated using Flowjo™ software. White and black bars represent the T-cell proliferative responses to Leishmania antigens prior to and after Amphotericin B treatment, respectively. Dashes represent the threshold value with respect to a positive proliferative response (above 0.06 for CD4+ T-cell and above 0.09 CD8+ T-cell subset).\n\nFigure 4 \nProportion of CD4+ and CD8+ T-cells producing intracellular IFN-γ\n, TNF-α and IL-10 after culturing without stimulus, and in the presence of SLA. Blood samples were collected in August 2009 from a patient with mucocutaneous leishmaniasis as manifestation of IRIS before (A) and one day after the end (B) of Amphotericin B and corticosteroid treatment (September 2009).\n\nTable 1 \nCytokine levels in the plasma of a patient with mucocutaneous leishmaniasis as manifestation of IRIS, before and after Amphotericin B treatment\n\n\n\nCytokine\n\t\nAmphotericin B treatment\n\t\n\nBefore\n\t\nAfter\n\t\nIFN-γ\t0.0\t47.7\t\nTNF-α\t11.1\t17.8\t\nIL-10\t5.3\t13.3\t\nIL-2\t15.0\t22.5\t\nIL-4\t7.1\t8.2\t\nIL-6\t17.6\t10.6\t\nIFN-γ/IL-10 ratio\t0.0\t3.6\t\nData are presented in pg/mL. Cytokine levels were quantified before and one day after the end of Amphotericin B and corticosteroid treatment.\n\n\n\nDiscussion\nCutaneous leishmaniasis as a manifestation of IRIS may appearance, following the introduction of HAART and consequent restoration of immunity, as a new disease or as the progression of latent disease [12]. In the present report, the patient’s lesions developed five months after the initiation of antiretroviral therapy, concurrent with the recovery of the number of CD4+ T-cells.\n\nTo the best of our knowledge, only two other cases of patients infected with HIV and the clinical form of mucocutaneous leishmaniasis as a manifestation of IRIS have been described to date [6]. In both of these cases, disseminated skin lesions (on the arms, lower limbs and feet) and lesions in the nasal, oropharyngeal, as well as genital mucosa were reported. Although genital lesions have been reported in one-third of HIV/Leishmania co-infected patients [12,13], the patient described herein did not show genital involvement or widespread skin lesions. His lesions were restricted to the facial area, especially in the nasal and oropharyngeal mucosa, with intense inflammation resulting in destruction of the nasal septum.\n\nOur results suggest that the mucosal damage resulting from mucocutaneous leishmaniasis as a manifestation of IRIS in this patient was correlated with an unspecific inflammatory milieu. During the course of IRIS, CD4+ and CD8+ T-lymphocytes produced very low levels of IFN-γ and TNF-α in response to Leishmania antigens, yet high levels of IFN-γ by both CD4+ and CD8+ T-cells were observed in the absence of antigen stimulation. Conversely, after the lesions healed, a specific immune response to Leishmania antigens was reestablished and a profound reduction in the spontaneous production of cytokines was observed. The decreased T-cell proliferation and low antigen-induced cytokine responses observed in this patient during the course of IRIS could be more suggestive of immunosuppression to Leishmania antigens than a hyper-responsive state. However, the fact that the lesions appeared at the same time the patient’s immune system demonstrated recovery (the CD4+ T lymphocyte count was higher than 500 cells/mm3 and HIV viral load was undetectable) is supportive of an IRIS diagnosis. Moreover, the initial clinical presentation of mucosal leishmaniasis, which appeared five months after HAART initiation, progressed to an intense inflammatory response with partial destruction of the nasal septum in less than four months.\n\nDuring IRIS, the patient had a positive skin test for Leishmania, while his antigen-specific T-cell proliferation was undetectable. This discrepancy could be explained by the dynamic of immune restoration following HAART. The restoration of antigen-specific CD4+ T-cell responses in vitro is mostly correlated with CD4+ memory T-cell reconstitution; whereas the improvement of delayed type hypersensitivity is associated with the suppression of viraemia [14]. However, it was not possible to quantify antigen-specific central and effector memory CD4+ T-lymphocytes for this patient, during IRIS or after healing of lesions. In addition, an impairment of in vitro proliferative response to Leishmania antigens could be linked to the activation and exhaustion of immune system found during IRIS [15]. Yet, intrinsic differences among tests for measuring cellular immune function could explain these divergent results.\n\nIn the present case, the participation of a specific response to Leishmania antigens with respect to the development of skin and mucosal lesions cannot be excluded, since a Leishmania-specific response was not evaluated in situ. A specific recruitment of CD4+ and CD8+ T-cells to the ulcerative lesion is described in patients with both cutaneous and mucosal leishmaniasis [16,17]. Specifically, in the mucosal lesions it is observed high number of IFN-γ-producing cells [16]. Indeed, a decreased type-1 immune response to Leishmania antigens in peripheral blood is associated with intense recruitment of Leishmania-specific T-cells to the lesions, which is classically found in HIV-uninfected patients with disseminated leishmaniasis, yet cytokine production in tegumentary lesions was observed to be similar to that found in patients with mucocutaneous and cutaneous leishmaniasis [18]. Following healing, though CD4+ and CD8+ T-cells persist in treated lesions, the number of circulating antigen-specific CD4+ and CD8+ T-cells increases in peripheral blood [19,20]. Thus, in this patient the absence of proliferative response to Leishmania antigens during IRIS might be due to sequestration of T-cells inside lesions. After healing, these cells were redistributed to peripheral blood.\n\nThe elevated cytokine production observed in non-stimulated cells may be a consequence of activated memory CD4+ T-cells specific for pathogens other than Leishmania. These cells recirculate from lymphoid organs into the peripheral blood stream during the first two months of HAART [1,21]. Moreover, the chronic activation of the immune system by HIV itself may also contribute to the inflammatory state observed during the course of IRIS [22].\n\nHigh levels of IL-6 and TNF-α have been previously described in patients with other infectious diseases in association with IRIS [23-25]. Additionally, elevated pro-inflammatory cytokine production is considered to be a predictor of IRIS development in HIV-infected patients at the onset of HAART [26]. Considering the plasma levels of TNF-α in two HIV-uninfected patients with active mucocutaneous leishmaniasis evaluated at our laboratory (22 pg/mL and 13 pg/mL) [27], the levels observed in this patient during IRIS were similar. Following treatment with Amphotericin B and corticosteroids, an increase in plasmatic IFN-γ, as well as in the IFN-γ/IL-10 ratio, was observed in the present case, while TNF-α remained stable. Although treatment with corticosteroids usually decreases the production of inflammatory cytokines [28], a decrease in the spontaneous production of IFN-γ and TNF-α was observed in this patient only in vitro, but not in his plasma. This finding may be due to the fact that post-treatment cytokine quantification was performed in the plasma by a single measurement just one day following the conclusion of treatment. It is possible that subsequent measurements would have found decreases in TNF-α in the plasma.\n\nFurthermore, the nonspecific activation of the immune system could be a consequence of an impaired regulatory T-cell response or a decrease in the proportion of these cells, since IL-10 produced by Leishmania-specific CD4+ T-lymphocytes was not detected during the course of IRIS [8]. The proportion of regulatory T-cells (1.8%) in our patient prior to treatment was found to be low (data not shown). An imbalance between the effector and regulatory responses may also play a role in the pathogenesis of IRIS [29,30].\n\nIRIS is characterized by an intense inflammatory reaction, leading to tissue destruction concurrent with an increase in the number of CD4+ T-cells following HAART. No convincing evidence has been presented in regard to whether CD4+ T-cells specific to opportunistic pathogens are deregulated during IRIS, much less if these cells are involved in the pathogenesis of IRIS. Moreover, the literature contains no reports that directly link CD4+ T-cells specific to Leishmania antigens with clinical manifestations of leishmaniasis in association with IRIS. However, several reports have shown a recovery of CD4+ T-cells specific to Mycobacterium tuberculosis, Mycobacterium avium complex and Cryptococcal neoformans in patients who developed IRIS in association with these infections [18,29,31]. Interestingly, another study found no clear association between the recovery of M. tuberculosis-specific CD4+ T-cells and tuberculosis in association with IRIS [29].\n\nIt has been suggested that the absence of T-cells, such as occurs in the course of AIDS, may lead to the growth of intracellular pathogens inside macrophages that never become fully activated, and thus exert no effector function. When antigen-specific CD4+ T-cells are restored following HAART, these cells may intensely stimulate macrophages and possibly other innate immune cells that produce large amounts of proinflammatory cytokines, resulting in inflammation and tissue destruction [31].\n\nConclusion\nIn summary, the results presented herein suggest that Leishmania-associated IRIS occurred concurrently with the production of proinflammatory cytokines by unstimulated T-lymphocytes, which is supported by the absence of a specific host immune response against Leishmania antigens in the peripheral blood of this patient.\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 of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nLG carried out the immunoassays, performed the statistical analysis and prepared of manuscript. RB participated in the design of the study, carried out the case report and helped to draft the manuscript. RS participated in the design of the STUDY and of the revised the manuscript. MFRG conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgment\nSoluble Leishmania antigen (SLA) was kindly provided by Dr. Geraldo Gileno at the LPBI-(Laboratório de Patologia e Biointervenção) Fiocruz Bahia-Brazil. We would like thank Andris K. Walter for his assistance in English revision.\n\nFinancial support\nThis study was supported by the UCSD Center for AIDS Research, NIH grant P30AI036214.\n==== Refs\nReferences\n1. Autran B Carcelain G Li TS Blanc C Mathez D Tubiana R Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease Science 1997 277 5322 112 6 10.1126/science.277.5322.112 9204894 \n2. Palella FJ Jr Delaney KM Moorman AC Loveless MO Fuhrer J Satten GA Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators N Engl J Med 1998 338 13 853 60 10.1056/NEJM199803263381301 9516219 \n3. Murdoch DM Venter WD Van Rie A Feldman C Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options AIDS Res Ther 2007 4 9 10.1186/1742-6405-4-9 17488505 \n4. Shelburne SA 3rd Hamill RJ Rodriguez-Barradas MC Greenberg SB Atmar RL Musher DW Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy Medicine (Baltimore) 2002 81 3 213 27 10.1097/00005792-200205000-00005 11997718 \n5. French MA HIV/AIDS: immune reconstitution inflammatory syndrome: a reappraisal Clin Infect Dis 2009 48 1 101 7 10.1086/595006 19025493 \n6. Posada-Vergara MP Lindoso JA Tolezano JE Pereira-Chioccola VL Silva MV Goto H Tegumentary leishmaniasis as a manifestation of immune reconstitution inflammatory syndrome in 2 patients with AIDS J Infect Dis 2005 192 10 1819 22 10.1086/497338 16235183 \n7. Sinha S Fernandez G Kapila R Lambert WC Schwartz RA Diffuse cutaneous leishmaniasis associated with the immune reconstitution inflammatory syndrome Int J Dermatol 2008 47 12 1263 70 10.1111/j.1365-4632.2008.03804.x 19126013 \n8. Chrusciak-Talhari A Ribeiro-Rodrigues R Talhari C Silva RM Jr Ferreira LC Botileiro SF Tegumentary leishmaniasis as the cause of immune reconstitution inflammatory syndrome in a patient co-infected with human immunodeficiency virus and Leishmania guyanensis Am J Trop Med Hyg 2009 81 4 559 64 10.4269/ajtmh.2009.09-0077 19815866 \n9. Carvalho EM Johnson WD Barreto E Marsden PD Costa JL Reed S Cell mediated immunity in American cutaneous and mucosal leishmaniasis J Immunol 1985 135 6 4144 8 4067312 \n10. Lyons AB, Doherty KV: Flow cytometric analysis of cell division by dye dilution. Curr Protoc Cytom 2004, Chapter 9:Unit 9 11.\n11. Weirather JL Jeronimo SM Gautam S Sundar S Kang M Kurtz MA Serial quantitative PCR assay for detection, species discrimination, and quantification of Leishmania spp. in human samples J Clin Microbiol 2011 49 11 3892 904 10.1128/JCM.r00764-11 22042830 \n12. Goto H Lindoso JA Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis Expert Rev Anti Infect Ther 2010 8 4 419 33 10.1586/eri.10.19 20377337 \n13. Lindoso JA Barbosa RN Posada-Vergara MP Duarte MI Oyafuso LK Amato VS Unusual manifestations of tegumentary leishmaniasis in AIDS patients from the New World Br J Dermatol 2009 160 2 311 8 10.1111/j.1365-2133.2008.08908.x 19187345 \n14. Wendland T Furrer H Vernazza PL Frutig K Christen A Matter L HAART in HIV-infected patients: restoration of antigen-specific CD4 T-cell responses in vitro is correlated with CD4 memory T-cell reconstitution, whereas improvement in delayed type hypersensitivity is related to a decrease in viraemia AIDS 1999 13 14 1857 62 10.1097/00002030-199910010-00007 10513643 \n15. Nakanjako D Ssewanyana I Mayanja-Kizza H Kiragga A Colebunders R Manabe YC High T-cell immune activation and immune exhaustion among individuals with suboptimal CD4 recovery after 4 years of antiretroviral therapy in an African cohort BMC Infect Dis 2011 11 43 10.1186/1471-2334-11-43 21299909 \n16. Faria DR Gollob KJ Barbosa J Jr Schriefer A Machado PR Lessa H Decreased in situ expression of interleukin-10 receptor is correlated with the exacerbated inflammatory and cytotoxic responses observed in mucosal leishmaniasis Infect Immun 2005 73 12 7853 9 10.1128/IAI.73.12.7853-7859.2005 16299275 \n17. Santos Cda S Boaventura V Ribeiro Cardoso C Tavares N Lordelo MJ Noronha A CD8(+) granzyme B(+)-mediated tissue injury vs. CD4(+)IFNgamma(+)-mediated parasite killing in human cutaneous leishmaniasis J Invest Dermatol 2013 133 6 1533 40 10.1038/jid.2013.4 23321919 \n18. Machado PR Rosa ME Costa D Mignac M Silva JS Schriefer A Reappraisal of the immunopathogenesis of disseminated leishmaniasis: in situ and systemic immune response Trans R Soc Trop Med Hyg 2011 105 8 438 44 10.1016/j.trstmh.2011.05.002 21723576 \n19. Amato VS de Andrade HF Duarte MI Mucosal leishmaniasis: in situ characterization of the host inflammatory response, before and after treatment Acta Trop 2003 85 1 39 49 10.1016/S0001-706X(02)00260-7 12505182 \n20. Brelaz-de-Castro MC de Almeida AF de Oliveira AP de Assis-Souza M da Rocha LF Pereira VR Cellular immune response evaluation of cutaneous leishmaniasis patients cells stimulated with Leishmania (Viannia) braziliensis antigenic fractions before and after clinical cure Cell Immunol 2012 279 2 180 6 10.1016/j.cellimm.2012.11.006 23246680 \n21. Kelleher AD Carr A Zaunders J Cooper DA Alterations in the immune response of human immunodeficiency virus (HIV)-infected subjects treated with an HIV-specific protease inhibitor, ritonavir J Infect Dis 1996 173 2 321 9 10.1093/infdis/173.2.321 8568292 \n22. Pantaleo G Graziosi C Fauci AS New concepts in the immunopathogenesis of human immunodeficiency virus infection N Engl J Med 1993 328 5 327 35 10.1056/NEJM199302043280508 8093551 \n23. Stone SF Price P Keane NM Murray RJ French MA Levels of IL-6 and soluble IL-6 receptor are increased in HIV patients with a history of immune restoration disease after HAART HIV Med 2002 3 1 21 7 10.1046/j.1464-2662.2001.00096.x 12059947 \n24. Antonelli LR Mahnke Y Hodge JN Porter BO Barber DL DerSimonian R Elevated frequencies of highly activated CD4+ T cells in HIV+ patients developing immune reconstitution inflammatory syndrome Blood 2010 116 19 3818 27 10.1182/blood-2010-05-285080 20660788 \n25. Morlese JF Orkin CM Abbas R Burton C Qazi NA Nelson MR Plasma IL-6 as a marker of mycobacterial immune restoration disease in HIV-1 infection AIDS 2003 17 9 1411 3 10.1097/00002030-200306130-00025 12799572 \n26. Grant PM Komarow L Lederman MM Pahwa S Zolopa AR Andersen J Elevated interleukin 8 and T-helper 1 and T-helper 17 cytokine levels prior to antiretroviral therapy in participants who developed immune reconstitution inflammatory syndrome during ACTG A5164 J Infect Dis 2012 206 11 1715 23 10.1093/infdis/jis604 23002445 \n27. Rodrigues MZ Grassi MF Mehta S Zhang XQ Gois LL Schooley RT Th1/Th2 Cytokine Profile in Patients Coinfected with HIV and Leishmania in Brazil Clin Vaccine Immunol 2011 18 10 1765 9 10.1128/CVI.00076-11 21832098 \n28. Meintjes G Skolimowska KH Wilkinson KA Matthews K Tadokera R Conesa-Botella A Corticosteroid-modulated immune activation in the tuberculosis immune reconstitution inflammatory syndrome Am J Respir Crit Care Med 2012 186 4 369 77 10.1164/rccm.201201-0094OC 22700860 \n29. Meintjes G Wilkinson KA Rangaka MX Skolimowska K van Veen K Abrahams M Type 1 helper T cells and FoxP3-positive T cells in HIV-tuberculosis-associated immune reconstitution inflammatory syndrome Am J Respir Crit Care Med 2008 178 10 1083 9 10.1164/rccm.200806-858OC 18755923 \n30. Lim A D’Orsogna L Price P French MA Imbalanced effector and regulatory cytokine responses may underlie mycobacterial immune restoration disease AIDS Res Ther 2008 5 9 10.1186/1742-6405-5-9 18442415 \n31. Barber DL Andrade BB Sereti I Sher A Immune reconstitution inflammatory syndrome: the trouble with immunity when you had none Nat Rev Microbiol 2012 10 2 150 6 22230950\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "15()",
"journal": "BMC infectious diseases",
"keywords": null,
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D000953:Antigens, Protozoan; D023241:Antiretroviral Therapy, Highly Active; D003937:Diagnosis, Differential; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D007891:Leishmania; D007897:Leishmaniasis, Mucocutaneous; D008297:Male",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "38",
"pmc": null,
"pmid": "25645330",
"pubdate": "2015-02-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "19815866;4067312;17488505;18755923;16299275;9204894;12799572;8568292;11997718;9516219;20377337;23321919;8093551;19187345;18770808;18442415;22230950;12059947;20660788;16235183;21832098;23246680;22042830;19126013;23002445;21299909;10513643;22700860;19025493;21723576;12505182",
"title": "Immune response to Leishmania antigens in an AIDS patient with mucocutaneous leishmaniasis as a manifestation of immune reconstitution inflammatory syndrome (IRIS): a case report.",
"title_normalized": "immune response to leishmania antigens in an aids patient with mucocutaneous leishmaniasis as a manifestation of immune reconstitution inflammatory syndrome iris a case report"
} | [
{
"companynumb": "BR-GLAXOSMITHKLINE-BR2015GSK043089",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": nul... |
{
"abstract": "BACKGROUND\nLymphangioleiomyomatosis is a progressive interstitial lung disease that affects young women. It has been suggested that estrogens play a role in its evolution, and progesterone therapy is often provided in these cases.\n\n\nMETHODS\nWe present a case of a postmenopausal woman with LAM treated with progesterone; subsequently, rapid growth of multiple intracranial meningiomas was observed. One prominent lesion was excised, and 3 other lesions regressed spontaneously over 2 years.\n\n\nCONCLUSIONS\nThis is a rare case of a non-pregnancy-related regression of meningiomas in a woman affected by LAM. The significance of this association and the hormonal treatment of the disease are discussed.",
"affiliations": "Division of Neurosurgery and Service of Pathology, Bellaria Hospital and Respiratory Pathophysiology, S. Orsola Policlinic, Bologna 40100, Italy. Electronic address: eugenio.pozzati@ausl.bologna.it.;Division of Neurosurgery and Service of Pathology, Bellaria Hospital and Respiratory Pathophysiology, S. Orsola Policlinic, Bologna 40100, Italy.;Division of Neurosurgery and Service of Pathology, Bellaria Hospital and Respiratory Pathophysiology, S. Orsola Policlinic, Bologna 40100, Italy.;Division of Neurosurgery and Service of Pathology, Bellaria Hospital and Respiratory Pathophysiology, S. Orsola Policlinic, Bologna 40100, Italy.;Division of Neurosurgery and Service of Pathology, Bellaria Hospital and Respiratory Pathophysiology, S. Orsola Policlinic, Bologna 40100, Italy.",
"authors": "Pozzati|Eugenio|E|;Zucchelli|Mino|M|;Schiavina|Mario|M|;Contini|Paola|P|;Foschini|Maria Pia|MP|",
"chemical_list": "D011372:Progestins; D011374:Progesterone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.surneu.2006.11.063",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-3019",
"issue": "68(6)",
"journal": "Surgical neurology",
"keywords": null,
"medline_ta": "Surg Neurol",
"mesh_terms": "D000075202:Contraindications; D005260:Female; D006801:Humans; D018192:Lymphangioleiomyomatosis; D008279:Magnetic Resonance Imaging; D008577:Meningeal Neoplasms; D008579:Meningioma; D008875:Middle Aged; D011374:Progesterone; D011372:Progestins",
"nlm_unique_id": "0367070",
"other_id": null,
"pages": "671-674",
"pmc": null,
"pmid": "17586005",
"pubdate": "2007-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rapid growth and regression of intracranial meningiomas in lymphangioleiomyomatosis: case report.",
"title_normalized": "rapid growth and regression of intracranial meningiomas in lymphangioleiomyomatosis case report"
} | [
{
"companynumb": "IT-PFIZER INC-2017486844",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MEDROXYPROGESTERONE ACETATE"
},
"drugadditiona... |
{
"abstract": "BACKGROUND\nTreatment for metastatic castrate-resistant prostate cancer in community settings is not well understood.\n\n\nOBJECTIVE\nTo examine treatment patterns, sequencing, and outcomes in patients receiving second- and third-line treatment after first-line docetaxel.\n\n\nMETHODS\nWe used a community oncology database to identify patients who progressed after line 1 docetaxel (D) and received line 2 cabazitaxel (DC), abiraterone (DA), or other therapy (DO). Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan- Meier and Cox regression models. Line 3 included subsets DCA and DAC.\n\n\nRESULTS\nLine 2 groups (DC = 60 patients, DA = 71, DO = 153) did not differ significantly on demographic and clinical characteristics or median PFS on docetaxel therapy. Cox regression for OS by line 2 groups showed increased risk for DA compared with DC (HR, 1.69; P = .026) when 24 untreated DO patients were excluded. A similar nonsignificant pattern was observed when the 24 untreated patients were included. Of patients receiving DC in line 2, a nominally greater proportion received A in line 3 (57%, 34 of 60 patients) than did patients who received DA in line 2 followed by C in line 3 (25%, 18 of 71).\n\n\nCONCLUSIONS\nThere was a small sample for line 3, and unexamined confounds and selection biases in observational research. Conclusions Treatment patterns in community settings following docetaxel are complex and may involve multiple hormonal agents prior to disease progression. Cabazitaxel may not be optimally used in advanced disease. Although Cox regression showed increased risk of death for DA compared with DC, results need to be validated prospectively.\n\n\nCONCLUSIONS\nTreatment patterns in community settings following docetaxel are complex and may involve multiple hormonal agents prior to disease progression. Cabazitaxel may not be optimally used in advanced disease. Although Cox regression showed increased risk of death for DA compared with DC, results need to be validated prospectively.",
"affiliations": "ACORN Research LLC, Memphis, Tennessee, USA.;Sanofi US LLC, Bridgewater, New Jersey, USA.;ACORN Research LLC, Memphis, Tennessee, USA. mwalker@acorncro.com.;Sanofi US LLC, Bridgewater, New Jersey, USA.;Sanofi US LLC, Bridgewater, New Jersey, USA.;ACORN Research LLC, Memphis, Tennessee, USA.;The West Clinic, Memphis, Tennessee, USA.",
"authors": "Houts|Arthur C|AC|;Hennessy|Daniel|D|;Walker|Mark S|MS|;Nicacio|Leonardo|L|;Thompson|Stephen F|SF|;Miller|Paul Je|PJ|;Somer|Bradley G|BG|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12788/jcso.0072",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2330-7749",
"issue": "12(9)",
"journal": "The Journal of community and supportive oncology",
"keywords": null,
"medline_ta": "J Community Support Oncol",
"mesh_terms": null,
"nlm_unique_id": "101621609",
"other_id": null,
"pages": "321-8",
"pmc": null,
"pmid": "25848909",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment patterns and clinical effectiveness in metastatic castrate resistant prostate cancer after first-line docetaxel.",
"title_normalized": "treatment patterns and clinical effectiveness in metastatic castrate resistant prostate cancer after first line docetaxel"
} | [
{
"companynumb": "US-JNJFOC-20150412955",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ABIRATERONE ACETATE"
},
"drugadditional": null,
... |
{
"abstract": "Using calcium salts in management of amlodipine overdose is challenging. A 25-year-old male with known history of adult polycystic kidney disease presented with hypotension, tachycardia, and intact neurological status after ingestion of 450 mg of amlodipine. Immediately, normal saline infusion and norepinephrine were initiated. Two grams of calcium gluconate was injected, followed by intravenous infusion of 1.16 mg/kg/h. The patient was put on insulin-glucose protocol to maintain euglycemia and hyperinsulinemia. Electrocardiography demonstrated junctional rhythm. Serum creatinine was 2.5 mg/dL with metabolic acidosis. By the end of 24 h post-admission, his consciousness, blood pressure, and urine output were normal. Almost 32 h post-admission, he became disoriented and his oxygen saturation decreased and therefore was mechanically ventilated. Second chest X-ray showed pulmonary edema. Serum calcium level increased to 26.1 mg/dL. Calcium was discontinued, and furosemide infusion and calcitonin were intravenously administrated. Urine output increased and hemodialysis improved pulmonary edema and serum calcium level with no change in consciousness. Three days after admission, the patient became anuric and developed multi-organ failure and died 5 days post-admission. To avoid the consequences of excessive infusion of calcium in renal failure patients, the minimum calcium dose with close monitoring is recommended.",
"affiliations": "Department of Nephrology, Loghman Hakim Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Social Determinants of Health Research Center, Shahid Beheshti University of Medical Sciences, Koodakyar Ave., Daneshju Blvd., Velenjak, Tehran, 1985717443, Iran. hassanian@sbmu.ac.ir.;Social Determinants of Health Research Center, Shahid Beheshti University of Medical Sciences, Koodakyar Ave., Daneshju Blvd., Velenjak, Tehran, 1985717443, Iran.",
"authors": "Zahed|Narges-Sadat|NS|;Hassanian-Moghaddam|Hossein|H|0000-0003-4370-0544;Zamani|Nasim|N|",
"chemical_list": "D002121:Calcium Channel Blockers; D017311:Amlodipine; D002125:Calcium Gluconate",
"country": "United States",
"delete": false,
"doi": "10.1007/s12012-018-9445-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-7905",
"issue": "18(3)",
"journal": "Cardiovascular toxicology",
"keywords": "Amlodipine toxicity; Antidotes; Calcium channel blocker; High-dose calcium therapy; Renal failure",
"medline_ta": "Cardiovasc Toxicol",
"mesh_terms": "D000328:Adult; D017311:Amlodipine; D002121:Calcium Channel Blockers; D002125:Calcium Gluconate; D004562:Electrocardiography; D017809:Fatal Outcome; D006801:Humans; D006934:Hypercalcemia; D007022:Hypotension; D007049:Iatrogenic Disease; D007668:Kidney; D007676:Kidney Failure, Chronic; D008297:Male; D009102:Multiple Organ Failure; D012307:Risk Factors; D013405:Suicide; D013610:Tachycardia",
"nlm_unique_id": "101135818",
"other_id": null,
"pages": "290-293",
"pmc": null,
"pmid": "29383633",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Fatal Case of Amlodipine Toxicity Following Iatrogenic Hypercalcemia.",
"title_normalized": "a fatal case of amlodipine toxicity following iatrogenic hypercalcemia"
} | [
{
"companynumb": "IR-UNICHEM PHARMACEUTICALS (USA) INC-UCM201802-000029",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CALCIUM GLUCONATE"
},
... |
{
"abstract": "Cardiac lymphomas are rare extranodal lymphomas involving primarily and secondarily the heart and/or pericardium. Here we describe three cases of cardiac involvement from lymphoma with specific peculiarities: two primary cardiac Diffuse Large B-cell Lymphomas and one secondary involvement from Marginal Zone Lymphoma (MZL). The first case highlights the issue of early CNS relapse and the possible role for CNS prophylaxis; the second case demonstrates the difficulties of interpretation and possible mistakes of different radiologic techniques adopted to evaluate cardiac involvement by lymphoma during follow-up; the third is a unique case of MZL with cardiac involvement. Our aim is to share the findings observed in these cases putting them in relation with data from the literature.",
"affiliations": "S.C. Ematologia, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy.;S.C. Cardiologia, Dipartimento Cardiotoracovascolare, Centro per la Diagnosi e Cura delle Cardiomiopatie, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy.;S.C. Ematologia, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy.;S.C. Cardiologia, Dipartimento Cardiotoracovascolare, Centro per la Diagnosi e Cura delle Cardiomiopatie, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy.;S.C. Cardiologia, Dipartimento Cardiotoracovascolare, Centro per la Diagnosi e Cura delle Cardiomiopatie, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy.;S.C. Radiologia diagnostica ed Interventistica, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy.;S.C. Medicina Nucleare, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy.;S.C. (UCO) Anatomia ed Istologia Patologica, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy.;Dipartimento di Scienze Mediche e Chirurgiche e della Salute (DSM), Università degli Studi, Trieste, Italy.;S.C. Ematologia, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy.;S.C. Ematologia, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy.",
"authors": "Lucchini|Elisa|E|;Merlo|Marco|M|;Ballerini|Mario|M|;Porcari|Aldostefano|A|;Sinagra|Gianfranco|G|;Pagnan|Lorenzo|L|;Rensi|Marco|M|;Romano|Andrea|A|;Bussani|Rossana|R|;Ballotta|Laura|L|;Zaja|Francesco|F|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2021.665736",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.665736\nOncology\nCase Report\nCase Report: Cardiac Involvement by Lymphoma: Rare but Heterogeneous Condition With Challenging Behaviors\nLucchini Elisa 1\nMerlo Marco 2 3\nBallerini Mario 1\n\nPorcari Aldostefano 2\nSinagra Gianfranco 2 3\nPagnan Lorenzo 4\nRensi Marco 5\nRomano Andrea 6\nBussani Rossana 3 6\nBallotta Laura 1\nZaja Francesco 1 3 *\n\n1 S.C. Ematologia, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy\n2 S.C. Cardiologia, Dipartimento Cardiotoracovascolare, Centro per la Diagnosi e Cura delle Cardiomiopatie, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy\n3 Dipartimento di Scienze Mediche e Chirurgiche e della Salute (DSM), Università degli Studi, Trieste, Italy\n4 S.C. Radiologia diagnostica ed Interventistica, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy\n5 S.C. Medicina Nucleare, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy\n6 S.C. (UCO) Anatomia ed Istologia Patologica, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy\nEdited by: Luca Arcaini, University of Pavia, Italy\n\nReviewed by: Alessandro Broccoli, University of Bologna, Italy; Michele Merli, University of Insubria, Italy\n\n*Correspondence: Francesco Zaja, francesco.zaja@asugi.sanita.fvg.it\nThis article was submitted to Hematologic Malignancies, a section of the journal Frontiers in Oncology\n\n27 4 2021\n2021\n11 66573608 2 2021\n18 3 2021\nCopyright © 2021 Lucchini, Merlo, Ballerini, Porcari, Sinagra, Pagnan, Rensi, Romano, Bussani, Ballotta and Zaja\n2021\nLucchini, Merlo, Ballerini, Porcari, Sinagra, Pagnan, Rensi, Romano, Bussani, Ballotta and Zaja\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.\nCardiac lymphomas are rare extranodal lymphomas involving primarily and secondarily the heart and/or pericardium. Here we describe three cases of cardiac involvement from lymphoma with specific peculiarities: two primary cardiac Diffuse Large B-cell Lymphomas and one secondary involvement from Marginal Zone Lymphoma (MZL). The first case highlights the issue of early CNS relapse and the possible role for CNS prophylaxis; the second case demonstrates the difficulties of interpretation and possible mistakes of different radiologic techniques adopted to evaluate cardiac involvement by lymphoma during follow-up; the third is a unique case of MZL with cardiac involvement. Our aim is to share the findings observed in these cases putting them in relation with data from the literature.\n\nlymphoma\ndiffuse large B cell lymphoma\nmarginal zone lymphoma\nMRI\nPET/CT (18)F-FDG\ncentral nervous system relapse/progression\nheart involvement\nprimary cardiac lymphoma\n==== Body\nIntroduction\n\nPrimary cardiac lymphoma (PCL), an extranodal lymphoma involving only the heart and/or pericardium, is a rare entity, accounting for 2% of primary cardiac tumors and 0.5% of extranodal lymphomas (1). It is more frequent in males, with a median age around 63 years, even if it can occur at any age (2). PCL involves more frequently the right side of the heart, right atrium being the most frequently affected site, followed by right ventricle, left ventricle, left atrium, atrial septum and ventricular septum (3). Due to its peculiar location, PCL clinically manifests with cardiac symptoms, usually secondary to congestive heart failure (54-64%) (2). Chest pain and rhythm alterations are also common presenting symptoms (2, 4), the latter manifesting as atrial arrhythmias or atrioventricular block, less frequently left or right bundle branch block and ventricular arrhythmias; rarely, sudden death can be the initial presentation of PCL. Pericardial effusion is frequently found (up to 58% of patients) (2), which may be complicated with cardiac tamponade. Due to its aggressive histology, together with cardiac symptoms, constitutional and “B” symptoms can also be found (4).\n\nPCL is more often an aggressive lymphoma, diffuse large B cell lymphoma (DLBCL) being the most common histology (2–5); other histologies have been more rarely reported (6). Diagnosis of PCL requires histologic sample, which can be obtained by endomyocardial biopsy or even by surgical resection, when debulking is clinically needed (7). In selected cases, cytological examination of pericardial fluid may allow to omit a biopsy approach, if monoclonal lymphocytes are found by flow cytometry analysis. Echocardiography is in the majority of cases the first imaging evaluation, allowing a quick assessment of the local extent of the disease (3). Cardiac magnetic resonance imaging (MRI) is the gold standard imaging technique for cardiac masses, commonly hypointense on T1-weighted and hyperintense on T2-weighted sequences (8, 9). CT-scan and 18-FDG-PET/CT are useful to assess the extension of the disease, thus confirming the diagnosis of PCL. There are no guidelines for the management of PCL. Chemo-immunotherapy regimens used in aggressive B-cell lymphomas, such as R-CHOP or R-CHOP like regimens, are the standard first-line choices in DLBCL; chemotherapy regimens then vary according to the specific histology. PCL has historically been considered a poor prognosis lymphoma; a retrospective analysis more recently published found a trend in improved overall survival, with an estimated survival of 53% at 4-years in the 2013-2016 cohort, compared to 38.1% in the 2003-2006 group (10).\n\nDifferently from PCL, secondary cardiac involvement from lymphoma is a relatively frequent occurrence, reported in up to 25% of patients with nodal disease (11); the incidence is probably underestimated, due to a percentage of asymptomatic cases. Most frequently secondary cardiac involvement occurs in patients with DLBCL (2–5) while it is more rare in patients suffering from CLL/SLL, follicular lymphoma and T-cell lymphoma (12, 13) and extremely rare (14) in Hodgkin lymphoma. In secondary cardiac lymphoma (SCL) symptoms are non-specific, frequently attributed to other causes and concomitant conditions; therefore in a proportion of patients cardiac involvement is not even sought. Clinical presentation is similar to that of PCL, with symptoms attributable to heart failure or rhythm alterations in the majority of cases (5).\n\nDue to the rarity of this condition, several case reports and few reviews have been reported so far. Here we describe three cases of cardiac involvement from lymphoma that were observed at our institution in these last years. These cases show how heterogeneous can be the presentation and the clinical behavior of cardiac lymphoma and highlight some issues that clinicians may face in the management of this disease.\n\nCases Description Case Report 1\n\nA 72-years-old Caucasian man presented on March 2019 with worsening dyspnea. Physical examination showed mild bibasal reduction of vesicular murmur, slight jugular turgor, mild hepatomegaly, rhythmic cardiac activity, and normal blood pressure. Echocardiography revealed a mass in the right atrium. The total body CT scan confirmed the mass in the right atrium and superior vena cava, and showed conspicuous bibasal pleural effusion. A few days later the patient developed atrial fibrillation, which was cardioverted with amiodarone. Echocardiography showed a slight increase in pericardial effusion with signs of hemodynamic compromise. The patient underwent surgical debulking. Histology showed the presence of widespread proliferation of large-sized lymphocytes positive for CD20, CD5, CD10, Bcl-2, Bcl-6, PAX5, MUM1, high Ki67 (80%), consistent with DLBCL CD5 positive, GCB-type according to Hans algorithm. IPI score resulted low-intermediate (age, increased LDH).\n\nThe patient was then referred to our Department and started on chemoimmunotherapy according to the R- COMP scheme (Rituximab, Cyclophosphamide, non-pegylated Liposomal Doxorubicin, Vincristine, Prednisone) for six courses every 21 days, followed by two administrations of Rituximab alone. Liposomal Doxorubicin was chosen due its lower cardiac toxicity. The echocardiography performed after 4 courses of therapy showed normal size, kinetics and pump function of the left ventricle and normal atria. The CT-PET scan performed after the 6th R-COMP course showed a complete metabolic response.\n\nAt the check-up prior to the eighth Rituximab course, the patient reported pain and disorders of the visual acuity in the left eye. A brain MRI was consistent with central nervous system (CNS) lymphoma localization involving the lenticular nucleus, internal and external capsule of the left hemisphere and the left optic nerve. Lumbar puncture showed the presence of pathological monoclonal B-lymphocytes, which confirmed CNS relapse. Cardiac MRI revealed no elements of disease recurrence. The patient was then treated with a single course of dose-adapted Methotrexate, Cytarabine, Thiotepa, Rituximab (MATRIX chemotherapy) with poor tolerance and development of acute renal failure. For this reason the patient was treated with CNS radiotherapy followed by 5 cycles of temozolomide, dexamethasone and intra-thecal methylprednisolone, cytarabine, methotrexate achieving partial response. The patients died on April 2020 because of disease progression.\n\nCase Report 2\n\nA 56-years-old Chinese man was referred on December 2017 to our Center with a diagnosis of primary cardiac DLBCL, IPI score low (0), treated with 6 cycles R-CHOP in China from January to May 2017. A restaging CT-PET performed in October 2017 showed an abnormal 18-FDG uptake on the right ventricle (SUV 4.7) and absence of any other lymphoma localization; an echocardiography and a cardiac MRI revealed a mass of 3 x 5 cm infiltrating the anterior wall of the right ventricle. An endomyocardial biopsy was not performed because considered too risky. The patient was then started to second-line chemotherapy R-ICE (rituximab, etoposide, carboplatin, ifosfamide) and consolidation with autologous stem cell transplantation (ASCT; FEAM conditioning). Cardiac MRI performed before the ASCT showed only a slight reduction of the right ventricle thickening (11 mm vs 13 mm). Echocardiography performed shortly after ASCT showed the persistence of a hyperechoic mass infiltrating the anterior wall of the right ventricle (46x10 mm). The possibility of a myocardial biopsy to confirm the relapse was discussed with the cardiologists, but due to the risks related to the procedure, and the substantial asymptomaticity of the patient, he was kept under close observation. Three months after ASCT, a cardiac MRI was repeated, which resulted unchanged; a CT-PET was performed, showing abnormal 18-FDG uptake on right ventricle thickening (SUV 4.9 – Deauville score (DS) 4) – Figure 1A . Watch and wait approach was pursued, due to the stability of the radiological findings and the asymptomaticity of the patient. Cardiac MRIs performed on October 2018, June 2019 and November 2019 showed a substantial stability of the picture, with the persistence of the right ventricle anterior wall thickening – Figures 1D–F . The CT-PET performed in June 2019 confirmed the abnormal 18-FDG uptake on right ventricle thickening (SUV 5 – DS 4) – Figures 1B, C . Echocardiography showed substantial stability. The patient is now 2 years off-therapy, with both clinical and radiological stability, in clinical follow-up. The “watch and wait” strategy, although eventually correct, raised many concerns and fears in the patient, and generated anxiety related to the impossibility to ascertain the disease status.\n\nFigure 1 CT-PET abnormal 18-FDG uptake on right ventricle thickening 3 months (SUV 4.9, DS 4) (A) and 18 months (SUV 5 – DS 4) (B, C) after ASCT. Cardiac MRI images of June 2019 (from D to F) show the persistence of the right ventricle anterior wall thickening (14x56 mm). (D) Short tau inversion recovery (STIR) T2 black blood image in short axis on the cardiac base. (E) Steady-state free precession (SSFP) balance image with T2/T1 weighting in short axis on the cardiac base. (F) IR TSET1 image for evaluation of myocardial late enhancement in short axis on the cardiac base.\n\nCase Report 3\n\nA 70-years-old Caucasian man presented on May 2019 to the Cardiology department with new-onset, worsening dyspnea (NYHA II) and episodes of tachycardia with spontaneous resolution. Physical examination showed tachycardia (110 beats/min), mild hypotension (115/75 mmHg), systolic murmur grade 2/6; no clinical findings suggestive of heart failure, no lymphadenopathies nor organomegalies. The ECG showed sinus tachycardia, first degree atrioventricular block, left anterior hemiblock, minor right bundle branch block. Echocardiography revealed biventricular hypertrophy, mild bi-atrial dilatation, interventricular septum thickening (18 mm), mild pericardial effusion (18 mm), with normal kinetics and pump function (ejection fraction left ventricle 62%) - Figures 2A, C, E . Chest x-ray showed hilar enlargement, without pleural effusion. Blood tests showed mild normocytic anemia (Hemoglobin 128 g/L), normal platelet count, white blood cell count and differential, increased ESR (87 mm/h; ULN 35 mm/h), normal LDH, renal and liver function, BNP and Troponin I. An IgM/K paraprotein of 20 g/L was found on serum protein electrophoresis, with decreased IgG and IgA levels (5.4 g/L and 0.48 g/L respectively), and an altered serum free light chain ratio (serum free light chain kappa 411 mg/L, lambda 6.72, kappa/lambda ratio 61.21) – Figure 2G . Serologies for HBV and HCV were negative. In the suspicion of cardiac amyloidosis, a cardiac scintigraphy was performed, which resulted negative for cardiac transthyretin- related amyloidosis (score 1).\n\nFigure 2 Decrease in cardiac wall thickness after chemotherapy at echocardiographic evaluation (from A to F). (A, C) interventricular septum (IVS) and posterior wall (PW) thickness, 18 mm and 15 mm respectively, from parasternal long-axis and short-axis view, before chemotherapy. (B, D) IVS and PW thickness, 12 mm and 10 mm, respectively, from parasternal long-axis and short-axis view, after chemotherapy. (E, F) right ventricular lateral wall (RV-LW) thickness, 9 mm and 6 mm, respectively, from 4 chamber view; of note, pericardial effusion decreases from 18 mm to 6 mm after chemotherapy. (G) monoclonal IgM/K before starting treatment. (H) no more detectable monoclonal paraprotein after treatment. (I) histologic sample of endomyocardial biopsy, hematoxylin-eosin staining.\n\nThe patient was then referred to our Department; a bone marrow trephine showed a massive infiltration of small-sized lymphocytes positive for CD20 and Bcl-2, negative for CD5, CD23, CD138, CD10, Cyclin D1, SOX11, Ki67 was low (3-5%), consistent with infiltration from marginal zone lymphoma (MZL); Congo red- staining for amyloidosis was negative; the number of plasma cells was normal. For a strong suspicion of AL amyloidosis, abdominal fat pad and salivary glands biopsy were performed: both resulted negative for Congo red-staining. Cardiac MRI showed concentric hypertrophy of the left ventricle, without signs of cardiac amyloidosis or Fabry disease, and persistence of pericardial effusion (max 15 mm). Clinically the patient developed several episodes of atrial flutter/atrial fibrillation with rapid ventricular response, which required a biventricular pace-maker implantation. An endomyocardial biopsy showed massive cardiac infiltration by B-lymphocytes from MZL, with no signs of amyloidosis – Figure 2I . A total-body CT-scan showed mild supra and sub-diaphragmatic lymphadenopathies (max 29 mm); mild splenomegaly (16 cm). 18-FGD-PET didn’t show any increased uptake in lymphadenopathies nor in the myocardium. Immunophenotype on peripheral blood revealed a tiny population of clonal CD19+CD20+ kappa B cells (0.12% of total WBC). MALT IPI score was high (2: age, stage).\n\nThe patient was started on Bendamustine – Rituximab, for 6 courses every 28 days. After 4 courses of therapy the echocardiography displayed a substantial stability of the picture, with persistence of mild bi- atrial dilatation and pericardial effusion (max 10 mm). After six courses of therapy, bone marrow trephine was negative for lymphoma, and flow cytometry on bone marrow aspirate didn’t find clonal B cells. On serum protein electrophoresis the monoclonal paraprotein was not detectable – Figure 2H . CT-scan showed a radiologic complete response according to Lugano criteria. Echocardiography showed a reduction of interventricular septum thickness (12 mm), normal function of left ventricle (ejection fraction 72%), bi- atrial mild dilatation and reduction of pericardial effusion (6mm) - Figures 2B, D, F . Cardiac MRI was not performed due to the presence of pace-maker, which shields a significant part of the myocardium. Due to the clinical, laboratory and radiologic response and the negativity of bone marrow examination, and considering the risks associated with the procedure, endomyocardial biopsy was not repeated.\n\nDiscussion\n\nWe reported three cases of cardiac involvement from lymphoma: two PCL and a unique case of secondary cardiac involvement from MZL.\n\nDue to the rarity of this condition, isolated case reports and a few reviews have been published in literature so far, which include a population collected in a wide period of time and heterogeneously managed. Petrich et al (2) collected 197 cases of cardiac involvement from lymphoma (1949-2009), of which 68% met strict criteria for PCL. Median reported OS was 12 months. More recently, Chen et al. published a collection of cardiac lymphoma case reports from 2009 to 2019, including 101 PCLs (15). Voigt et al (4) collected 616 cases of cardiac hematological malignancies, including 558 patients with cardiac involvement from lymphoma, which was DLBCL in 77% of cases. Our two PCL confirm what previously reported: male predominance, onset with cardiac symptoms, involvement of the right chambers and DLBCL histology. Both patients were treated with first-line R-CHOP.\n\nCase report 1 points out the issue of CNS prophylaxis in patients with PCL. In patients with DLBCL, CNS-IPI (16) has been used to identify high-risk patients, however some disease characteristics, such as involvement of specific sites (e.g.: testicular, breast), remain a risk factor for CNS involvement and requires CNS prophylaxis. Our patient had a CNS-IPI score 2 (intermediate-risk: age > 60 years, increased LDH) before treatment and experienced CNS progression very shortly after the end of R-CHOP. We didn’t find any specific recommendation in literature on this topic and in the two large literature reviews previously reported no CNS progression was described (2, 4). A few case reports (17–21) described isolated parenchymal CNS relapse in patients with PCL: in most cases, similarly to what happened in our patient, relapsed occurred shortly after the completion of chemotherapy (within two months) in responders. Only one patient had received CNS prophylaxis with intermediate-dose (1.5 g/m2) methotrexate, administered every two weeks for four doses (20). A proportion of these patients responded to second-line therapy, but long-term follow-up is missing.\n\nBased on these previous experiences and literature reviews, it seems that CNS relapse in PCL is a rare but possible occurrence. Due to its particular solitary extranodal location, CNS-IPI is probably not the best tool to assess the risk of CNS involvement in PCL. According to our and previous experiences in literature, CNS evaluation at baseline and CNS prophylaxis with methotrexate should be considered early in DLBCL fit patients, concomitantly with R-CHOP or as a single agent after the first three or four R-CHOP courses; further studies, however, are needed in order to better clarify this issue.\n\nCase report 2 highlights the pitfalls of radiologic assessment during follow-up that, as it can be expected, generated profound anxiety and uncertainties in the patient and physicians. Indeed, multiple cardiac MRIs, 18-FDG-PET/CTs and echocardiography showed the persistence of cardiac involvement in the two years follow-up after ASCT, which contrasted with the wellbeing and clinical stability of the patient. Despite the radiological findings and considering the aggressive histology and the cardiac location, we are rather confident that the patient does not have an active disease, which would have become manifest meanwhile. The less reliable test, in this case, was 18-FDG-PET/CT, which continued to detect a pathological 18-FDG uptake, remaining positive according to Lugano criteria (Deauville score 4). Being aggressive lymphomas, PCLs are usually 18-FDG avid tumors (22), however, the utility of FDG-PET/CT alone in the diagnosis and follow-up of cardiac involvement is controversial, due to the physiological uptake of the heart and the low anatomic resolution of FDG-PET (3, 23).\n\nTo our knowledge case report 3 describes for the first time a secondary cardiac involvement by MZL. Gordon et al. (5) collected from literature 94 cases of cardiac non-Hodgkin lymphoma, including 43 patients with secondary cardiac involvement. Most of these patients were males (67%), in one third of cases aged > 60 years. The most common histologic subtype was DLBCL (42%), followed by T-cell lymphoma (33%),\n\nBurkitt lymphoma (9%), CLL/SLL and follicular lymphoma (4% each). No cases of secondary involvement of the heart by MZL were reported. MZLs are a group of indolent B-cell lymphomas that derive from memory B lymphocytes of marginal zone origin and comprise extranodal MZL of mucosa-associated lymphoid tissue (also known as MALT lymphoma), splenic MZL and nodal MZL. They can arise at any extranodal site, more frequently in the contest of chronic antigen stimulation (24). In our patient, the clinical picture was dominated by cardiac symptoms, in particular rhythm abnormalities, which led to further investigations. The first hypothesis to explain echocardiography and ECG results was cardiac amyloidosis, AL-type due to the presence of monoclonal paraprotein, however some findings did not match with this suspicion: BNP and troponin were negative, cardiac scintigraphy and cardiac MRI were not suggestive for cardiac amyloidosis and Congo red staining resulted negative in bone marrow, fat pad and salivary gland biopsies. Furthermore, AL amyloidosis secondary to lymphoma has been reported in 2-4% of cases (25), while no cases of cardiac amyloidosis secondary to MZL have been published so far. Once cardiac infiltration by lymphoma was found, the patient started chemo-immunotherapy with Bendamustine and Rituximab, as per our clinical practice for indolent lymphomas, and in order to avoid anthracycline-related cardiotoxic effects. A further issue that we experienced with this patient was the evaluation of the response at the end of treatment, since 18-FDG-PET, which was negative at baseline, resulted negative at restaging as well, cardiac-MRI was not reliable due to the pacemaker implant, and the only radiological test on which we could rely was the echocardiography. The only test which could provide a response would have been the EMB, but due to the risks associated with the procedure, we preferred to avoid it, considering that all the remaining parameters of activity of disease showed a response to therapy.\n\nThrough these experiences, we observed that sometimes the complicated medical management, especially in rare disease where guidelines are lacking, could impact the patient’s wellbeing.\n\nIn conclusion, primary or secondary cardiac lymphoma are a rare well described conditions that require careful inspection in patients with lymphoma and cardiologic signs or symptoms. Given the heterogenous pattern of presentation this condition often requires individualized management and a multidisciplinary approach.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Informed consent was obtained from the relevant individuals, and next of kin, for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nEL: her contribution was to design the project, collect the patients’ clinical history patients, review the literature, and write the paper. MM: his contribution was to outline and integrate the cardiological management of patients in the paper. MB: his contribution was to collect the patients’ clinical history and write the paper. AP: his contribution was to outline and integrate the cardiological management of patients in the paper. GS: his contribution was to outline and integrate the cardiological management of patients in the paper. LP: his contribution was to outline the radiological management of patients with particular reference to case report 2. MR: his contribution was to outline the nuclear medicine management of patients with particular reference to case report 2. AR: his contribution was to characterize histological samples with particular reference to case report 3. RB: her contribution was to characterize histological samples with particular reference to case report 3. LB: her contribution was to collect the patients’ clinical history and write the paper. FZ: he directed the project and also helped to design and write the paper. All authors contributed to the article and approved the submitted version.\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==== Refs\nReferences\n\n1 Burke A Tavora F . The 2015 WHO Classification of tumors of the heart and pericardium. J Thoracic Oncol (2016) 11 :441–52. 10.1016/j.jtho.2015.11.009\n2 Petrich A Cho SI Billett H . Primary cardiac lymphomaan analysis of presentation, treatment, and outcome patterns. Cancer (2011) 117 :581–9. 10.1002/cncr.25444\n3 Jeudy J Burke AP Frazier AA . Cardiac Lymphoma. Radiol Clinics North America (2016) 54 :689–710. 10.1016/j.rcl.2016.03.006\n4 Voigt P Wienbeck S Weber MA Oyama-Manabe N Beimler M Schob S . Cardiac Hematological Malignancies: Typical Growth Patterns, Imaging Features, and Clinical Outcome. Angiology (2017) 69 :170–6. 10.1177/0003319717713581\n5 Gordon MJ Danilova O Spurgeon S Danilov AV . Cardiac non-Hodgkin’s lymphoma: clinical characteristics and trends in survival. Eur J Haematol (2016) 97 :445–52. 10.1111/ejh.12751\n6 Patel J Melly L Sheppard MN . Primary cardiac lymphoma: B- and T-cell cases at a specialist UK centre. Ann Oncol (2009). 10.1093/annonc/mdp424\n7 Yin K Brydges H Lawrence KW Wei Y Karlson KJ McAneny DB . Primary cardiac lymphoma. J Thoracic an Cardiovasc Surg (2020) 7 S0022-5223(20)32706-09. 10.1016/j.jtcvs.2020.09.102\n8 Jeudy J Kirsch J Tavora F Burke AP Franks TJ Mohammed TL . From the radiologic pathology archives: Cardiac lymphoma: Radiologic-pathologic correlation. RadioGraphics (2012) 32 :1369–80. 10.1148/rg.325115126\n9 Araoz PA Eklund HE Welch TJ Breen JF . CT and MR imaging of primary cardiac malignancies. Radiographics (1999) 19 :1421–34. 10.1148/radiographics.19.6.g99no031421\n10 Sultan I Aranda-Michel E Habertheuer A Kilic A Arnaoutakis G Bianco V . Long-Term Outcomes of Primary Cardiac Lymphoma. Circulation (2020) 142 :2194–5. 10.1161/circulationaha.120.047215\n11 O’Mahony D Peikarz RL Bandettini WP Arai AE Wilson WH Bates S . Cardiac involvement with lymphoma: A review of the literature. Clin Lymphoma Myeloma (2008) 8 :249–52. 10.3816/CLM.2008.n.034\n12 Müller AMS Ihorst G Mertelsmann R Engelhardt M . Epidemiology of non-Hodgkin’s lymphoma (NHL): trends, geographic distribution, and etiology. Ann Hematol (2005) 84 :1–12. 10.1007/s00277-004-0939-7 15480663\n13 Groves FD Linet MS Travis LB Devesa SS . Cancer surveillance series: Non-Hodgkin’s lymphoma incidence by histologic subtype in the United States from 1978 through 1995. J Natl Cancer Institute (2000) 92 :1240–51. 10.1093/jnci/92.15.1240\n14 McDonnell PJ Mann RB Bulkley BH . Involvement of the heart by malignant lymphoma: A clinicopathologic study. Cancer (1982) 49 :944–51. 10.1002/1097-0142(19820301)49:5<944::AID-CNCR2820490519>3.0.CO;2-C\n15 Chen H Qian S Shi P Liu L Yang F . A presentation, treatment, and survival analysis of primary cardiac lymphoma cases reported from 2009 to 2019. Internal J Hematol (2020) 112 (1 ):65–73. 10.1007/s12185-020-02881-2\n16 Schmitz N Zeynalova S Nickelsen M Kansara R Villa D Sehn LH . CNS International Prognostic Index: A risk model for CNS relapse in patients with diffuse large B-Cell lymphoma treated with R-CHOP. J Clin Oncol (2016) 34 :3150–6. 10.1200/JCO.2015.65.6520\n17 Montalbetti L Della Volpe A Airaghi ML Landoni C Brambilla-Pisoni G Pozzi S . Primary cardiac lymphoma: A case report and review. Minerva Cardioangiologica (1999) 47 :175–82.\n18 Bulum J Banfić L Strozzi M Aurer I Jelasić D . Primary cardiac lymphoma presenting as atrial flutter and total heart block. Heart Vessels (2007) 22 :52–4. 10.1007/s00380-006-0924-2\n19 Jung YH Woo IS Ko YJ Lee JH Lim JW Han CW . A case of primary cardiac lymphoma showing isolated central nervous system relapse. Clin Lymphoma Myeloma Leukemia (2014) 14 :e31–3. 10.1016/j.clml.2013.09.003\n20 Montoro J Mattia L Bertazzoni P Liptrott S Colombo N Civelli M . Primary cardiac lymphoma with isolated parenchymal central nervous system relapse: report of two cases and review of the literature. Ecancermedicalscience (2014) 8 :474. 10.3332/ecancer.2014.474 25374622\n21 van Rooijen CR Scholtens AM de Jong CN Saraber CE van de Donk NWCJ . Primary cardiac lymphoma with central nervous system relapse. Clin Case Rep (2017) 5 :1454–8. 10.1002/ccr3.1094\n22 Kaida H Kumode T Kimura M Ishii K . 18F-FDG PET/CT Finding of Primary Cardiac Lymphoma. Clin Nucl Med (2020) 45 :319–21. 10.1097/RLU.0000000000002957\n23 Freudenberg LS Antoch G Schütt P Beyer T Jentzen W Müller SP . FDG-PET/CT in re-staging of patients with lymphoma. Eur J Nucl Med Mol Imaging (2004) 31 :325–9. 10.1007/s00259-003-1375-y\n24 Zucca E Arcaini L Buske C Johnson PW Ponzoni M Raderer M . Marginal zone lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol (2020) 31 :17–29. 10.1016/j.annonc.2019.10.010 31912792\n25 Sanchorawala V Blanchard E Seldin DC O'Hara C Skinner M Wright DG . AL Amyloidosis Associated with B-cell Lymphoproliferative Disorders: Frequency and Treatment Outcomes. Am J Hematol (2006) 81 :692–5. 10.1002/ajh.20635\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "11()",
"journal": "Frontiers in oncology",
"keywords": "MRI; PET/CT (18)F-FDG; central nervous system relapse/progression; diffuse large B cell lymphoma; heart involvement; lymphoma; marginal zone lymphoma; primary cardiac lymphoma",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "665736",
"pmc": null,
"pmid": "33987101",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "24220617;10922409;15480663;31912792;17285447;27265603;25374622;10479855;33253006;28602141;19846467;32285360;27382100;26725181;20922788;28878902;16795060;22977025;10555666;14647988;33158567;32049734;7037154;18765314;26935129",
"title": "Case Report: Cardiac Involvement by Lymphoma: Rare but Heterogeneous Condition With Challenging Behaviors.",
"title_normalized": "case report cardiac involvement by lymphoma rare but heterogeneous condition with challenging behaviors"
} | [
{
"companynumb": "IT-CELLTRION HEALTHCARE HUNGARY KFT-2021IT014712",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadd... |
{
"abstract": "Background: Azacitidine is commonly used in the treatment of relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the effectiveness of this monotherapy is still very low. A possible mechanism of resistance to hypomethylating agents (HMAs) is the upregulation of the expression of inhibitory checkpoint receptors and their ligands, making the combination of HMAs and immune checkpoint blockade therapy a rational approach. Although the safety of anti-programmed cell death protein (PD)-1 antibodies for patients with post-allo-HSCT remains a complicated issue, the preliminary clinical result of combining azacitidine with anti-PD-1 antibodies is encouraging; however, the safety and efficacy of this approach need further investigation. Case Presentation: We reported a case of treated secondary (ts)-AML in a patient who received tislelizumab (an anti-PD-1 antibody) in combination with azacitidine. The patient relapsed after allo-HSCT and was previously exposed to HMAs-based therapy. The patient received tislelizumab for compassionate use. After the combination treatment, the patient achieved complete remission with incomplete hematologic recovery, negative minimal residual disease (MRD) by flow cytometry (FCM), and negative Wilms' tumor protein 1 (WT1). However, the patient successively developed serious immune-related adverse events (irAEs) and graft vs. host disease (GVHD) and eventually died from complications of GVHD. Conclusion: To our knowledge, this is the first case to report the combined use of tislelizumab and azacitidine to treat relapsed AML posttransplantation. This report highlights the safety concerns of using an anti-PD-1 antibody in combination with azacitidine after allo-HSCT, especially the risk of GVHD, and provides a basis for future studies.",
"affiliations": "Department of Hematology, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China.;Department of Hematology, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China.;Department of Hematology, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China.;Department of Hematology, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China.;Department of Hematology, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China.;Institute of Hematology, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China.;Department of Hematology, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China.;Institute of Hematology, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China.;Department of Hematology, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China.",
"authors": "Yao|Sun|S|;Jianlin|Chen|C|;Zhuoqing|Qiao|Q|;Yuhang|Li|L|;Jiangwei|Hu|H|;Guoliang|Hu|H|;Hongmei|Ning|N|;Bin|Zhang|Z|;Liangding|Hu|H|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C000707970:tislelizumab; D001374:Azacitidine",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2021.639217",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224\nFrontiers Media S.A.\n\n10.3389/fimmu.2021.639217\nImmunology\nCase Report\nCase Report: Combination Therapy With PD-1 Blockade for Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation Resulted in Fatal GVHD\nYao Sun 1†\n\nJianlin Chen 1†\nZhuoqing Qiao 1†\nYuhang Li 1\nJiangwei Hu 1\nGuoliang Hu 23\nHongmei Ning 1\nBin Zhang 23\nLiangding Hu 1*\n1Department of Hematology, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China\n2Institute of Hematology, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China\n3Beijing Key Laboratory of Hematopoietic Stem Cell Therapy and Transformation Research, Beijing, China\nEdited by: Bruno Fattizzo, IRCCS Ca 'Granda Foundation Maggiore Policlinico Hospital, Italy\n\nReviewed by: Rodabe N. Amaria, University of Texas MD Anderson Cancer Center, United States; Maria Teresa Lupo Stanghellini, San Raffaele Hospital (IRCCS), Italy\n\n*Correspondence: Hu Liangding huliangding@sohu.com\nThis article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology\n\n†These authors have contributed equally to this work\n\n01 4 2021\n2021\n12 63921708 12 2020\n12 2 2021\nCopyright © 2021 Yao, Jianlin, Zhuoqing, Yuhang, Jiangwei, Guoliang, Hongmei, Bin and Liangding.\n2021\nYao, Jianlin, Zhuoqing, Yuhang, Jiangwei, Guoliang, Hongmei, Bin and Liangding\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: Azacitidine is commonly used in the treatment of relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the effectiveness of this monotherapy is still very low. A possible mechanism of resistance to hypomethylating agents (HMAs) is the upregulation of the expression of inhibitory checkpoint receptors and their ligands, making the combination of HMAs and immune checkpoint blockade therapy a rational approach. Although the safety of anti-programmed cell death protein (PD)-1 antibodies for patients with post-allo-HSCT remains a complicated issue, the preliminary clinical result of combining azacitidine with anti-PD-1 antibodies is encouraging; however, the safety and efficacy of this approach need further investigation.\n\nCase Presentation: We reported a case of treated secondary (ts)-AML in a patient who received tislelizumab (an anti-PD-1 antibody) in combination with azacitidine. The patient relapsed after allo-HSCT and was previously exposed to HMAs-based therapy. The patient received tislelizumab for compassionate use. After the combination treatment, the patient achieved complete remission with incomplete hematologic recovery, negative minimal residual disease (MRD) by flow cytometry (FCM), and negative Wilms' tumor protein 1 (WT1). However, the patient successively developed serious immune-related adverse events (irAEs) and graft vs. host disease (GVHD) and eventually died from complications of GVHD.\n\nConclusion: To our knowledge, this is the first case to report the combined use of tislelizumab and azacitidine to treat relapsed AML posttransplantation. This report highlights the safety concerns of using an anti-PD-1 antibody in combination with azacitidine after allo-HSCT, especially the risk of GVHD, and provides a basis for future studies.\n\nacute myeloid leukemia\npost-transplantation relapse\nGvHD\nimmune checkpoint blockade\nhypomethylating agents\nBeijing Council of Science and Technology10.13039/501100005081Z171100001017188\n==== Body\nIntroduction\n\nAlthough allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), the relapse of the disease remains the major cause of treatment failure in these patients and carries a dismal prognosis (1–4). Hypomethylating agents (HMAs), such as azacitidine and decitabine, are the most common, non-targeted pharmacologic agents used to treat and prevent the relapse in posttransplantation AML and MDS in recent times. However, a single-agent HMA therapy in relapsed/refractory (r/r) HMAs-naïve AML has only achieved a low response rate (5–8). Previous studies have shown that, while HMAs promote antitumor immune signaling (9), they concurrently dampen antitumor immunity by increasing the expression of programmed cell death protein (PD)-1 and programmed death-ligand (PD-L)1 in solid tumors (10) and MDS/AML (11). This could be a possible mechanism of resistance to HMAs (8). For patients with relapsed AML after human leukocyte antigen (HLA) matching and incompatible transplantation without HLA loss, the mechanism of recurrence after the transplantation is mainly by the downregulation of HLA class two molecules (30–40%) and the upregulation of immune checkpoints (~20%) at the epigenetic level, which can be treated by HMAs and immune checkpoint blockade (ICB) therapy, respectively (12). Thus, for posttransplantation AML, the combination therapy of azacitidine with anti-PD-1 antibody may be a better approach in comparison to monotherapy. In fact, single-agent anti-PD-1 antibodies exhibit only minimal activity in patients with relapsed AML and high-risk MDS (13–15). ICB therapy after allo-HSCT has been reported to cause severe graft vs. host disease (GVHD) in both preclinical (16–18) and clinical studies (15, 19–22). However, the combination therapy of azacitidine and nivolumab (an anti-PD-1 antibody) showed an encouraging response with no GVHD and moderate immune-related adverse events (irAEs) with respect to the relapse of AML/MDS (prior allo-HSCT-19%) in a clinical trial (8). Given these promising preliminary clinical results, the safety and efficacy of combining azacitidine and anti-PD-1 antibodies in post-allo-HSCT patients should be urgently investigated further. Tislelizumab® (BeiGene, China), an antihuman PD-1 monoclonal IgG4 antibody, has been approved in China for patients with r/r classical Hodgkin lymphoma (HL) after at least a second-line chemotherapy (23). In the present study, we report a case of compassionate use of tislelizumab combined with azacitidine to treat a patient with relapsed AML after allo-HSCT. The report highlights the importance of the prudent use of an anti-PD-1 antibody in patients who are undergoing HSCT.\n\nCase Presentation\n\nA 56-year-old man was diagnosed with follicular lymphoma [FL; grade IIIA, stage IVA, Follicular Lymphoma International Prognostic Index (FLIPI) stage: high risk] 18 years ago. The patient was cured by four sequential cycles of fludarabine, cyclophosphamide, rituximab (FCR) chemotherapy; four cycles of rituximab, cyclophosphamide, hydroxyldaunorubicin, oncovin, and prednisone (R-CHOP) chemotherapy; and local lymph node radiotherapy. Unfortunately, the patient was diagnosed with therapy-related MDS (t-MDS) in February 2019 according to the WHO classification (Figure 1A). The baseline characteristics of the patient diagnosed with t-MDS are presented in the Supplementary Material.\n\nFigure 1 (A) Clinical course of the patient. (B,C) Numbers of (B) leukocytes, lymphocytes, neutrophils, monocytes, and (C) platelets in the peripheral blood after the AML diagnosis. (D) Donor cell chimerism in the bone marrow (BM) following allo-HSCT. In (B–D), the dotted vertical line indicates the timing of tislelizumab administration. GC, glucocorticoid; AZA, azacytidine; t-MDS, therapy-related myelodysplastic syndrome; ts-AML, treated secondary-acute myeloid leukemia. URD-HSCT, unrelated donor hematopoietic stem cell transplantation.\n\nThe patient received induction chemotherapy with a decitabine, cytarabine, aclacinomycin, and recombinant human granulocyte colony-stimulating factor (G-CSF) (DCAG) scheme in March 2019 and achieved a partial response (PR). Then, the patient received another cycle of consolidation chemotherapy with DCAG and achieved a complete response (CR); at this stage, the patient was positive for minimal residual disease (MRD), confirmed through flow cytometry (FCM). The patient underwent allo-HSCT from a HLA-mismatched unrelated donor (8/10), after preconditioning with decitabine, fludarabine, and busulfan, followed by cyclosporine A, mycophenolate mofetil, basiliximab (a monoclonal anti-CD25 antibody), and short-term methotrexate for prophylaxis of GVHD. The patient achieved CR with MRD negativity (CRMRD-) 1 month after allo-HSCT and developed extensive skin chronic GVHD (cGVHD) and bronchiolitis obliterans with organizing pneumonia (BOOP) 6 months after allo-HSCT but improved after glucocorticoids and antifungal therapy. During the treatment for BOOP, the patient remained CRMRD- but was positive for Wilms' tumor protein 1 (WT1+). In January 2020, the disease progressed to AML, and the evaluation of bone marrow (BM) showed that 34.5% of blasts, 36.14% of donor chimeric,; 28.8% of FCM–MRD; and 7.57% of WT1. The patient was diagnosed with treated secondary (ts)-AML, arising from an antecedent hematologic disorder that was previously treated with chemotherapy or immunomodulatory therapy, an entity known to have an extremely dismal prognosis (24–26). The gene mutation test from a BM sample showed casitas B-lineage lymphoma (CBL) of 5.92% and Kirsten rat sarcoma (KRAS) of 6.3%. The immunosuppressor was immediately withdrawn. We performed the HLA-loss test, but no HLA gene loss was detected.\n\nThe patient was counseled on the risks and benefits of azacitidine in combination with tislelizumab. Although the patient did not have any signs or symptoms of GVHD at the time of relapse, we decided to administer anti-PD-1 after one course of azacitidine to ensure the use of tislelizumab for at least 4 weeks after the withdrawal of immunosuppressive agents according to a previous study (15). Thus, the patient received azacitidine monotherapy and achieved 0.611% of CRiMRD- and WT1 1 month later. The patient subsequently developed herpes zoster infection, but the condition of the patient improved with antiviral therapy. The patient also developed a drug-induced liver injury, but the condition of the patient improved after the drugs causing liver injury were discontinued, namely estazolam and zopiclone, which had been prescribed for insomnia. In March 2020, the patient received 100 mg of azacitidine on days 1–7 subcutaneously and 200 mg of tislelizumab on day 1 intravenously. About 20 days later, the patient remained CRiMRD- and was WT1 negative (WT1–) (0.11%, the cutoff value of WT1/ABL in our laboratory is 0.5%). The patient successively developed hypoadrenocorticism, infectious diarrhea, fever, and shock. Although the symptoms of the patient were relieved with symptomatic and antimicrobial treatment, diarrhea continued to worsen. No definite infection was found after repeated etiological examinations, and multiple antibiotic treatments proved to be ineffective.\n\nThe patient refused to undergo a colonoscopy and further biopsies, so the diagnosis of G3 gut acute GVHD (aGVHD) was mainly based on history and clinical manifestation. Prednisone, 2 mg/kg/day, combined with ruxolitinib, 10 mg (bid), was prescribed. The patient continued to have diarrhea even after 5 days. Prednisone was tapered and basiliximab was started. The patient subsequently developed delirious behavior, involuntary tremors, decreased muscle strength, and dystonia. A diagnosis of autoimmune-related encephalopathy was hypothesized after consultation with a neurologist, based on history, clinical manifestations, and imaging. CT showed multiple spots and patches of low-density lesions around bilateral lateral ventricles, and MRI showed scattered spots and patchy lesions near both frontal lobes and lateral ventricles that showed equal or long signal on T1 images, a long signal on T2 images, and a high signal on T2WI fluid-attenuated inversion recovery (FLAIR). Gamma globulins were administered, but the nervous system symptoms were not relieved. Gut aGVHD was resistant to steroid and second-line treatment, and the patient subsequently developed hematochezia, enteric infections, septic shock, and metabolic acidosis secondary to gut GVHD and died 6 days later (Figures 1B–D).\n\nDiscussion and Literature Review\n\nThe patient with MDS mentioned in the study was previously exposed to HMA therapy, which rapidly progressed to ts-AML after allo-HSCT. At the time of relapse, neither HLA loss nor active GVHD was present. First, the patient received azacitidine monotherapy and achieved CRiMRD- but was WT1+. Subsequently, the patient received a combination of azacitidine and tislelizumab and remained CRiMRD- and became WT1-. Unfortunately, the patient developed serious irAEs, including hypoadrenocorticism, autoimmune-related encephalopathy, and fatal gut GVHD. We have summarized the safety and efficacy of using checkpoint inhibitors in post-allo-HSCT myeloid malignancies in Table 1. Clinical studies showed that the CTLA-4 blockade induces lower GVHD as compared to anti-PD-1 (14% vs. 39%) (15, 28). Furthermore, CTLA-4 inhibitors as single agents demonstrated activity in patients with high-risk MDS after the therapy of HMAs and relapsed AML post-allo-HSCT, while anti-PD-1 antibodies showed limited efficacy (28, 34). Currently, clinical trials of the combination of HMAs with ICB therapy are ongoing (8, 34). Table 2 shows a summary of autoimmune complications of the published clinical trials using checkpoint inhibitors in post-allo-HSCT hematologic malignancies other than myeloid malignancies. On the whole, the incidence of autoimmune diseases, including GVHD, after ICB monotherapy is high: 21–39% in AML/MDS (15, 28) and 30%−55% in other hematological malignancies (20, 36).\n\nTable 1 The safety and efficacy of the published clinical trials of immune checkpoint blockade in post-allo-HSCT myeloid malignancies.\n\nReferences\tImmune checkpoint inhibitors/ pathway\tHMAs\tStudy design\tTrial regimen\tStudy population (N)\tEfficacy\tSafety\t\nICB THERAPY ONLY\t\nBashey et al. (27)\tIpilimumab/CTLA-4\t-\tPhase 1\tSingle arm in relapsed\nMalignancies after allo-HSCT\tTotal (29)\nAML (2)\nCML (2)\tNo response in the four patients\tIn all myeloid malignancies after allo-HSCT, no patient developed DLT and GVHD. One patient with AML developed G3 polyarthropathy with nodules clinically consistent with rheumatoid arthritis.\t\nDavids et al. (28)\tIpilimumab/CTLA-4\t-\tphase 1/1b\tSingle arm in relapsed HMs\nAfter allo-HSCT\tTotal (28)\nAML (12)\nRelapse with extramedullary disease (4)\nMDS (2)\nMPN (1)\tIn myeloid malignancies, four patients with extramedullary and one patient with MDS/AML achieved CR.\tIn all patients, 6 (21%) developed irAEs including 1 death, 4 (14%) developed GVHD. All of GVHD resolved with glucocorticoids. Other sAEs: acute kidney injury, corneal ulcer, thrombocytopenia, neutropenia, anemia, and pleural effusion. *\t\nHolderried et al. (22)\tNivolumab/PD-1\nIpilimumab/CTLA-4\t-\tRetrospective study\tDisease recurrence after allo-HSCT other than HL\tTotal (21)\nAML/MDS (12)\tOne patient with AML received Niv + DLI survived > 2 years after Niv with ongoing CR. One AML received Niv survived > 2 years after Niv with PD.\t2/12 patients with AML/MDS developed GVHD. One received Niv, the other one received Niv + Ipi.\t\nWong et al. (29)\tNivolumab/PD-1\t-\tPhase 2a\tSingle arm in relapsed or persistent HMs after allo-HSCT\tTotal (6)\nAML (2)\tOne patient with AML achieved transient blast reduction but progressed subsequently.\t2/6 patents with HMs developed G3 aGVHD 2 weeks after first dose of Niv. *\t\nDavids et al. (15)\tNivolumab/PD-1\t-\tPhase 1\tSingle arm in relapsed HMs\nafter allo-HSCT\tTotal (28)\nAML (10)\nMDS (7)\nCMML (1)\tless activity in patients with myeloid malignancies (ORR 21%).\t11 HMs pts (39%) developed new or worsening a/c-GVHD (two acute, eight chronic, and one both). Additional sAEs: pneumonitis, transaminitis, respiratory syncytial virus pneumonia, rash, orthostatic hypotension, and lipase elevation. *\t\nSchoch et al. (30)\tNivolumab/PD-1\nPembrolizumab/PD-1\nIpilimumab/CTLA-4\t-\tRetrospective study\tRelapsed cancers afterallo-HSCT.\tTotal (9)\nAML (1)\nMDS (1)\t*\tIn all the 9 patients (including two with solid tumors), one developed G2 cutaneous aGVHD when DLI was given for relapsed disease after ipilimumab. *\t\nLiao et al. (31)\tPembrolizumab/PD-1\t-\t\tSingle arm in relapsed\nAML after allo-HSCT\tAML (8)\tNo response\tCan induce early and severe irAEs.\t\nWang et al. (32)\tNivolumab/PD-1\t-\tCases report\tMaintenance therapy after allo-HSCT in myeloid malignancies\tAML (3)\nt-MDS (1)\t-\tAll the 4 patients rapidly developed irAEs, 2 of them ≥G3.\t\nAlbring et al. (33)\tNivolumab/PD-1\t-\tCases report\tMonotherapy in relapsed\nAML after allo-HSCT\tAML (3)\t1 CR, 1 SD, 1 NR\tPancytopenia and skin GVHD in one patient, muscle and joint pain in another. No severe GVHD.\t\nHMAs+ICB\t\nDaver et al. (8)\tNivolumab/PD-1\tAZA\tPhase 2\tsingle arm in R/R AML\tAML (70)\nPost-allo-HSCT (13)\nPost-transplantation AML (13)\tORR 33%, CRR 22% in all patients, ORR 58% in HMAs-naïve and 22% in HMAs-pre-treated patients. ORR 13% in post-allo-HSCT r/r AML.\tGrade 3–4 irAEs occurred in 8/70 (11%) R/R AML patients. No GVHD was reported.\t\nR/R, Relapsed/refractory; NR, Not reported; ORR, Overall response rate; OS, Overall survival; CR, Complete remission; CRR, Complete remission rate; PR, Partial response; HMAs, Hypomethylating agents; ICB, Immune checkpoint blockade; allo-HSCT, Allogeneic hematopoietic stem cell transplantation; SD, Stable disease; PD, Progressive disease; GVHD, Graft vs. host disease; DLT, Dose-limiting toxicity; AML, Acute myeloid leukemia; MDS, Myelodysplastic syndrome; CML, Chronic myeloid leukemia; CMML, Chronic myelomonocytic leukemia; HL, Hodgkin lymphoma; DLI, Donor lymphocyte infusion; irAEs, immune-related adverse events; AZA, Azacytidine; ITP, Immune thrombocytopenic purpura; HMs, Hematological malignancies; MPN, Myeloproliterative neoplasms.\n\n* Detailed data about the separate disease are unavailable.\n\nTable 2 Autoimmune complications of the published clinical trials using checkpoint inhibitors in post-allo-HSCT hematologic malignancies other than myeloid malignancies.\n\nReferences\timmune checkpoint inhibitors/pathway\tOther drugs\tStudy design\tTrial regimen\tStudy population (N)\tAutoimmune complications\t\nBashey et al. (27)\tIpilimumab/CTLA-4\t-\tPhase 1\tSingle arm in relapsed\nmalignancies after allo-HSCT\tTotal (29)\nHL (14)\nMyeloma (6)\nCLL (2)\nNHL (1)\t3 patients developed organ-specific irAEs, including G2 hyperthyroidism, recurrent G4 pneumonitis, and G3 dyspnea.\t\nDavids et al. (28)\tIpilimumab/CTLA-4\t-\tPhase 1/1b\tSingle arm in relapsed HMs\nafter allo-HSCT\tTotal (28)\nHL (7)\nNHL (4)\nMM (1)\nALL (1)\tIn all patients, 6 (21%) developed irAEs including 1 death, 4 (14%) developed GVHD. *\t\nHolderried et al. (22)\tNivolumab/PD-1\nIpilimumab/CTLA-4\t-\tRetrospective study\tDisease recurrence after allo-HSCT other than HL\tTotal (21)\nALL (2)\nNHL (5)\nMF (2)\t4/9 patients with non-myeloid hematologic malignancies developed GVHD, 1 received Niv, 3 received Niv + DLI.\t\nWong et al. (29)\tNivolumab/PD-1\t-\tphase 2a\tSingle arm in relapsed or persistent HMs after allo-HSCT\tTotal (6)\nHL (2)\ntCLL (1)\nMCL (1)\t2/6 HMs patients developed G3 aGVHD 2. *\t\nKhouri et al. (35)\tIpilimumab/CTLA-4\tLenalidomide\tPhase ii\tRelapsed lymphomas after allo-HSCT and high-risk patients after autologous HSCT\t17 pts (10 allo, 7 auto)\tAllogeneic: 1 cGVHD of liver, mouth, 1 G2 hypothyroid; Autologous: 1 G2 dermatitis, 1 G1 hypothyroid.\t\nSchoch et al. (30)\tNivolumab/PD-1\nPembrolizumab/PD-1\nIpilimumab/CTLA-4\t-\tRetrospective study\trelapsed cancers after allo-HSCT.\tTotal (9)\nHL (4)\nDsmoplastic small round cell tumor (1)\tIn all the 9 patients (including 2 with solid tumors), 1 developed G2 cutaneous aGVHD when DLI was given for relapsed disease after ipilimumab. *\t\nDavids et al. (15)\tNivolumab/PD-1\t-\tPhase 1\tSingle arm in relapsed HMs\nafter allo-HSCT\tTotal (28)\nHL (5)\nNHL (3)\nCLL (1)\t11 HMs patients (39%) developed new or worsening a/c-GVHD (2 acute, 8 chronic, and 1 both). *\t\nHerbaux et al. (36)\tNivolumab/PD-1\t-\tRetrospective study\tHL patients relapsing after allo-HSCT.\tr/r HL (20)\t30% (6/20) patients developed GVHD, all of them had prior history of aGVHD. 1 developed possibly related G2 hepatic cytolysis.\t\nHaverkos et al. (20)\tNivolumab/PD-1\nPembrolizumab/PD-1\t-\tRetrospective study\tRelapsed lymphomas after allo-HSCT\tHL (29)\nOther lymphomas (2)\t55% (17/31) patients developed treatment-emergent GVHD (6 acute, 4 overlap, and 7 chronic). 29% developed ≥G3 a/cGVHD. 26% deaths related to GVHD. Only 2 of these 17 achieved CR to GVHD treatment, and 14/17 required ≥2 systemic therapies. The majority experienced cutaneous and hepatic GVHD.\t\nAngenendt et al. (37), Covut et al. (38), and Shad et al. (39)\tNivolumab/PD-1\t-\tCases report\tRelapsed HL after allo-HSCT\tHL (4)\tNone\t\nChan et al. (40) and Villasboas et al. (41)\tPembrolizumab/PD-1\t-\tCases report\tRelapsed lymphoma after allo-HSCT\tHL (2)\nALCL (1)\tNone\t\nSingh et al. (19)\tPembrolizumab/PD-1\t-\tCase report\tRelapsed HL after allo-HSCT\tHL (1)\tStage IV skin, stage II gut and stage IV liver leading to an overall grade IV aGvHD.\t\nKwong et al. (42)\tPembrolizumab/PD-1\t-\tCases report\tRelapsed or refractory NK/T-cell lymphoma after allo-HSCT\tNK/T-cell lymphoma (7)\tG2 skin GVHD disease in 1 patient with previous allo-HSCT.\t\nGodfrey et al. (43)\tNivolumab/PD-1\t-\tCases report\tRelapsed HL after allo-HSCT\tHL (3)\tG3 polyarthritis in 1 patient, G2 keratoconjunctivits in 2, G1 rash (possibly representing limited-stage chronic GVHD) in 1.\t\nBoekstegers et al. (44)\tPembrolizumab/PD-1\t-\tCase report\tRelapsed ALL after allo-HSCT\tALL (1)\tG4 aGVHD of the skin, mucosa, liver, lung, CNS and eyes. A severe lethal inflammatory disease.\t\nEl Cheikh et al. (45)\tNivolumab/PD-1\t-\tCases report\tRelapsed HL after allo-HSCT\tHL (2)\tG3 aGVHD involving ocular, liver and skin in 1 patient, G3 aGVHD involving skin, GI and liver in the other pt.\t\nYared et al. (46)\tNivolumab/PD-1\t-\tCase report\tRelapsed HL after allo-HSCT\tHL (1)\tG2 pneumonitis and hepatitis\t\nNHL, Non-Hodgkin's lymphoma; ALL, Acute lymphoblastic leukemia; CLL, Chronic lymphoblastic leukemia; ALCL, Anaplastic large cell lymphoma; R/R, Relapsed/refractory; CR, Complete remission; CRR, Complete remission rate; allo-HSCT, Allogeneic hematopoietic stem cell transplantation; GVHD, Graft vs. host disease; HL, Hodgkin lymphoma; DLI, Donor lymphocyte infusion; irAEs, immune-related adverse events; DLT, Dose-limiting toxicity; MF, Marrow failure; MM, Multiple myeloma; tCLL, transformed chronic lymphocytic leukemia; MCL, Mantle cell lymphoma; HMs, Hematological malignancies.\n\n* Detailed data about separate disease are unavailable.\n\nA possible pathogenic mechanism of GVHD in the patient could involve enteric infection that may have damaged gastrointestinal tissue, favoring T-cell activation against self-antigens. The blockage of PD-1/PD-L1 increases the proliferation, activation, Th1 cytokine-production, and metabolic stress of donor T cells, along with increased homing in the GVHD target tissues such as the gut, due to the loss of intestinal epithelial integrity (47). Moreover, the blockage of PD-1/PD-L1 accelerated donor CD8+ T-cell expansion and exacerbated aGVHD (48). It is challenging to distinguish between gut GVHD and GI-irAEs even after biopsies. We diagnosed a gut aGVHD for the following reasons: first, the patient had a history of cGVHD and was more likely to be susceptible to develop GVHD after the treatment of PD-1 as described in the previous studies (36, 49). Meanwhile, the patient remained completely donor chimeric after anti-PD-1 therapy. However, other studies have suggested that prior a/cGVHD has no significant impact on the development of GVHD after ICB therapy (15, 22). Although this issue is controversial and remains to be clarified, it is a possibility that deserves attention. In addition, the cumulative incidence of gastrointestinal aGVHD might be as high as 60% (50), while the incidence of diarrhea was 11–17% after the treatment of anti-PD-1 (51).\n\nPrevious studies showed that 0.5 mg/kg of nivolumab monotherapy for every 3 weeks and 100 mg of nivolumab plus azacitidine for every 2 weeks are considered safe (8, 15). In addition, the low affinity of tislelizumab for the Fc receptor and Fc-γ receptor 1 (FcγRI) may contribute to improved anticancer efficacy as compared to other anti-PD-1 antibodies (52), which means that the dose of tislelizumab may need to be further reduced. It is interesting that the patient developed a delayed and steroid-resistant GVHD nearly 4 weeks after anti-PD-1 therapy. This could be related to the highest terminal half-life of tislelizumab compared to other ICB (23). Therefore, reducing the dose of tislelizumab or extending the interval of administration should be evaluated to improve safety in future studies on patients with post-allo-HSCT.\n\nSome other factors may also cause the occurrence of GVHD after ICB therapy in posttransplantation patients. Although it is still controversial (22), two studies observed that a shorter interval between the transplantation and the first nivolumab infusion was associated with a higher risk of developing GVHD (15, 36). Extreme caution should be followed during the enrollment of patients with active cGVHD (21). Furthermore, the question remains as to whether anti-PD-L1 is safer than anti-PD-1. Hematopoietic cells upregulate the expression of both PD-L2 and PD-L1 after HSCT, but only PD-L1 is broadly expressed by parenchymal cells in host GVHD target tissues (47). Host PD-L1 is dominant over PD-L2 in regulating GVHD lethality (47), and the PD-L1 expression on donor T cells may drive GVHD lethality (53). Thus, PD-L1 may play a vital role in the development of GVHD. At present, there is still a lack of reliable data on the clinical application of anti-PD-L1 for posttransplantation patients, and the safety and efficacy of PD-L1 inhibitors need to be investigated clinically.\n\nConclusion\n\nAzacitidine in combination with anti-PD-1 seems to be a rational strategy for posttransplantation relapsed AML but needs further urgent clinical investigation. The report highlights the safety issues of an anti-PD-1 antibody in combination with azacitidine after allo-HSCT, especially GVHD. Additionally, we conducted an in-depth discussion around safety issues and provided suggestions for follow-up research. For such patients, the type, dosage, and timing of ICB drugs should be selected with caution.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\n\nHL was involved in the identification, selection, and management of the patient and manuscript review. SY was involved in the management of the patient and manuscript drafting. CJ and QZ were involved in the selection and management of the patient and manuscript review. LY, ZB, HJ, NH, and ZB were involved in manuscript editing. HG was involved in the detection of samples. All authors have read and approved the final manuscript.\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\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.639217/full#supplementary-material\n\nClick here for additional data file.\n\nFunding. This work was supported by a grant from the Science and Technology Planning Project of Beijing City (Z171100001017188).\n==== Refs\nReferences\n\n1. Oran B Giralt S Couriel D Hosing C Shpall EJ de Meis E . Treatment of AML and MDS relapsing after reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation. Leukemia. (2007) 21 :2540–4. 10.1038/sj.leu.2404828 17611563\n2. Bishop MR Alyea EP III Cairo MS Falkenburg JH June CH Kroger N . National Cancer Institute's First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: summary and recommendations from the organizing committee. Biol Blood Marrow Transplant. (2011) 17 :443–54. 10.1016/j.bbmt.2010.12.713 21224011\n3. Wayne AS Giralt S Kroger N Bishop MR . Proceedings from the national cancer institute's second international workshop on the biology, prevention, and treatment of relapse after hematopoietic stem cell transplantation: introduction. Biol Blood Marrow Transplant. (2013) 19 :1534–6. 10.1016/j.bbmt.2013.08.016 24035783\n4. Bejanyan N Weisdorf DJ Logan BR Wang H-L Devine SM de Lima M . Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation: a center for international blood and marrow transplant research study. Biol Blood Marrow Transpl. (2015) 21 :454–9. 10.1016/j.bbmt.2014.11.007 25460355\n5. George TJ Woolery JE Wetzstein GA Ho VQ Lancet JE List AF . A retrospective study of decitabine for the treatment of relapsed or refractory acute myeloid leukemia: lack of response observed in a heavily pretreated population. Blood. (2010) 116 :2186–6. 10.1182/blood.V116.21.2186.2186\n6. Tawfik B Sliesoraitis S Lyerly S Klepin HD Lawrence J Isom S . Efficacy of the hypomethylating agents as frontline, salvage, or consolidation therapy in adults with acute myeloid leukemia (AML). Ann Hematol. (2014) 93 :47–55. 10.1007/s00277-013-1940-9 24149914\n7. Stahl M DeVeaux M Montesinos P Itzykson R Ritchie EK Sekeres MA . Hypomethylating agents in relapsed and refractory AML: outcomes and their predictors in a large international patient cohort. Blood Adv. (2018) 2 :923–32. 10.1182/bloodadvances.2018016121 29685952\n8. Daver N Garcia-Manero G Basu S Boddu PC Alfayez M Cortes JE . Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/refractory acute myeloid leukemia: a nonrandomized, open-label, phase II study. Cancer Discov. (2019) 9 :370–83. 10.1158/2159-8290.Cd-18-0774 30409776\n9. Daver N Boddu P Garcia-Manero G Yadav SS Sharma P Allison J . Hypomethylating agents in combination with immune checkpoint inhibitors in acute myeloid leukemia and myelodysplastic syndromes. Leukemia. (2018) 32 :1094–105. 10.1038/s41375-018-0070-8 29487386\n10. Wrangle J Wang W Koch A Easwaran H Mohammad HP Vendetti F . Alterations of immune response of Non-Small Cell Lung Cancer with Azacytidine. Oncotarget. (2013) 4 :2067–79. 10.18632/oncotarget.1542 24162015\n11. Yang H Bueso-Ramos C DiNardo C Estecio MR Davanlou M Geng QR . Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. (2014) 28 :1280–8. 10.1038/leu.2013.355 24270737\n12. Vago L . Clonal evolution and immune evasion in posttransplantation relapses. Hematol Am Soc Hematol Educ Program. (2019) 2019 :610–6. 10.1182/hematology.2019000005 31808847\n13. Berger R Rotem-Yehudar R Slama G Landes S Kneller A Leiba M . Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. (2008) 14 :3044–51. 10.1158/1078-0432.Ccr-07-4079 18483370\n14. Daver N Basu S Garcia-Manero G Cortes JE Ravandi F Ning J . Defining the immune checkpoint landscape in patients (pts) with acute myeloid leukemia (AML). Blood. (2016) 128 :2900. 10.1182/blood.V128.22.2900.2900\n15. Davids MS Kim HT Costello C Herrera AF Locke FL Maegawa RO . A multicenter phase 1 study of nivolumab for relapsed hematologic malignancies after allogeneic transplantation. Blood. (2020) 135 :2182–91. 10.1182/blood.2019004710 32478814\n16. Blazar BR Taylor PA Panoskaltsis-Mortari A Sharpe AH Vallera DA . Opposing roles of CD28:B7 CTLA-4:B7 pathways in regulating in vivo alloresponses in murine recipients of MHC disparate T cells. J Immunol. (1999) 162 :6368–77.10352249\n17. Blazar BR Carreno BM Panoskaltsis-Mortari A Carter L Iwai Y Yagita H . Blockade of programmed death-1 engagement accelerates graft-vs.-host disease lethality by an IFN-gamma-dependent mechanism. J Immunol. (2003) 171 :1272–7. 10.4049/jimmunol.171.3.1272 12874215\n18. Koestner W Hapke M Herbst J Klein C Welte K Fruehauf J . PD-L1 blockade effectively restores strong graft-vs.-leukemia effects without graft-vs.-host disease after delayed adoptive transfer of T-cell receptor gene-engineered allogeneic CD8+ T cells. Blood. (2011) 117 :1030–41. 10.1182/blood-2010-04-283119 21063028\n19. Singh AK Porrata LF Aljitawi O Lin T Shune L Ganguly S . Fatal GvHD induced by PD-1 inhibitor pembrolizumab in a patient with Hodgkin's lymphoma. Bone Marrow Transplant. (2016) 51 :1268–70. 10.1038/bmt.2016.111 27111048\n20. Haverkos BM Abbott D Hamadani M Armand P Flowers ME Merryman R . PD-1 blockade for relapsed lymphoma post-allogeneic hematopoietic cell transplant: high response rate but frequent GVHD. Blood. (2017) 130 :221–8. 10.1182/blood-2017-01-761346 28468799\n21. McDuffee E Aue G Cook L Ramos-Delgado C Shalabi R Worthy T . Tumor regression concomitant with steroid-refractory GvHD highlights the pitfalls of PD-1 blockade following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. (2017) 52 :759–61. 10.1038/bmt.2016.346 28067871\n22. Holderried TAW Fraccaroli A Schumacher M Heine A Brossart P Stelljes M . The role of checkpoint blockade after allogeneic stem cell transplantation in diseases other than Hodgkin's Lymphoma. Bone Marrow Transplant. (2019) 54 :1662–7. 10.1038/s41409-019-0498-0 30833743\n23. Lee A Keam SJ . Tislelizumab: first approval. Drugs. (2020) 80 :617–24. 10.1007/s40265-020-01286-z 32185681\n24. Bello C Yu D Komrokji RS Zhu W Wetzstein GA List AF . Outcomes after induction chemotherapy in patients with acute myeloid leukemia arising from myelodysplastic syndrome. Cancer. (2011) 117 :1463–9. 10.1002/cncr.25598 21425147\n25. Prébet T Gore SD Thépot S Esterni B Quesnel B Beyne Rauzy O . Outcome of acute myeloid leukaemia following myelodysplastic syndrome after azacitidine treatment failure. Br J Haematol. (2012) 157 :764–6. 10.1111/j.1365-2141.2012.09076.x 22390719\n26. Oliai C Schiller G . How to address second and therapy-related acute myelogenous leukaemia. Br J Haematol. (2020) 188 :116–28. 10.1111/bjh.16354 31863469\n27. Bashey A Medina B Corringham S Pasek M Carrier E Vrooman L . CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood. (2009) 113 :1581–8. 10.1182/blood-2008-07-168468 18974373\n28. Davids MS Kim HT Bachireddy P Costello C Liguori R Savell A . Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. (2016) 375 :143–53. 10.1056/NEJMoa1601202 27410923\n29. Wong E Dawson E Davis J Koldej R Ludford-Menting M Lansdown M . Nivolumab for relapsed or residual haematological malignancies after allogeneic haematopoietic stem cell transplantation (NIVALLO). Blood. (2018) 132 (Suppl. 1 ), 4633. 10.1182/blood-2018-99-112310\n30. Schoch LK Borrello I Fuchs EJ Bolanos-Meade J Huo JS Gojo I . Checkpoint inhibitor therapy and graft vs. host disease in allogeneic bone marrow transplant recipients of haploidentical and matched products with post-transplant cyclophosphamide. Blood. (2016) 128 :4571. 10.1182/blood.V128.22.4571.4571\n31. Liao D Wang M Liao Y Li J Niu T . A review of efficacy and safety of checkpoint inhibitor for the treatment of acute myeloid leukemia. Front Pharmacol. (2019) 10 :609. 10.3389/fphar.2019.00609 31244654\n32. Wang AY Kline J Stock W Kosuri S Artz A Larson RA . Unexpected toxicities when nivolumab was given as maintenance therapy following allogeneic stem cell transplantation. Biol Blood Marrow Transpl. (2020) 26 :1025–7. 10.1016/j.bbmt.2020.01.021 32018063\n33. Albring JC Inselmann S Sauer T Schliemann C Altvater B Kailayangiri S . PD-1 checkpoint blockade in patients with relapsed AML after allogeneic stem cell transplantation. Bone Marrow Transplant. (2017) 52 :317–20. 10.1038/bmt.2016.274 27892950\n34. Garcia-Manero G Daver NG Montalban-Bravo G Jabbour EJ DiNardo CD Kornblau SM . A phase II study evaluating the combination of nivolumab (Nivo) or Ipilimumab (Ipi) with azacitidine in pts with previously treated or untreated myelodysplastic syndromes (MDS). Blood. (2016) 128 :344–4. 10.1182/blood.V128.22.344.344\n35. Khouri IF Fernandez Curbelo I Turturro F Jabbour EJ Milton DR Bassett RL Jr . Ipilimumab plus lenalidomide after allogeneic and autologous stem cell transplantation for patients with lymphoid malignancies. Clin Cancer Res. (2018) 24 :1011–8. 10.1158/1078-0432.Ccr-17-2777 29246938\n36. Herbaux C Gauthier J Brice P Drumez E Ysebaert L Doyen H . Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma. Blood. (2017) 129 :2471–8. 10.1182/blood-2016-11-749556 28270452\n37. Angenendt L Schliemann C Lutz M Rebber E Schulze AB Weckesser M . Nivolumab in a patient with refractory Hodgkin's lymphoma after allogeneic stem cell transplantation. Bone Marrow Transplant. (2016) 51 :443–5. 10.1038/bmt.2015.266 26551782\n38. Covut F Pinto R Cooper BW Tomlinson B Metheny L Malek E . Nivolumab before and after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. (2017) 52 :1054–6. 10.1038/bmt.2017.44 28346414\n39. Shad AT Huo JS Darcy C Abu-Ghosh A Esposito G Holuba MJ . Tolerance and effectiveness of nivolumab after pediatric T-cell replete, haploidentical, bone marrow transplantation: a case report. Pediatr Blood Cancer. (2017) 64 :26257. 10.1002/pbc.26257 27650634\n40. Chan TS Khong PL Kwong YL . Pembrolizumab for relapsed anaplastic large cell lymphoma after allogeneic haematopoietic stem cell transplantation: efficacy and safety. Ann Hematol. (2016) 95 :1913–5. 10.1007/s00277-016-2764-1 27473193\n41. Villasboas JC Ansell SM Witzig TE . Targeting the PD-1 pathway in patients with relapsed classic Hodgkin lymphoma following allogeneic stem cell transplant is safe and effective. Oncotarget. (2016) 7 :13260–4. 10.18632/oncotarget.7177 26848626\n42. Kwong YL Chan TSY Tan D Kim SJ Poon LM Mow B . PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood. (2017) 129 :2437–42. 10.1182/blood-2016-12-756841 28188133\n43. Godfrey J Bishop MR Syed S Hyjek E Kline J . PD-1 blockade induces remissions in relapsed classical Hodgkin lymphoma following allogeneic hematopoietic stem cell transplantation. J Immunother Cancer. (2017) 5 :11. 10.1186/s40425-017-0211-z 28239465\n44. Boekstegers AM Blaeschke F Schmid I Wiebking V Immler S Hoffmann F . MRD response in a refractory paediatric T-ALL patient through antiprogrammed cell death 1 (PD-1) Ab treatment associated with induction of fatal GvHD. Bone Marrow Transplant. (2017) 52 :1221–4. 10.1038/bmt.2017.107 28581460\n45. El Cheikh J Massoud R Abudalle I Haffar B Mahfouz R Kharfan-Dabaja M . Nivolumab salvage therapy before or after allogeneic stem cell transplantation in Hodgkin lymphoma. Bone Marrow Transplant. (2017) 52 :1074–7. 10.1038/bmt.2017.69 28394366\n46. Yared JA Hardy N Singh Z Hajj S Badros AZ Kocoglu M . Major clinical response to nivolumab in relapsed/refractory Hodgkin lymphoma after allogeneic stem cell transplantation. Bone Marrow Transplant. (2016) 51 :850–2. 10.1038/bmt.2015.346 26828905\n47. Saha A Aoyama K Taylor PA Koehn BH Veenstra RG Panoskaltsis-Mortari A . Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-vs.-host disease lethality. Blood. (2013) 122 :3062–73. 10.1182/blood-2013-05-500801 24030385\n48. Li X Deng R He W Liu C Wang M Young J . Loss of B7-H1 expression by recipient parenchymal cells leads to expansion of infiltrating donor CD8+ T cells and persistence of graft-vs.-host disease. J Immunol. (2012) 188 :724–34. 10.4049/jimmunol.1102630 22156590\n49. Klobuch S Weber D Holler B Herr W Holler E Wolff D . Potential role of the PD-1/PD-L1 axis in the immune regulation of chronic GVHD. Oncol Res Treat. (2017) 40 :447–50. 10.1159/000471768 28683452\n50. Naymagon S Naymagon L Wong SY Ko HM Renteria A Levine J . Acute graft-vs.-host disease of the gut: considerations for the gastroenterologist. Nat Rev Gastroenterol Hepatol. (2017) 14 :711–26. 10.1038/nrgastro.2017.126 28951581\n51. Collins M Soularue E Marthey L Carbonnel F . Management of patients with immune checkpoint inhibitor-induced enterocolitis: a systematic review. Clin Gastroenterol Hepatol. (2020) 18 :1393–403.e1391. 10.1016/j.cgh.2020.01.033 32007539\n52. Zhang T Song X Xu L Ma J Zhang Y Gong W . The binding of an anti-PD-1 antibody to FcγR? has a profound impact on its biological functions. Cancer Immunol Immunother. (2018) 67 :1079–90. 10.1007/s00262-018-2160-x 29687231\n53. Saha A O'Connor RS Thangavelu G Lovitch SB Dandamudi DB Wilson CB . Programmed death ligand-1 expression on donor T cells drives graft-vs.-host disease lethality. J Clin Invest. (2016) 126 :2642–60. 10.1172/jci85796 27294527\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "12()",
"journal": "Frontiers in immunology",
"keywords": "GvHD; acute myeloid leukemia; hypomethylating agents; immune checkpoint blockade; post-transplantation relapse",
"medline_ta": "Front Immunol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine; D003131:Combined Modality Therapy; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008224:Lymphoma, Follicular; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D014184:Transplantation, Homologous",
"nlm_unique_id": "101560960",
"other_id": null,
"pages": "639217",
"pmc": null,
"pmid": "33868266",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": "32007539;27294527;22156590;31808847;25460355;28581460;27892950;27650634;24162015;24018393;27111048;31244654;30833743;28270452;28239465;18974373;24030385;28468799;24270737;28188133;32185681;31863469;29685952;30409776;21425147;28394366;32018063;24149914;29687231;26551782;28067871;18483370;32478814;28951581;21063028;21224011;26828905;10352249;27473193;26848626;22390719;27410923;29487386;28683452;17611563;12874215;29246938;28346414",
"title": "Case Report: Combination Therapy With PD-1 Blockade for Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation Resulted in Fatal GVHD.",
"title_normalized": "case report combination therapy with pd 1 blockade for acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation resulted in fatal gvhd"
} | [
{
"companynumb": "CN-NATCO PHARMA-2021NAT00021",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
"drugadditional": null,
... |
{
"abstract": "A 66-year-old Japanese male patient was referred to Saitama Medical University International Medical Center for treatment of bladder cancer (clinical stage T2 or higher without metastasis), and underwent radical cystectomy with pelvic lymphadenectomy. The histopathological diagnosis was high-grade urothelial carcinoma (pathological stage T2bN2, ly1, v0) and 2 cycles of adjuvant systemic chemotherapy (gemcitabine plus cisplatin) were administered. At 15 months after the operation, mediastinal and lung hilar lymph nodes and multiple bone metastases were identified on computed tomography imaging. After 3 cycles of the previous regimen as salvage systemic chemotherapy, the lymph node metastases had shrunk and the bone metastases were stable; therefore, further chemotherapy was planned. At 26 days after the initiation of the 4th cycle, the patient felt nausea and lower limb weakness. Spinal and brain magnetic resonance imaging with contrast medium revealed diffuse enhancement at the surface of the spinal cord and brain. In addition, abnormal signal intensity in the subarachnoid space was observed on fluid-attenuated inversion recovery imaging; therefore, the patient was diagnosed with meningeal carcinomatosis (MC). Treatment, including whole-brain radiotherapy, was planned for MC; however, the patient's condition rapidly worsened and he succumbed to the disease 14 days after the diagnosis of MC. The definitive diagnosis of MC was confirmed at autopsy.",
"affiliations": "Department of Uro-Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama 350-1298, Japan.;Department of Uro-Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama 350-1298, Japan.;Department of Uro-Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama 350-1298, Japan.;Department of Uro-Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama 350-1298, Japan.;Department of Diagnostic Radiology, Saitama Medical University International Medical Center, Hidaka, Saitama 350-1298, Japan.;Department of Diagnostic Radiology, Saitama Medical University International Medical Center, Hidaka, Saitama 350-1298, Japan.;Department of Diagnostic Pathology, Saitama Medical University International Medical Center, Hidaka, Saitama 350-1298, Japan.;Department of Uro-Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama 350-1298, Japan.",
"authors": "Umezawa|Yuta|Y|;Shirotake|Suguru|S|;Kaneko|Go|G|;Nishimoto|Koshiro|K|;Okada|Yoshitaka|Y|;Uchino|Akira|A|;Yasuda|Masanori|M|;Oyama|Masafumi|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2019.1820",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-9450",
"issue": "10(5)",
"journal": "Molecular and clinical oncology",
"keywords": "cancer autopsy; meningeal carcinomatosis bladder",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "506-510",
"pmc": null,
"pmid": "31007911",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article",
"references": "10071105;10434951;12622144;12814256;15822823;16632315;2032089;20572600;20622726;20679917;20689429;20740192;21766515;21941490;2219624;22550058;23292836;23588955;23717798;25928457;26112812;26834903;27375033;2795119;28494780;28625652;28881917;29407369;3992779;6952725;8319186;9266450",
"title": "Meningeal carcinomatosis from bladder cancer: A case report and review of the literature.",
"title_normalized": "meningeal carcinomatosis from bladder cancer a case report and review of the literature"
} | [
{
"companynumb": "JP-AMGEN-JPNSP2019073407",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": null,
... |
{
"abstract": "We report here a patient with stage IV mucosal melanoma treated with dual immune checkpoint inhibitor (ICI) therapy (Nivolumab/Ipilimumab) who experienced rapid disease progression and metastatic spread within three weeks of first infusion. Surprisingly, this patient also developed fulminant myocarditis within the same time frame. Immunohistochemical staining of the primary tumor and a metastatic omental lesion revealed robust CD8+ PD-1+ T cell infiltration after ICI treatment, as would be expected following immune activation. However, the CD8+ T cell infiltrate was largely negative for both Granzyme B and TIA-1, suggesting these T cells were not capable of effective tumor lysis. We discuss the possibility that heightened pro-inflammatory T cell activity (rather than tumor-directed cytolytic activity) was induced by anti-PD-1 and anti-CTLA-4, which could have provoked both rapid tumor resistance mechanisms and myocarditis. This case highlights the fact that the mere presence of tumor infiltrating lymphocytes (TILs) does not necessarily correlate to ICI response and that additional functional markers are necessary to differentiate between inflammatory and cytolytic CD8+ TILs.",
"affiliations": "Department of Immunology, Mayo Clinic, Rochester, MN, United States.;Dermatopathology Section, Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States.;Department of Radiation Oncology, Mayo Clinic, Rochester, MN, United States.;Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States.;Department of Immunology, Mayo Clinic, Rochester, MN, United States.;Division of Medical Oncology, Mayo Clinic, Rochester, MN, United States.",
"authors": "Barham|Whitney|W|;Guo|Ruifeng|R|;Park|Sean S|SS|;Herrmann|Joerg|J|;Dong|Haidong|H|;Yan|Yiyi|Y|",
"chemical_list": "D015415:Biomarkers; D014408:Biomarkers, Tumor; D000082082:Immune Checkpoint Inhibitors",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2020.561083",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224 Frontiers Media S.A. \n\n10.3389/fimmu.2020.561083\nImmunology\nCase Report\nCase Report: Simultaneous Hyperprogression and Fulminant Myocarditis in a Patient With Advanced Melanoma Following Treatment With Immune Checkpoint Inhibitor Therapy\nBarham Whitney \n1\n\n2\n Guo Ruifeng \n3\n Park Sean S. \n4\n Herrmann Joerg \n5\n Dong Haidong \n1\n\n6\n Yan Yiyi \n7\n\n*\n \n1\nDepartment of Immunology, Mayo Clinic, Rochester, MN, United States\n\n\n2\nMedical Scientist Training Program, Mayo Clinic, Rochester, MN, United States\n\n\n3\nDermatopathology Section, Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States\n\n\n4\nDepartment of Radiation Oncology, Mayo Clinic, Rochester, MN, United States\n\n\n5\nDepartment of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States\n\n\n6\nDepartment of Urology, Mayo Clinic, Rochester, MN, United States\n\n\n7\nDivision of Medical Oncology, Mayo Clinic, Rochester, MN, United States\n\nEdited by: José Mordoh, IIBBA-CONICET Leloir Institute Foundation, Argentina\n\nReviewed by: Rodabe N. Amaria, University of Texas MD Anderson Cancer Center, United States; William K. Decker, Baylor College of Medicine, United States\n\n*Correspondence: Yiyi Yan, Yan.Yiyi@mayo.edu\nThis article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology\n\n\n02 2 2021 \n2020 \n11 56108311 5 2020 17 12 2020 Copyright © 2021 Barham, Guo, Park, Herrmann, Dong and Yan2021Barham, Guo, Park, Herrmann, Dong and YanThis 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.We report here a patient with stage IV mucosal melanoma treated with dual immune checkpoint inhibitor (ICI) therapy (Nivolumab/Ipilimumab) who experienced rapid disease progression and metastatic spread within three weeks of first infusion. Surprisingly, this patient also developed fulminant myocarditis within the same time frame. Immunohistochemical staining of the primary tumor and a metastatic omental lesion revealed robust CD8+ PD-1+ T cell infiltration after ICI treatment, as would be expected following immune activation. However, the CD8+ T cell infiltrate was largely negative for both Granzyme B and TIA-1, suggesting these T cells were not capable of effective tumor lysis. We discuss the possibility that heightened pro-inflammatory T cell activity (rather than tumor-directed cytolytic activity) was induced by anti-PD-1 and anti-CTLA-4, which could have provoked both rapid tumor resistance mechanisms and myocarditis. This case highlights the fact that the mere presence of tumor infiltrating lymphocytes (TILs) does not necessarily correlate to ICI response and that additional functional markers are necessary to differentiate between inflammatory and cytolytic CD8+ TILs.\n\nmelanomaimmune checkpoint inhibitorshyperprogressionmyocarditiscytolytic T lymphocytescase reportNational Institutes of Health10.13039/100000002K12CA090628, R01 CA 200551, P30 CA 15083Richard M. Schulze Family Foundation10.13039/100007093\n==== Body\nIntroduction\nCytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death 1 ligand 1 (PD-L1) are immune-regulatory molecules which function to limit adaptive immune activity within the normal host. However, these “checks” on the immune system can be coopted by malignant cells to create an immunosuppressive environment and evade apoptosis induced by cytolytic T cells. Monoclonal antibodies that bind to CTLA-4, PD-1, and PD-L1 are designed to block these proteins from interacting with their respective binding partners, and are collectively known as immune checkpoint inhibitors (ICIs). Since their approval in 2011 (anti-CTLA-4) and 2014 (anti-PD-1/L1), ICIs have revolutionized the treatment of solid tumor malignancies including melanoma, non-small cell lung cancer, renal cell carcinoma, and gastric cancer, among others (1–6). A number of trials have reported striking results, as patients with stage IV metastatic cancers have had significant responses and achieved remission, some for extended periods of time (7, 8). However, the majority of patients treated do not respond, and some suffer significant adverse events such as inflammation of normal, non-tumor tissue (9). In addition, patients may experience accelerated growth of their tumor following ICI therapy, a phenomenon that has been termed hyperprogression (9–11). At present we cannot predict which patients may benefit from ICI and which patients will develop adverse effects.\n\nThe case presented here uniquely highlights this gap in knowledge, as our patient experienced both rapidly progressive metastatic disease and a life-threatening immune related adverse event (myocarditis) within three weeks of initiating ICI therapy. Our current understanding would predict that induction of a systemic immune response strong enough to manifest as myocarditis should lead to a clinical response in the form of tumor shrinkage. In this case, the opposite occurred, as evidenced by aggressive tumor spread. This emphasizes the urgent need for a better understanding of what factors are critical for coupling the immune response induced by ICI to a positive clinical outcome. We propose that the phenotype of CD8+ T cells activated by ICI therapy may be key in this determination.\n\nCase Presentation\nIn October 2018, a 79-year-old female experienced new onset postprandial abdominal cramping. Over the next several days, she noted constipation, dark stools, and vaginal bleeding. This prompted her to visit her local primary care provider who detected a vaginal wall lesion during physical exam, and excisional biopsy confirmed malignant mucosal melanoma. Staging PET/CT and pelvic MRI confirmed a 2.5 × 2.7 × 2.9 cm mass in the vaginal mucosa and pre-sacral lymph nodes which were later biopsy-confirmed metastases. No other distant metastasis was found. After this initial diagnosis and workup elsewhere, she presented to our clinic in February 2019 for a second opinion having received no prior treatment. The patient’s medical history, review of systems and physical exam at the time were unremarkable, except for moderate vaginal bleeding and discomfort near coccyx. Her ECOG performance was 0. Due to > 2 months lapse since her diagnosis without initiation of therapy, she was restaged with PET/CT which demonstrated distant osseous and visceral metastases involving lungs as well as progression of distant and regional nodal metastases and primary vagina melanoma (\nFigures 1A, B\n). Lactate dehydrogenase (LDH) level was elevated (564 U/L, upper limit of normal is 222 U/L). Foundation One® testing was performed on the primary tumor specimen, which revealed CDKN2A deletion, with no other mutations or alterations.\n\nFigure 1 Radiographic evidence of hyperprogression and inflammation following dual immune checkpoint inhibition. Pre-treatment CT chest with a lung metastasis (A); solid arrow) and a normal abdominal CT (B). Three weeks after ipilimumab and nivolumab, prior lung metastasis grew (C; solid arrow) and new metastasis developed (C; dotted arrow). In addition, abdominal distention, omental caking, peritoneal metastases, and pelvic ascites developed as shown in axial (D) and mid-sagittal (E) abdominal/pelvic CT.\n\nA single fraction palliative radiotherapy was delivered to vagina (10 Gy) and pelvic/para-aortic lymph nodes (8 Gy) to alleviate her vaginal bleeding and pelvic discomfort, respectively. Systemic therapy with ICI (3 mg/kg Nivolumab + 1 mg/kg Ipilimumab) was initiated concurrently. First infusion of ICI was uneventful, and patient returned three weeks later for follow-up and subsequent ICI cycle. LDH level remained elevated (365 U/L). Two days after her second infusion, she presented to the emergency department (ED) with complaints of dizziness, a light-headed “spell,” and abdominal bloating. She was hypoxic, and chest, abdominal, and pelvic CT showed rapid progression of known and new metastatic disease including omental caking, peritoneal metastases, pelvic ascites, and lung nodules (\nFigures 1C–E\n). CT-guided core biopsy of an omental mass confirmed metastatic melanoma. Given her rapid disease progression, carboplatin (AUC 2, day 1) and paclitaxel (60 mg/m2, days 1, 8, 15 every 28 days) was initiated as salvage therapy after the patient was medically stabilized.\n\nTwo days later, the patient presented again to the ED following a syncopal episode. While in the ED, she had two episodes of bradycardia in the 20s and progressed to complete heart block. She was given IV atropine and transferred to the Cardiac Critical Care Unit for an emergent pacemaker placement. Poor R wave sensing and consistently high thresholds upon multiple lead repositioning attempts caused the team to consider myocarditis, likely induced by ICI, which was later confirmed via endomyocardial biopsy. The patient was stabilized, but remained critically ill. Based on goals of care, she was discharged on corticosteroids to hospice care and passed away shortly afterwards.\n\nConsidering the significant disease progression within just three weeks of initiating dual ICI, we pursued further investigation of the tumor biopsy samples. Analysis of the initial primary vaginal melanoma specimen revealed epithelioid morphology, and tumor cell staining for PD-L1 was almost completely negative (\nFigure 2A\n). In contrast, the metastatic omental specimen from three weeks post-ICI exhibited small cell morphology, mimicking lymphocytes, and approximately 10% of tumor cells within the metastasis stained positive for PD-L1. Due to the drastic difference in morphology, we completed an additional stain demonstrating strong positivity of the metastatic tumor cells to a specific melanocytic marker (Mel-A), which confirmed the biopsy tissue was indeed metastatic melanoma (\nFigures 2B, C\n). Also consistent with rapid clinical and radiographic disease progression, the omental lesion was highly proliferative with 60% of cells staining positive for Ki67 (\nFigure 2C\n). In addition to progressive tumor expansion at metastatic sites, this patient also experienced the onset of grade 4 myocarditis which was confirmed by endomyocardial biopsy of the right ventricle. The biopsy demonstrated a solitary focus of interstitial lymphocytic infiltrate in association with focal myocyte injury (\nFigure 2D\n).\n\nFigure 2 Histological evaluation of tumor tissue and endomyocardial biopsy. H&E staining of the pre-treatment primary vaginal melanoma specimen (A) reveals epithelioid morphology and largely negative staining for PD-L1. This is in stark contrast to the metastatic omental specimen from three weeks post-ICI (B), which exhibited small cell morphology and was positive for PD-L1 (100× images, insets are 400×; clone 22C3 used for PD-L1 stain). The omental metastasis stained positive for Mel-A and Ki67 (C, 100× images). Endomyocardial biopsy confirms myocarditis (D, 100×).\n\nAssessment of the T cell infiltrate within the tumors revealed minimal CD8+ or PD-1+ T cells in the primary vaginal lesion (5–10% and 1% of total cells, respectively) (\nFigure 3A\n), which were predominantly distributed in the areas adjacent to rather than within the tumor foci. Interestingly, the metastatic omental specimen contained a much more robust CD8+ T cell infiltrate (~30% of total cells), which also showed a consistent staining pattern with PD-1, suggesting that the T cells were antigen-engaged (12, 13) (\nFigure 3B\n). Importantly, these lymphocytes were completely distributed within tumor foci. However, only a minority of the CD8+ T cells stained positive for the cytolytic granule protein Granzyme B (a serine-protease that mediates apoptosis in target cells) or TIA-1 (an RNA-binding protein associated with cytolytic granules), suggesting the CD8+ T cells were not capable of tumor cell killing. The presence of FoxP3+ cells was also assessed as others have reported that immunosuppressive regulatory T cells (Tregs) could be responsible for rapid progression following ICI (14). Treg component was minimal at approximately 3% of total cells in the most densely staining area (\nFigure 3B\n).\n\nFigure 3 Analysis of T cell infiltrate in pre and post treatment tumor tissue. CD8+, PD-1+ cells were essentially absent from the pre-treatment primary vaginal melanoma specimen (A), but were abundant in the metastatic omental specimen from three weeks post-ICI (B). The CD+PD-1+ T cells within the omental metastasis were largely negative for Granzyme B, T1A-1, and Foxp3 (All images 100×).\n\nDiscussion\nHerein we present a case of metastatic mucosal melanoma with rapid disease progression and myocarditis within three weeks of initiation of dual ICI therapy (\nFigure 4\n). Such phenomenon of accelerated tumor growth within months of starting ICI has recently been recognized and referred to as hyperprogression (9–11). The definition of hyperprogression is not widely agreed upon. Some use measurements of a target lesion over multiple time points to compute the pretreatment growth rate of the tumor vs. growth rate while on therapy, but the series of scans spaced at appropriate timepoints necessary to calculate these metrics limits the pool of patients that can practically be assessed. Lo Russo et al. used a more inclusive definition which categorizes patients as having hyperprogressive disease if they meet three of five clinical criteria (15). Our patient met three of these benchmarks, including: (i) time-to-treatment failure < 2 months; (ii) spread of the disease to a new organ between baseline and first radiologic evaluation; (iii) and clinical deterioration with decrease in ECOG performance status ≥ 2 during the first 2 months of treatment.\n\nFigure 4 Summary of case.\n\nNo common tumor mutations or disease characteristics have been identified among those who experience any form of this early, aggressive tumor growth while on ICI, and little has been elucidated in terms of a mechanism for how this may happen. In fact, the occurrence of true ICI-induced hyperprogression has been questioned altogether, as the accelerated tumor growth could be the result of factors intrinsic to the tumor itself which would lead to rapid growth over time even without the initiation of ICI (16). To this end, recent communication from Bristol Meyer Squibb highlights data from their CheckMate 451 and ATTRACTION-2 clinical trials which show that hyperprogression can be found at similar incidence in both placebo and ICI-treated patients (17, 18).\n\nThough there is controversy surrounding whether ICI-directly causes rapid tumor progression in any or all of the “hyperprogression” cases in the literature, there is still relative agreement on the fact that a small subset of patients do very poorly on ICI, and progress quickly, whatever the root cause. Thus, even if ICI is not having a direct detrimental effect, it is obvious that some tumors are able to continue growing rapidly, un-checked by the immune system, even though therapy is being given to stimulate an immune response. Some might argue that in these cases no immune response is ever being induced, perhaps due to lack of appropriate antigen expression or failure of lymphocytes to infiltrate into the tumor. That is why we found this case particularly interesting: there was an obvious immune related side-effect (myocarditis) which confirms that at least systemically, the ICI therapy had a strong immune-stimulatory impact. Thus, the question remains: why was this immune response so ineffective? It was unable to contain the tumor, despite creating a massive inflammatory side-effect in the cardiac tissue. Below we discuss possible immunological mechanisms that would connect an immune response induced by ICI to the development of both the aggressive metastatic disease as well as the myocarditis. While there are some supportive lines of evidence for this from the literature, it should be stated that we certainly cannot prove a causal connection.\n\nIt has been reported that anti-PD-1 therapy could be paradoxically enhancing immunosuppression through Tregs or myeloid cells, rather than enhancing anti-tumor activity through CD8+ T cells (14, 15). This is in contrast to our patient, as analysis of post-treatment tumor tissue revealed an active immune environment with scant Tregs and significantly greater numbers of CD8+ TILs. These TILs appear to have been stimulated with antigen, given their PD-1+ status, and were likely secreting cytokines, given the up-regulation of PD-L1 on the tumor cells, which can be seen in response to IFN-gamma secretion by CD8+ T cells (19, 20). Though CD8+ T cells are thought to be the primary mediators of the anti-tumor effects following ICI, it is apparent that a mere increase in tumor infiltrating cell counts does not correlate with better prognosis (21). This may be because all CD8+ T cells are not equal in their ability to eliminate tumors. Indeed, recent studies have suggested that an entire spectrum of PD-1+, antigen-stimulated CD8+ T cells exist, with phenotypes that range from “stem-like” to “effector” to “truly exhausted,” all of which differ in their cytolytic abilities (22, 23). Thus, it is plausible that certain patients possess a group of T cells that are both tumor-specific and PD-1 positive, but functionally unable to kill. In the presence of anti-PD-1 or anti-CTLA-4 therapy these cells may increase their cytokine production, kindling the tumor rather than killing it. Stein et al. recently tested this hypothesis in a breast cancer model, in which they show that tumor cell interactions with nonlytic T cells, which secrete inflammatory cytokines but lack cytolytic granules, were able to induce signatures characteristic for adaptive immune resistance and tissue regeneration in breast cancer cells (24). These changes were induced rapidly (within hours of co-culture), and resulted in faster tumor outgrowth and increased metastatic spread when the cells were injected in vivo. Thus, if inflammatory signaling outweighs cytolytic competency, CD8+ T cells themselves could lead to tumor resistance and accelerated tumor progression. Interestingly, our staining showed an absence of both Granzyme B and TIA-1 staining within the CD8+ T cells infiltrating the metastatic lesion, suggesting they lack tumor-killing capabilities and could have instead been the source of cytokines that induced rapid resistance.\n\nKim et al. provide additional evidence that the relative abundance of different functional phenotypes of T cells prior to therapy can determine whether a tumor might hyperprogress. Using 144 pre-treatment peripheral blood samples from patients with NSCLC, they found that lower frequency of effector/memory subsets (CD8+CCR7−CD45RA−) and higher frequency of “severely exhausted” (CD8+TIGIT+PD-1+) T cells were associated with hyperprogressive disease (25). Similarly, changes in CD4+ T cell profiles before and after treatment differentiated responders, non-responders, and hyperprogressors in a prospective study of NSCLC patients (26). Thus, the findings from our case as well as these larger cohorts highlight the need for better immune-monitoring tools that can assess the functional capabilities of T lymphocytes in tumor biopsies and in the peripheral blood prior to initiation of ICI. Here we have used Granzyme B and TIA-1, which have been used previously to assess cytolytic capacity, but additional tools are needed (27, 28). Ideally, we would have the ability to determine not only the number and frequency of CD8+ T cell subsets, but also whether they contain the appropriate machinery to induce cytotoxicity once activated by ICI. This could be important for identifying those patients who may hyperprogress and also for determining what molecules need to be restored in T cells in order to increase positive response rates to these therapies.\n\nWhile experiencing rapid tumor growth and metastatic spread, our patient also developed fulminant myocarditis secondary to immune checkpoint blockade. Several studies have shown a correlation between immune-related adverse events (irAEs) and response to ICI, while others have found no such relationship (29, 30). Myocarditis is an irAE observed in approximately 1% of patients on ICI therapy (31, 32). It most often occurs in the first 30 days after initiation of therapy, as it did in our patient (32). To our knowledge this is the first report of simultaneous rapid acceleration of tumor growth and irAE myocarditis experienced by the same patient. Given the immune status of the metastatic lesion, this may reflect heightened inflammatory T cell activity, induced by anti-PD-1 and anti-CTLA-4, which could have resulted in both rapid tumor resistance mechanisms and myocarditis. The number, type, and timing of irAEs experienced by patients who hyperprogress have not been reported in the studies published to date. It would be interesting to determine if a subset of hyperprogressors also experience rapidly induced irAEs, and if these patients perhaps share a common hyper-inflammatory mechanism.\n\nThough we were able to compare staining of the pre-treatment and post-treatment samples from this patient for a number of immune-relevant markers, tissue sections were limited, especially of the primary tumor and the endomyocardial biopsy. This prevented us from doing further analysis of myeloid populations or cytokine molecules and from assessing clonality of the T cells infiltrating the tumor tissues vs. the heart to determine if they were related. We also lacked pre- and post-treatment peripheral blood samples which would have facilitated comparison of immune cell populations via flow cytometry with the immunohistochemistry (IHC) staining in the tumor tissues. Despite these limitations, this case provides intriguing evidence that suggests CD8+ T cell infiltration and activation can be concurrent with rapid disease progression following ICI. We conclude that assessment of inflammatory vs. cytolytic function of CD8+ T cells may be critical for determining why some tumors continue to progress despite ICI-therapy, and could give insight into why patients experience severe irAEs.\n\nData Availability Statement\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by Mayo Clinic Institutional Review Board. 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\nYY was the patient’s medical oncology provider and initiated the research. SP completed the radiological analysis. RG completed the histological and pathological tissue analysis. WB wrote the paper. WB, RG, SP, JH, HD, and YY critically evaluated data, reviewed the paper, and approved the final version of the article to be published. All authors contributed to the article and approved the submitted version.\n\nFunding\nThis work was supported by K12CA090628 (YY), The Richard M. Schulze Family Foundation Award in Cancer Research (HD), R01 CA 200551 (SP and HD), P30 CA 15083 (HD).\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\nAcknowledgments\nThe authors thank the patient and her family for allowing the publication of this work. \nFigure 4\n was created using BioRender.com.\n==== Refs\nReferences\n1 \nPoole RM \nPembrolizumab: first global approval\n. Drugs (2014 ) 74 (16 ):1973–81. 10.1007/s40265-014-0314-5 \n\n2 \nFashoyin-Aje L Donoghue M Chen H He K Veeraraghavan J Goldberg KB \nFDA Approval Summary: Pembrolizumab for Recurrent Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma Expressing PD-L1\n. Oncologist (2019 ) 24 (1 ):103–9. 10.1634/theoncologist.2018-0221 \n\n3 \nPai-Scherf L Blumenthal GM Li H Subramaniam S Mishra-Kalyani PS He K \nFDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond\n. Oncologist (2017 ) 22 (11 ):1392–9. 10.1634/theoncologist.2017-0078 \n\n4 \nKazandjian D Suzman DL Blumenthal G Mushti S He K Libeg M \nFDA Approval Summary: Nivolumab for the Treatment of Metastatic Non-Small Cell Lung Cancer With Progression On or After Platinum-Based Chemotherapy\n. Oncologist (2016 ) 21 (5 ):634–42. 10.1634/theoncologist.2015-0507 \n\n5 \nMcDermott DF Lee JL Szczylik C Donskov F Malik J Alekseev BY \nPembrolizumab monotherapy as first-line therapy in advanced clear cell renal cell carcinoma (accRCC): Results from cohort A of KEYNOTE-427\n. J Clin Oncol (2018 ) 36 (15 ):4500–4500. 10.1200/JCO.2018.36.15_suppl.4500 \n\n6 \nMotzer RJ Escudier B McDermott DF George S Hammers HJ Srinivas S \nNivolumab versus Everolimus in Advanced Renal-Cell Carcinoma\n. N Engl J Med (2015 ) 373 (19 ):1803–13. 10.1056/NEJMoa1510665 \n\n7 \nFischer S Ali OH Jochum W Kluckert T Flatz L Siano M \nAnti-PD-1 Therapy Leads to Near-Complete Remission in a Patient with Metastatic Basal Cell Carcinoma\n. Oncol Res Treat (2018 ) 41 (6 ):391–4. 10.1159/000487084 \n\n8 \nGauci ML Lanoy E Champiat S Caramella C Ammari S Aspeslagh S \nLong-Term Survival in Patients Responding to Anti-PD-1/PD-L1 Therapy and Disease Outcome upon Treatment Discontinuation\n. Clin Cancer Res (2019 ) 25 (3 ):946–56. 10.1158/1078-0432.CCR-18-0793 \n\n9 \nChampiat S Dercle L Ammari S Massard C Hollebecque A Postel-Vinay S \nHyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated by Anti-PD-1/PD-L1\n. Clin Cancer Res (2017 ) 23 (8 ):1920–8. 10.1158/1078-0432.CCR-16-1741 \n\n10 \nFerrara R Mezquita L Texier M Lahmar J Audigier-Valette C Tessonnier L \nHyperprogressive Disease in Patients With Advanced Non-Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy\n. JAMA Oncol (2018 ) 4 (11 ):1543–52. 10.1001/jamaoncol.2018.3676 \n\n11 \nBorcoman E Nandikolla A Long G Goel S Le Tourneau C \nPatterns of Response and Progression to Immunotherapy\n. Am Soc Clin Oncol Educ Book (2018 ) 38 :169–78. 10.1200/EDBK_200643 \n\n12 \nAgata Y Kawasaki A Nishimura H Ishida Y Tsubata T Yagita H \nExpression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes\n. Int Immunol (1996 ) 8 (5 ):765–72. 10.1093/intimm/8.5.765 \n\n13 \nVibhakar R Juan G Traganos F Darzynkiewicz Z Finger LR \nActivation-induced expression of human programmed death-1 gene in T-lymphocytes\n. Exp Cell Res (1997 ) 232 (1 ):25–8. 10.1006/excr.1997.3493 \n\n14 \nKamada T Togashi Y Tay C Ha D Sasaki A Nakamura Y \nPD-1(+) regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer\n. Proc Natl Acad Sci U S A (2019 ) 116 (20 ):9999 –10008\n. 10.1073/pnas.1822001116 \n31028147 \n15 \nLo Russo G Moro M Sommariva M Cancila V Boeri M Centonze G \nAntibody-Fc/FcR Interaction on Macrophages as a Mechanism for Hyperprogressive Disease in Non-small Cell Lung Cancer Subsequent to PD-1/PD-L1 Blockade\n. Clin Cancer Res (2019 ) 25 (3 ):989–99. 10.1158/1078-0432.CCR-18-1390 \n\n16 \nPearson AT Sweis RF \nHyperprogression-Immunotherapy-Related Phenomenon vs Intrinsic Natural History of Cancer\n. JAMA Oncol (2019 ) 5 (5 ):743 . 10.1001/jamaoncol.2019.0130 \n30896751 \n17 \nReck M Feng Y Kim HR Plautz G Kang YK Owonikoko TK \nAnalysis of tumour hyperprogression (HP) with nivolumab (Nivo) in randomized, placebo (Pbo)-controlled trials\n. Ann Oncol (2019 ) 30 (suppl_5):v475–532. 10.1093/annonc/mdz253 \n\n18 \nBerry S Giraldo N Nguyen P Green B Xu H Ogurtsova A \nCorrection to: 33rd Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2018)\n. J Immunother Cancer (2019 ) 7 (1 ):46 . 10.1186/s40425-019-0519-y \n30760319 \n19 \nAbiko K Matsumura N Hamanishi J Horikawa N Murakami R Yamaguchi K \nIFN-gamma from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer\n. Br J Cancer (2015 ) 112 (9 ):1501–9. 10.1038/bjc.2015.101 \n\n20 \nSpranger S Spaapen RM Zha Y Williams J Meng Y Ha TT \nUp-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells\n. Sci Transl Med (2013 ) 5 (200 ):200ra116 . 10.1126/scitranslmed.3006504 \n\n21 \nNakano O Sato M Naito Y Suzuki K Orikasa S Aizawa M \nProliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity\n. Cancer Res (2001 ) 61 (13 ):5132–6.\n22 \nJansen CS Prokhnevska N Master VA Sanda MG Carlisle JW Bilen MA \nAn intra-tumoral niche maintains and differentiates stem-like CD8 T cells\n. Nature (2019 ) 576 (7787 ):465–70. 10.1038/s41586-019-1836-5 \n\n23 \nMiller BC Sen DR Al Abosy R Bi K Virkud YV LaFleur MW \nSubsets of exhausted CD8(+) T cells differentially mediate tumor control and respond to checkpoint blockade\n. Nat Immunol (2019 ) 20 (3 ):326–36. 10.1038/s41590-019-0312-6 \n\n24 \nStein RG Ebert S Schlahsa L Scholz CJ Braun M Hauck P \nCognate Nonlytic Interactions between CD8(+) T Cells and Breast Cancer Cells Induce Cancer Stem Cell-like Properties\n. Cancer Res (2019 ) 79 (7 ):1507–19. 10.1158/0008-5472.CAN-18-0387 \n\n25 \nKim CG Kim KH Pyo KH Xin CF Hong MH Ahn BC \nHyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer\n. Ann Oncol (2019 ) 30 (7 ):1104–13. 10.1093/annonc/mdz123 \n\n26 \nArasanz H Zuazo M Bocanegra A Gato M Martinez-Aguillo M Morilla I \nEarly Detection of Hyperprogressive Disease in Non-Small Cell Lung Cancer by Monitoring of Systemic T Cell Dynamics\n. Cancers (Basel) (2020 ) 12 (2 ):344 . 10.3390/cancers12020344 \n\n27 \nLipson EJ Lilo MT Ogurtsova A Esandrio J Xu H Brothers P \nBasal cell carcinoma: PD-L1/PD-1 checkpoint expression and tumor regression after PD-1 blockade\n. J Immunother Cancer (2017 ) 5 :23 . 10.1186/s40425-017-0228-3 \n28344809 \n28 \nSabbatino F Marra A Liguori L Scognamiglio G Fusciello C Botti G \nResistance to anti-PD-1-based immunotherapy in basal cell carcinoma: a case report and review of the literature\n. J Immunother Cancer (2018 ) 6 (1 ):126 . 10.1186/s40425-018-0439-2 \n30458852 \n29 \nAttia P Phan GQ Maker AV Robinson MR Quezado MM Yang JC \nAutoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4\n. J Clin Oncol (2005 ) 23 (25 ):6043–53. 10.1200/JCO.2005.06.205 \n\n30 \nHorvat TZ Adel NG Dang TO Momtaz P Postow MA Callahan MK \nImmune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center\n. J Clin Oncol (2015 ) 33 (28 ):3193–8. 10.1200/JCO.2015.60.8448 \n\n31 \nJohnson DB Balko JM Compton ML Chalkias S Gorham J Xu Y \nFulminant Myocarditis with Combination Immune Checkpoint Blockade\n. N Engl J Med (2016 ) 375 (18 ):1749–55. 10.1056/NEJMoa1609214 \n\n32 \nMahmood SS Fradley MG Cohen JV Nohria A Reynolds KL Heinzerling LM \nMyocarditis in Patients Treated With Immune Checkpoint Inhibitors\n. J Am Coll Cardiol (2018 ) 71 (16 ):1755–64. 10.1016/j.jacc.2018.02.037\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "11()",
"journal": "Frontiers in immunology",
"keywords": "case report; cytolytic T lymphocytes; hyperprogression; immune checkpoint inhibitors; melanoma; myocarditis",
"medline_ta": "Front Immunol",
"mesh_terms": "D000368:Aged; D015415:Biomarkers; D014408:Biomarkers, Tumor; D001706:Biopsy; D019468:Disease Management; D018450:Disease Progression; D004198:Disease Susceptibility; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008545:Melanoma; D064847:Multimodal Imaging; D009205:Myocarditis; D016176:T-Lymphocyte Subsets",
"nlm_unique_id": "101560960",
"other_id": null,
"pages": "561083",
"pmc": null,
"pmid": "33603731",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "29567210;30206165;27806233;16087944;30760319;29734143;11431351;30896751;30120163;32033028;26406148;30692216;30297458;26282644;9141617;30778252;25867264;8671665;30231380;30977778;26984449;25331768;28835513;31827286;27827313;28344809;31028147;23986400;30458852;30193240",
"title": "Case Report: Simultaneous Hyperprogression and Fulminant Myocarditis in a Patient With Advanced Melanoma Following Treatment With Immune Checkpoint Inhibitor Therapy.",
"title_normalized": "case report simultaneous hyperprogression and fulminant myocarditis in a patient with advanced melanoma following treatment with immune checkpoint inhibitor therapy"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-024700",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "This report describes the successful transition of two familial patients with HAE from injectable to oral prophylaxis without tapering prior therapy or employing a complex transition protocol.",
"affiliations": "Asthma and Allergy Associates Colorado Springs Colorado USA.;Asthma and Allergy Associates Colorado Springs Colorado USA.",
"authors": "Soteres|Daniel F|DF|https://orcid.org/0000-0002-7433-0171;Grimes|Fellicia|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.5086",
"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/ccr3.5086\nCCR35086\nCase Report\nCase Report\nPatient and caregiver perspectives on transitioning to oral prophylaxis in the emerging hereditary angioedema treatment landscape\nSOTERES and GRIMES\nSoteres Daniel F. https://orcid.org/0000-0002-7433-0171\n1 DSoteres@aacos.com\n\nGrimes Fellicia 1\n1 Asthma and Allergy Associates Colorado Springs Colorado USA\n* Correspondence\nDaniel F. Soteres, Asthma and Allergy Associates, 2709 N. Tejon Street Colorado Springs, CO 80907, USA.\nEmail DSoteres@aacos.com\n\n16 11 2021\n11 2021\n9 11 10.1002/ccr3.v9.11 e0508617 8 2021\n31 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\nThis report describes the successful transition of two familial patients with HAE from injectable to oral prophylaxis without tapering prior therapy or employing a complex transition protocol.\n\nThis report describes the successful transition of two familial patients with HAE from injectable to oral prophylaxis without tapering prior therapy or employing a complex transition protocol.\n\nberotralstat\nHaegarda\nhereditary angioedema\nshared decision‐making\nswitching\ntreatment burden\nBioCryst 10.13039/100014935 source-schema-version-number2.0\ncover-dateNovember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.9 mode:remove_FC converted:16.11.2021\nSoteres DF , Grimes F . Patient and caregiver perspectives on transitioning to oral prophylaxis in the emerging hereditary angioedema treatment landscape. Clin Case Rep. 2021;9 :e5086. doi:10.1002/ccr3.5086\n\nFunding information\n\nBioCryst funded the APeX‐S study and provided financial support for writing assistance and publication of this case series.\n==== Body\npmc1 INTRODUCTION\n\nIn this study, we describe the experiences of a mother and daughter pair with HAE who transitioned from a long‐term injectable prophylactic treatment to oral berotralstat while enrolled in the APeX‐S (NCT03472040) study. Both patients safely transitioned to berotralstat monotherapy without tapering prior therapy or employing a complex transition protocol.\n\nHereditary angioedema (HAE) is a rare inherited disorder affecting an estimated 1 in 50,000 individuals worldwide. 1 , 2 It is characterized by recurrent, debilitating episodes of swelling in various parts of the body, such as the extremities, face, gastrointestinal (GI) system, and larynx (which can be life‐threatening). 3 , 4 Type 1 and type 2 HAE are caused by an inherited (~75% of cases) or sporadic (~25% of cases) deleterious mutation in the gene coding for the C1 esterase inhibitor (C1‐INH) protein, resulting in either a protein deficiency (type 1) or a dysfunctional protein (type 2). 3 , 4 C1‐INH is a serine protease inhibitor that plays an important role in regulating the kallikrein–bradykinin cascade involved in stimulating blood vessel permeability. When C1‐INH activity is reduced, bradykinin production increases, enhancing blood vessel permeability and triggering episodes of angioedema. 3\n\nThere is no cure for HAE; therefore, therapeutic strategies focus on preventing (prophylactic) or treating (on‐demand) HAE attacks. 1 , 4 Many patients whose symptoms are not well controlled choose to receive long‐term prophylactic therapy supplemented by on‐demand treatment for breakthrough attacks. 1 , 4 Prophylactic therapy options have expanded rapidly in the past decade to now include two plasma‐derived C1‐INH concentrates, CINRYZE® (C1‐INH) and HAEGARDA® (subcutaneously delivered C1‐INH; C1‐INH‐SC), and two specific plasma kallikrein inhibitors, namely, TAKHZYRO™ (lanadelumab) and ORLADEYO™ (berotralstat). 5 , 6 , 7 , 8 Prior to these approvals, long‐term prophylactic HAE treatment options were restricted to attenuated androgens, which are associated with an adverse toxicity profile, and tranexamic acid, which has demonstrated limited efficacy as a preventive therapy. 1\n\nAdvances in the treatment of HAE prophylaxis have greatly benefited patients by reducing symptoms and enabling self‐administration at home, which has increased patient satisfaction and quality of life. 6 , 7 , 9 , 10 , 11 Despite these advances, some patients with HAE in the United States still experience a high burden of illness that affects their work and other activities. 12 Many patients with HAE report having an informal caregiver, most commonly a family member with HAE, who assists in their HAE‐related medical care. 13 , 14 Patients with HAE can also experience burdens related to repetitive long‐term injectable treatments such as lanadelumab and C1‐INH‐SC, which are administered subcutaneously and can be burdensome, inconvenient, and associated with injection‐site reactions. 9 , 10 , 15 In a 2018 report by the Center for Biologics Evaluation and Research and the U.S. Food and Drug Administration, patients with HAE considered the route of treatment administration to be an important factor in making treatment decisions, with oral preferred over subcutaneous (SC) administration and SC preferred over intravenous. 16\n\nBerotralstat, an orally available selective plasma kallikrein inhibitor for patients aged 12 years or older, provides patients with a safe and effective oral prophylactic option. 8 In a 24‐week, double‐blind, placebo‐controlled phase 3 clinical trial (APeX‐2), the safety and efficacy of berotralstat (110 mg and 150 mg doses) were assessed in 121 patients aged ≥12 years old with type 1 or type 2 HAE. 17 Both doses demonstrated a significant reduction in HAE attack rate compared with placebo; at week 24, the placebo group experienced an average of 2.35 attacks/month (baseline: 2.91 attacks/month), whereas the 110 mg group experienced an average of 1.65 attacks/month (p = 0.024; baseline: 2.97 attacks/month), and the 150 mg group experienced an average of 1.31 attacks/month (p < 0.001; baseline: 3.06 attacks/month). 17 The most frequent adverse events (AEs) that occurred in ≥10% of patients in any treatment arm were upper respiratory tract infection, nausea, abdominal pain, vomiting, diarrhea, headache, and back pain, but no serious drug‐related AEs were observed in the study. 17 The long‐term safety, effectiveness, and impact on the quality of life of oral berotralstat are being investigated further in an ongoing open‐label study in patients with type 1 or type 2 HAE who are ≥12 years of age (APeX‐S; NCT03472040). 18 The primary endpoint of the study is safety, and the secondary endpoints of the study are efficacy and quality of life. 19 Patients received open‐label berotralstat 110 mg or 150 mg; following the results from the APeX‐2 trial showing superior efficacy at 150 mg, patients on 110 mg were switched to the 150 mg dose. All data included in the following case reports are interim data from the APeX‐S trial.\n\nWith a new oral option available, some patients who are averse to scheduled injections may wish to switch from their long‐term injectable prophylactic medication to berotralstat. Currently, there is no consensus provided in the US HAE guidelines on how to transition patients from one long‐term prophylactic medication to another. 1 Patients and physicians may have concerns about the safety and efficacy associated with switching prophylactic treatments, which may include concerns over possible worsening of symptoms and consequences of abruptly discontinuing one medication and initiating a new medication. It is important for patients to be involved in the decision to switch treatment and how and when the switch will occur to maximize safety and minimize patient anxiety. 1 In this study, we report on two familial cases (daughter and mother) from the APeX‐S trial, describing patient and caregiver experiences with transitioning from previous SC prophylactic treatment to oral berotralstat monotherapy as a long‐term prophylactic therapy.\n\n2 METHODS\n\nThis study conformed to the Declaration of Helsinki, and both patients provided informed consent prior to their inclusion in the study.\n\nTwo questionnaires, one patient and one caregiver, were developed by the authors regarding patient and caregiver experiences with prophylactic transition from C1‐INH‐SC to berotralstat. The patient questionnaire consisted of ten open‐ended questions, and the caregiver questionnaire consisted of three open‐ended questions. Interviews were conducted by the author Fellicia Grimes via web call a few months after the berotralstat transition. Open‐ended responses were provided by each patient/caregiver, and quotes from responses were used in the narrative provided in each case report.\n\n2.1 Case 1: Daughter (adolescent patient)\n\nCase 1 reports on a 13‐year‐old girl with type 1 HAE who was initially diagnosed at age 10. Her first prophylactic therapy was C1‐INH‐SC; 2,000 units injected subcutaneously every 4 days, which she received for 23 months prior to her entry in the APeX‐S study. Regular C1‐INH‐SC treatments worked well; in her words: “I barely had any attacks.” She decided to enroll in the APeX‐S trial “Because I would rather take a pill than take an injection twice a week.” After enrollment in the study, she initiated berotralstat therapy (150 mg once‐daily oral pill) while continuing her regular C1‐INH‐SC treatment schedule. Initially, she experienced mild GI discomfort related to berotralstat if she did not take the pill with a full meal. In her words: “If I forgot to take it at dinner and just took it with a snack, I would have a stomachache.” She did not take any medication to alleviate the discomfort, but she switched to consistently taking berotralstat with dinner, and her symptoms resolved. She continued to receive dual therapy (full doses of C1‐INH‐SC plus berotralstat) for ~4 months with no additional adverse effects or HAE attacks experienced.\n\nShe then decided to switch to single‐agent berotralstat because she “did not like taking injections, and a pill sounded easier and saved more time.” She noted that prior to the switch, “I was a little nervous, as I did not want to start swelling up again.” A smooth transition to oral berotralstat was achieved by discontinuing C1‐INH‐SC injections without tapering dose or reducing injection frequency. The patient did not report any challenges with this transition method.\n\nThe patient has received berotralstat monotherapy for ~3 months and experienced one HAE attack during that period. In her words: “I had an attack in my hand, but I am not sure what caused it.” The attack was treated with one dose of her usual on‐demand therapy, intravenous RUCONEST® [C1‐INH (recombinant)], which resolved the symptoms within a few hours. Since transitioning to oral monotherapy, she described improvements to her quality of life: “I am doing great! I have not had any reactions and do prefer taking a pill to an injection.” and “When I was on [C1‐INH‐SC], I couldn't do extracurricular activities Wednesday nights and now I can.” A summary of treatment durations and HAE attacks experienced by Patient 1 is provided in Table 1.\n\nTABLE 1 Number of attacks experienced during prophylactic treatment periods\n\n\tC1‐INH‐SC monotherapy\tDual therapy\tBerotralstat monotherapy a\t\nPatient 1\t\nDuration of treatment\t23 months\t4 months\t3 months\t\nNumber of attacks\t1\t0\t1\t\nPatient 2\t\nDuration of treatment\t9 months\t3.5 months\t4 months\t\nNumber of attacks\t2\t0\t1\t\nAbbreviation: C1‐INH‐SC, subcutaneously delivered C1 esterase inhibitor.\n\na Berotralstat monotherapy still ongoing.\n\nJohn Wiley & Sons, Ltd\n\n2.2 Case 2: Mother (patient and caregiver)\n\nCase 2 reports on a 41‐year‐old woman with type 1 HAE who was initially diagnosed at age 14. She is the mother and primary caregiver of the adolescent patient in Case 1 and one other child with HAE (who was too young to enroll in the APeX‐S study at the time); thus, there are three individuals with HAE in her household. Her perspectives as a patient and a caregiver will be described in this section.\n\n2.3 Patient perspective\n\nAs a patient, she previously received 6 months of weekly prophylactic intravenous injections of C1‐INH (recombinant). The injections were challenging; in her words: “my husband had to do it; I couldn't do it on myself, which was difficult.” She then switched to C1‐INH‐SC prophylaxis (5,000 units injected subcutaneously every 4 days), which she received for 9 months prior to enrolling in the APeX‐S trial. She experienced two HAE attacks during this 9‐month period. In describing the switch to C1‐INH‐SC, she said, “I don't know if it was necessarily better, but it was easier. I could give it to myself and it took a lot less time and a lot less prep.”\n\nShe decided to enroll in the APeX‐S trial because “I do not like taking injections. The process is cumbersome and requires more planning and time than a pill. With three of us needing medication and supplies, it takes up traveling space and time.” After enrollment, she initiated berotralstat therapy (150 mg once‐daily oral pill) while continuing her regular C1‐INH‐SC treatment schedule. She has regularly taken her pill with her largest meal of the day (dinner), but she occasionally experiences an “upset stomach, almost like indigestion” depending on the composition of the meal she consumes with her pill. In her words: “I don't notice it all the time; it depends on what I eat. If I tend to make poorer choices about what I eat, then it tends to be worse. It's not even just the medication doing it, it is more likely the diet.” She did not treat the discomfort with any medication. She received dual therapy (full doses of C1‐INH‐SC plus berotralstat) for ~3.5 months, which, in her words, “worked really well. I actually didn't experience any attacks at all while I was on the dual therapy.”\n\nShe decided to transition to berotralstat monotherapy because “I wanted to see if a pill would work on its own. I hadn't had attacks for some time, so I didn't mind taking a minor risk to see if a tablet would be enough [to control my symptoms].” She was “mildly concerned about having attacks return” if she switched to single‐agent therapy. The transition to the single‐agent berotralstat was achieved by immediate discontinuation of C1‐INH‐SC injections without tapering dose or reducing injection frequency, which did not present with any new challenges to the patient.\n\nShe has received berotralstat monotherapy for ~4 months and has experienced one HAE attack (abdominal) during that period, which responded well to her usual on‐demand therapy [(C1‐INH (recombinant)]. When describing the HAE attack, she said, “On demand worked the same; within 2–2.5 h, I was feeling better.”\n\nSince transitioning to oral monotherapy, she described the impact on her quality of life: “I got some time back, and I don't have to worry about planning my injection around plans” and “It's much more convenient, much easier, and requires less preparation and planning.” In her words: “Most people, including myself, would much rather take a pill to control this, daily, than have to come up with twice‐a‐week injections.” A summary of treatment durations and HAE attacks experienced by Patient 2 is provided in Table 1.\n\n2.4 Caregiver perspective\n\nWhen describing her experiences as a caregiver prior to her daughter switching to berotralstat monotherapy, she noted, “It was a little stressful at times. If they did have an attack, we had to give intravenous injections, which is much harder to give in kids.” Also, she mentioned that “On [C1‐INH‐SC], we would all have to take injections together, so it was extremely time consuming. We made it part of our routine.” She also described travel constraints: “Any time we would have to travel … we had to take our rescue meds and [C1‐INH‐SC] with us.”\n\nWhen describing her experiences as a caregiver after her daughter switched to berotralstat monotherapy, she reported, “It takes a lot less time. Even having one kid take the pill has been much easier.” She added, “It's made it easier to take care of normal life things, without having something get in the way. It's not even noticeable to take a pill; it takes two seconds as opposed to this huge ordeal of mixing medication, injecting it, etc.” She described reduced anxiety and stress as a caregiver: “It's less stress on everyone. It's a lot easier to make the decision to let her travel independently. I don't have to worry about her taking that medication on a plane or injecting it in a hotel room with a bunch of kids.”\n\nShe described changes in the quality of life of her daughter since switching to berotralstat monotherapy: “She loves it, she enjoys it; she has never liked needles.” She added, “She would much rather take a pill because it doesn't interfere with her other activities.”\n\n3 DISCUSSION\n\nIn this study, we report on a mother and daughter with type 1 HAE who safely transitioned from C1‐INH‐SC to berotralstat prophylaxis. Both patients decided to switch to berotralstat treatment because they desired more personal time and freedom from injections. While in the APeX‐S trial, both patients overlapped therapies until they transitioned to berotralstat monotherapy (Table 1). It is important to note that this extended dual therapy period occurred during a clinical trial and is not medically necessary for transition to berotralstat in clinical practice; berotralstat reaches a steady state after 6–12 days of once‐daily dosing. 8 No drug‐to‐drug interactions were observed for either patient during the dual therapy phase. Of note, C1‐INH‐SC treatments were not tapered prior to discontinuation and no changes in attack rate were observed during or immediately after the transition to berotralstat monotherapy. As of April 1, 2021, both patients remained on berotralstat monotherapy, experiencing only one attack each since transitioning (3‐ to 4‐month period); both attacks responded well to the usual on‐demand treatments of the patients.\n\nAfter the initiation of berotralstat, both patients experienced occasional, mild abdominal discomfort when taking the capsule with certain foods (mother) or not enough food (daughter). These symptoms resolved for the mother when she chose healthier meal options and for the daughter when she took the capsule with a full meal (dinner). In the APeX‐2 study, the most common adverse events associated with berotralstat were GI related; however, these symptoms were generally mild and well tolerated and typically resolved on their own without the use of concomitant medication. 8 , 20\n\nInitially, the patients had some concerns about the possibility of emergent attacks during the transition period, but the availability of on‐demand treatment eased these concerns. Both patients noted general improvements in quality of life after switching to oral berotralstat monotherapy, including increased independence from their disease and time gained from discontinuing their regular injections. The mother also described additional benefits as a caregiver, such as less stress, anxiety, and planning around the scheduled injections of her daughter.\n\nCurrently, there is a lack of consensus guidelines and related literature on the topic of HAE prophylactic transition, likely because most of the new therapies have only become available in the United States in recent years. The rapid expansion of the HAE prophylactic armamentarium has increased the complexity of prophylactic care, with new medications having different mechanisms of action, formulations, dosing schedules, and associated adverse effects. Therefore, making decisions about prophylactic HAE therapies requires effective communication between patient, physician, and caregiver to guide treatment decisions that consider all aspects of the treatment goals of the patient. Shared decision‐making and a personalized approach were taken with the patient treatment plans reported here. The treatment goals for both the patients and the physician were to optimize disease management and reduce the overall burden of disease and treatment.\n\nIn the absence of consensus guidelines, this case series provides two examples of patients who switched from C1‐INH‐SC to berotralstat safely. However, both patients transitioned to berotralstat in a clinical trial and their experiences may not be representative of the larger HAE population in clinical practice; therefore, we have not developed a detailed protocol for HAE prophylaxis transition in this report. Important considerations that contributed to the successful transition of both patients in this report include (1) shared decision‐making that included the goals and preferences of the patients before, during, and after transition, (2) scheduling the therapy transition during a time when the patient felt comfortable and was not experiencing high levels of stress, and (3) observing the patient closely during the transition period for any changes in HAE symptoms or adverse events related to the new prophylactic medication. Additional real‐world evidence is needed to develop a standard protocol for transitioning patients from one HAE prophylactic therapy to another in clinical practice.\n\nIn conclusion, this clinical report describes the successful transition of two patients with HAE in the same family from injectable prophylaxis to oral prophylaxis without tapering prior therapy or employing a complex transition protocol. Currently, there is no consensus or previous reports in the literature for transitioning patients with HAE from one prophylactic medication to another; however, in this case series, a mother and daughter transitioned to berotralstat after a dual therapy period and then discontinued C1‐INH‐SC without tapering. A limitation of this report is the small number of patient and caregiver examples described; more research studies are necessary to develop a specific protocol for the safe and effective transition of prophylactic HAE medications.\n\nCONFLICT OF INTEREST\n\nDaniel F. Soteres, MD, MPH, is a clinical research investigator for Takeda and BioCryst and has accepted speaker or advisory board fees from Takeda, BioCryst, CSL Behring, and Pharming. Fellicia Grimes, BS, has no conflicts of interest to declare.\n\nAUTHOR CONTRIBUTIONS\n\nDaniel F. Soteres served as treating physician, contributed to the development of questionnaires, and involved in the writing of the manuscript. Fellicia Grimes served as treating nurse, conducted patient interviews, and involved in the writing of the manuscript.\n\nETHICAL APPROVAL\n\nInstitutional approval was not sought as the patient data were anonymized, and both patients provided written consent for their information to be published.\n\nPATIENT CONSENT STATEMENT\n\nBoth patients were informed that their anonymized information would be used for publication and provided their informed written consent prior to inclusion in the study.\n\nACKNOWLEDGEMENTS\n\nWe would like to thank the patients who contributed to this study. Editorial and writing assistance was provided by Ashly Pavlovsky, PhD, from Porterhouse Medical US.\n\nDATA AVAILABILITY STATEMENT\n\nData requests should be addressed to Daniel F. Soteres at DSoteres@aacos.com.\n==== Refs\nREFERENCES\n\n1 Busse PJ , Christiansen SC , Riedl MA , et al. US HAEA Medical Advisory Board 2020 guidelines for the management of hereditary angioedema. J Allergy Clin Immunol Pract. 2021;9 (1 ):132‐150.32898710\n2 Lumry WR , Settipane RA . Hereditary angioedema: epidemiology and burden of disease. Allergy Asthma Proc. 2020;41 (6 ):S08‐S13.33109318\n3 Banday AZ , Kaur A , Jindal AK , Rawat A , Singh S . An update on the genetics and pathogenesis of hereditary angioedema. Genes Dis. 2020;7 (1 ):75‐83.32181278\n4 Longhurst HJ , Bork K . Hereditary angioedema: an update on causes, manifestations and treatment. Br J Hosp Med (Lond). 2019;80 (7 ):391‐398.31283393\n5 CINRYZE (C1 esterase inhibitor [human]) for intravenous use, freeze‐dried powder for reconstitution [prescribing information]. 2018. Lexington, MA: Shire ViroPharma Incorporated.\n6 HAEGARDA® (C1 esterase inhibitor subcutaneous [human]) for subcutaneous injection, freeze‐dried powder for reconstitution [prescribing information]. 2020. Marburg, HE: CSL Behring GmbH.\n7 TAKHZYRO™ (lanadelumab‐flyo) Injection, for Subcutaneous Use [prescribing information]. 2018. Lexington, MA: Dyax Corp.\n8 ORLADEYO™ (berotralstat) capsules, for oral use [prescribing information]. 2020. Durham, NC: BioCryst Pharmaceuticals, Inc.\n9 Banerji A , Riedl MA , Bernstein JA , et al. Effect of lanadelumab compared with placebo on prevention of hereditary angioedema attacks: a randomized clinical trial. JAMA. 2018;320 (20 ):2108‐2121.30480729\n10 Longhurst H , Cicardi M , Craig T , et al. Prevention of hereditary angioedema attacks with a subcutaneous C1 inhibitor. N Engl J Med. 2017;376 (12 ):1131‐1140.28328347\n11 Riedl MA , Banerji A , Gower R . Current medical management of hereditary angioedema: follow‐up survey of US physicians. Ann Allergy Asthma Immunol. 2021;126 (3 ):264‐272.33122123\n12 Banerji A , Davis KH , Brown TM , et al. Patient‐reported burden of hereditary angioedema: findings from a patient survey in the United States. Ann Allergy Asthma Immunol. 2020;124 (6 ):600‐607.32169514\n13 Craig TJ , Banerji A , Riedl MA , et al. Caregivers’ role in managing hereditary angioedema and perceptions of treatment‐related burden. Allergy Asthma Proc. 2021;42 (3 ):S11‐S16.33980328\n14 Radojicic C , Riedl MA , Craig TJ , et al. Patient perspectives on the treatment burden of injectable medication for hereditary angioedema. Allergy Asthma Proc. 2021;42 (3 ):S4‐S10.33980327\n15 Geba D , Mohd Sani J , Gascon M , Hahn R , Aggarwal K , Rosselli J . Hereditary angioedema patients would prefer newer‐generation oral prophylaxis. J Drug Assess. 2021;10 (1 ):51‐56.33489436\n16 Center for Biologics Evaluation and Research. U.S. Food and Drug Administration . The voice of the patient: hereditary angioedema. 2018. https://www.fda.gov/media/113509/download. Accessed July 28, 2021.\n17 Zuraw B , Lumry WR , Johnston DT , et al. Oral once‐daily berotralstat for the prevention of hereditary angioedema attacks: a randomized, double‐blind, placebo‐controlled phase 3 trial. J Allergy Clin Immunol. 2020;148 (1 ):164‐172.e9.33098856\n18 BioCryst Pharmaceuticals . A long term safety study of BCX7353 in hereditary angioedema (APeX‐S). 2021. https://clinicaltrials.gov/ct2/show/NCT03472040. Accessed July 28, 2021.\n19 Reshef A , Maurer M , Kiani S , Wu A , Stobiecki M , Kinaciyan T . Long‐term effectiveness of berotralstat (BCX7353) for the prophylaxis of hereditary angioedema (HAE) attacks: interim results from the APeX‐S study. Eur Academy Allergy Clin Immunol. 2020;6‐8. Poster 1406 presented at the European Academy of Allergy and Clinical Immunology (EAACI) Digital Congress 2020, June 6–8.\n20 Johnston D , Lumry WR , Banerji A , et al. Gastrointestinal adverse events observed with berotralstat (BCX7353) treatment for hereditary angioedema are primarily mild, self‐limited, and diminish with time on treatment. J Allergy Clin Immunol. 2020;145 (2 ):AB102. Poster 315 presented at the 2020 American Academy of Allergy, Asthma & Immunology (AAAAI) Virtual Annual MeetingMarch 13‐16.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "9(11)",
"journal": "Clinical case reports",
"keywords": "Haegarda; berotralstat; hereditary angioedema; shared decision‐making; switching; treatment burden",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "e05086",
"pmc": null,
"pmid": "34815876",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports",
"references": "33122123;33109318;30480729;33489436;33980327;33098856;33980328;32169514;32181278;28328347;31283393;32898710",
"title": "Patient and caregiver perspectives on transitioning to oral prophylaxis in the emerging hereditary angioedema treatment landscape.",
"title_normalized": "patient and caregiver perspectives on transitioning to oral prophylaxis in the emerging hereditary angioedema treatment landscape"
} | [
{
"companynumb": "US-PHARMING-PHAUS2021000661",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HUMAN C1-ESTERASE INHIBITOR"
},
"drugadditi... |
{
"abstract": "Rituximab is an antibody that binds to B-lymphocytes and is increasingly used during pregnancy. As an immunoglobulin G, it will transfer across the placenta. Previous case reports describe a diversity of clinical presentations in neonates born following rituximab exposure in utero. Our case is the first to offer the long-term experience in the care of an infant with severe neutropenia and prolonged profound hypogammaglobulinemia and class-switching B cell defect after in utero rituximab exposure.",
"affiliations": "Department of Pediatric Hematology and Oncology, Brooke Army Medical Center.;Departments of Allergy and Immunology.;Department of Pediatric Hematology and Oncology, Brooke Army Medical Center.;Departments of Allergy and Immunology.;Pediatric Hematology and Oncology, Walter Reed National Military Medical Center.",
"authors": "Clark|Rebecca|R|;Lindsey|Diana|D|;Whiteway|Susan|S|;Mikita|Cecilia|C|;Lieuw|Kenneth|K|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001871",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "43(4)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000361:Agammaglobulinemia; D000074322:Antineoplastic Agents, Immunological; D001402:B-Lymphocytes; D005260:Female; D006801:Humans; D000074243:Immune Reconstitution; D007231:Infant, Newborn; D008875:Middle Aged; D009503:Neutropenia; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011297:Prenatal Exposure Delayed Effects; D000069283:Rituximab",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e601-e604",
"pmc": null,
"pmid": "32590421",
"pubdate": "2021-05-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dysfunctional Immune System Reconstitution After Rituximab Exposure In Utero.",
"title_normalized": "dysfunctional immune system reconstitution after rituximab exposure in utero"
} | [
{
"companynumb": "US-MYLANLABS-2021M1033075",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPembrolizumab is an immune checkpoint inhibitor targeting the programmed death receptor with clinical effect on multiple malignancies including sarcoma. Associated cardio-toxicities include myocarditis, cardiomyopathy, heart failure, and arrhythmias. Although in most cases of immune checkpoint inhibitor cardiotoxicity the offending agent is discontinued, we report a case of successful and safe re-challenge with a checkpoint inhibitor in a patient with mild myocarditis.\n\n\nMETHODS\nWe describe a 37-year-old female with alveolar soft part sarcoma, metastatic to the lungs on cycle 13 of pembrolizumab who presented with dyspnea, cough, and vague chest discomfort. Telemetry showed bigeminal bradycardia that transitioned to self-terminating torsades de pointes. Cardiac MRI showed subtle patchy T2 signal increase within the left ventricular septum without late gadolinium uptake, suggesting mild focal myocarditis.Management and outcome: The patient was started on a steroid taper without additional arrhythmias. We have re-challenged the patient who safely tolerated re-challenge with pembrolizumab despite an episode of torsades de pointes and documented myocarditis. She continues to receive pembrolizumab at seven months after the initial event without further cardiovascular events.\n\n\nCONCLUSIONS\nTo the best of our knowledge, this is the first reported case of successful re-challenge of pembrolizumab after an episode of myocarditis. In patients with mild myocarditis and no evidence of left ventricular dysfunction, re-challenge may be a viable option. However, close monitoring for the development of heart failure, cardiomyopathy, or serious arrhythmias is necessary to ensure patient safety.",
"affiliations": "Department of Cardiovascular Sciences, University of South Florida, Morsani College of Medicine and Cardio-Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Cardiovascular Sciences, University of South Florida, Morsani College of Medicine and Cardio-Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Cardiovascular Sciences, University of South Florida, Morsani College of Medicine and Cardio-Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Sarcoma, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Cardiovascular Sciences, University of South Florida, Morsani College of Medicine and Cardio-Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.",
"authors": "Lee|Dae Hyun|DH|https://orcid.org/0000-0001-8141-0404;Armanious|Merna|M|;Huang|Jessica|J|;Jeong|Daniel|D|;Druta|Mihaela|M|;Fradley|Michael G|MG|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C582435:pembrolizumab",
"country": "England",
"delete": false,
"doi": "10.1177/1078155220904152",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "26(6)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Pembrolizumab; cardio-oncology; cardiotoxicity; immune checkpoint inhibitor; myocarditis",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D066126:Cardiotoxicity; D005260:Female; D006801:Humans; D009205:Myocarditis; D016171:Torsades de Pointes",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1544-1548",
"pmc": null,
"pmid": "32089073",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case of pembrolizumab-induced myocarditis presenting as torsades de pointes with safe re-challenge.",
"title_normalized": "case of pembrolizumab induced myocarditis presenting as torsades de pointes with safe re challenge"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK202011446",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null... |
{
"abstract": "OBJECTIVE\nTo compare time to retreatment and visual function between patients with treatment-naïve neovascular age-related macular degeneration (AMD) treated with either intravitreal ranibizumab (IVR) or intravitreal aflibercept (IVA) in routine clinical practice.\n\n\nMETHODS\nRetrospective, interventional comparative case series.\n\n\nMETHODS\nA total of 200 eyes of 197 patients with neovascular AMD.\n\n\nMETHODS\nA total of 99 patients in the IVR group and 101 patients in the IVA group who met the inclusion criteria with 12 months of follow-up were included in the present study. All patients received 3 consecutive monthly injections of 0.5 mg/0.05 mL ranibizumab or 2.0 mg/0.05 mL aflibercept as loading doses. Retreatment was allowed if evidence of clinical deterioration or the presence of intraretinal edema or subretinal fluid on spectral-domain optical coherence tomography examination performed at the 1-month follow-up was noted. The time to retreatment after the third injection during the loading phase to the first recurrence during the maintenance phase was compared between treatments using the Kaplan-Meier analysis. Functional and anatomic outcomes were also compared between the IVR and IVA groups.\n\n\nRESULTS\nThe median time to retreatment after the last induction dose was 5 months in both groups. The proportion of IVR patients who required injection retreatment was not significantly higher than that of IVA patients (67.7% and 63.4%, respectively, at the 12-month follow up; log-rank test, P = .554). In both groups, significant improvements in postoperative best-corrected visual acuity (BCVA) compared with preoperative visual acuity was observed over the 12-month follow-up period (P < .05 for both). Central foveal thickness (CFT) decreased from the baseline values in both groups during the follow-up period (P < .001 for both). Although there was a trend toward greater BCVA improvements in the IVA group, no significant differences in BCVA or CFT were observed between the treatment groups.\n\n\nCONCLUSIONS\nBoth IVR and IVA were well tolerated and demonstrated efficacy in improving the visual acuity in treatment-naïve patients with AMD. Despite a trend toward greater BCVA improvements in the IVA group, a similar injection burden was observed following the loading phases of both ranibizumab and aflibercept.",
"affiliations": "Department of Ophthalmology, Yokohama City University Medical Center, Yokohama, Japan. Electronic address: maicoo@urahp.yokohama-cu.ac.jp.;Department of Ophthalmology, Yokohama City University Medical Center, Yokohama, Japan.;Department of Ophthalmology, Yokohama City University Medical Center, Yokohama, Japan.;Department of Biostatistics, Yokohama City University Medical Center, Yokohama, Japan.;Department of Ophthalmology, Yokohama City University Medical Center, Yokohama, Japan.;Department of Ophthalmology, Yokohama City University Medical Center, Yokohama, Japan.",
"authors": "Inoue|Maiko|M|;Yamane|Shin|S|;Sato|Shimpei|S|;Sakamaki|Kentaro|K|;Arakawa|Akira|A|;Kadonosono|Kazuaki|K|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajo.2016.06.021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9394",
"issue": "169()",
"journal": "American journal of ophthalmology",
"keywords": null,
"medline_ta": "Am J Ophthalmol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D000069579:Ranibizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D019233:Retreatment; D012189:Retrospective Studies; D058471:Subretinal Fluid; D061665:Time-to-Treatment; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity; D057135:Wet Macular Degeneration",
"nlm_unique_id": "0370500",
"other_id": null,
"pages": "95-103",
"pmc": null,
"pmid": "27320059",
"pubdate": "2016-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Comparison of Time to Retreatment and Visual Function Between Ranibizumab and Aflibercept in Age-Related Macular Degeneration.",
"title_normalized": "comparison of time to retreatment and visual function between ranibizumab and aflibercept in age related macular degeneration"
} | [
{
"companynumb": "JP-ROCHE-1816503",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
},
"drugadditional": "1",
"drug... |
{
"abstract": "We report a man with advanced adenocarcinoma who harboring exon 19 (E746-A750del) epidermal growth factor receptor (EGFR) deletion and echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) gene translocation in the re-biospy specimen. The patient was treated with erlotinib with a stable disease but progressed slowly, while crizotinib showed a complete response.",
"affiliations": "Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine Tongji University Medical School Cancer Institute Tongji University, No 507 Zhengmin Road, Shanghai 200433, People's Republic of China.",
"authors": "Chen|Xiaoxia|X|;Zhang|Jie|J|;Hu|Qiong|Q|;Li|Xuefei|X|;Zhou|Caicun|C|",
"chemical_list": "C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "81(2)",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "Acquired resistance; Adenocarcinoma; EGFR mutation; EML4-ALK fusion; Lung",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D066246:ErbB Receptors; D005091:Exons; D017353:Gene Deletion; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "308-10",
"pmc": null,
"pmid": "23731739",
"pubdate": "2013-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of lung adenocarcinoma harboring exon 19 EGFR deletion and EML4-ALK fusion gene.",
"title_normalized": "a case of lung adenocarcinoma harboring exon 19 egfr deletion and eml4 alk fusion gene"
} | [
{
"companynumb": "CN-MYLANLABS-2015M1002864",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ERLOTINIB"
},
"drugadditional": null,
... |
{
"abstract": "Although rare, tuberculosis has been reported with biologic treatment against psoriasis in Japan, a tuberculosis medium-burden country. Mycobacterial infection often develops after a long incubation period and might not have been adequately identified in clinical trials or post-marketing surveillance. To determine the real-world incidence of tuberculosis in psoriatic patients treated with biologics, we conducted a retrospective, multicenter, observational study in 18 facilities in Western Japan. Psoriatic patients who visited a participating facility between 2010 and March 2017 and received biologic reagents were enrolled. Information on sex, age at first biologic treatment, results of interferon-γ release assay (IGRA) for Mycobacterium tuberculosis, treatment history with isoniazid, and onset of active and/or latent tuberculosis was collected. A total of 1117 patients (830 men and 287 women) were enrolled. The mean duration of biologic treatment was 3.54 years. Sixty-five patients (5.8%) showed positive IGRA results at screening. Active tuberculosis developed in two patients after the administration of tumor necrosis factor inhibitors (both involved miliary tuberculosis). Latent tuberculosis was observed in two patients treated with anti-interleukin-12/23p40 antibody. The incidence rate of tuberculosis, including latent tuberculosis, in this survey was 0.36%. Although the incidence rate of tuberculosis was low considering the observation period of biologic treatment, active tuberculosis was found in both the screening-negative group and a screening-positive subject after isoniazid prophylaxis (both miliary tuberculosis), concluding that negative screening or isoniazid treatment does not always assure that an individual has no tuberculosis. Hence, dermatologists still need to pay careful attention to tuberculosis at every patient visit.",
"affiliations": "Department of Dermatology, Shimane University Faculty of Medicine, Izumo, Japan.;Department of Dermatology, Fukuoka University Faculty of Medicine, Fukuoka, Japan.;Department of Dermatology, Fukuoka University Faculty of Medicine, Fukuoka, Japan.;Department of Dermatology, Graduate School of Medicine University of the Ryukyus, University of the Ryukyus, Nishihara, Japan.;Department of Dermatology, Graduate School of Medicine University of the Ryukyus, University of the Ryukyus, Nishihara, Japan.;Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.;Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.;Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.;Department of Dermatology, Yamaguchi University Graduate School of Medicine, Ube, Japan.;Hino Dermatology Clinic, Fukutsu, Japan.;Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu, Japan.;Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu, Japan.;Department of Dermatology, Kurume University School of Medicine, Kurume, Japan.;Department of Dermatology, Kurume University School of Medicine, Kurume, Japan.;Department of Dermatology, Imamura General Hospital, Kagoshima, Japan.;Department of Dermatology, Kawasaki Medical School, Okayama, Japan.;Department of Dermatology, Hiroshima City Asa Citizens Hospital, Hiroshima, Japan.;Department of Dermatology, Onomichi General Hospital, Onomichi, Japan.;Division of Dermatology, Department of Medicine of Sensory and Motor Organs, Tottori University Faculty of Medicine, Yonago, Japan.;Department of Dermatology, Kyushu Central Hospital, Fukuoka, Japan.;Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Dermatology, Fukuyama City Hospital, Fukuyama, Japan.;Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.;Department of Dermatology, Fukuoka University Faculty of Medicine, Fukuoka, Japan.",
"authors": "Kaneko|Sakae|S|https://orcid.org/0000-0002-6366-8505;Tsuruta|Noriko|N|https://orcid.org/0000-0002-2907-9205;Yamaguchi|Kazuki|K|;Miyagi|Takuya|T|;Takahashi|Kenzo|K|;Higashi|Yuko|Y|https://orcid.org/0000-0003-3867-0555;Morizane|Shin|S|https://orcid.org/0000-0003-1374-065X;Nomura|Hayato|H|;Yamaguchi|Michiya|M|;Hino|Ryosuke|R|;Sawada|Yu|Y|https://orcid.org/0000-0001-8793-708X;Nakamura|Motonobu|M|;Ohyama|Bungo|B|;Ohata|Chika|C|https://orcid.org/0000-0001-8341-7300;Yonekura|Kentaro|K|;Hayashi|Hiroaki|H|;Yanase|Tetsuji|T|;Matsuzaka|Yuki|Y|;Sugita|Kazunari|K|;Kikuchi|Satoko|S|;Mitoma|Chikage|C|https://orcid.org/0000-0002-1043-8175;Nakahara|Takeshi|T|https://orcid.org/0000-0003-2811-8273;Furue|Masutaka|M|https://orcid.org/0000-0002-2967-1073;Okazaki|Fusako|F|;Koike|Yuta|Y|https://orcid.org/0000-0002-7921-8840;Imafuku|Shinichi|S|https://orcid.org/0000-0001-8568-4349;|||",
"chemical_list": "D000995:Antitubercular Agents; D001688:Biological Products; D007538:Isoniazid",
"country": "England",
"delete": false,
"doi": "10.1111/1346-8138.15156",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-2407",
"issue": "47(2)",
"journal": "The Journal of dermatology",
"keywords": "biologics; isoniazid; mycobacteria; psoriasis; tuberculosis",
"medline_ta": "J Dermatol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000995:Antitubercular Agents; D001688:Biological Products; D002648:Child; D005260:Female; D006801:Humans; D015994:Incidence; D059425:Interferon-gamma Release Tests; D007538:Isoniazid; D007564:Japan; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis; D011565:Psoriasis; D012189:Retrospective Studies; D014376:Tuberculosis; D055815:Young Adult",
"nlm_unique_id": "7600545",
"other_id": null,
"pages": "128-132",
"pmc": null,
"pmid": "31763718",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Mycobacterium tuberculosis infection in psoriatic patients treated with biologics: Real-world data from 18 Japanese facilities.",
"title_normalized": "mycobacterium tuberculosis infection in psoriatic patients treated with biologics real world data from 18 japanese facilities"
} | [
{
"companynumb": "JP-JNJFOC-20200309960",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "USTEKINUMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nInvasive pulmonary mycosis is the most common type of invasive fungal infection. It is often severe and difficult to treat, and is accompanied by high mortality. In this study, we aimed to evaluate the efficacy and safety of intravenous itraconazole followed by oral itraconazole solution in the treatment of invasive pulmonary mycosis and to determine the distribution of different fungi species.\n\n\nMETHODS\nThis was a multi-center, open-label study which enrolled 71 patients who were diagnosed as invasive pulmonary mycosis between July 2007 and January 2009. All patients received intravenous itraconazole therapy followed by oral itraconazole solution with a total treatment duration of 6 weeks. Intravenous itraconazole was given at a dose of 200 mg bid (intravenous infusion every 12 hours) for the first two days, 200 mg qd for the subsequent 12 days. Sequential oral itraconazole solution was given at a dose of 100 mg bid for 4 weeks. Efficacy and safety were assessed according to clinical as well as microbiological criteria.\n\n\nRESULTS\nSeventy one patients participated in this study. Of the 60 patients in the full analysis dataset, the clinical response rate was 61.7% and the mycological eradication rate was 66.7%. The overall response rate was 66.7%. Drug-related adverse events occurred in 18.0% of patients: hypokalemia, liver function impairment and mild gastrointestinal side effects were the most common. One patient suffered from severe adverse event, with limb and facial swelling.\n\n\nCONCLUSIONS\nThis study showed that in patients with invasive pulmonary mycosis, intravenous itraconazole followed by oral itraconazole solution therapy was safe and effective.",
"affiliations": "Department of Respiratory Medicine, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200080, China.",
"authors": "Zhang|Ying-Ying|YY|;Zhou|Xin|X|;|||",
"chemical_list": "D000935:Antifungal Agents; D017964:Itraconazole",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0366-6999",
"issue": "124(20)",
"journal": "Chinese medical journal",
"keywords": null,
"medline_ta": "Chin Med J (Engl)",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000935:Antifungal Agents; D005260:Female; D006801:Humans; D017964:Itraconazole; D008172:Lung Diseases, Fungal; D008297:Male; D008875:Middle Aged; D009181:Mycoses",
"nlm_unique_id": "7513795",
"other_id": null,
"pages": "3415-9",
"pmc": null,
"pmid": "22088546",
"pubdate": "2011-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy and safety of intravenous itraconazole followed by oral itraconazole solution in the treatment of invasive pulmonary mycosis.",
"title_normalized": "efficacy and safety of intravenous itraconazole followed by oral itraconazole solution in the treatment of invasive pulmonary mycosis"
} | [
{
"companynumb": "CN-JNJFOC-20120413570",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Epithelioid inflammatory myofibroblastic sarcoma (EIMS), a specific subtype of inflammatory myofibroblastic tumors (IMT), is a relatively rare malignant mesenchymal tumor with clinical features of positive anaplastic lymphoma kinase (ALK), high invasiveness, treatment resistance and poor prognosis. Therefore, ALK inhibitors represent specific effective drugs for patients with this type of tumor. However, acquired resistance remains inevitable without a clear mechanism of action and therapeutic strategy to counteract this. Herein, a chromosomal ALK-G1269A mutation was identified using next-generation sequencing (NGS) and the mutation was confirmed by Sanger sequencing in a patient with crizotinib-resistant EIMS who benefited from treatment with the second-generation ALK inhibitor AP26113. To the best of our knowledge, a few rare cases of crizotinib-resistance in IMTs have been reported, and there are no reported cases in EIMS. In this article, we present the case of a patient with a secondary mutation of ALK-G1269A in EIMS, and suggest that AP26113 (Brigatinib) may represent an ideal treatment for these patients.",
"affiliations": "Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.;Department of Oncology, Jiahui International Hospital, Shanghai 200032, P.R. China.;Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.;Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.;Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.;Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.;Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.;Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.;Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.",
"authors": "Xu|Xiaojing|X|;Li|Hong|H|;Peng|Ke|K|;Yu|Yiyi|Y|;Chen|Lingli|L|;Fang|Yong|Y|;Sun|Yihong|Y|;Hou|Yingyong|Y|;Liu|Tianshu|T|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2018.9865",
"fulltext": "\n==== Front\nOncol LettOncol LettOLOncology Letters1792-10741792-1082D.A. Spandidos 10.3892/ol.2018.9865OL-0-0-9865ArticlesALK-G1269A mutation in epithelioid inflammatory myofibroblastic sarcoma after progression on crizotinib: A case report Xu Xiaojing 1*Li Hong 2*Peng Ke 1*Yu Yiyi 1Chen Lingli 3Fang Yong 4Sun Yihong 4Hou Yingyong 3Liu Tianshu 11 Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China2 Department of Oncology, Jiahui International Hospital, Shanghai 200032, P.R. China3 Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China4 Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. ChinaCorrespondence to: Dr Tianshu Liu, Department of Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, P.R. China, E-mail: liutianshu1969@126.com* Contributed equally\n\n2 2019 21 12 2018 21 12 2018 17 2 2370 2376 23 12 2017 28 11 2018 Copyright: © Xu et al.2019This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Epithelioid inflammatory myofibroblastic sarcoma (EIMS), a specific subtype of inflammatory myofibroblastic tumors (IMT), is a relatively rare malignant mesenchymal tumor with clinical features of positive anaplastic lymphoma kinase (ALK), high invasiveness, treatment resistance and poor prognosis. Therefore, ALK inhibitors represent specific effective drugs for patients with this type of tumor. However, acquired resistance remains inevitable without a clear mechanism of action and therapeutic strategy to counteract this. Herein, a chromosomal ALK-G1269A mutation was identified using next-generation sequencing (NGS) and the mutation was confirmed by Sanger sequencing in a patient with crizotinib-resistant EIMS who benefited from treatment with the second-generation ALK inhibitor AP26113. To the best of our knowledge, a few rare cases of crizotinib-resistance in IMTs have been reported, and there are no reported cases in EIMS. In this article, we present the case of a patient with a secondary mutation of ALK-G1269A in EIMS, and suggest that AP26113 (Brigatinib) may represent an ideal treatment for these patients.\n\nepithelioid inflammatory myofibroblastic sarcomaanaplastic lymphoma kinasekinase inhibitorcrizotinibBrigatinibdrug resistance\n==== Body\nIntroduction\nEpithelioid inflammatory myofibroblastic sarcomas (EIMSs) were first described by Mariño-Enríquez in 2011 (1), and are rare malignant mesenchymal tumors commonly identified in the lung, abdominal/pelvic cavity and retroperitoneal cavity irrespective of age (2). In contrast to the conventional spindle-cell inflammatory myofibroblastic tumors (IMTs), the characteristics of EIMSs include extensive epithelial cell infiltration pathologically and a dismal prognosis (3). Given its low incidence and inadequate recognition, standard guidelines for EIMSs are presently not available. Based on experience, surgery is the primary choice for patients with localized lesions; however, in the event of recurrence or metastasis, traditional chemotherapeutic drugs such as anthracyclines are typically ineffective (2).\n\nSimilar to 50% of IMTs, EIMSs primarily express the anaplastic lymphoma kinase (ALK) protein (1). The gene encoding ALK is located on the short arm of chromosome 2 (2p23) (https://www.ncbi.nlm.nih.gov/gene/238). The protein typically manifests as RAN-binding protein 2 (RANBP2)-ALK fusion oncoprotein with distinctive nuclear membrane localization (4). Therefore, patients expressing this fusion protein may benefit from treatment with targeted ALK inhibitors such as crizotinib (5). Crizotinib is a small molecule ALK kinase inhibitor that has been approved for use in patients with various types of ALK+ advanced cancer, such as non-small cell lung cancer (6). However, acquired resistance remains inevitable and largely limits the efficacy of crizotinib (7). Despite this limitation, the mechanism and therapeutic strategy for crizotinib-resistance in EIMSs have been rarely documented in the literature.\n\nIn the case presented herein article, a chromosomal ALK-G1269A mutation was identified in a patient with crizotinib-resistant EIMS by next generation sequencing (NGS) and Sanger sequencing. Treatment with the chemically distinct ALK inhibitor AP26113 (brigatinib) was an effective therapeutic modality in this patient, and a significant partial response was observed. The aim of the present study was to explore the resistance mechanisms and develop follow-up treatment strategies for patients with EIMSs, and to ultimately improve the symptoms and survival time of these patients.\n\nCase report\nA 28-year-old male suffering from recurrent fever, abdominal distention, night sweats and obvious fatigue since May 2016 presented at our institution in July 2018. Examination with computed tomography (CT) and magnetic resonance imaging (MRI) revealed substantial ascites and a huge caking in the abdomen and pelvis. Radical surgery was impossible due to discrete miliary nodules on the abdominal wall surface and extensive peritoneal adhesions, which were revealed by an exploratory laparotomy. Thus, a mass biopsy was performed, and the patient was diagnosed with epithelioid inflammatory myofibroblastic sarcoma composed of predominantly epithelioid cells (Fig. 1A). IHC performed as previously described (8) revealed that ALK was positive (3+) in tumor cells (Fig. 1B), whereas other indicators, including cytokeratin, smooth muscle actin, calretinin, epithelial membrane antigen and myogenin were negative (data not shown). ALK rearrangement was assessed by fluorescence in situ hybridization (FISH) using a Vysis ALK Break Apart Probe kit (Abbott Pharmaceutical Co., Ltd., Lake Bluff, IL, USA), and tests were performed according to the manufacturer's protocol (8). ALK rearrangement was defined as positive when >15% tumor cells exhibited split probe signals. Ten randomly chosen visual fields were observed on each section under microscope. The proportion of positive stained cells was ~30% (Fig. 1C). NGS suggested that RANBP2-ALK gene fusion had occurred (Fig. 1D). Following the exploratory laparotomy, the patient's condition deteriorated rapidly, with obvious abdominal distention, dyspnea, electrolyte disturbances, a high level of uric acid (800 µmol/l) and extreme fatigue. From July 2016, crizotinib (200 mg) was administered to the patient twice a day orally. In September 2016, the patient's previous clinical symptoms were significantly relieved, and the response evaluation reached a partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (http://recist.eortc.org/recist-1-1-2/) (Fig. 2) with slight adverse events, such as grade 1 edema and myelosuppression according to the NCI Common Terminology Criteria version 4.0 (https://evs.nci.nih.gov/ftp1/CTCAE/). Until April 2017, the patient presented with abdominal distention, and MRI scanning confirmed the reappearance of a large amount of ascites, which was classified as progressive disease (PD). NGS, using the second aspiration biopsy specimen of the abdominal mass identified RANBP2 as fusion partner and revealed the acquisition of an ALK-G1269A mutation with a mutational abundance of 22.9% (data not shown), which was confirmed by Sanger sequencing (Fig. 3A). Primers designed were as shown in Table I. No additional mutations were detected. Treatment with AP26113 was initiated in April 2017 (90 mg daily), and the tumor-associated symptoms resolved rapidly. On July 2017, MRI scanning revealed a 50% reduction in the abdominal mass, which was classified as a partial response (Fig. 3B). The patient is currently alive.\n\nDiscussion\nHerein, we identified a chromosomal ALK-G1269A mutation in a rare and special case of a patient with EIMS who responded to treatment with AP26113, following the failure of crizotinib. Given the rarity of EIMSs, no large, well-powered clinical trials are available, with only ~40 cases being reported to date. In 2016, Yu et al (2) reviewed the clinical characteristics and pathological features of 25 cases of EIMS. The present study summarized an additional 18 cases of EIMS reported since 2016 (Table II). From these reports, certain factors, including age, sex, tumor location, tumor size, proliferation index, mitosis and necrosis degree, were not associated with clinical progression. However, positive ALK expression was closely associated with recurrence or metastasis. The positive rate of ALK rearrangements is presently unknown in EIMSs. However, according to the reported cases, several ALK fusion proteins, including RNA binding protein 2 (RANBP2)-ALK, tropomyosin 3 (TPM3)-ALK, TRK-fused Gene (TFG)-ALK and ribosome binding protein 1 (RRBP1)-ALK, were identified in EIMS (Table II). RANBP2-ALK fusion oncoproteins exhibit distinctive nuclear membrane localization, indicating that they may be sensitive to targeted kinase inhibitors, such as crizotinib (3,9–11). In the present case, the young male was diagnosed with EIMS characterized with predominant epithelioid cells and ALK positivity via immunohistochemistry. In addition, FISH using break apart probes revealed ALK rearrangement, and the NGS assay suggested that RANBP2-ALK gene fusion had occurred. These findings are consistent with the diagnostic criteria of EIMS.\n\nCrizotinib has a significant effect in EIMS patients with ALK-rearrangement; however, it is difficult to avoid acquired resistance. In the present case report, the patient with EIMS was resistant to crizotinib after 9 months. Secondary NGS detection revealed an ALK point mutation G1269A in addition to RANBP2-ALK fusion, suggesting that the base G was changed to C at position 3806 of the ALK gene. Consequently, the coded amino acid was changed from glycine to alanine at position 1269, which was located at the end of the adenosine triphosphate (ATP) binding pocket. The steric hindrance effect of the mutation affects ALK protein binding to oxazolidine, therefore ALK G1269A is an acquired resistance mutation in EIMS. However, only a few cases describing the mechanisms of crizotinib-resistance have been reported in IMTs and even fewer in EIMSs, as summarized in Table III (12–14).\n\nIn addition to G1269A, other secondary mutations, such as L1152R, C1156Y, F1174L, L1196M, G1202R and S1206Y, were also identified in vitro, xenograft models or patients with ALK-rearranged tumors, such as non-small-cell lung cancers (7). These patients were sensitive to high dosages of crizotinib or second-generation ALK inhibitors, such as ceritinib and alectinib (15,16). In the present article, AP26113 was still effective in the patient with crizotinib resistance. AP26113 is also a second-generation ALK inhibitor with a double inhibitory effect on ALK and EGFR (17). Similar to crizotinib, AP26113 could relieve the clinical symptoms of the patient, without obvious side effects. Thus, the quality of life of this patient was greatly improved. Previously, certain novel agents, such as heat shock protein (HSP) 90 inhibitors, have been demonstrated to be effective in overcoming crizotinib-resistance in preclinical models and Phase I–II studies (14). With a deeper understanding of EIMS, more molecular mechanisms and potential treatments will be available in the future.\n\nAcknowledgements\nThe authors would like to thank Ms. Huiyan Li from the institute of Precision Medicine, 3D Medicines Inc. (Shanghai, China) for their excellent technical assistance with NGS and Sanger sequencing.\n\nFunding\nThe present study was supported by the National Nature Science Foundation of China (grant no. 81502003) and the Shanghai Committee of Science and Technology (grant nos. 14ZR1406500 and 15411961900).\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors' contributions\nXX, YY and TL conceived and designed the study. XX, HL and KP performed the experiments. LC and YH provided the FISH results. YF and YS performed the operation on the patient. XX wrote the paper. YY and TL reviewed and edited the manuscript. All authors read and approved the manuscript.\n\nEthics approval and consent to participate\nThe study was approved by the Ethics Committee of Zhongshan Hospital Affiliated to Fudan University (Shanghai, China). The research involved one patient and their tissues, and informed consent for use of their clinical images and tissues was obtained from the patient.\n\nPatient consent for publication\nIdentifying information, including names, initials, date of birth or hospital numbers, images or statements were not included in the manuscript. And the patient has provided written informed consent for publication.\n\nCompeting interests\nThe authors have declared that they have no competing interests.\n\nAbbreviations\nEIMSepithelioid inflammatory myofibroblastic sarcoma\n\nALKanaplastic lymphoma kinase\n\nIMTinflammatory myofibroblastic tumor\n\nNGSnext-generation sequencing\n\nH&Ehematoxylin and eosin\n\nFFPEformalin fixed paraffin embedded\n\nPCRpolymerase chain reaction\n\nIHCimmunohistochemistry\n\nRECISTResponse Evaluation Criteria in Solid Tumors\n\nPRpartial response\n\nPDprogressive disease\n\nFigure 1. Characters of EIMS. (A) The tumor was predominantly composed of epithelioid cells (H&E ×100 magnification); (B) IHC revealed ALK positivity (3+) in tumor cells, indicating that the tumor was ALK immunopositive (H&E ×100 magnification); (C) Fluorescence in situ hybridization using break apart probes revealed ALK rearrangement in 30% tumor cells (H&E ×1,000 magnification); (D) NGS assays suggested RANBP2-ALK gene fusion. NGS, next generation sequencing; IHC immunohistochemistry; EIMS, epithelioid inflammatory myofibroblastic sarcoma; ALK, anaplastic lymphoma kinase.\n\nFigure 2. CT revealed a PR following treatment with crizotinib. On July 2016, computed tomography revealed massive ascites and significant caking in the abdomen and pelvis. crizotinib was administered to the patient. On October 2016, their ascites disappeared, and the response evaluation revealed a PR. Continuous PR was noted until January 2017. CT, computed tomography; PR, partial response.\n\nFigure 3. Assessment of resistance mutation. (A) Sanger sequencing confirmed the ALK point mutation G1269A in the crizotinib-resistant tumor tissue (No. 2). Specifically, base G was changed to C at position 3806 of the ALK gene, and the coded amino acid of was the changed from glycine to alanine. (B) On April 2017, MRI scanning confirmed the presence of a large number of ascites, this was classified as progressive disease (PD). Following the administration of AP26113, MRI scanning revealed a 50% reduction, which was classified as a partial response again on July 2017. MRI, magnetic resonance imaging.\n\nTable I. Sequences for Sanger test.\n\nPrimer\tSequence (5′-3′)\tTemplate strand\tLength\tStart\tStop\tTemperature\tGC%\tSelf complementarity\tSelf 3′ complementarity\t\nForward\tTAAGGCTGTTTCTCTCACAC\tPlus\t20\t213\t232\t55.02\t45.00\t3.00\t0.00\t\nReverse\tCCATAGCCTGAAAAGGAACT\tMinus\t20\t615\t596\t55.02\t45.00\t3.00\t1.00\t\nProduct length, base pairs\t403\t\t\t\t\t\t\t\t\t\nTable II. Clinical features of 18 cases of EIMS since 2016.\n\nAge/sex\tSite\tALK rearrangement\tFusion type\tCrizotinib\tFollow up (months)\tReference\t\n15/F\tOvary\t+\tRANBP2-ALK\tYes\tND\tI9\t\n42/M\tAbdominal cavity\t+\tRANBP2-ALK\tYes\tRecurred at 8 m, AWD at 40 m\t\t\n10/F\tAbdominal cavity\t+\tTFG-ALK\tNo\tANED at 81 m\t\t\n34/M\tLiver\t+\tRANBP2-ALK\tNo\tDOD at 5 m\t\t\n62/M\tAbdominal cavity\t+\tRRBP1-ALK\tNo\tDOD at 2 m\t\t\n14/M\tPelvis\t+\tTPM3-ALK\tNo\tDOD at 3 m\t10\t\n76/F\tAbdominal cavity\t+\tRANBP2-ALK\tNo\tDOD at 4 m\t\t\n30/M\tAbdominal cavity\t+\tND\tNo\tDOD at 8 m\t\t\n26/M\tAbdominal cavity\t+\tRRBP1-ALK\tNo\tRecurred at 7 and 16 m, AWD at 16 m\t\t\n39/F\tAbdominal cavity\t+\tRRBP1-ALK\tNo\tRecurred and AWD at 10 m\t\t\n7/M\tAbdominal cavity\t+\tRRBP1-ALK-negative\tNo\tDOD at 36 m\t\t\n16/F\tLung\t+\tRRBP1-ALK-negative\tYes\tRecurred at 1 m, AWD at 48 m\t\t\n52/F\tSmall bowel mesentery\t+\tND\tNo\tDOD at 8 m\t11\t\n37/F\tRectum\t+\tND\tNo\tANED at 8 m\t2\t\n55/M\tMesentery of ileum\t+\tND\tNo\tANED AT 10 m\t\t\n22/M\tMesentery of colon\t+\tND\tYes\tRecurred at 2 m, AWD at 14 m\t\t\n58/F\tOmentum\t+\tND\tNo\tRecurred at 2 m, DOD at 8 m\t\t\n15/F\tTransverse colon\t+\tND\tNo\tANED at 7 m\t\t\nAWD, alive with disease; ANED, alive with no evidence of disease; DOD, died of disease; ND, not determined; ALK, anaplastic lymphoma kinase; RNA binding protein 2 (RANBP2)-ALK, tropomyosin 3 (TPM3)-ALK, TRK-fused gene (TFG)-ALK, and ribosome binding protein 1 (RRBP1)-ALK; m, months.\n\nTable III. ALK crizotinib-resistance reported in IMTs or EIMSs.\n\nCase\tAge/sex\tSite\tDisease\tALK fusion\tTreatment 1\tFollow Up 1\tSecondary mutation\tTreatment 2\tFollow Up 2\t(Refs.)\t\n1\tNA\tNA\tIMT\tRANBP2-ALK\tCrizotinib\tNA\tF1174L\tHigh dosage of crizotinib;\tIn vitro (effective)\t14\t\n\t\t\t\t\t\tTAE684\t\t\t\t\t\n2\t32/M\tLung\tIMT\tTPM3-ALK\tCrizotinib\tPFS(8m)\tNumerous genes\tCeritinib\tAWD (8 m); ANED (18 m)\t12\t\n3\t36/F\tLung\tIMT\tDCTN1-ALK\tCrizotinib\tPFS(29m)\tG1269A\tCeritinib\tPFS (3 m)\t13\t\n\t\t\t\t\t\t\t\tOncology, 2017\t\t\t\n4\t28/M\tAbdomen\tEIMS\tRANBP2-ALK\tCrizotinib\tPFS(9m)\tALK-G1269A\tAP26113\tAWD at 8 m\tPresent study\t\nAWD, alive with disease; ANED, alive with no evidence of disease; PFS, progression-free survival; NA, not available; EIMS, epithelioid inflammatory myofibroblastic sarcoma; ALK, anaplastic lymphoma kinase; IMT, inflammatory myofibroblastic tumor; m, months.\n==== Refs\nReferences\n1 Mariño-Enríquez A Wang WL Roy A Lopez-Terrada D Lazar AJ Fletcher CD Coffin CM Hornick JL Epithelioid inflammatory myofibroblastic sarcoma: An aggressive intra-abdominal variant of inflammatory myofibroblastic tumor with nuclear membrane or perinuclear ALK Am J Surg Pathol 35 135 144 2011 10.1097/PAS.0b013e318200cfd5 21164297 \n2 Yu L Liu J Lao IW Luo Z Wang J Epithelioid inflammatory myofibroblastic sarcoma: A clinicopathological, immunohistochemical and molecular cytogenetic analysis of five additional cases and review of the literature Diagn Pathol 11 67 2016 10.1186/s13000-016-0517-z 27460384 \n3 Liu Q Kan Y Zhao Y He H Kong L Epithelioid inflammatory myofibroblastic sarcoma treated with ALK inhibitor: A case report and review of literature Int J Clin Exp Pathol 8 15328 15332 2015 26823889 \n4 Kruczynski A Delsol G Laurent C Brousset P Lamant L Anaplastic lymphoma kinase as a therapeutic target Expert Opin Ther Targets 16 1127 1138 2012 10.1517/14728222.2012.719498 22998583 \n5 Kimbara S Takeda K Fukushima H Inoue T Okada H Shibata Y Katsushima U Tsuya A Tokunaga S Daga H A case report of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion gene treated with the ALK inhibitor, crizotinib Jpn J Clin Oncol 44 868 871 2014 10.1093/jjco/hyu069 25028698 \n6 Heigener DF Reck M Crizotinib Recent Results Cancer Res 211 57 65 2018 10.1007/978-3-319-91442-8_4 30069759 \n7 Voena C Chiarle R The battle against ALK resistance: Successes and setbacks Expert Opin Investig Drugs 21 1751 1754 2012 10.1517/13543784.2012.717930 22920921 \n8 Su D Zhang D Chen K Lu J Wu J Cao X Ying L Jin Q Ye Y Xie Z High performance of targeted next generation sequencing on variance detection in clinical tumor specimens in comparison with current conventional methods J Exp Clin Cancer Res 36 121 2017 10.1186/s13046-017-0591-4 28882180 \n9 Fang H Langstraat CL Visscher DW Folpe AL Schoolmeester JK Epithelioid inflammatory myofibroblastic sarcoma of the ovary with RANB2-ALK fusion: Report of a case Int J Gynecol Pathol 37 468 472 2018 28787324 \n10 Lee JC Li CF Huang HY Zhu MJ Mariño-Enríquez A Lee CT Ou WB Hornick JL Fletcher JA ALK oncoproteins in atypical inflammatory myofibroblastic tumours: Novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma J Pathol 241 316 323 2017 10.1002/path.4836 27874193 \n11 Fang N Yang QJ Deng YT Feng X Xia HS Zhang YG Wang MW Wu D Zhou H Guo F Epithelioid inflammatory myofibroblastic sarcoma of small bowel mesentery: Report of a case Zhonghua Bing Li Xue Za Zhi 46 201 202 2017 (In Chinese) 28297765 \n12 Mansfield AS Murphy SJ Harris FR Robinson SI Marks RS Johnson SH Smadbeck JB Halling GC Yi ES Wigle D Chromoplectic TPM3-ALK rearrangement in a patient with inflammatory myofibroblastic tumor who responded to ceritinib after progression on crizotinib Ann Oncol 27 2111 2117 2016 10.1093/annonc/mdw405 27742657 \n13 Michels SYF Scheel AH Wündisch T Heuckmann JM Menon R Puesken M Kobe C Pasternack H Heydt C Scheffler M ALKG1269A mutation as a potential mechanism of acquired resistance to crizotinib in an ALK-rearranged inflammatory myofibroblastic tumor NPJ Precis Oncol 1 4 2017 10.1038/s41698-017-0004-3 29872693 \n14 Sasaki T Okuda K Zheng W Butrynski J Capelletti M Wang L Gray NS Wilner K Christensen JG Demetri G The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers Cancer Res 70 10038 10043 2010 10.1158/0008-5472.CAN-10-2956 21030459 \n15 Nishio M Murakami H Horiike A Takahashi T Hirai F Suenaga N Tajima T Tokushige K Ishii M Boral A Phase I study of ceritinib (ldk378) in Japanese patients with Advanced, Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer or other tumors J Thorac Oncol 10 1058 1066 2015 10.1097/JTO.0000000000000566 26020125 \n16 Katayama R Lovly CM Shaw AT Therapeutic targeting of anaplastic lymphoma kinase in lung cancer: A paradigm for precision cancer medicine Clin Cancer Res 21 2227 2235 2015 10.1158/1078-0432.CCR-14-2791 25979929 \n17 Huang WS Liu S Zou D Thomas M Wang Y Zhou T Romero J Kohlmann A Li F Qi J Discovery of brigatinib (AP26113), a phosphine oxide-containing, potent, orally active inhibitor of anaplastic lymphoma kinase J Med Chem 59 4948 4964 2016 10.1021/acs.jmedchem.6b00306 27144831\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1792-1074",
"issue": "17(2)",
"journal": "Oncology letters",
"keywords": "Brigatinib; anaplastic lymphoma kinase; crizotinib; drug resistance; epithelioid inflammatory myofibroblastic sarcoma; kinase inhibitor",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "2370-2376",
"pmc": null,
"pmid": "30675302",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": "21030459;21164297;22920921;22998583;25028698;25979929;26020125;26823889;27144831;27460384;27742657;27874193;28297765;28787324;28882180;29872693;30069759",
"title": "ALK-G1269A mutation in epithelioid inflammatory myofibroblastic sarcoma after progression on crizotinib: A case report.",
"title_normalized": "alk g1269a mutation in epithelioid inflammatory myofibroblastic sarcoma after progression on crizotinib a case report"
} | [
{
"companynumb": "CN-PFIZER INC-2019042216",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CRIZOTINIB"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND Cardiac resynchronization therapy (CRT) has been demonstrated to reduce morbidity and mortality in patients with advanced, drug-refractory heart failure. Procedure-related mortality is less than 1% in larger studies. Approximately10% of CRT patients have to undergo surgical revision because of infections, dislocations, or unacceptable electrical behavior manifested as high threshold, unstable sensing, or unwanted phrenic nerve stimulation. CASE REPORT A 70-year-old man with symptomatic congestive heart failure underwent implantation of a biventricular pacemaker on the left anterior chest wall in 2003 and pulse generator exchange in August 2009. The patient responded well to CRT. At follow-up, the pacing system functioned normally. In September 2009, in the context of a predialysis program, an abdominal computed tomography (CT) scan was performed in another hospital for assessment and evaluation of chronic kidney disease. This procedure was complicated with peripheral thrombophlebitis that was managed appropriately with complete recovery. Eight months later (May 2010), the patient was admitted to our hospital with fever, anemia, and elevated infection parameters. During admission, blood cultures grew Staphylococcus epidermidis. The chest X-ray, lung perfusion scintigraphy, and CT scan depicted pulmonary embolism and infarction. The right ventricular lead threshold was found to be increased to 7 volts with unsuccessful capture. Echocardiography demonstrated vegetations on leads. The entire pacing system was explanted, but the patient expired few days later following percutaneous removal due to multiorgan failure. CONCLUSIONS In heart failure, replacement of the CRT device may be complicated by bacterial endocarditis. As noted from this case report, sudden elevation of the pacing lead threshold should prompt thorough and immediate investigation to unravel its causes, not only the electrical characteristics but also the anatomical features.",
"affiliations": "Department of Cardiology, Hospital Group Twente, Almelo-Hengelo, Netherlands.;Department of Cardiology, Hospital Group Twente, Almelo-Hengelo, Netherlands.;Department of Cardiology, Hospital Group Twente, Almelo-Hengelo, Netherlands.;Department of Cardiology, Hospital Group Twente, Almelo-Hengelo, Netherlands.",
"authors": "Said|Salah A M|SA|;Nijhuis|Rogier|R|;Derks|Anita|A|;Droste|Herman|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/ajcr.898009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-5923",
"issue": "17()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000368:Aged; D004452:Echocardiography; D004866:Equipment Contamination; D017809:Fatal Outcome; D006333:Heart Failure; D006352:Heart Ventricles; D006801:Humans; D008297:Male; D010138:Pacemaker, Artificial; D049268:Positron-Emission Tomography; D011655:Pulmonary Embolism; D013902:Radiography, Thoracic; D018805:Sepsis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "507-11",
"pmc": null,
"pmid": "27435910",
"pubdate": "2016-07-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10763187;16360070;495404;17481444;11907286;12063368;12378025;15824874;12891205;9133520;10997756;3893487;11259720;17096742;7270461;20417799;16606389;18658253;19239701;20921437",
"title": "Septic Pulmonary Embolism Caused by Infected Pacemaker Leads After Replacement of a Cardiac Resynchronization Therapy Device.",
"title_normalized": "septic pulmonary embolism caused by infected pacemaker leads after replacement of a cardiac resynchronization therapy device"
} | [
{
"companynumb": "NL-LUPIN PHARMACEUTICALS INC.-2016-04043",
"fulfillexpeditecriteria": "2",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BUMETANIDE"
},
"drugadditiona... |
{
"abstract": "Despite the effectiveness of the currently available antiviral drugs in treating cytomegalovirus (CMV) infection, high rates of adverse effects are associated with their use. Moreover, a problem of increasing importance is the emergence of drug-resistant CMV infection. Here, we describe the first case of off-label use of letermovir (LMV) as preemptive antiviral therapy, in a pediatric allogeneic peripheral blood stem cell transplant recipient with ganciclovir-resistant CMV infection who was intolerant to foscarnet and unable to achieve viral clearance after seven doses of cidofovir. After the administration of LMV, a gradual reduction in viral load was observed and within 6 weeks of LMV treatment, after more than 6 months of positive CMV-DNAemia, the patient cleared the infection. No adverse effects associated with LMV were observed during treatment. In this pediatric study case, the off-label use of LMV for the treatment of CMV infection has been well tolerated and proved to be effective in leading to the suppression of viral replication.",
"affiliations": "Section of Microbiology, Department of Specialized, Experimental, and Diagnostic Medicine, University of Bologna, Bologna, Italy.;Pediatric Oncology and Haematology Unit \"Lalla Seragnoli\", Department of Pediatrics, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy.;Microbiology Unit, Department of Specialized, Experimental, and Diagnostic Medicine, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy.;Nuclear Medicine Unit, Department of Specialized, Experimental, and Diagnostic Medicine, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy.;Microbiology Unit, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy.;Pediatric Oncology and Haematology Unit \"Lalla Seragnoli\", Department of Pediatrics, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy.;Microbiology Unit, Department of Specialized, Experimental, and Diagnostic Medicine, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy.;Microbiology Unit, Department of Specialized, Experimental, and Diagnostic Medicine, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy.;Microbiology Unit, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy.;Pediatric Oncology and Haematology Unit \"Lalla Seragnoli\", Department of Pediatrics, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy.;Pediatric Oncology and Haematology Unit \"Lalla Seragnoli\", Department of Pediatrics, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy.;Nuclear Medicine Unit, Department of Specialized, Experimental, and Diagnostic Medicine, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy.;Microbiology Unit, Department of Specialized, Experimental, and Diagnostic Medicine, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy.",
"authors": "Chiereghin|Angela|A|0000-0002-7509-297X;Belotti|Tamara|T|;Borgatti|Eva Caterina|EC|;Fraccascia|Nicola|N|;Piccirilli|Giulia|G|;Fois|Maura|M|;Borghi|Michele|M|;Turello|Gabriele|G|;Gabrielli|Liliana|L|;Masetti|Riccardo|R|0000-0002-1264-057X;Prete|Arcangelo|A|;Fanti|Stefano|S|;Lazzarotto|Tiziana|T|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/IDR.S296927",
"fulltext": "\n==== Front\nInfect Drug Resist\nInfect Drug Resist\nidr\nidr\nInfection and Drug Resistance\n1178-6973\nDove\n\n296927\n10.2147/IDR.S296927\nCase Report\nOff-Label Use of Letermovir as Preemptive Anti-Cytomegalovirus Therapy in a Pediatric Allogeneic Peripheral Blood Stem Cell Transplant\nChiereghin et al\nChiereghin et al\nhttp://orcid.org/0000-0002-7509-297X\nChiereghin Angela 12\nBelotti Tamara 3\nBorgatti Eva Caterina 4\nFraccascia Nicola 5\nPiccirilli Giulia 6\nFois Maura 3\nBorghi Michele 4\nTurello Gabriele 4\nGabrielli Liliana 6\nhttp://orcid.org/0000-0002-1264-057X\nMasetti Riccardo 3\nPrete Arcangelo 3\nFanti Stefano 5\nLazzarotto Tiziana 4\n1 Section of Microbiology, Department of Specialized, Experimental, and Diagnostic Medicine, University of Bologna, Bologna, Italy\n2 Department of Public Health, Local Health Authority of Bologna, Bologna, Italy\n3 Pediatric Oncology and Haematology Unit “Lalla Seragnoli”, Department of Pediatrics, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy\n4 Microbiology Unit, Department of Specialized, Experimental, and Diagnostic Medicine, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy\n5 Nuclear Medicine Unit, Department of Specialized, Experimental, and Diagnostic Medicine, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy\n6 Microbiology Unit, IRCCS St. Orsola Polyclinic, University of Bologna, Bologna, Italy\nCorrespondence: Tiziana Lazzarotto Microbiology Unit, Department of Specialized, Experimental, and Diagnostic Medicine, IRCCS St. Orsola Polyclinic, University of Bologna, via Massarenti 9, Bologna, 40138, ItalyTel +39 0512143360Fax +39 0512143514 Email tiziana.lazzarotto@unibo.it\n23 3 2021\n2021\n14 11851190\n12 12 2020\n19 2 2021\n© 2021 Chiereghin et al.\n2021\nChiereghin et al.\nThis work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nAbstract\n\nDespite the effectiveness of the currently available antiviral drugs in treating cytomegalovirus (CMV) infection, high rates of adverse effects are associated with their use. Moreover, a problem of increasing importance is the emergence of drug-resistant CMV infection. Here, we describe the first case of off-label use of letermovir (LMV) as preemptive antiviral therapy, in a pediatric allogeneic peripheral blood stem cell transplant recipient with ganciclovir-resistant CMV infection who was intolerant to foscarnet and unable to achieve viral clearance after seven doses of cidofovir. After the administration of LMV, a gradual reduction in viral load was observed and within 6 weeks of LMV treatment, after more than 6 months of positive CMV-DNAemia, the patient cleared the infection. No adverse effects associated with LMV were observed during treatment. In this pediatric study case, the off-label use of LMV for the treatment of CMV infection has been well tolerated and proved to be effective in leading to the suppression of viral replication.\n\nKeywords\n\npediatric allogeneic peripheral blood stem cell transplant\nGCV-resistant CMV\nintolerance to FOS\noff-label letermovir use\n==== Body\nIntroduction\n\nCytomegalovirus (CMV) reactivation is a major infectious complication after allogeneic hematopoietic stem cell transplant (allo-HSCT).1 The incidence of CMV reactivation among the patients at high risk for infection (CMV seronegative donor/seropositive recipient; D-/R+) is about 60–70% and CMV replication itself has been associated with increased non-relapse mortality.2,3 The current strategies for the management of infection consist of the administration of CMV DNA polymerase inhibitors. However, despite their effectiveness in treating CMV infection, high rates of adverse effects are associated with their use.4 Moreover, a problem of increasing importance is the emergence of drug-resistant CMV infection.5 In this scenario, a recently developed anti-CMV drug, letermovir (LMV), having a favorable side effect profile and a different viral target (ie, the viral terminase) was approved by the Food and Drug Administration in November 2017 for CMV prophylaxis in adult CMV-seropositive allo-HSCT recipients.4,6\n\nTo the best of our knowledge, here we describe the first case of off-label use of LMV as preemptive antiviral therapy in a pediatric allo-HSCT recipient with ganciclovir (GCV)-resistant CMV infection who was intolerant to foscarnet (FOS) and unable to achieve viral clearance with cidofovir (CDV).\n\nDescription of the Case Report\n\nThe post-transplant course (up to day +670) of a 17-year-old male suffering from beta-thalassemia who developed two episodes of acute graft-versus-host-disease (aGVHD) received a diagnosis of early probable EBV disease and experienced an early asymptomatic CMV infection characterized by an incomplete suppression of viral replication. Despite more than a five-month-long administration of CMV standard therapy, it was necessary to administer LMV for 56 days in order to achieve complete viral clearance.\n\nAt the Operative Unit of Pediatrics – Oncology, Haematology, and Stem Cell Transplantation Program – of the IRCCS St. Orsola Polyclinic of Bologna, the patient received CD34+ peripheral blood stem cells at the dose of 9.61x106/kg, from an unrelated mismatched 39-year-old male donor provided by the German Bone Marrow Donor Registry – DKMS Deutsche Knochenmarkspenderdatei GmbH. The conditioning regimen consisted of treosulfan (14g/mq day −6 to −4), thiotepa (10 mg/kg/day on day −7) and fludarabine (40 mg/mq day −6 to −3). GVHD prophylaxis consisted of an association of Cyclosporine A (CsA; 3 mg/kg/die) starting on day −1 and short-term methotrexate (on days +1, +3, +6 and +11). CsA was maintained at a blood concentration ranging from 200 to 300 ng/mL. Acyclovir (ACV) prophylaxis was administered from day −1 to +18 at a dose of 250 mg/mq three times a day, followed by a 400 mg oral dose, three times a day until anti-CMV therapy was given (day +41). At the time of transplant, CMV serostatus was D-/R+. As previously described,7 a post-transplant surveillance of CMV infection was performed on whole blood samples by quantitative real-time PCR assay (CMV ELITe MGB™ kit; ELITech Group, Italy). Whole blood samples were also investigated for the search of Epstein-Barr virus (EBV)-DNA (EBV ELITe MGB™ kit; ELITech Group, Italy);8 EBV serostatus was D-/R+. CMV and EBV-DNA kinetics, the clinical management of the infections and the immunosuppressive therapies are shown in Figure 1.Figure 1 CMV and EBV-DNA kinetics, infections’ clinical management and immunosuppressive treatments. Please refer text for dosages of all drugs. Lower limit of quantification (LLQ) of CMV and EBV PCR assays: 2.4 Log10 copies/mL whole blood.\n\nAbbreviations: ACV, acyclovir; GCV, ganciclovir; VGCV, valganciclovir; FOS, foscarnet; CDV, cidofovir; LMV, letermovir; R, resistant; PDN, prednisone; MMF, mycophenolate mofetil.\n\nEngraftment was achieved with a neutrophil count > 500/mmc at 14 days post-transplant. Three days later (day +17), the patient showed clinical signs related to cutaneous aGVHD (grade II) and, as a consequence, steroids (ie, prednisone [PDN] at 2 mg/kg/day) were administered for 12 days and then tapered until discontinuation after 15 days. At day +33, the patient resulted positive for CMV-DNA (954 copies/mL) and when blood viral load was equal to 17,511 copies/mL (day +42), anti-CMV therapy (iv GCV at a full dose of 5mg/kg twice daily, renal function adjusted) was initiated. At day +47, mycophenolate mofetil (MMF; 750 mg three times a day) for grade II aGVHD (skin and gastrointestinal involvement) was given; MMF was discontinued after 24 days when GVHD manifestations resolved. At day +64, after 3 weeks of anti-CMV therapy at full dose, blood viral load was reduced by 1 log10 and iv GCV was administered once daily for the next 2 weeks; no CMV-related symptoms were observed since the onset of CMV infection. At day +78, the patient was discharged from the hospital in stable conditions, CMV-DNAemia was 1099 copies/mL and valganciclovir (VGCV) treatment at a dosage of 450 mg twice daily (renal function adjusted) was initiated. During the next 4 weeks, CMV-DNA levels decreased up to 620 copies/mL (median: 615 copies/mL). However, at day +125 a CMV-DNA value of 12,925 copies/mL was detected, the patient was hospitalized and FOS was initiated (90 mg/kg every 12 hours, renal function adjusted; iv hydration prior to each dose of foscarnet was administered). Adverse effects such as paresthesia in arms and legs, asthenia, pre-cordial pain, agitated and confusional state were observed after FOS doses, therefore antiviral drug dosing was decreased to 60 mg/kg every 8 hours. Despite this, the adverse effects continued leading to treatment discontinuation after 5 days; hereafter a complete resolution of the symptoms was observed. During the next days, a sudden increase of viral load was observed underuse of VGCV alone (450 mg twice daily, renal function adjusted) and then of iv GCV (5 mg/kg twice daily, renal function adjusted). Consequently, at day +153 antiviral treatment was changed to CDV (5 mg/kg/week), and the genotypic resistance testing by Sanger sequencing of PCR-amplified UL97 and UL54 gene segments was performed showing mutant CMV strain (L595S, UL97 gene).9,10 Since high levels of CMV-DNAemia (median: 214,174 copies/mL; range: 47,687–223,602) persisted throughout four weeks of treatment with CDV, a request for off-label use of LMV was submitted to the IRCCS St. Orsola Polyclinic of Bologna Drug-Ethics Committee (day +182). While waiting for the Institution’s replay, another three doses of CDV were administered and the levels of CMV-DNAemia decreased to 923 copies/mL (day +202). CDV was well tolerated and no worsening of renal function was observed during the preemptive treatment period (serum creatinine values < 0.7 mg/dL). After the achievement of the favorable opinion from the Drug-Ethics Committee, the patient was discharged on oral LMV treatment at a dose of 240 mg/day given that it was co-administered with CsA (day +203). One week later, the patient showed signs compatible with peripheral paralysis of the seventh cranial nerve. The patient achieved CMV-DNA negativity within 42 days of LMV treatment. Since LMV inhibits new virion formation,11 the shell vial culture for the detection of CMV viremia was performed during the duration of antiviral therapy and resulted negative at each visit.12 LMV was discontinued at day +259; in the meantime, the resolution of the peripheral paralysis of the seventh cranial nerve was observed. From here onwards, no other episode of CMV infection occurred.\n\nSimultaneously to CMV infection (day +27), the patient resulted positive for EBV-DNA and two days later, given that EBV-DNAemia was equal to 28,416 copies/mL and patient presented fever and significant lymphadenopathy, treatment with anti-CD20 monoclonal antibody rituximab (375 mg/m2/week) was started. At day +51, whole body 18F-fluoro-2-deoxy-D-glucose (18F-FDG)–positron emission tomography-computed tomography (PET/CT) was performed and showed positive uptake in multiple supra and subdiaphragmatic lymph nodes in right and left laterocervical region, right and left axillary region, right pulmonary hilum and, together with abdominal, right iliac and inguinal regions (Figure 2A). Based on patients’ clinical status and 18F-FDG PET/CT imaging, a probable EBV disease was diagnosed.13 At day +67, after a total of 4 administrations of anti-CD20 therapy, the patient achieved EBV-DNA negativity and a further 18F-FDG PET/CT scan performed one month later the diagnosis of probable EBV disease, showed a complete disease remission (Figure 2B). No relapse of EBV infection was observed during the remaining post-transplant period.Figure 2 Baseline (at diagnosis) 18F-FDG PET/CT (A) and post-treatment 18F-FDG PET/CT (B). (A) 18F-FDG PET/CT shows pathological uptake in the following lymph nodes (blue arrows): bilateral laterocervical (SUVmax 21.3 at left station III), bilateral axillary (SUVmax 9.8 in left axilla), right costophrenic recess (SUVmax 6.6), right pulmonary hilum (SUVmax 11.5), celiac, left paraaortic (SUVmax 4.7), right iliac (SUVmax 5.5), bilateral inguinal (SUVmax 11.8 left node) and a pathological uptake at VIs/VIIs liver segment (SUVmax 3.3, red arrow). (B) Post-treatment 18F-FDG PET/CT shows a complete metabolic response (no pathological uptake); two foci uptake can be seen at central venous catheter in right subclavian vein, suspicious for infection (black arrowheads).\n\nDiscussion\n\nFindings from a Phase III, multicenter, double-blind, placebo-controlled, randomized, prospective clinical trial for the evaluation of the safety and efficacy of LMV for CMV prophylaxis in adult CMV‐seropositive allo-HSCT recipients (without detectable CMV-DNA at randomization) by Marty and colleagues showed that the administration of LMV reduced the risk of clinically significant CMV infection and the all-cause mortality through week 24 post-transplant.14 Furthermore, a subsequent analysis on this trial population performed by Ljungman et al showed that the patients receiving LMV had a lower risk for all-cause mortality than patients receiving placebo also at 48 weeks after HSCT.15 Finally, similar outcomes in terms of lower rates of both clinically significant CMV infection and all-cause mortality were observed by Marty et al in patients who received LMV with detectable CMV-DNA at randomization (median value, 150 copies/mL plasma [range, 150–716 LMV; range 150–253 placebo]) compared with those without detectable CMV-DNA at randomization.16\n\nWith regard to the currently available literature on the efficacy of off-label use of LMV for both the treatment and the secondary prophylaxis of CMV infection after solid organ and hematopoietic stem cell transplant, it is scarce and mostly limited to case reports.6,17–24\n\nHere, we describe a case of successful off-label use of LMV as pre-emptive therapy for GCV-resistant CMV infection in a pediatric allo-HSCT recipient who was unable to clear the infection after treatment with the other standard anti-CMV drugs currently available. Risk factors for drug-resistant CMV infection were reverse D-/R+ mismatch, unrelated mismatched donor and episodes of aGVHD (<100 days post-HSCT). As expected, CMV reactivation occurred in the early post-transplant period (< 100 days post-HSCT) and according to literature data reporting that GVHD and its treatment represent a risk for CMV replication,25,26 it was preceded by an episode of aGVHD. Furthermore, evidence for a bidirectional relationship between CMV replication and aGVHD has been reported and the patient developed a second episode of aGVHD during the first weeks of active viral replication.26 Simultaneously to CMV reactivation, the patient developed a symptomatic EBV infection. An early (< 1 year post-transplant) probable EBV disease was diagnosed and was effectively treated by administering anti-CD20 therapy, confirming the literature data.13,27\n\nAfter the first course of antiviral therapy with GCV at standard dose followed by GCV at maintenance dose, the patient did not achieve CMV-DNA negativity. No viral genotypic resistance testing was performed due to the low levels of CMV-DNAemia (ie, < 1200 copies/mL).9 When the subsequent combined GCV – FOS therapy was administered, an intolerance to FOS was observed. Soon after, when CMV antiviral resistance was suspected, viral genotypic analysis revealed one of the most important canonical UL97 mutations, ie, L595S, that confer a 9.2-fold resistance to GCV.28,29 It is known that a risk factor for the emergence of drug-resistance is a prolonged anti-CMV drug exposure with ongoing replication.5 The only other available standard anti-CMV drug among those approved for CMV treatment was CDV, and given that is known that it is nephrotoxic, the incomplete suppression of viral replication after a long drug exposure led to the off-label use of LMV as preemptive anti-CMV therapy. After the LMV administration, a gradual reduction in viral load was observed proving the efficacy of the drug. Within 6 weeks of LMV treatment, after more than 6 months of positive CMV-DNAemia, the patient achieved CMV-DNA negativity and no infectious virions were isolated from patient blood during LMV treatment. The patient did not show adverse effects associated with LMV and, as often happens, the etiology of the peripheral paralysis of the seventh cranial nerve remained unknown. At the time of writing, the patient is alive and well and remained CMV-infection free.30\n\nConclusion\n\nIn this pediatric study case, the off-label use of LMV as preemptive anti-CMV treatment has been well tolerated and proved to be effective in leading to the resolution of CMV infection. Of note, we are aware that in vitro studies report that LMV has a relatively low genetic barrier to resistance and generally support at least an additive effect (if not a synergistic one) of combining LMV with DNA polymerase inhibitors.31 However, in our patient, due to GCV-resistance, intolerance to FOS and risk of CDV-related side effects, the use of LMV-based combination therapy was not possible and LMV was administrated as monotherapy.\n\nMany real-world data need to be collected to adequately support the use of LMV as salvage therapy for refractory/resistant CMV infection mostly associated with poor outcome and/or as an alternative in case of adverse effects due to standard anti-CMV drugs. In particular, regarding LMV, appropriate dosage for treatment of CMV infection or disease, clinical efficacy, safety, the in vivo evolution of LMV-resistant CMV as well as the rate of resistance compared with that of other antiviral drugs need to be evaluated in the near future.\n\nAcknowledgments\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors would like to thank Dr. Marta Leone for contributing to data collection and their Linguistic Consultant, Lucy Scioscia, for editing the English language text.\n\nEthics and Consent Statement\n\nThe approval for off-label use of letermovir was obtained by the IRCCS St. Orsola Polyclinic of Bologna Drug-Ethics Committee (Prot. n. 19149/CF AVEC, on May 20, 2019). Written informed consent was obtained from the patient, having come of age during our monitoring, for the publication of this case report and the accompanying image. Institutional approval was not required to publish the case details.\n\nDisclosure\n\nThe authors declare no conflicts of interest for this work.\n==== Refs\nReferences\n\n1. Stern L, Withers B, Avdic S, et al. Human cytomegalovirus latency and reactivation in allogeneic hematopoietic stem cell transplant recipients. Front Microbiol. 2019;10 :1186. doi:10.3389/fmicb.2019.01186 31191499\n2. Ruell J, Barnes C, Mutton K, et al. Active CMV disease does not always correlate with viral load detection. Bone Marrow Transplant. 2007;40 :55–61. doi:10.1038/sj.bmt.1705671 17468776\n3. Ljungman P, de la Camara R, Robin C, et al.; on behalf of the 2017 European Conference on Infections in Leukaemia group. Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis. 2019;19 :e260–e272. doi:10.1016/S1473-3099(19)30107-0 31153807\n4. El Helou G, Razonable RR. Letermovir for the prevention of cytomegalovirus infection and disease in transplant recipients: an evidence-based review. Infect Drug Resist. 2019;12 :1481–1491. doi:10.2147/IDR.S180908 31239725\n5. Chemaly RF, Chou S, Einsele H, et al. Definitions of resistant and refractory cytomegalovirus infection and disease in transplant recipients for use in clinical trials. Clin Infect Dis. 2019;68 :1420–1426. doi:10.1093/cid/ciy696 30137245\n6. Phoompoung P, Ferreira VH, Tikkanen J, et al. Letermovir as salvage therapy for cytomegalovirus infection in transplant recipients. Transplantation. 2020;104 :404–409. doi:10.1128/AAC.02337-18 32000236\n7. Chiereghin A, Potena L, Borgese L, et al. Monitoring of cytomegalovirus (CMV)-specific cell-mediated immunity in heart transplant recipients: clinical utility of the QuantiFERON-CMV assay for management of posttransplant CMV infection. J Clin Microbiol. 2018;56 :e01040–17. doi:10.1128/JCM.01040-17 29305542\n8. Chiereghin A, Piccirilli G, Belotti T, et al. Clinical utility of measuring Epstein–Barr virus specific cell mediated immunity after HSCT in addition to virological monitoring: results from a prospective study. Med Microbiol Immunol. 2019;208 :825–834. doi:10.1007/s00430-019-00629-2 31289930\n9. Allice T, Busca A, Locatelli F, Falda M, Pittaluga F, Ghisetti V. Valganciclovir as preemptive therapy for cytomegalovirus infection post allogenic stem cell transplantation: implications for the emergence of drug-resistant cytomegalovirus. J Antimicrob Chemother. 2009;63 :600–608. doi:10.1093/jac/dkn521 19147520\n10. Lurain NS, Chou S. Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev. 2010;23 :689–712. doi:10.1128/CMR.00009-10 20930070\n11. Gentry BG, Bogner E, Drach JC. Targeting the terminase: an important step forward in the treatment and prophylaxis of human cytomegalovirus infections. Antiviral Res. 2019;161 :116–124. doi:10.1016/j.antiviral.2018.11.005 30472161\n12. Cassaniti I, Colombo AA, Bernasconi P, et al. Positive HCMV DNAemia in stem cell recipients undergoing letermovir prophylaxis is expression of abortive infection. Am J Transplant. 2021:1–7. doi:10.1111/ajt.16450.\n13. Styczynski J, van der Velden W, Fox CP, et al.; Sixth European Conference on Infections in Leukemia, a joint venture of the Infectious Diseases Working Party of the European Society of Blood and Marrow Transplantation (EBMT-IDWP), the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer (EORTC-IDG), the International Immunocompromised Host Society (ICHS) and the European Leukemia Net (ELN). Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: sixth European Conference on Infections in Leukemia (ECIL-6) guidelines. Haematologica. 2016;101 :803–811. doi:10.3324/haematol.2016.144428 27365460\n14. Marty FM, Ljungman P, Chemaly RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med. 2017;377 :2433–2444. doi:10.1056/nejmoa1706640 29211658\n15. Ljungman P, Schmitt M, Marty FM, et al. A mortality analysis of letermovir prophylaxis for cytomegalovirus (CMV) in CMV-seropositive recipients of allogeneic hematopoietic cell transplantation. Clin Infect Dis. 2020;70 :1525–1533. doi:10.1093/cid/ciz490 31179485\n16. Marty FM, Ljungman PT, Chemaly RF, et al. Outcomes of patients with detectable CMV DNA at randomization in the Phase III trial of letermovir for the prevention of CMV infection in allogeneic hematopoietic cell transplantation. Am J Transplant. 2020;20 :1703–1711. doi:10.1111/ajt.15764 31883426\n17. Cherrier L, Nasar A, Goodlet KJ, Nailor MD, Tokman S, Chou S. Emergence of letermovir resistance in a lung transplant recipient with ganciclovir-resistant cytomegalovirus infection. Am J Transplant. 2018;18 :3060–3064. doi:10.1111/ajt.15135 30286286\n18. Koepf US, Klehr HU, Eis-Huebinger AM, et al. Suppression of CMV infection with letermovir in a kidney transplant patient. Eur J Case Rep Intern Med. 2020;7 :001622. doi:10.12890/2020_001622 32665929\n19. Frietsch JJ, Michel D, Stamminger T, et al. In vivo emergence of UL56 C325Y cytomegalovirus resistance to letermovir in a patient with acute myeloid leukemia after hematopoietic cell transplantation. Mediterr J Hematol Infect Dis. 2019;11 :e2019001. doi:10.4084/MJHID.2019.001 30671207\n20. Kaul DR, Stoelben S, Cober E, et al. First report of successful treatment of multidrug-resistant cytomegalovirus disease with the novel anti-CMV compound AIC246. Am J Transplant. 2011;11 :1079–1084. doi:10.1111/j.1600-6143.2011.03530.x 21521474\n21. Kilgore JT, Becken B, Varga MG, et al. Use of letermovir for salvage therapy for resistant cytomegalovirus in a pediatric hematopoietic stem cell transplant recipient. J Pediatric Infect Dis Soc. 2020;9 :486–489. doi:10.1093/jpids/piz050 31362308\n22. Turner N, Strand A, Grewal DS, et al. Use of letermovir as salvage therapy for drug-resistant cytomegalovirus retinitis. Antimicrob Agents Chemother. 2019;63 :e02337–18. doi:10.1128/AAC.02337-18 30642941\n23. Lin A, Maloy M, Su Y, et al. Letermovir for primary and secondary cytomegalovirus prevention in allogeneic hematopoietic cell transplant recipients: real-world experience. Transpl Infect Dis. 2019;21 :e13187. doi:10.1111/tid.13187 31585500\n24. Robin C, Thiebaut A, Alain S, et al. Letermovir for secondary prophylaxis of CMV infection and disease after allogeneic hematopoietic cell transplantation: results from the French compassionate program. Biol Blood Marrow Transplant. 2020;26 (5 ):978–984. doi:10.1016/j.bbmt.2020.01.027 32035273\n25. Sousa H, Boutolleau D, Ribeiro J, et al. Cytomegalovirus infection in patients who underwent allogeneic hematopoietic stem cell transplantation in Portugal: a five-year retrospective review. Biol Blood Marrow Transplant. 2014;20 :1958e1967. doi:10.1016/j.bbmt.2014.08.010 25139217\n26. Cantoni N, Hirsch HH, Khanna N, et al. Evidence for a bidirectional relationship between cytomegalovirus replication and acute Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2010;16 :1309–1314. doi:10.1016/j.bbmt.2010.03.020 20353832\n27. Chiereghin A, Bertuzzi C, Piccirilli G, et al. Successful management of EBV-PTLD in allogeneic bone marrow transplant recipient by virological-immunological monitoring of EBV infection, prompt diagnosis and early treatment. Transpl Immunol. 2016;34 :60–64. doi:10.1016/j.trim.2015.12.002 26687013\n28. Campos AB, Ribeiro J, Boutolleau D, Sousa H. Human cytomegalovirus antiviral drug resistance in hematopoietic stem cell transplantation: current state of the art. Rev Med Virol. 2016;26 :161–182. doi:10.1002/rmv.1873 26990717\n29. Göhring K, Hamprecht K, Jahn G. Antiviral drug- and multidrug resistance in cytomegalovirus infected SCT patients. Comput Struct Biotechnol J. 2015;13 :153–159. doi:10.1016/j.csbj.2015.01.003 25750703\n30. Ciorba A, Corazzi V, Conz V, Bianchini C, Aimoni C. Facial nerve paralysis in children. World J Clin Cases. 2015;3 :973–979. doi:10.12998/wjcc.v3.i12.973 26677445\n31. Hakki M. Moving past ganciclovir and foscarnet: advances in CMV therapy. Curr Hematol Malig Rep. 2020;15 :90–102. doi:10.1007/s11899-020-00557-6 31981100\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6973",
"issue": "14()",
"journal": "Infection and drug resistance",
"keywords": "GCV-resistant CMV; intolerance to FOS; off-label letermovir use; pediatric allogeneic peripheral blood stem cell transplant",
"medline_ta": "Infect Drug Resist",
"mesh_terms": null,
"nlm_unique_id": "101550216",
"other_id": null,
"pages": "1185-1190",
"pmc": null,
"pmid": "33790588",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "30642941;17468776;31362308;31981100;30472161;31179485;31153807;30286286;20353832;26677445;31191499;29211658;32035273;21521474;27365460;32000236;25750703;30137245;31585500;33320429;25139217;30671207;26990717;29305542;20930070;31239725;19147520;32665929;31883426;26687013;31289930",
"title": "Off-Label Use of Letermovir as Preemptive Anti-Cytomegalovirus Therapy in a Pediatric Allogeneic Peripheral Blood Stem Cell Transplant.",
"title_normalized": "off label use of letermovir as preemptive anti cytomegalovirus therapy in a pediatric allogeneic peripheral blood stem cell transplant"
} | [
{
"companynumb": "IT-MYLANLABS-2021M1059993",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GANCICLOVIR"
},
"drugadditional": "1",
... |
{
"abstract": "Cutaneous manifestation is a newly reported clinical manifestation of COVID-19 infection. The clinical description of cutaneous manifestation is still not fully described. Our patient, a medical person, had viral exanthem distributed in the extremities along with a \"Spins and needles sensation,\" which differs from a previously published paper on cutaneous manifestations. The differential diagnosis of drug-induced skin rash and hand-foot-mouth disease was ruled out based on the patient's previous history and course of the disease.",
"affiliations": "Department of Cardiology and Vascular Medicine, Faculty of Medicine Universitas Indonesia/Harapan Kita National Cardiovascular Centre, Jakarta, Indonesia. Electronic address: ekaputra_bayushi@yahoo.com.;Department of Cardiology and Vascular Medicine, Faculty of Medicine Universitas Indonesia/Harapan Kita National Cardiovascular Centre, Jakarta, Indonesia.;Harapan Kita National Cardiovascular Centre, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia.;Department of Cardiology and Vascular Medicine, Faculty of Medicine Universitas Indonesia/Harapan Kita National Cardiovascular Centre, Jakarta, Indonesia.",
"authors": "Putra|Bayushi Eka|BE|;Adiarto|Suko|S|;Dewayanti|Santi Rahayu|SR|;Juzar|Dafsah Arifa|DA|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.1016/j.ijid.2020.05.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1201-9712",
"issue": "96()",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": "COVID-19; Cutaneous manifestation; Medical personnel; Pins and needles sensation",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D000328:Adult; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D003937:Diagnosis, Differential; D005076:Exanthema; D006801:Humans; D008297:Male; D058873:Pandemics; D011024:Pneumonia, Viral; D000086402:SARS-CoV-2; D057566:Self Report",
"nlm_unique_id": "9610933",
"other_id": null,
"pages": "355-358",
"pmc": null,
"pmid": "32437936",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28726337;32215952;27871252;31178104;25386550;32031570",
"title": "Viral exanthem with \"Spins and needles sensation\" on extremities of a COVID-19 patient: A self-reported case from an Indonesian medical frontliner.",
"title_normalized": "viral exanthem with spins and needles sensation on extremities of a covid 19 patient a self reported case from an indonesian medical frontliner"
} | [
{
"companynumb": "ID-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-258328",
"fulfillexpeditecriteria": "1",
"occurcountry": "ID",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OSELTAMIVIR"
},
"dru... |
{
"abstract": "The deletion of the distal 7q region is a rare chromosomal syndrome characterized by wide phenotypic manifestations including growth and psychomotor delay, facial dysmorphisms, and genitourinary malformations.\n\n\n\nWe describe a 6-year-old child with a 12-Mb deletion of the region 7q35q36.3.\n\n\n\nAmong the deleted genes, two genes have cardiac implications: PRKAG2 (OMIM #602743), associated with hypertrophic cardiomyopathy, cardiac conduction disease, and sudden death, and KCNH2 (OMIM #152427), coding for a cardiac potassium channel involved in long QT syndrome, unmasked by the chlorpheniramine treatment. At same time, the SHH gene (OMIM #600725), encoding sonic hedgehog, a secreted protein that is involved in the embryonic development, is deleted.\n\n\n\nOur report underlines potential cardiac complications linked to the common pharmacological treatment in this rare multiorgan and proteiform disease.",
"affiliations": "Cardiovascular Department, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.;Medical Genetics Service, Hospital \"Cardinale G. Panico\", Tricase, Lecce, Italy.;Cardiovascular Department, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.;Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.;Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.;Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.;Cardiovascular Department, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.;Paediatric Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.;Paediatric Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.;Cardiovascular Department, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.;Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.",
"authors": "Di Stolfo|Giuseppe|G|0000-0003-1758-7138;Accadia|Maria|M|;Mastroianno|Sandra|S|;Leone|Maria P|MP|;Palumbo|Orazio|O|;Palumbo|Pietro|P|;Potenza|Domenico|D|;Maccarone|Pasquale|P|;Sacco|Michele|M|;Russo|Aldo|A|;Carella|Massimo|M|",
"chemical_list": "D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human; D002744:Chlorpheniramine",
"country": "United States",
"delete": false,
"doi": "10.1002/mgg3.855",
"fulltext": "\n==== Front\nMol Genet Genomic MedMol Genet Genomic Med10.1002/(ISSN)2324-9269MGG3Molecular Genetics & Genomic Medicine2324-9269John Wiley and Sons Inc. Hoboken 10.1002/mgg3.855MGG3855Original ArticleOriginal ArticlesLong QT syndrome in chromosome 7q35q36.3 deletion involving KCNH2 gene: Warning for chlorpheniramine prescription Long QT syndrome in chromosome 7q35q36.3 deletion involving KCNH2 gene: Warning for chlorpheniramine prescriptionDI STOLFO et al.Di Stolfo Giuseppe https://orcid.org/0000-0003-1758-7138giuseppedistolfo@yahoo.it \n1\nAccadia Maria \n2\nMastroianno Sandra \n1\nLeone Maria P. \n3\nPalumbo Orazio \n3\nPalumbo Pietro \n3\nPotenza Domenico \n1\nMaccarone Pasquale \n4\nSacco Michele \n4\nRusso Aldo \n1\nCarella Massimo \n3\n\n1 \nCardiovascular Department\nFondazione IRCCS Casa Sollievo della Sofferenza\nSan Giovanni Rotondo\nFoggia\nItaly\n\n2 \nMedical Genetics Service\nHospital “Cardinale G. Panico”\nTricase\nLecce\nItaly\n\n3 \nDivision of Medical Genetics\nFondazione IRCCS Casa Sollievo della Sofferenza\nSan Giovanni Rotondo\nFoggia\nItaly\n\n4 \nPaediatric Unit\nFondazione IRCCS Casa Sollievo della Sofferenza\nSan Giovanni Rotondo\nFoggia\nItaly\n* Correspondence\n\nGiuseppe Di Stolfo, Cardiovascular Department, Fondazione IRCCS Casa Sollievo della Sofferenza, viale Cappuccini, 1, 71013 San Giovanni Rotondo, Foggia, Italy.\n\nEmail: giuseppedistolfo@yahoo.it\n25 7 2019 9 2019 7 9 10.1002/mgg3.v7.9e85520 11 2018 12 5 2019 17 6 2019 © 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nBackground\nThe deletion of the distal 7q region is a rare chromosomal syndrome characterized by wide phenotypic manifestations including growth and psychomotor delay, facial dysmorphisms, and genitourinary malformations.\n\nMethods\nWe describe a 6‐year‐old child with a 12‐Mb deletion of the region 7q35q36.3.\n\nResults\nAmong the deleted genes, two genes have cardiac implications: PRKAG2 (OMIM #602743), associated with hypertrophic cardiomyopathy, cardiac conduction disease, and sudden death, and KCNH2 (OMIM #152427), coding for a cardiac potassium channel involved in long QT syndrome, unmasked by the chlorpheniramine treatment. At same time, the SHH gene (OMIM #600725), encoding sonic hedgehog, a secreted protein that is involved in the embryonic development, is deleted.\n\nConclusion\nOur report underlines potential cardiac complications linked to the common pharmacological treatment in this rare multiorgan and proteiform disease.\n\nchlorpheniraminechromosome 7q35q36.3 deletionlong QT syndromesyncope source-schema-version-number2.0component-idmgg3855cover-dateSeptember 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.8 mode:remove_FC converted:08.09.2019\n\n\nDi Stolfo \nG \n, \nAccadia \nM \n, \nMastroianno \nS \n, et al. Long QT syndrome in chromosome 7q35q36.3 deletion involving KCNH2 gene: Warning for chlorpheniramine prescription . Mol Genet Genomic Med . 2019 ;7 :e855\n10.1002/mgg3.855\n==== Body\n1 INTRODUCTION\nThe deletion of the distal 7q region is a rare chromosomal syndrome characterized by wide phenotypic manifestations including growth and psychomotor delay, facial dysmorphisms, and genitourinary malformations; more severe phenotypes, such as sacral agenesis and holoprosencephaly (HPE) may occur (Harris et al., 1977; Vance et al., 1998; Wang et al., 1999). We describe a 6‐year‐old child with a 12‐Mb deletion of the region 7q35q36.3. Among the deleted genes, two genes have cardiac implications: KCNH2, coding for a cardiac potassium channel involved in long QT syndrome (LQTS) (Perrin, Subbiah, Vandenberg, & Hill, 2008); and PRKAG2, associated with hypertrophic cardiomyopathy, cardiac conduction disease, and sudden death (Porto et al., 2016). Our report underlines the relationship among potential cardiac complications and rare multiorgan and proteiform disease, with pharmacological implications in the daily management.\n\n2 CLINICAL REPORT\nA 6‐year‐old child was admitted to our Pediatric Department after a prolonged self‐limited episode of loss of consciousness while he was at school. The teacher described a 30‐min loss of consciousness, pallor, and hypotonia with generalized cyanosis compatible with an ALTE (Apparent Life‐Threatening Event) (Piumelli et al., 2017). The child was already known to our hospital for a previous diagnosis of 12‐Mb de novo deletion of the region 7q35q36.3. His clinical picture was characterized by growth and psychomotor delay, hypotonia, microcephaly (occipitofrontal head circumference 42.6 cm, below −3 SD for age and sex), and craniofacial dysmorphic features (bitemporal narrowing, prominent supraorbital ridges, eyelid ptosis, deep‐set eyes, bulbous nasal tip, microretrognathia, high palate, and large protruding ears) (Figure 1a,b). An echocardiogram performed in the first month of life showed ventricular septal defect, common in this chromosome deletion (Tiller et al., 1988), and self‐resolved at subsequent control. At the age of 4 years, he underwent urologic surgery for curved penis and hypospadias. A recent brain MRI did not show significant abnormalities. The presence of high palate resulted in feeding problem and rhinorrhea, with recurrent infections of the upper respiratory airways characterized by glue ear and rhinogenous deafness. These complications were often treated by steroids and antihistamines.\n\nFigure 1 Clinical features (a and b show frontal and lateral view)\n\nAt the time of admission, vital signs were normal and the ECG showed sinus rhythm and normal ventricular repolarization. The patient underwent complete evaluation; in particular, the echocardiogram was normal and subsequent EEGs did not reveal epileptiform anomalies. A 24‐hr Holter ECG recording showed repetitive QTc prolongation (QTc 520 ms, Figure 2a), concurrent with daily consumption of syrup containing acetaminophen and chlorpheniramine; another relevant ECG features was the short PR interval, up to 80 ms (Figure 2b).\n\nFigure 2 (a) Long QT interval after clorpheniramine consumption. (b) Evidence of short PR interval and normal QT interval\n\nThe 7q35q36.3 region contains the KCNH2 gene, coding for the human Ether‐à‐go‐go‐related gene (hERG) potassium channel involved in LQTS and chlorpheniramine represents a plausible hERG potassium blocker in an already compromised receptor malfunction. Since the strict correlation between syrup consumption and QT prolongation was manifest, the parents were advised to avoid a list of proarrhythmic drugs to the patient affected by LQTS ([Link]). Moreover, the deletion includes the PRKAG2 gene, implicated in a nonsarcomeric form of hypertrophic cardiomyopathy, associated with accessory pathway, short PR, and late evidence of supraventricular and ventricular tachycardia, complete heart block, and sudden death. The suspect for a seizure episode remained as the hypothesis of a prolonged self‐terminated ventricular arrhythmia was not documented and the need for a secondary prevention ICD implantation did not fulfill current guidelines. Therefore, the patient was referred to a tertiary cardiology pediatric center for loop recorder implantation, to better assess future hypotonic episode, and to avoid the dangerous arrhythmic event.\n\n3 MATERIALS AND METHODS\nSNP array‐based copy number variations (CNVs) analysis was performed on genomic DNA extracted from peripheral blood lymphocytes of the patient and his parents using the CytoScan HD Array (Affymetrix) as previously described (Palumbo et al., 2014). Data analysis was performed using the Chromosome Analysis Suite software version 3.1 (Affymetrix). A CNV was validated if at least 25 contiguous probes showed an abnormal log2 ratio.\n\n4 ETHICAL COMPLIANCE\nInformed consent, approved by the Fondazione IRCCS Casa Sollievo della Sofferenza Ethical Committee, was obtained from both parents for the genetic analysis, case history, and picture publication.\n\n5 RESULTS\nAn interstitial 12‐Mb deletion of the chromosome 7q35‐36 was observed, a mapping between linear sequence locations 143,873,921 and 155,888,203, according to the GRCh37/hg19 build of the human genome. No other clinically significant copy number changes were detected. Parental analysis using the same platform yielded normal results and the deletion identified in the patient was determined to be de novo. The molecular karyotype of the patient, according to the ISCN 2016, was: arr[GRCh37] 7q35q36.3 (143873377x2,143873921‐155888203x1, 155888261x2)dn.\n\nThe deleted region resulted in the loss of one copy of 131 genes, including SHH, KCNH2, and PRKAG2.\n\n6 DISCUSSION\nComplex syndromes originating from the deletion of the region concerning multiple genes are characterized by multisystemic involvement. Dysmorphisms and systemic malformations generally arise medical attention at the beginning, while further associated manifestations need a methodological approach concerning both genetic analysis and clinical evaluation.\n\nIn common practice, upper respiratory way complications secondary to palate involvement often cause a clinician's Pavlovian reflex leading to corticosteroid and antihistamines prescription. In this case, chlorpheniramine consumption was clearly associated with QT prolongation.\n\nAccording to the DECIPHER database, the haploinsufficiency index for KCNH2 is 8.86%, indicating that not only the point mutations but also its deletion could lead to deleterious effect (Huang, Lee, Marcotte, & Hurles, 2010). Three other patients harboring the deletion of distal 7q encompassing KCNH2 were found to have a LQTS (Bisgaard, Rackauskaite, Thelle, Kirchhoff, & Bryndorf, 2006; Caselli et al., 2008).\n\nPrevious literature suggests that chlorpheniramine, an H1 antihistamine, is a blocker of the hERG channels, providing a molecular mechanism for the drug‐induced arrhythmogenic side effects (Hong & Jo, 2009). Indeed, the hERG potassium ion channel plays a key role in cardiotoxicity and is therefore a key target as a part of preclinical drug discovery toxicity screening (Shen, Su, Esposito, Hopfinger, & Tseng, 2011; Sun, Xia, Austin, & Huang, 2012). Altogether, these observations underline a clear role of the pharmacogenomic integrated approach in daily practice toward rare complex disease, leading to a desirable personalized medicine (Salari, Watkins, & Ashley, 2012).\n\nNevertheless, the screening approach by means of electrocardiography should play a key role in the management of multifaceted genetic disorder to avoid arrhythmic complication, in both single case treatment and global awareness by building a gene‐related International Registry (Narayanan & Chugh, 2015).\n\nThe phenotypic involvement of PRKAG2 expression may be realized in the previous ventricular septal defect self‐resolved and in the presence of short PR (up to 80 ms). PRKAG2 syndrome is characterized by ventricular preexcitation, supraventricular arrhythmias, and cardiac hypertrophy, often associated with advanced heart blocks, needing strict follow‐up by echocardiography, and Holter ECG recording, to promptly recognize and treat pathological clinical expression (Porto et al., 2016). In this case, it represents a syndrome in syndrome, like a matryoshka doll.\n\nIn 7q35q36.3 syndrome, the SHH gene is deleted. The SHH gene encodes sonic hedgehog, a secreted protein that is involved in establishing cell fates at several points during the development and his strictly associated with HPE (Echelard et al., 1993; Solomon et al., 2010); nevertheless, the patient had no brain anomalies of HPE spectrum in the MRI scan of brain, but only microcephaly; clinical expression of microform HPE may be represented by midline anomalies as high palate, according to the wide spectrum of clinical manifestations caused by mutation in the SHH gene (Kruszka, Hart, Hadley, Muenke, & Habal, 2015; Solomon et al., 2010). Furthermore, the SHH gene deletion effect is represented by hypospadias, as a consequence of SHH role in genital ectoderm differentiation during urethra genesis (Joodi et al., 2019).\n\nNeurological expression of HPE could include atonic seizures, causing a loss of normal muscle tone, fall down, and prolonged unconsciousness; according to this point, in the absence of clear demonstration of threatening tachyarrhythmias and heart block, we decided to implant a loop recorder for a further clinical follow‐up and better treatment decision (Avari Silva, Bromberg, Emge, Bowman, & Van Hare, 2016).\n\nIt is clearly evident that a multidisciplinary approach represents a cornerstone in the daily management of fragile patients affected by insidious genetic disease as 7q35q36.3 deletion.\n\n7 CONCLUSION\nThe deletion of the distal 7q region is a rare chromosomal anomaly associated with multisystemic involvement and considerable cardiac implications, and threatening drug‐related side effect.\n\nA clear phenotypic manifestation has to lead the physicians to a deeper and accurate analysis of the proband genetic constitution, for subsequent finer clinical evaluation of possible gene‐related disease. Physicians and geneticists should get down deep into individual DNA code of syndromic patients, to clearly discover any further possible implication for the correct management, improving many physicians awareness about a widespread cold relief drug that may turn a mother's smile to a screaming nightmare.\n\nCONFLICT OF INTERESTS\nNone declared.\n==== Refs\nREFERENCES\n\n\nAvari Silva , J. N. \n, \nBromberg , B. I. \n, \nEmge , F. K. \n, \nBowman , T. M. \n, & \nVan Hare , G. F. \n (2016 ). Implantable loop recorder monitoring for refining management of children with inherited arrhythmia syndromes . Journal of the American Heart Association , 5 (6 ), 1 –6 . 10.1161/JAHA.116.003632 \n\n\n\nBisgaard , A.‐M. \n, \nRackauskaite , G. \n, \nThelle , T. \n, \nKirchhoff , M. \n, & \nBryndorf , T. \n (2006 ). Twins with mental retardation and an interstitial deletion 7q34q36.2 leading to the diagnosis of long QT syndrome . American Journal of Medical Genetics. Part A , 140 (6 ), 644 –648 . 10.1002/ajmg.a.31130 \n16470702 \n\n\nCaselli , R. \n, \nMencarelli , M. A. \n, \nPapa , F. T. \n, \nAriani , F. \n, \nLongo , I. \n, \nMeloni , I. \n, … \nMari , F. \n (2008 ). Delineation of the phenotype associated with 7q36.1q36.2 deletion: Long QT syndrome, renal hypoplasia and mental retardation . American Journal of Medical Genetics. Part A , 146A (9 ), 1195 –1199 . 10.1002/ajmg.a.32197 \n18348270 \nDrugsToAvoidList.pdf. (n.d.). Retrieved from https://crediblemeds.org/pdftemp/pdf/DrugsToAvoidList.pdf\n\n\n\nEchelard , Y. \n, \nEpstein , D. J. \n, \nSt‐Jacques , B. \n, \nShen , L. \n, \nMohler , J. \n, \nMcMahon , J. A. \n, & \nMcMahon , A. P. \n (1993 ). Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity . Cell , 75 (7 ), 1417 –1430 . 10.1016/0092-8674(93)90627-3 \n7916661 \n\n\nHarris , E. L. \n, \nWappner , R. S. \n, \nPalmer , C. G. \n, \nHall , B. \n, \nDinno , N. \n, \nSeashore , M. R. \n, & \nBreg , W. R. \n (1977 ). 7q deletion syndrome (7q32 leads to 7qter) . Clinical Genetics , 12 (4 ), 233 –238 .912940 \n\n\nHong , H.‐K. \n, & \nJo , S.‐H. \n (2009 ). Block of hERG K+ channel by classic histamine H1 receptor antagonist chlorpheniramine . The Korean Journal of Physiology and Pharmacology , 13 (3 ), 215 –220 . 10.4196/kjpp.2009.13.3.215 \n19885040 \n\n\nHuang , N. \n, \nLee , I. \n, \nMarcotte , E. M. \n, & \nHurles , M. E. \n (2010 ). Characterising and predicting haploinsufficiency in the human genome . PLoS Genetics , 6 (10 ), e1001154 \n10.1371/journal.pgen.1001154 \n20976243 \n\n\nJoodi , M. \n, \nAmerizadeh , F. \n, \nHassanian , S. M. \n, \nErfani , M. \n, \nGhayour‐Mobarhan , M. \n, \nFerns , G. A. \n, … \nAvan , A. \n (2019 ). The genetic factors contributing to hypospadias and their clinical utility in its diagnosis . Journal of Cellular Physiology , 234 (5 ), 5519 –5523 . 10.1002/jcp.27350 \n30238986 \n\n\nKruszka , P. \n, \nHart , R. A. \n, \nHadley , D. W. \n, \nMuenke , M. \n, & \nHabal , M. B. \n (2015 ). Expanding the phenotypic expression of Sonic Hedgehog mutations beyond holoprosencephaly . The Journal of Craniofacial Surgery , 26 (1 ), 3 –5 . 10.1097/SCS.0000000000001377 \n25569381 \n\n\nNarayanan , K. \n, & \nChugh , S. S. \n (2015 ). The 12‐lead electrocardiogram and risk of sudden death: Current utility and future prospects . Europace , 17 (suppl 2 ), ii7 –ii13 . 10.1093/europace/euv121 \n26842119 \n\n\nPalumbo , O. \n, \nFichera , M. \n, \nPalumbo , P. \n, \nRizzo , R. \n, \nMazzolla , E. \n, \nCocuzza , D. M. \n, … \nMattina , T. \n (2014 ). TBR1 is the candidate gene for intellectual disability in patients with a 2q24.2 interstitial deletion . American Journal of Medical Genetics. Part A , 164A (3 ), 828 –833 . 10.1002/ajmg.a.36363 \n24458984 \n\n\nPerrin , M. J. \n, \nSubbiah , R. N. \n, \nVandenberg , J. I. \n, & \nHill , A. P. \n (2008 ). Human ether‐a‐go‐go related gene (hERG) K+ channels: Function and dysfunction . Progress in Biophysics and Molecular Biology , 98 (2–3 ), 137 –148 . 10.1016/j.pbiomolbio.2008.10.006 \n19027781 \n\n\nPiumelli , R. \n, \nDavanzo , R. \n, \nNassi , N. \n, \nSalvatore , S. \n, \nArzilli , C. \n, \nPeruzzi , M. \n, … \nCutrera , R. \n (2017 ). Apparent life‐threatening events (ALTE): Italian guidelines . Italian Journal of Pediatrics , 43 (1 ), 111 \n10.1186/s13052-017-0429-x \n29233182 \n\n\nPorto , A. G. \n, \nBrun , F. \n, \nSeverini , G. M. \n, \nLosurdo , P. \n, \nFabris , E. \n, \nTaylor , M. R. G. \n, … \nSinagra , G. \n (2016 ). Clinical spectrum of PRKAG2 syndrome . Circulation: Arrhythmia and Electrophysiology , 9 (1 ), 1 –8 . 10.1161/CIRCEP.115.003121 \n\n\n\nSalari , K. \n, \nWatkins , H. \n, & \nAshley , E. A. \n (2012 ). Personalized medicine: Hope or hype? \nEuropean Heart Journal , 33 (13 ), 1564 –1570 . 10.1093/eurheartj/ehs112 \n22659199 \n\n\nShen , M.‐Y. \n, \nSu , B.‐H. \n, \nEsposito , E. X. \n, \nHopfinger , A. J. \n, & \nTseng , Y. J. \n (2011 ). A comprehensive support vector machine binary hERG classification model based on extensive but biased end point hERG data sets . Chemical Research in Toxicology , 24 (6 ), 934 –949 . 10.1021/tx200099j \n21504223 \n\n\nSolomon , B. D. \n, \nMercier , S. \n, \nVélez , J. I. \n, \nPineda‐Alvarez , D. E. \n, \nWyllie , A. \n, \nZhou , N. \n, … \nMuenke , M. \n (2010 ). Analysis of genotype‐phenotype correlations in human holoprosencephaly . American Journal of Medical Genetics. Part C: Seminars in Medical Genetics , 154C (1 ), 133 –141 . 10.1002/ajmg.c.30240 \n\n\n\nSun , H. \n, \nXia , M. \n, \nAustin , C. P. \n, & \nHuang , R. \n (2012 ). Paradigm shift in toxicity testing and modeling . The AAPS Journal , 14 (3 ), 473 –480 . 10.1208/s12248-012-9358-1 \n22528508 \n\n\nTiller , G. E. \n, \nWatson , M. S. \n, \nDuncan , L. M. \n, \nDowton , S. B. \n, \nOptiz , J. M. \n, & \nReynolds , J. F. \n (1988 ). Congenital heart defect in a patient with deletion of chromosome 7q . American Journal of Medical Genetics , 29 (2 ), 283 –287 . 10.1002/ajmg.1320290206 \n3354600 \n\n\nVance , G. H. \n, \nNickerson , C. \n, \nSarnat , L. \n, \nZhang , A. \n, \nHenegariu , O. \n, \nMorichon‐Delvallez , N. \n, … \nPalmer , C. G. \n (1998 ). Molecular cytogenetic analysis of patients with holoprosencephaly and structural rearrangements of 7q . American Journal of Medical Genetics , 76 (1 ), 51 –57 . 10.1002/(SICI)1096-8628(19980226)76:1<51:AID-AJMG9>3.0.CO;2-S \n9508065 \n\n\nWang , J. \n, \nSpitz , L. \n, \nHayward , R. \n, \nKiely , E. \n, \nHall , C. M. \n, \nO'Donoghue , D. P. \n, … \nReardon , W. \n (1999 ). Sacral dysgenesis associated with terminal deletion of chromosome 7q: A report of two families . European Journal of Pediatrics , 158 (11 ), 902 –905 . 10.1007/s004310051238 \n10541945\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2324-9269",
"issue": "7(9)",
"journal": "Molecular genetics & genomic medicine",
"keywords": "chlorpheniramine; chromosome 7q35q36.3 deletion; long QT syndrome; syncope",
"medline_ta": "Mol Genet Genomic Med",
"mesh_terms": "D002648:Child; D002744:Chlorpheniramine; D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7; D056915:DNA Copy Number Variations; D011307:Drug Prescriptions; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008133:Long QT Syndrome; D008297:Male",
"nlm_unique_id": "101603758",
"other_id": null,
"pages": "e855",
"pmc": null,
"pmid": "31347270",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20976243;25569381;26729852;20104608;24458984;26842119;7916661;21504223;22659199;31347270;27231019;16470702;3354600;30238986;29233182;9508065;19885040;912940;22528508;19027781;18348270;10541945",
"title": "Long QT syndrome in chromosome 7q35q36.3 deletion involving KCNH2 gene: Warning for chlorpheniramine prescription.",
"title_normalized": "long qt syndrome in chromosome 7q35q36 3 deletion involving kcnh2 gene warning for chlorpheniramine prescription"
} | [
{
"companynumb": "IT-ACELLA PHARMACEUTICALS, LLC-2090910",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CHLORPHENIRAMINE MALEATE\\HYDROCODONE BITARTRATE"
... |
{
"abstract": "We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.",
"affiliations": "Department of Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Medicine, All India Institute of Medical Sciences, New Delhi, India.;Department of Medicine, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Soneja|Manish|M|;Aggarwal|Anivita|A|;Kodan|Parul|P|;Gupta|Nitin|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/omcr/omaa147",
"fulltext": "\n==== Front\nOxf Med Case Reports\nOxf Med Case Reports\nomcr\nOxford Medical Case Reports\n2053-8855\nOxford University Press\n\n10.1093/omcr/omaa147\nomaa147\nEducational Case Report\nAcademicSubjects/MED00010\nomcrep/1200\nHuman immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient\nSoneja Manish\nAggarwal Anivita\nKodan Parul\nGupta Nitin\nDepartment of Medicine, All India Institute of Medical Sciences, New Delhi, India\nCorrespondence address. Senior Resident Infectious Disease, Department of Medicine, All India Institute of Medical Sciences, Sri Aurobindo Marg, Ansari Nagar, Ansari Nagar East, New Delhi, Delhi 110029, India. Tel: 7838340627; E-mail: nityanitingupta@gmail.com\n3 2021\n08 3 2021\n08 3 2021\n2021 3 omaa14725 3 2020\n26 5 2020\n23 12 2020\n© The Author(s) 2021. Published by Oxford University Press.\n2021\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nWe report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.\n==== Body\nINTRODUCTION\n\nPatients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.\n\nCASE REPORT\n\nA 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.\n\nHis CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.\n\nHe continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.\n\nDISCUSSION\n\nCryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].\n\nCMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.\n\nIndia has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.\n\nVariable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.\n\nPotential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.\n\nACKNOWLEDGEMENTS\n\nNil.\n\nCONFLICT OF INTEREST STATEMENT\n\nNone declared.\n\nFUNDING\n\nNone to declare.\n\nETHICAL APPROVAL\n\nNot applicable.\n\nConsent was taken prior to publications.\n\nGuarantor—same as the corresponding author.\n==== Refs\nREFERENCES\n\n1. Wang R-J, Li J-Q, Chen Y-C, Zhang L-X, Xiao L-H. Widespread occurrence of cryptosporidium infections in patients with HIV/AIDS: epidemiology, clinical feature, diagnosis, and therapy. Acta Trop 2018;187 :257–63.30118699\n2. Abubakar I, Aliyu SH, Arumugam C, Hunter PR, Usman NK. Prevention and treatment of cryptosporidiosis in immunocompromised patients. Cochrane Database Syst Rev 2007;1 :CD004932.\n3. Gianella S, Letendre S. Cytomegalovirus and HIV: a dangerous pas de Deux. J Infect Dis 2016;214 :S67–74.27625433\n4. Grønborg HL, Jespersen S, Hønge BL, Jensen-Fangel S, Wejse C. Review of cytomegalovirus coinfection in HIV-infected individuals in Africa. Rev Med Virol 2017;27 :1–14.\n5. Tanwar S, Rewari BB, Rao CD, Seguy N. India’s HIV programme: successes and challenges. J Virus Erad 2016;2 :15–9.28275445\n6. Lal V, Kant S, Dewan R, Rai SK, Biswas A. A two-site hospital-based study on factors associated with nonadherence to highly active antiretroviral therapy. Indian J Public Health 2010;54 :179–83.21372363\n7. Altice F, Evuarherhe O, Shina S, Carter G, Beaubrun AC. Adherence to HIV treatment regimens: systematic literature review and meta-analysis. Patient Prefer Adherence 2019;13 :475–90.31040651\n8. Heestermans T, Browne JL, Aitken SC, Vervoort SC, Klipstein-Grobusch K. Determinants of adherence to antiretroviral therapy among HIV-positive adults in sub-Saharan Africa: a systematic review. BMJ Glob Health 2016;1 :e000125.\n9. Nachega JB, Uthman OA, Peltzer K, Richardson LA, Mills EJ, Amekudzi K et al. Association between antiretroviral therapy adherence and employment status: systematic review and meta-analysis. Bull World Health Organ 2015;93 :29–41.25558105\n10. Sharma SK, Dhooria S, Prasad K, George N, Ranjan S, Gupta D et al. Outcomes of antiretroviral therapy in a northern Indian urban clinic. Bull World Health Organ 2010;88 :222–6.20428391\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2053-8855",
"issue": "2021(3)",
"journal": "Oxford medical case reports",
"keywords": null,
"medline_ta": "Oxf Med Case Reports",
"mesh_terms": null,
"nlm_unique_id": "101642070",
"other_id": null,
"pages": "omaa147",
"pmc": null,
"pmid": "33732476",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports",
"references": "21372363;20428391;28588979;31040651;17253532;27625433;25558105;30118699;27714898;28275445",
"title": "Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.",
"title_normalized": "human immunodeficiency virus infection with multiple opportunistic infections lessons learnt from a non adherent patient"
} | [
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2021-21204",
"fulfillexpeditecriteria": "2",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
... |
{
"abstract": "OBJECTIVE\nLiver failure from non-alcoholic fatty liver disease (NAFLD) is an increasing indication for liver transplant and recurrence of fatty liver in transplanted grafts has been documented. Herein is described an atypical recurrence of steatosis as a de novo focal fatty lesion that mimicked a more ominous cancerous lesion. This presentation of recurrent NAFLD has not previously been described in the literature.\n\n\nMETHODS\nChart review.\n\n\nRESULTS\nBiopsy of an atypical lesion was found to be focal fat with surrounding steatohepatitis.\n\n\nCONCLUSIONS\nNon-alcoholic fatty liver disease may recur after liver transplant and manifest as a focal fatty lesion. It is important to catalogue the atypical presentations of the increasingly common NAFLD developing in transplanted livers.",
"affiliations": "Department of Medicine, University of North Carolina, Chapel Hill, NC 27599-7080, USA.",
"authors": "Patrick|Caitlyn M|CM|;Hayashi|Paul H|PH|;Kozlowski|Tomasz|T|;Greene|Kevin G|KG|;Semelka|Richard C|RC|;Barritt|A Sidney|AS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s10620-011-1739-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-2116",
"issue": "56(11)",
"journal": "Digestive diseases and sciences",
"keywords": null,
"medline_ta": "Dig Dis Sci",
"mesh_terms": "D006528:Carcinoma, Hepatocellular; D003937:Diagnosis, Differential; D005234:Fatty Liver; D006801:Humans; D008099:Liver; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D012008:Recurrence",
"nlm_unique_id": "7902782",
"other_id": null,
"pages": "3382-5",
"pmc": null,
"pmid": "21559737",
"pubdate": "2011-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "19344467;11005276;17241384;20040915;9346733;15084161;20373454;20733515;19938117;11349722;8990367;18936622;19562337",
"title": "Focal fat masquerading as malignancy in the liver graft of a post-transplant patient.",
"title_normalized": "focal fat masquerading as malignancy in the liver graft of a post transplant patient"
} | [
{
"companynumb": "US-TEVA-2019-US-1074026",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3"... |
{
"abstract": "A 14-year-old girl presented with a history of left-sided headache and acute bilateral blurred vision. She had a remote history of oral tetracycline use for the treatment of acne vulgaris, which had been discontinued for 1 month. The patient was diagnosed with drug-induced intracranial hypertension (IH) and treated with oral acetazolamide with subsequent resolution of symptoms. IH, a known rare complication of the tetracycline class of antibiotics, can also have a delayed presentation after discontinuation of the medication.",
"affiliations": "Department of Ophthalmology, Hotel Dieu Hospital, Queen's University, Kingston, Ontario, Canada.",
"authors": "Law|Christine|C|;Yau|Gary L|GL|;ten Hove|Martin|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002257:Carbonic Anhydrase Inhibitors; D013752:Tetracycline; D000086:Acetazolamide",
"country": "United States",
"delete": false,
"doi": "10.1097/WNO.0000000000000301",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1070-8022",
"issue": "36(1)",
"journal": "Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society",
"keywords": null,
"medline_ta": "J Neuroophthalmol",
"mesh_terms": "D000086:Acetazolamide; D000152:Acne Vulgaris; D000293:Adolescent; D000900:Anti-Bacterial Agents; D002257:Carbonic Anhydrase Inhibitors; D005260:Female; D006801:Humans; D019586:Intracranial Hypertension; D013752:Tetracycline; D014786:Vision Disorders; D014792:Visual Acuity; D058609:Visual Field Tests; D014794:Visual Fields; D028761:Withholding Treatment",
"nlm_unique_id": "9431308",
"other_id": null,
"pages": "67-9",
"pmc": null,
"pmid": "26397465",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Delayed Development of Intracranial Hypertension After Discontinuation of Tetracycline Treatment for Acne Vulgaris.",
"title_normalized": "delayed development of intracranial hypertension after discontinuation of tetracycline treatment for acne vulgaris"
} | [
{
"companynumb": "CA-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-114039",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TETRACYCLINE"
},
"d... |
{
"abstract": "Treatment of recurrent nasopharyngeal carcinoma is a challenging clinical problem. We report the case of a 46 year old male showing excellent response and signs of immunostimulation following re-re-irradiation for recurrent nasopharyngeal carcinoma under systemic treatment with pembrolizumab.\n\n\n\nPatient was first diagnosed with locoregionally advanced, non-keratinizing nasopharyngeal carcinoma in 2010. After achieving complete remission following induction chemotherapy and concurrent curative chemoradiation, the patient subsequently developed distant and locoregionally recurrent disease. He received various treatments (neck dissection, radiotherapy to a bony metastasis, palliative chemotherapy, stereotactic re-irradiation of local recurrence) before initiation of anti- PD-1 immunotherapy with pembrolizumab in January of 2016. Following marked local progression 6 months thereafter, we performed re-re-irradiation of the recurrent tumor after careful evaluation and treatment planning. While treatment was well tolerated, the patient subsequently developed marked clinical and radiological signs of immunostimulation with mucosal irritation and swelling of lacrimal and salivary glands as described in the report. Immunotherapy with pembrolizumab was reinitiated, with re- staging showing excellent response with regression of all tumorous lesions. At the time of this report, following near complete recovery of inflammatory symptoms, the patient remains in excellent condition and free from recurrence under treatment with pembrolizumab.\n\n\n\nTo our knowledge, we report the first observation of a combined effect of immunotherapy and radiotherapy in a patient with recurrent nasopharyngeal carcinoma. Demonstrating distinct signs of immunostimulation as well as excellent tumor response in a heavily pretreated patient progressing under anti-PD-1 immunotherapy, the case adds to the rising paradigm of an immunostimulatory effect of radiotherapy in patients undergoing treatment with immune checkpoint inhibitors.",
"affiliations": "Department of Radiation Oncology, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland.;Department of Oncology, University Hospital Zurich, Zurich, Switzerland.;Department of Pathology, University Hospital Zurich, Zurich, Switzerland.;Department of Otorhinolaryngology, University Hospital Zurich, Zurich, Switzerland.;Department of Radiation Oncology, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland.;Department of Radiation Oncology, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland. helena.garcia@usz.ch.",
"authors": "Finazzi|T|T|;Rordorf|T|T|;Ikenberg|K|K|;Huber|G F|GF|;Guckenberger|M|M|;Garcia Schueler|H I|HI|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D015415:Biomarkers; D061026:Programmed Cell Death 1 Receptor",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-018-4295-8",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 429510.1186/s12885-018-4295-8Case ReportRadiotherapy-induced anti-tumor immune response and immune-related adverse events in a case of recurrent nasopharyngeal carcinoma undergoing anti-PD-1 immunotherapy Finazzi T. tobias.finazzi@usz.ch 1Rordorf T. tamara.rordorf@usz.ch 2Ikenberg K. kristian.ikenberg@usz.ch 3Huber G. F. gerry.huber@usz.ch 4Guckenberger M. matthias.guckenberger@usz.ch 1Garcia Schueler H. I. helena.garcia@usz.ch 11 0000 0004 0478 9977grid.412004.3Department of Radiation Oncology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland 2 0000 0004 0478 9977grid.412004.3Department of Oncology, University Hospital Zurich, Zurich, Switzerland 3 0000 0004 0478 9977grid.412004.3Department of Pathology, University Hospital Zurich, Zurich, Switzerland 4 0000 0004 0478 9977grid.412004.3Department of Otorhinolaryngology, University Hospital Zurich, Zurich, Switzerland 6 4 2018 6 4 2018 2018 18 3954 10 2017 22 3 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nTreatment of recurrent nasopharyngeal carcinoma is a challenging clinical problem. We report the case of a 46 year old male showing excellent response and signs of immunostimulation following re-re-irradiation for recurrent nasopharyngeal carcinoma under systemic treatment with pembrolizumab.\n\nCase presentation\nPatient was first diagnosed with locoregionally advanced, non-keratinizing nasopharyngeal carcinoma in 2010. After achieving complete remission following induction chemotherapy and concurrent curative chemoradiation, the patient subsequently developed distant and locoregionally recurrent disease. He received various treatments (neck dissection, radiotherapy to a bony metastasis, palliative chemotherapy, stereotactic re-irradiation of local recurrence) before initiation of anti- PD-1 immunotherapy with pembrolizumab in January of 2016. Following marked local progression 6 months thereafter, we performed re-re-irradiation of the recurrent tumor after careful evaluation and treatment planning. While treatment was well tolerated, the patient subsequently developed marked clinical and radiological signs of immunostimulation with mucosal irritation and swelling of lacrimal and salivary glands as described in the report. Immunotherapy with pembrolizumab was reinitiated, with re- staging showing excellent response with regression of all tumorous lesions. At the time of this report, following near complete recovery of inflammatory symptoms, the patient remains in excellent condition and free from recurrence under treatment with pembrolizumab.\n\nConclusions\nTo our knowledge, we report the first observation of a combined effect of immunotherapy and radiotherapy in a patient with recurrent nasopharyngeal carcinoma. Demonstrating distinct signs of immunostimulation as well as excellent tumor response in a heavily pretreated patient progressing under anti-PD-1 immunotherapy, the case adds to the rising paradigm of an immunostimulatory effect of radiotherapy in patients undergoing treatment with immune checkpoint inhibitors.\n\nKeywords\nNasopharyngealRadiotherapy, immunotherapyImmunostimulationPembrolizumabissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nTreatment of recurrent nasopharyngeal carcinoma is a challenging clinical problem. We report the case of a 46 year old male showing excellent response and signs of immunostimulation following re-re-irradiation for recurrent nasopharyngeal carcinoma under systemic treatment with pembrolizumab.\n\nCase presentation\nPatient was originally diagnosed with locoregionally advanced, non-keratinizing nasopharyngeal carcinoma (stage IVB; cT2 cN3a cM0; EBV-associated) in November of 2010 (Fig. 1). He underwent treatment with neoadjuvant chemotherapy (two 3-weekly cycles of cisplatin 100 mg/m2 d1 and fluorouracil 1000 mg/m2 d1–4) followed by concurrent curative chemoradiation. Intensity-modulated radiotherapy (volumetric modulated arc therapy; VMAT) was delivered to the primary tumor and nodal metastases in 35 daily fractions of 2 Gy to a total dose of 70 Gy as an integrated boost with elective nodal irradiation to 54 Gy (Fig. 2). Due to cisplatin-induced ototoxicity and anaphylactic reaction to cetuximab, concurrent chemotherapy was delivered with 4 cycles of carboplatin 100 mg/m2 weekly (stopped prematurely due to thrombocytopenia). Having achieved complete remission, the patient first presented with distant and locoregionally recurrent disease in October 2011, with PET-CT showing a highly suspicious FDG-avid lesion in the thoracic spine which was diagnosed as bony metastasis after further examination in contrast-enhanced MRI (additional biopsy was omitted after interdisciplinary discussion since clinical significance was deemed low). The patient received radiotherapy (45 Gy in fractions of 3 Gy) to the solitary bony metastasis as well as bilateral neck dissection, removing a total of three metastatic lymph nodes of the left neck. He was subsequently free from recurrence and without symptoms for two years, allowing him to work full-time.Fig. 1 T1-weighted MRI in November of 2010 showing contrast-enhancing right-sided nasopharyngeal primary tumor (red arrow) as well as bilateral metastatic lymph nodes of the neck (blue arrows)\n\nFig. 2 Intensity-modulated radiotherapy plan of 2010 showing 95%-isodose coverage of bilateral cervical lymph nodes with simultaneous integrated boost (SIB) of 70 Gy to the primary tumor and metastatic lymph nodes\n\n\n\nIn September of 2013, PET-CT and MRI first raised suspicion of a small bony metastasis of the right occipital condyle and the adjacent clivus. Since this region bordered the initial primary tumor and had therefore received the full dose of 70 Gy during chemoradiation, re-irradiation was declined, given that the patient was asymptomatic. However, the patient developed progressive diplopia due to right-sided abducens nerve palsy after a few weeks. A biopsy of the occipital condyle was performed, confirming cancer recurrence. Due to surrounding dural thickening and contrast enhancement suspicious of meningeal carcinomatosis, the patient received one cycle of intrathecal methotrexate; however, lumbar puncture did not show malignant cells. The patient subsequently received 4 cycles of combination chemotherapy (carboplatin, fluorouracil, docetaxel) with good radiological and clinical response.\n\nDue to progressive diplopia in September of 2014, an MRI was performed, showing tumorous infiltration of the cavernous sinus affecting the abducens nerve. The patient underwent stereotactic re-irradiation (single fraction of 14 Gy to the cavernous sinus) at an external institution using CyberKnife®, achieving mild improvement of symptoms. Due to allergic reaction to carboplatin, systemic treatment was switched to docetaxel and gemcitabine for a total of 6 cycles. The patient was again free from disease progression for one year, before developing tumor progression at the skull base involving the cavernous sinus, Meckel’s cave and the internal carotid artery on the right side as well the middle cranial fossa including the hypoglossal canal in autumn of 2015.\n\nFollowing the presentation of promising preliminary data for heavily pretreated patients with nasopharyngeal carcinoma in the KEYNOTE-028 cohort [1], a request for medical insurance coverage of immunotherapy with pembrolizumab was made whilst re-challenge chemotherapy with docetaxel and gemcitabine was administered during the decision process. Having received approval, immunotherapy with pembrolizumab was initiated in January of 2016. At this point, PET-CT did not show any distant metastases and circulating EBV DNA (a biomarker for nasopharyngeal carcinoma) was not measurable.\n\nWhile restaging 3 months after initiation of pembrolizumab demonstrated an overall stable situation, the patient progressed again in June of 2016 after 6 months of pembrolizumab, with MRI showing marked increase of tumorous infiltration in the cavernous sinus, Meckel’s cave, the right carotid artery, the occipital condyle as well as the prevertebral space (Fig. 3). During the same period, the patient developed clinical symptoms with progressive trismus, right sided hypoglossal and glossopharyngeal nerve palsy with dysphagia as well as right sided facial hypesthesia, fitting the radiological diagnosis of progressive disease rather than pseudoprogression under immunotherapy. Since the tumor remained unresectable (large tumor extension affecting dura, cavernous sinus, clivus and internal carotid artery without realistic chance of achieving an R0 resection), the patient was once again presented for radiotherapy. After careful evaluation and treatment planning, we performed stereotactic image-guided re-re-irradiation of the recurrent lesion to a total dose of 45 Gy in 25 daily fractions of 1.8 Gy over 6 weeks (Fig. 4). Immunotherapy with pembrolizumab was paused during radiotherapy, which was completed in early October of 2016. Apart from marked fatigue, irradiation was well tolerated, with only mild dysphagia and two episodes of nausea (self-limiting without need for steroids).Fig. 3 T1-weighted MRI in June of 2016 showing bulky tumor recurrence (red arrows) in axial and coronal plane\n\nFig. 4 Treatment plan for stereotactic re-re-irradiation using rotational intensity-modulated radiotherapy (volumetric modulated arc therapy; VMAT). The 95%-isodose coverage of the prescribed 45 Gy is shown on fused MRI in axial and sagittal plane, with the latter demonstrating extensive craniocaudal (including prevertebral) tumor extension\n\n\n\nTwo weeks after treatment completion, the patient first reported symptoms of a common cold with nasal congestion. The patient was seen by our otorhinolaryngologists and received symptomatic treatment and antibiotics (amoxicillin / clavulanic acid) due to thick, putrid mucus in the nasal cavity and the nasopharynx. The patient also reported symptoms of ocular irritation with a burning sensation, dryness and epiphora as well as pronounced swelling of the eyelids in the early morning, also receiving symptomatic treatment after consultation with our ophthalmologists. Having achieved some symptomatic improvement, the patient then presented with a painful swelling of the left submandibular gland suspicious of sialadenitis without sonographic signs of sialolithiasis (fine-needle aspiration was refused by the patient). Days later, he also developed an itching maculopapular rash on the whole body with skin biopsy showing perivascular lymphohistiocytic infiltration mixed with eosinophils. Suspecting cutaneous drug eruption caused by amoxicillin, our dermatologists prescribed topical and systemic steroids which led to slow recovery (over 6 weeks).\n\nTreatment with pembrolizumab was ultimately reinitiated 7 weeks after completion of radiotherapy, and we performed a re-staging with PET-CT and MRI in December of 2016, showing an excellent response with regression of all tumorous lesions (Fig. 5). Notably, a marked swelling of the lacrimal and salivary glands was observed (Fig. 6), which we interpreted as a sign of increased immunologic response to immunotherapy following irradiation. Treatment with pembrolizumab was continued and well tolerated, with slow regression of the inflammatory symptoms described above as well as remarkable neurological improvement (dysphagia, diplopia, trigeminal function). Fittingly, re-staging MRI in February and May of 2017 showed an ongoing response with further regression of the tumorous lesions in MRI (Fig. 7). Following near complete recovery of inflammatory symptoms, PET-MRI in August of 2017 showed regression of inflammatory signs as well as ongoing local control without distant metastases (almost 6 years after first receiving radiotherapy for a bony metastasis). At the time of this report, the patient is in excellent condition, continuing treatment with pembrolizumab as well as rehabilitative treatments under regular follow-up.Fig. 5 T1-weighted MRI in December of 2016 showing excellent subtotal tumor response following re-re-irradiation in sagittal, coronal and axial plane\n\nFig. 6 T1-weighted MRI in December of 2016 showing signs of inflammation with marked swelling of salivary glands (sublingual, red arrow; submandibular, blue arrows; parotids, orange arrows) as well as lacrimal glands (green arrows)\n\nFig. 7 T1-weighted MRI in May of 2017 demonstrating ongoing, subtotal tumor response\n\n\n\nDiscussion\nTreatment of recurrent nasopharyngeal carcinoma remains a significant clinical problem, with local recurrence representing a major cause of mortality and morbidity [2]. Management of these patients is challenging, with salvage strategies including surgery as well as various forms of radiotherapy (external intensity-modulated radiotherapy (IMRT) including stereotactic radiotherapy or radiosurgery, proton irradiation, brachytherapy) with or without chemotherapy [2–16].\n\nWe assume that the case discussed demonstrates distinct signs of a combined effect of immunotherapy and radiotherapy in a heavily pretreated patient with recurrent nasopharyngeal carcinoma progressing under anti-PD-1 immunotherapy. To our knowledge, it is thus the first reported observation of such an effect in a patient with recurrent nasopharyngeal carcinoma. Showing both an excellent local response as well as clinical and radiological inflammatory signs outside of the radiation field, the case adds to the rising paradigm of an immunostimulatory effect of radiotherapy in patients undergoing therapy with immune checkpoint inhibitors [17–19].\n\nWhile differentiating delayed effects of immunotherapy from responses caused partially or completely by local treatment is intrinsically difficult, the chronological association with radiotherapy as well as the regional distribution of inflammatory effects (not solely accountable to direct radiation effects due to the dose distribution) seem striking. Since the first clinical signs of a possible immunostimulation appeared 10 months after initiation of pembrolizumab and tumor response was first seen 2 months thereafter, the time to response would be on the far end of what has been reported for anti-PD-1 immunotherapy in various types of cancer, with most clinical trials showing a median time to response of around 2 months [20–29]. Notably, re-irradiation using modern external beam radiation techniques to apply high biological doses (with or without brachytherapy) has been shown to achieve adequate local control rates in various series of recurrent nasopharyngeal carcinoma, utilizing both standard fractionation as well as hypofractionated regimens and sometimes chemotherapy as a radiosensitizer [30–32]. It is therefore difficult to discriminate good local control achieved by radiation from synergistic effects of any bimodality treatment. However, given the extent and duration of response to a very moderate dose of 45 Gy in fractions of 1.8 Gy, we considered attribution of local control solely to radiotherapy as very unlikely, particularly since parts of the target volume had previously been re-irradiated using CyberKnife® without lasting effect.\n\nCheckpoint inhibitor immunotherapy is associated with a unique spectrum of immune-related adverse events, reflecting its underlying mechanisms of action aiming at T cell activation and enhanced antitumor immune response [33, 34]. While dermatologic toxicity is the most common (and often the earliest) inflammatory side effect, possible immune-related adverse events include mucosal and gastrointestinal toxicities, pneumonitis, hepatotoxicity, endocrinopathies and (more rarely) neurologic, renal, pancreatic and ocular toxicities [35]. Although the clinical signs seen in our patient (mucosal, including nasal and ocular, irritation; swelling of lacrimal and salivary glands; maculopapular rash) might well represent disorders of infectious and allergic nature, we believe that the assumption of immunostimulation as a common cause following irradiation under anti-PD-1 immunotherapy is reasonable, given the clinical course. Of note, dermatologic toxicities and radiological signs of immune-related adverse events have been associated with better outcome in patients treated with checkpoint inhibitor immunotherapy, although generalization of these observations is not possible [36–39].\n\nThe concept of a synergistic effect of radiotherapy and immune checkpoint inhibitors aiming at enhanced response rates and potential long term tumor control is based on an increasing amount of encouraging preclinical and clinical evidence [17–19, 40–44]. Radiation hereby acts as an immune stimulus, recruiting cytokines that enable anti-tumor responses within and outside the radiation field [45]. While the immunogenic properties of radiation (including observations of an abscopal effect following radiotherapy as an otherwise rare clinical phenomenon) have long been discussed, the emergence of immunotherapy and the growing amount of preclinical data have moved the rationale of a combined treatment approach into the spotlight of research, potentially indicating a paradigm shift in the utilization of radiotherapy in these patients [45–47]. Understandably, these observations have also sparked a particular interest in the management of heavily pretreated patients with limited options for effective salvage treatment, such as the case presented. However, with trials combining radiotherapy and immune checkpoint inhibitors currently ongoing [45], the remaining uncertainties surrounding the role and clinical implication of these approaches need to be emphasized.\n\nIn summary, we observed an excellent response to combined immunotherapy and re-re-irradiation in a case of recurrent nasopharyngeal carcinoma, and we are hopeful to see future developments that improve outcomes for these patients with otherwise limited treatment options.\n\nAbbreviations\nDNADeoxyribonucleic acid\n\nEBVEpstein-Barr Virus\n\nFDGFluorine-18 (F-18) fluorodeoxyglucose\n\nGyGray\n\nIMRTIntensity-modulated radiotherapy\n\nMRIMagnetic Resonance Imaging\n\nPD-1Programmed cell death protein 1\n\nPET-CTPositron emission tomography–computed tomography\n\nPET-MRIPositron emission tomography-magnetic resonance imaging\n\nSIBSimultaneous integrated boost\n\nVMATVolumetric modulated arc therapy\n\nAcknowledgements\nWe are grateful to the patient for permission to publish this case report.\n\nFunding\nNo funding to declare.\n\nAvailability of data and materials\nRepresentative imaging slices are included in the article.\n\nAuthors’ contributions\nTF wrote the first draft of the manuscript. HGS and MG provided first revision of the manuscript, which was then read and further revised by TR, KI and GFH. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nPatient has provided written informed consent for the publication of this case report.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Hsu C Lee S Ejadi S Antitumor activity and safety of pembrolizumab in patients with pd-l1-positive nasopharyngeal carcinoma: interim results from a phase 1b study 2015 Vienna European Cancer Congress; September 25–29 \n2. Suarez C Rodrigo JP Rinaldo A Current treatment options for recurrent nasopharyngeal cancer Eur Arch Otorhinolaryngol 2010 267 1811 1824 10.1007/s00405-010-1385-x 20865269 \n3. Chua DT Sham JS Leung LH Re-irradiation of nasopharyngeal carcinoma with intensity-modulated radiotherapy Radiother Oncol 2005 77 290 294 10.1016/j.radonc.2005.10.010 16289398 \n4. Roeder F Zwicker F Saleh-Ebrahimi L Intensity modulated or fractionated stereotactic reirradiation in patients with recurrent nasopharyngeal cancer Radiat Oncol 2011 6 22 10.1186/1748-717X-6-22 21356126 \n5. Langendijk JA Leemans CR Buter J The additional value of chemotherapy to radiotherapy in locally advanced nasopharyngeal carcinoma: a meta-analysis of the published literature J Clin Oncol 2004 22 4604 4612 10.1200/JCO.2004.10.074 15542811 \n6. Teo PM Kwan WH Chan AT How successful is high-dose (> or = 60 gy) reirradiation using mainly external beams in salvaging local failures of nasopharyngeal carcinoma? Int J Radiat Oncol Biol Phys 1998 40 897 913 10.1016/S0360-3016(97)00854-7 9531376 \n7. King WW Ku PK Mok CO Nasopharyngectomy in the treatment of recurrent nasopharyngeal carcinoma: a twelve-year experience Head Neck 2000 22 215 222 10.1002/(SICI)1097-0347(200005)22:3<215::AID-HED2>3.0.CO;2-B 10748443 \n8. Hsu MM Ko JY Sheen TS Salvage surgery for recurrent nasopharyngeal carcinoma Arch Otolaryngol Head Neck Surg 1997 123 305 309 10.1001/archotol.1997.01900030087011 9076238 \n9. Wang SY Lou JL Chen J Salvage surgery for neck residue or recurrence of nasopharyngeal carcinoma after primary radiotherapy: options of surgical methods and regions World J Surg Oncol 2016 14 89 10.1186/s12957-016-0822-8 27012522 \n10. Wei WI Salvage surgery for recurrent primary nasopharyngeal carcinoma Crit Rev Oncol Hematol 2000 33 91 98 10.1016/S1040-8428(99)00069-4 10737370 \n11. Xu Z Tu G Tang P Salvage surgery for nasopharyngeal carcinoma after irradiation failure Zhonghua Er Bi Yan Hou Ke Za Zhi 1998 33 103 105 11498848 \n12. Chang JT See LC Liao CT Locally recurrent nasopharyngeal carcinoma Radiother Oncol 2000 54 135 142 10.1016/S0167-8140(99)00177-2 10699476 \n13. Chua DT Sham JS Hung KN Predictive factors of tumor control and survival after radiosurgery for local failures of nasopharyngeal carcinoma Int J Radiat Oncol Biol Phys 2006 66 1415 1421 10.1016/j.ijrobp.2006.07.1364 17056191 \n14. Widesott L Pierelli A Fiorino C Intensity-modulated proton therapy versus helical tomotherapy in nasopharynx cancer: planning comparison and ntcp evaluation Int J Radiat Oncol Biol Phys 2008 72 589 596 10.1016/j.ijrobp.2008.05.065 18793962 \n15. Choy D Sham JS Wei WI Transpalatal insertion of radioactive gold grain for the treatment of persistent and recurrent nasopharyngeal carcinoma Int J Radiat Oncol Biol Phys 1993 25 505 512 10.1016/0360-3016(93)90073-5 8382202 \n16. Kwong DL Wei WI Cheng AC Long term results of radioactive gold grain implantation for the treatment of persistent and recurrent nasopharyngeal carcinoma Cancer 2001 91 1105 1113 10.1002/1097-0142(20010315)91:6<1105::AID-CNCR1106>3.0.CO;2-Z 11267955 \n17. Weichselbaum RR Liang H Deng L Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol 2017 14 6 365 379 10.1038/nrclinonc.2016.211 28094262 \n18. Deng L Liang H Burnette B Irradiation and anti-pd-l1 treatment synergistically promote antitumor immunity in mice J Clin Invest 2014 124 687 695 10.1172/JCI67313 24382348 \n19. Pilones KA Vanpouille-Box C Demaria S Combination of radiotherapy and immune checkpoint inhibitors Semin Radiat Oncol 2015 25 28 33 10.1016/j.semradonc.2014.07.004 25481263 \n20. Reck M Rodriguez-Abreu D Robinson AG Pembrolizumab versus chemotherapy for pd-l1-positive non-small-cell lung cancer N Engl J Med 2016 375 1823 1833 10.1056/NEJMoa1606774 27718847 \n21. Herbst RS Baas P Kim DW Pembrolizumab versus docetaxel for previously treated, pd-l1-positive, advanced non-small-cell lung cancer (keynote-010): a randomised controlled trial Lancet 2016 387 1540 1550 10.1016/S0140-6736(15)01281-7 26712084 \n22. Chow LQ Haddad R Gupta S Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase ib keynote-012 expansion cohort J Clin Oncol 2016 34 32 3838 3845 10.1200/JCO.2016.68.1478 27646946 \n23. Robert C Schachter J Long GV Pembrolizumab versus ipilimumab in advanced melanoma N Engl J Med 2015 372 2521 2532 10.1056/NEJMoa1503093 25891173 \n24. Bauml J Seiwert TY Pfister DG Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase ii study J Clin Oncol 2017 35 1542 1549 10.1200/JCO.2016.70.1524 28328302 \n25. Seiwert TY Burtness B Mehra R Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (keynote-012): an open-label, multicentre, phase 1b trial Lancet Oncol 2016 17 956 965 10.1016/S1470-2045(16)30066-3 27247226 \n26. Ferris RL Blumenschein G Jr Fayette J Nivolumab for recurrent squamous-cell carcinoma of the head and neck N Engl J Med 2016 375 1856 1867 10.1056/NEJMoa1602252 27718784 \n27. Borghaei H Paz-Ares L Horn L Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer N Engl J Med 2015 373 1627 1639 10.1056/NEJMoa1507643 26412456 \n28. Brahmer J Reckamp KL Baas P Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer N Engl J Med 2015 373 123 135 10.1056/NEJMoa1504627 26028407 \n29. Bellmunt J de Wit R Vaughn DJ Pembrolizumab as second-line therapy for advanced urothelial carcinoma N Engl J Med 2017 376 1015 1026 10.1056/NEJMoa1613683 28212060 \n30. Kong L Lu JJ Reirradiation of locally recurrent nasopharyngeal cancer: history, advances, and promises for the future Chinese Clin Oncol 2016 5 2 26 10.21037/cco.2016.03.19 \n31. Wu SX Chua DTT Deng ML Outcome of fractionated stereotactic radiotherapy for 90 patients with locally persistent and recurrent nasopharyngeal carcinoma Int J Radiat Oncol Biol Phys 2007 69 761 769 10.1016/j.ijrobp.2007.03.037 17601682 \n32. Koutcher L Lee N Zelefsky M Reirradiation of locally recurrent nasopharynx Cancer with external beam radiotherapy with or without brachytherapy Int J Radiat Oncol Biol Phys 2010 76 130 137 10.1016/j.ijrobp.2009.01.055 19467802 \n33. Villadolid J Amin A Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities Transl Lung Cancer Res 2015 4 560 575 26629425 \n34. Weber JS Postow M Lao CD Management of adverse events following treatment with anti-programmed death-1 agents Oncologist 2016 21 1230 1240 10.1634/theoncologist.2016-0055 27401894 \n35. Naidoo J Page DB Li BT Toxicities of the anti-pd-1 and anti-pd-l1 immune checkpoint antibodies Ann Oncol 2015 26 2375 2391 26371282 \n36. Sanlorenzo M Vujic I Daud A Pembrolizumab cutaneous adverse events and their association with disease progression JAMA Dermatol 2015 151 1206 1212 10.1001/jamadermatol.2015.1916 26222619 \n37. Lo JA Fisher DE Flaherty KT Prognostic significance of cutaneous adverse events associated with pembrolizumab therapy JAMA Oncol 2015 1 1340 1341 10.1001/jamaoncol.2015.2274 26270186 \n38. Bronstein Y Ng CS Hwu P Radiologic manifestations of immune-related adverse events in patients with metastatic melanoma undergoing anti-ctla-4 antibody therapy AJR Am J Roentgenol 2011 197 W992 W1000 10.2214/AJR.10.6198 22109345 \n39. Freeman-Keller M Kim Y Cronin H Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes Clin Cancer Res 2016 22 886 894 10.1158/1078-0432.CCR-15-1136 26446948 \n40. Vanpouille-Box C Pilones KA Wennerberg E In situ vaccination by radiotherapy to improve responses to anti-ctla-4 treatment Vaccine 2015 33 7415 7422 10.1016/j.vaccine.2015.05.105 26148880 \n41. Wennerberg E Lhuillier C Vanpouille-Box C Barriers to radiation-induced in situ tumor vaccination Front Immunol 2017 8 229 10.3389/fimmu.2017.00229 28348554 \n42. Sharabi AB Nirschl CJ Kochel CM Stereotactic radiation therapy augments antigen-specific pd-1-mediated antitumor immune responses via cross-presentation of tumor antigen Cancer Immunol Res 2015 3 345 355 10.1158/2326-6066.CIR-14-0196 25527358 \n43. Twyman-Saint Victor C Rech AJ Maity A Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer Nature 2015 520 373 377 10.1038/nature14292 25754329 \n44. Shaverdian N Lisberg AE Bornazyan K Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the keynote-001 phase 1 trial Lancet Oncol 2017 18 895 903 10.1016/S1470-2045(17)30380-7 28551359 \n45. Kang J Demaria S Formenti S Current clinical trials testing the combination of immunotherapy with radiotherapy J Immunother Cancer 2016 4 51 10.1186/s40425-016-0156-7 27660705 \n46. Reynders K Illidge T Siva S The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant Cancer Treat Rev 2015 41 503 510 10.1016/j.ctrv.2015.03.011 25872878 \n47. Levy A Chargari C Marabelle A Can immunostimulatory agents enhance the abscopal effect of radiotherapy? Eur J Cancer 2016 62 36 45 10.1016/j.ejca.2016.03.067 27200491\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2407",
"issue": "18(1)",
"journal": "BMC cancer",
"keywords": "Immunostimulation; Nasopharyngeal; Pembrolizumab; Radiotherapy, immunotherapy",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D015415:Biomarkers; D059248:Chemoradiotherapy; D006801:Humans; D007167:Immunotherapy; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms; D009364:Neoplasm Recurrence, Local; D000072078:Positron Emission Tomography Computed Tomography; D061026:Programmed Cell Death 1 Receptor; D018714:Radiotherapy, Adjuvant",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "395",
"pmc": null,
"pmid": "29625593",
"pubdate": "2018-04-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26412456;27660705;16289398;9531376;26148880;25481263;19467802;10699476;21356126;28551359;11267955;22109345;27247226;26629425;27200491;25872878;28094262;10748443;11498848;28328302;25527358;27718847;24382348;26712084;25891173;27646946;17601682;17056191;27401894;26371282;26446948;26222619;27718784;27121886;18793962;25754329;26270186;28348554;26028407;20865269;27012522;8382202;28212060;10737370;9076238;15542811",
"title": "Radiotherapy-induced anti-tumor immune response and immune-related adverse events in a case of recurrent nasopharyngeal carcinoma undergoing anti-PD-1 immunotherapy.",
"title_normalized": "radiotherapy induced anti tumor immune response and immune related adverse events in a case of recurrent nasopharyngeal carcinoma undergoing anti pd 1 immunotherapy"
} | [
{
"companynumb": "CH-TEVA-2018-CH-894677",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID"
},
"drugadditional... |
{
"abstract": "DNA repair mutations (BRCA1 and BRCA2) are found in metastatic castration-resistant prostate cancer (CRPC) patients. Here, we report a case of a 71-year-old male patient with metastatic CRPC along with BRCA2 and PTEN mutations. As per the genomic findings of the Foundation One report, FDA-approved therapies were available for other tumor types, such as olaparib for the loss of BRCA2 and everolimus for the loss of PTEN exons 2-9. These findings were confirmed in another novel phenotypic assay that revealed the sensitivity of olaparib and carboplatin combination therapy. After 4 cycles, our patient achieved a partial response along with a good performance status.",
"affiliations": "Max Institute of Cancer Care, New Delhi, India.;Max Institute of Cancer Care, New Delhi, India.;Catalyst Clinical Services Pvt. Ltd., New Delhi, India.",
"authors": "Julka|Pramod Kumar|PK|;Verma|Amit|A|;Gupta|Kush|K|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000505182",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000505182\ncro-0013-0055\nCase Report\nPersonalized Treatment Approach to Metastatic Castration-Resistant Prostate Cancer with BRCA2 and PTEN Mutations: A Case Report\nJulka Pramod Kumar a* Verma Amit a Gupta Kush b aMax Institute of Cancer Care, New Delhi, India\nbCatalyst Clinical Services Pvt. Ltd., New Delhi, India\n*Dr. Pramod Kumar Julka, Max Institute of Cancer Care, Lajpat Nagar, New Delhi 110024 (India), pkjulka18@yahoo.co.in\nJan-Apr 2020 \n4 2 2020 \n4 2 2020 \n13 1 55 61\n27 11 2019 28 11 2019 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.DNA repair mutations (BRCA1 and BRCA2) are found in metastatic castration-resistant prostate cancer (CRPC) patients. Here, we report a case of a 71-year-old male patient with metastatic CRPC along with BRCA2 and PTEN mutations. As per the genomic findings of the Foundation One report, FDA-approved therapies were available for other tumor types, such as olaparib for the loss of BRCA2 and everolimus for the loss of PTEN exons 2–9. These findings were confirmed in another novel phenotypic assay that revealed the sensitivity of olaparib and carboplatin combination therapy. After 4 cycles, our patient achieved a partial response along with a good performance status.\n\nKeywords\nCRPCBRCA2PTENOlaparibProstate cancer\n==== Body\nIntroduction\nProstate cancer is the second most common cancer among men worldwide, with an incidence of 1.3 million in 2018 [1]. It is also the fifth leading cause of cancer deaths among men [1]. Androgen deprivation therapy with or without docetaxel is the recommended first-line treatment modality for the management of metastatic hormone-naïve disease [2]. In chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (CRPC), abiraterone or enzalutamide is the recommended treatment option [3]. Docetaxel is recommended for patients with metastatic CRPC, whereas radium-223 is recommended for those without visceral disease [4]. The second-line treatment strategies for patients with metastatic CRPC after docetaxel include abiraterone, enzalutamide, cabazitaxel, and radium-223 [5, 6, 7]. Prostate cancer is a heterogenous disease at both the clinical and molecular level; however, its treatment strategies have not yet been molecularly stratified. The 2019 National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for prostate cancer recommend germline testing for homologous recombination genes (BRCA1, BRCA2, ATM, PALB2, and CHEK2) using next-generation sequencing (NGS) [8]. DNA repair mutations (BRCA1 and BRCA2) are found in metastatic CRPC lesions that are resistant to taxane and may respond well to platinum and poly-(ADP-ribose)-polymerase inhibitors, such as olaparib [9]. Here, we report the first case of metastatic CRPC with BRCA2 and PTEN mutations which was successfully treated with olaparib and carboplatin combination therapy.\n\nCase Presentation\nA 71-year-old hypertensive male patient presented with complaints of heaviness in the lower abdomen in April 2017. His general condition was good (Eastern Cooperative Oncology Group performance status of 1). His clinical workup included a prostate-specific antigen (PSA) assay and a contrast-enhanced computed tomography scan of the chest and the entire abdomen. The findings of the contrast-enhanced computed tomography scan were suggestive of an enlarged prostate with a focal area of hyperdensity in the right lobe, metastatic deposits in the lumbar spine and bilateral lung parenchyma, and small peri-pancreatic, pre-aortic, and para-aortic lymph nodes. The patient had an elevated PSA level of 101 ng/ml. A metastatic workup was performed via prostate-specific membrane antigen (PSMA) positron emission tomography CT (PET-CT) that showed a slightly increased PSMA uptake in the prostate gland (maximum standardized uptake value, 7.7) along with multiple PSMA-avid lung lesions of variable sizes (with the largest measuring 1.4 × 1.0 cm); subcarinal and right external iliac lymph nodes measuring 1.4 × 1.1 cm and 1.9 × 1.5 cm, respectively; and multiple sclerotic skeletal lesions. Transrectal ultrasound-guided biopsy revealed a poorly differentiated adenocarcinoma of the prostate, a Gleason score of 10, perineural invasion, angioinvasion, and the absence of neuroendocrine features.\n\nThe patient received two subcutaneous injections of goserelin (a gonadotropin-releasing hormone agonist) 3 months apart (10.8 mg in April and July 2017). The PSA levels in July and October 2017 were 19.25 and 89 ng/mL, respectively. Due to the increasing PSA level, the patient was started on abiraterone acetate (1,000 mg), prednisolone, and zoledronic acid. A PSMA PET-CT scan performed in October 2017 showed an increase in PSMA avidity in the skeletal lesions, and the patient was scheduled for external beam radiotherapy to the right iliac crest and sacral region using the stereotactic body radiotherapy technique. After radiotherapy, the PSA level remained elevated (111.72 ng/mL); thus, the patient was started on single-agent chemotherapy with docetaxel (50 mg/m2 every 2 weeks) in November 2017. The patient responded well to docetaxel therapy, and the PSA level reduced significantly to 9 ng/mL in December 2017. The patient completed 9 cycles of docetaxel until April 2018 and continued to receive abiraterone acetate, prednisolone, and zoledronic acid. The PSA level started to increase again (to 35.48 ng/mL) in April 2018, and a PSMA PET-CT scan performed to evaluate the disease status revealed that the disease was stable. The PSA level continued to increase progressively in the subsequent months with values of 123.98, 142.10, and 203.71 ng/mL, respectively. The PSMA PET-CT scan was repeated in August 2018 and showed disease progression (enlargement of the existing lesions and new lesions in the lung and liver). The patient was started on enzalutamide (160 mg) with a plan for NGS-based genomic profiling using Foundation One (Roche Products Pvt. Ltd., Mumbai, India).\n\nThe Foundation One report revealed loss of BRCA2 and PTEN exons 2–9 with stable microsatellite status and low tumor mutational burden (Fig. 1a). As per the Foundation One report, there was no Food and Drug Administration (FDA)-approved therapy for the patient's tumor type. However, there were FDA-approved therapies for the genomic findings detected for other tumor types, such as niraparib, olaparib, and rucaparib for the loss of BRCA2 and everolimus and temsirolimus for the loss of PTEN exons 2–9. Since no FDA-approved therapies could be found, we decided to perform another novel phenotypic multidimensional assay that tests the patient's tumor tissue against different drug combinations in an ex-vivo implant setting to help us select the most appropriate treatment protocol for this patient. The test could predict the response to either single-agent cancer therapeutics or combination therapeutic regimens for the patient under evaluation. This was accomplished using a fresh tumor tissue sample obtained from the patient in plates coated with a specific set of tumor matrix proteins. Further, patient-derived autologous ligands were added to the explant platform along with angiogenic factors and autologous immune cells to maintain the tumor vasculature. Essentially, the test recapitulated the tumor microenvironment ex vivo. The sensitivity test was performed as per the priority list of treatment protocols decided by the treating physician. The option with the highest assigned priority (Tx1) was considered as the physician's preferred choice. The test used a proprietary algorithm to generate an M score (0–100), with a score of ≤25 indicating predicted non-response and >26 indicating predicted response [10]. Six treatment arms were tested: Tx1 (olaparib), Tx2 (everolimus), Tx3 (enzalutamide + everolimus + olaparib), Tx4 (pembrolizumab), Tx5 (olaparib + carboplatin), and Tx6 (enzalutamide + everolimus), and the M score ranged between 1 and 48 (Fig. 1b). While the olaparib and everolimus arms indicated non-response with M scores of 16 and 2, respectively, Tx5 (olaparib + carboplatin) was the arm that indicated response with the highest M score of 48.\n\nBased on the clinical judgment of the molecular tumor board, a choice of combination therapy was made, and the patient was started on low dose olaparib (200 mg twice daily) and carboplatin (AUC 2 - D1, D8, and D15 every 28 days) combination chemotherapy (Tx5) in September 2018. Before starting the olaparib and carboplatin combination therapy, a baseline PSMA PET-CT scan revealed five target lesions with an overall tumor burden of 207.6 mm (Fig. 2a). The PSA level at this time was 211.23 ng/mL (Fig. 2d) with an Eastern Cooperative Oncology Group performance status of 3. After 2 cycles, the PSMA PET-CT scan demonstrated a partial response (36.3% reduction from baseline, overall tumor burden of 132.2 mm) as per the Response Evaluation Criteria in Solid Tumors version 1.1 (Fig. 2b). The PSA level at that time was 6.8 ng/mL (Fig. 2d). For the first time, the patient responded to treatment, and there were no associated grade 3/4 toxicities. After 4 cycles, the PSMA PET-CT scan revealed further regression (55.3% reduction from baseline) with an overall tumor burden of 92.8 mm along with complete regression of the lesion in the right hepatic lobe (Fig. 2c). The PSA level at that time was 5.99 ng/mL (Fig. 2d), and the performance status also improved to 1. After 4 cycles, the patient migrated to another country where he received 2 more treatment cycles. Currently, the patient is alive with a good performance status 9 months after initiation of olaparib and carboplatin combination therapy.\n\nDiscussion/Conclusion\nHomologous repair deficiency (HRD) genes (particularly BRCA1/2) are found in 20–25% of all patients with metastatic CRPC [11]. Although the 2019 National Comprehensive Cancer Network guidelines recommend germline testing for all prostate cancer patients, treatment based on molecular characterization is still not commonly practiced [8]. Even if germline or somatic mutation testing reveals BRCA1/2 mutations, there is currently no FDA-approved therapy for the treatment of this subset of patients with metastatic CRPC. The poly-(ADP-ribose)-polymerase inhibitor olaparib is known to have a significant synthetic lethal effect on tumors with BRCA1/2 mutations, particularly in ovarian and breast cancer [12]. Although there are few reports in the literature on the role of olaparib in the treatment of metastatic CRPC with DNA-repair defects, the combination of olaparib and carboplatin has never been studied earlier for this indication. We used the olaparib and carboplatin combination therapy based on two facts. First, HRD genes are known to be sensitive to platinum. Second, sensitivity testing confirmed that the patient would respond to olaparib and carboplatin (M score of 48) but not to olaparib or everolimus monotherapy (M scores of 16 and 2, respectively).\n\nIn a phase 2 study conducted by Mateo et al. [13], NGS revealed mutations in BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2 in 16 out of 49 patients with metastatic CRPC. Treatment with olaparib (400 mg twice daily) demonstrated a very good response rate of 88% (the biomarker suite had a specificity of 94%). The study revealed a significantly longer median progression-free survival period (9.8 vs. 2.7 months, p < 0.001) and median overall survival period (13.8 vs. 7.5 months, p = 0.05) in the biomarker-positive group as compared to the biomarker-negative group. The partial response achieved in our case corroborates the findings of this study. In the study conducted by Mateo et al. [13], 7 patients had loss of BRCA2 (4 cases of biallelic somatic loss and 3 cases of germline mutations), and all 7 responded to olaparib therapy. While 5 patients achieved partial response radiologically, the PSA level decreased by ≥ 50% from baseline in all 7 patients with BRCA2 loss. The 36.3 and 55.3% reductions in tumor burden after cycles 2 and 4, respectively, as well as the >96% reduction in PSA level observed in our patient suggest that olaparib and carboplatin combination therapy is superior to single-agent olaparib in this patient subset. The 9-month progression-free survival in our case is also in line with the findings of Mateo et al. [13].\n\nMa et al. [14] reported the response of a 67-year-old patient with metastatic CRPC carrying a BRCA2 germline mutation to olaparib. Although the patient showed a partial response after 2 months, the disease progressed after 6 months. Another phase 2 study conducted by Kaufman et al. [15] evaluated the efficacy and safety of olaparib in different malignant solid tumors with confirmed genetic BRCA1/2 mutation. Of the 298 patients enrolled in the study, 7 had metastatic CRPC with BRCA2 mutation. The study yielded an overall response rate of 50% with median progression-free and overall survival durations of 7.2 and 18.4 months, respectively. These results are consistent with our observations; however, our patient had only been followed up for 9 months at the time of writing this report.\n\nSo far, olaparib and carboplatin combination therapy has never been studied among CRPC patients; we report the first case on this chemotherapy and targeted therapy combination. This case demonstrates the clinical utility of olaparib and carboplatin combination therapy in patients with metastatic CRPC with BRCA2 loss. Further, the good partial response achieved in this case establishes the importance of germline testing for homologous recombination genes (BRCA1, BRCA2, ATM, PALB2, and CHEK2) using NGS among patients with metastatic CRPC.\n\nOlaparib and carboplatin combination therapy holds promise for the management of metastatic CRPC patients with BRCA2 loss. The administration of olaparib and carboplatin combination therapy can demonstrate a good response along with prolonged survival in patients with metastatic CRPC associated with DNA-repair defects.\n\nStatement of Ethics\nThe subject has given his written informed consent to publish this case (including publication of images). The study protocol was approved by the institute's Committee on Human Research.\n\nDisclosure Statement\nThe authors declare that there are no competing interests.\n\nFunding Sources\nNil.\n\nAuthor Contributions\nPramod Kumar Julka was responsible for the conception and design of this paper, acquisition of data, analysis and interpretation of data, drafting the article and final approval of the version to be published. Amit Verma and Kush Gupta were responsible for drafting the article and final approval of the version to be published.\n\nFig. 1 a The Foundation One report of the patient. b Sensitivity test results with the M score of each of the six treatment arms.\n\nFig. 2 a Baseline PSMA PET-CT images. b PSMA PET-CT images after 2 cycles of olaparib and carboplatin therapy. c PSMA PET-CT images after 4 cycles of olaparib and carboplatin therapy. d PSA level at baseline and after 8 and 16 weeks of therapy. PSMA PET-CT, prostate-specific membrane antigen positron emission tomography computed tomography; PSA, prostate-specific antigen.\n==== Refs\nReferences\n1 Bray F Ferlay J Soerjomataram I Siegel RL Torre LA Jemal A Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 2018 Nov 68 (6) 394 424 30207593 \n2 Parker C Gillessen S Heidenreich A Horwich A ESMO Guidelines Committee Cancer of the prostate: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2015 Sep 26 (Suppl 5) v69 v77 26205393 \n3 Ryan CJ Smith MR Fizazi K Saad F Mulders PF Sternberg CN COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study Lancet Oncol 2015 Feb 16 (2) 152 60 25601341 \n4 Tannock IF de Wit R Berry WR Horti J Pluzanska A Chi KN TAX 327 Investigators Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer N Engl J Med 2004 Oct 351 (15) 1502 12 15470213 \n5 de Bono JS Oudard S Ozguroglu M Hansen S Machiels JP Kocak I TROPIC Investigators Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial Lancet 2010 Oct 376 (9747) 1147 54 20888992 \n6 de Bono JS Logothetis CJ Molina A Fizazi K North S Chu L COU-AA-301 Investigators Abiraterone and increased survival in metastatic prostate cancer N Engl J Med 2011 May 364 (21) 1995 2005 21612468 \n7 Scher HI Fizazi K Saad F Taplin ME Sternberg CN Miller K AFFIRM Investigators Increased survival with enzalutamide in prostate cancer after chemotherapy N Engl J Med 2012 Sep 367 (13) 1187 97 22894553 \n8 Mohler JL Antonarakis ES NCCN guidelines updates: management of prostate cancer J Natl Compr Canc Netw 2019 May 17 (5.5) 583 6 31117038 \n9 Fong PC Boss DS Yap TA Tutt A Wu P Mergui-Roelvink M Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers N Engl J Med 2009 Jul 361 (2) 123 34 19553641 \n10 Majumder B Baraneedharan U Thiyagarajan S Radhakrishnan P Narasimhan H Dhandapani M Predicting clinical response to anticancer drugs using an ex vivo platform that captures tumour heterogeneity Nat Commun 2015 Feb 6 6169 25721094 \n11 Marshall CH Fu W Wang H Baras AS Lotan TL Antonarakis ES Prevalence of DNA repair gene mutations in localized prostate cancer according to clinical and pathologic features: association of Gleason score and tumor stage Prostate Cancer Prostatic Dis 2019 Mar 22 (1) 59 65 30171229 \n12 Ledermann J Harter P Gourley C Friedlander M Vergote I Rustin G Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer N Engl J Med 2012 366 1382 92 22452356 \n13 Mateo J Carreira S Sandhu S Miranda S Mossop H Perez-Lopez R DNA-repair defects and olaparib in metastatic prostate cancer N Engl J Med 2015 373 (18) 1697 708 26510020 \n14 Ma Y He L Huang Q Zheng S Zhang Z Li H Response to olaparib in metastatic castration-resistant prostate cancer with germline BRCA2 mutation: a case report BMC Med Genet 2018 Oct 17 19 (1) 185 30333000 \n15 Kaufman B Shapira-Frommer R Schmutzler RK Audeh MW Friedlander M Balmaña J Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation J Clin Oncol 2015 33 (3) 244 50 25366685\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "13(1)",
"journal": "Case reports in oncology",
"keywords": "BRCA2; CRPC; Olaparib; PTEN; Prostate cancer",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "55-61",
"pmc": null,
"pmid": "32110220",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "25601341;25721094;19553641;21612468;22452356;15470213;22894553;30207593;26205393;20888992;31117038;25366685;30171229;26510020;30333000",
"title": "Personalized Treatment Approach to Metastatic Castration-Resistant Prostate Cancer with BRCA2 and PTEN Mutations: A Case Report.",
"title_normalized": "personalized treatment approach to metastatic castration resistant prostate cancer with brca2 and pten mutations a case report"
} | [
{
"companynumb": "IN-GLENMARK PHARMACEUTICALS-2020GMK048531",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ABIRATERONE ACETATE"
},
"drug... |
{
"abstract": "A 70-year-old woman presented with progressive skin lesions on the face, limbs and trunk in the absence of systemic illness. Three months earlier, she had been prescribed six months prophylactic nitrofurantoin for recurrent urinary tract infections, treated with nitrofurantoin and trimethoprim. Positive immunology and histological inflammatory changes in a skin biopsy were consistent with a diagnosis of sub-acute cutaneous lupus erythematosus. Following treatment with topical steroids, the skin lesions regressed, but alopecia followed and required hydroxychloroquine. One year later, there are no new skin lesions and no evidence of systemic lupus erythematosus. Nitrofurantoin is associated with many side effects and hypersensitivity reactions. Possible drug-induced lupus reactions due to nitrofurantoin include pneumonitis, blood disorders and hepatotoxicity. This is the only published case of isolated sub-acute cutaneous lupus following maintenance nitrofurantoin.",
"affiliations": "GP Associate Adviser, NHS Education for Scotland (West Region), UK jillmurie@aol.com.;Consultant Pathologist, Monklands General Hospital, UK.",
"authors": "Murie|Jill|J|;Agarwal|Monica|M|",
"chemical_list": "D000892:Anti-Infective Agents, Urinary; D004791:Enzyme Inhibitors; D006886:Hydroxychloroquine; D009582:Nitrofurantoin",
"country": "Scotland",
"delete": false,
"doi": "10.1177/0036933014558000",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0036-9330",
"issue": "59(4)",
"journal": "Scottish medical journal",
"keywords": "Systemic lupus erythematosus; drug-induced lupus; nitrofurantoin; sub-acute cutaneous lupus erythematosus",
"medline_ta": "Scott Med J",
"mesh_terms": "D000368:Aged; D000505:Alopecia; D000892:Anti-Infective Agents, Urinary; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D008178:Lupus Erythematosus, Cutaneous; D009582:Nitrofurantoin; D016896:Treatment Outcome; D014552:Urinary Tract Infections",
"nlm_unique_id": "2983335R",
"other_id": null,
"pages": "e21-5",
"pmc": null,
"pmid": "25348483",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sub-acute cutaneous lupus erythematosus following nitrofurantoin: causative or coincidental?",
"title_normalized": "sub acute cutaneous lupus erythematosus following nitrofurantoin causative or coincidental"
} | [
{
"companynumb": "PHHY2015GB069479",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NITROFURANTOIN"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nThe aim of this study was to analyze the clinical characteristics of patients with adverse cutaneous drug reactions, which occur when a medicinal product results in cutaneous morbidity.\n\n\nMETHODS\nThe study included 308 patients who were diagnosed as having an adverse cutaneous drug reaction during the study period (2007-2009). In 84 cases, histopathologic examination of skin biopsies were also performed.\n\n\nRESULTS\nPatients with drug reactions were found to be more commonly female (63%) than male (37%). Beta-lactam antibiotics were found to be the most frequent cause of adverse cutaneous drug reactions (42.7%), followed by non-steroidal anti-inflammatory drugs (16.5%). Acute urticaria was the most common clinical presentation (59.2%) followed by fixed drug eruptions (18.5%), and maculopapular eruptions (14.9%).\n\n\nCONCLUSIONS\nAdverse cutaneous drug reactions in our study population were mainly induced by beta-lactam antibiotics and non-steroidal anti-inflammatory drugs. The most common forms of cutaneous adverse drug reactions were found to be acute urticaria, fixed drug eruptions, and maculopapular rashes.",
"affiliations": "Psoriasis Research Center, Department of Dermatology, Farshchian Hospital, Hamadan University of Medical Sciences, Hamedan, Iran.;Psoriasis Research Center, Department of Dermatology, Farshchian Hospital, Hamadan University of Medical Sciences, Hamedan, Iran.;Department of Dermatology, Iran University of Medical Sciences, Tehran, Iran.;Psoriasis Research Center, Department of Dermatology, Farshchian Hospital, Hamadan University of Medical Sciences, Hamedan, Iran.;Derm Surgery Associates, Houston, TX, USA.;Psoriasis Research Center, Department of Dermatology, Farshchian Hospital, Hamadan University of Medical Sciences, Hamedan, Iran ; Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland.",
"authors": "Farshchian|Mahmood|M|;Ansar|Akram|A|;Zamanian|Abbas|A|;Rahmatpour-Rokni|Ghasem|G|;Kimyai-Asadi|Arash|A|;Farshchian|Mehdi|M|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/CCID.S75849",
"fulltext": "\n==== Front\nClin Cosmet Investig DermatolClin Cosmet Investig DermatolClinical, Cosmetic and Investigational DermatologyClinical, Cosmetic and Investigational Dermatology1178-7015Dove Medical Press 10.2147/CCID.S75849ccid-8-053Original ResearchDrug-induced skin reactions: a 2-year study Farshchian Mahmood 1Ansar Akram 1Zamanian Abbas 2Rahmatpour-Rokni Ghasem 1Kimyai-Asadi Arash 3Farshchian Mehdi 141 Psoriasis Research Center, Department of Dermatology, Farshchian Hospital, Hamadan University of Medical Sciences, Hamedan, Iran2 Department of Dermatology, Iran University of Medical Sciences, Tehran, Iran3 Derm Surgery Associates, Houston, TX, USA4 Department of Dermatology, University of Turku and Turku University Hospital, Turku, FinlandCorrespondence: Arash Kimyai-Asadi, 7515 Main Street, Suite 290, Houston, TX 77030, USA, Tel +1 713 791 9966, Fax +1 713 791 9927, Email akimyai@yahoo.com2015 09 2 2015 8 53 56 © 2015 Farshchian et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2015The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Background\nThe aim of this study was to analyze the clinical characteristics of patients with adverse cutaneous drug reactions, which occur when a medicinal product results in cutaneous morbidity.\n\nMethods\nThe study included 308 patients who were diagnosed as having an adverse cutaneous drug reaction during the study period (2007–2009). In 84 cases, histopathologic examination of skin biopsies were also performed.\n\nResults\nPatients with drug reactions were found to be more commonly female (63%) than male (37%). Beta-lactam antibiotics were found to be the most frequent cause of adverse cutaneous drug reactions (42.7%), followed by non-steroidal anti-inflammatory drugs (16.5%). Acute urticaria was the most common clinical presentation (59.2%) followed by fixed drug eruptions (18.5%), and maculopapular eruptions (14.9%).\n\nConclusion\nAdverse cutaneous drug reactions in our study population were mainly induced by beta-lactam antibiotics and non-steroidal anti-inflammatory drugs. The most common forms of cutaneous adverse drug reactions were found to be acute urticaria, fixed drug eruptions, and maculopapular rashes.\n\nKeywords\nadverse drug reactionacute urticariaexanthematous eruption\n==== Body\nIntroduction\nAdverse drug reactions (ADRs) are undesirable and typically unanticipated reactions independent of the intended therapeutic purpose of a medication,1 that may result in significant morbidity and even mortality. Cutaneous reactions are the most common form of ADRs,2 occurring in 2%–3% of inpatient and in approximately 2% of outpatient patients referred for dermatologic evaluation; approximately 2% of ADRs are considered severe or fatal.3,4 Drug reactions are more common in women, and increase with age and the number of medications used.5\n\nADRs may be either immunologic (ie, drug allergy) or non-immunologic (ie, drug intolerance), with drug allergies estimated to account for 6%–10% of all ADRs, and drug intolerance accounting for the remaining 90%–94%.6 Cutaneous ADRs produce a wide range of clinical manifestations such as pruritus, maculopapular eruptions, urticaria, angioedema, phototoxic and photo allergic reactions, fixed drug reactions, erythema multiforme, vesiculobullous reactions (eg, Stevens–Johnson syndrome and toxic epidermal necrolysis), exfoliative dermatitis, acute generalized exanthematous pustulosis, and serum sickness.7,8 Whereas maculopapular rashes and urticaria are among the most common cutaneous drug reactions,9 anaphylaxis, Stevens–Johnson syndrome, and toxic epidermal necrolysis may result in mortality.10\n\nThe purpose of this study was to examine the clinical characteristics and purported etiologic agents for ADRs in our patient population.\n\nMaterials and methods\nA descriptive, prospective case-series study was performed during 2007–2009. Three hundred and eight consecutive inpatient and outpatient subjects with a diagnosis of ADR referred to the dermatology service of Sina hospital in Hamadan, Iran were enrolled in the study. All patients suspected of having an ADR were clinically evaluated by an attending dermatologist. In 84 cases, histopathological examination of skin biopsies were obtained, in many cases to distinguish between specific types of drug reaction, eg, DRESS syndrome versus exanthematous eruptions. The presence of eosinophils in dermal inflammatory infiltrates was considered to support a hypersensitivity reaction.\n\nEach patient was informed of the nature of the study and signed a consent form approved by the Research Council and Ethics Committee of Hamedan University of Medical Sciences, Hamedan, Iran. Written informed consent was obtained from patients for publication of this study and for any accompanying images. The study was performed in accordance with the ethical guidelines of the 1975 Declaration of Helsinki.\n\nExclusion criteria in this study included: 1) a history of taking more than one drug class likely to cause the adverse reaction; 2) clinical manifestations that were not compatible with drug reactions; 3) patient inability to produce the medication consumed the last 3 weeks that purportedly caused the reaction (to prevent recall bias); 4) cases involving overlapping diagnoses with other conditions; and 5) cases in which the clinical diagnosis did not match the findings cited in the pathology report.\n\nResults\nDuring the study period, 308 patients, including 114 men (37%) and 194 women (63%), were enrolled. Of the 308 patients, the diagnosis of ADR was made based on purely clinical manifestations in 224 cases; histological confirmation was obtained in 84 cases. The mean age of patients was 35.2±16.8 years (range 2–77 years). In the present study, ADRs were more frequently seen in the third and fourth decades of life, with 40% of reactions seen in this age group. The clinical manifestations of cutaneous ADRs are summarized in Table 1 and examples are provided in Figures 1 and 2. Only 20 of the 308 patients (6.5%) in our study reported a history of a previous drug reactions.\n\nIn patients with urticarial drug eruptions, 76 (46.6%) were attributed to antibiotics, 45 (27.4%) to non-steroidal anti-inflammatory drugs (NSAIDs), and 17 (10.4%) to codeine with acetaminophen. In patients with maculopapular eruptions, 21 (45.6%) were attributed to antibiotic use, 12 (26%) to anticonvulsant drugs, and four (8.6%) to NSAIDs. In the beta-lactam and NSAID subgroups, amoxicillin and ibuprofen were the most common offending agents, respectively. In patients with fixed drug eruptions, 34 (59.6%) were attributed to taking trimethoprim-sulfamethoxazole and nine (15.7%) to taking NSAIDs (Figure 3).\n\nIn patients with a diagnosis of fixed drug eruption induced by trimethoprim-sulfamethoxazole (34 patients), most lesions were present in the genital area (18 patients). Five patients had lesions in both the genital area and the lip, and only one patient suffered from a lesion present only on the lip. The remaining patients had lesions in other areas, including the hands and feet. In the group taking NSAIDs (nine patients), one patient had a fixed drug eruption on the lip, one patient had it on the genital area, and two patients had lesions on both the lip and genital area. The remaining five patients had lesions on other body areas, including the hands, feet, and trunk.\n\nAmong the seven patients with erythema multiforme, two had history of taking trimethoprim-sulfamethoxazole. In this study, only one patient had a diagnosis of DRESS syndrome, which was attributed to phenytoin.\n\nIn this study, the most common cutaneous clinical manifestations of ADRs in the order of frequency were urticaria, maculopapular eruptions, and fixed drug reactions (Table 1). Antibiotics (42.7%) and NSAIDs (16.5%) were the most common causes of drug reactions in our study population.\n\nDiscussion\nConsistent with the results of previous studies, we found that adverse cutaneous drug reactions are more common in women than in men.11 In the present study, 40% of drug reactions were seen in third and fourth decades of life, which is consistent with the findings of Sushma et al in their 2005 study.8\n\nIn the study performed by Souissi et al in 2007, the most common cutaneous clinical manifestations were maculopapular eruptions followed by fixed drug eruptions, and antibiotics and NSAIDs were the most commonly purported agents.12 Fiszenson-Albala et al, in a study of drug reactions in the French population, reported maculopapular eruptions followed by urticaria and erythroderma to be the most frequent ADRs in their population.13 Kacalak-Rzepka et al reported maculopapular eruptions and urticaria as the most common forms of ADR.11 The high prevalence of urticaria in our study may be due to the excessive use of beta-lactam antibiotics for the treatment of upper respiratory viral infections, often without proper medical indication.\n\nIn patients with a diagnosis of fixed drug eruption induced by trimethoprim-sulfamethoxazole, most lesions were seen in the genital area, whereas in the group taking NSAIDs, most lesions were seen on the hands and feet. In comparison, Justiniano et al reported that fixed drug eruptions induced by trimethoprim-sulfamethoxazole were most commonly present on the genital area, while those induced by NSAIDs were most commonly seen on the lip.14\n\nIt should be noted that our study does not address the mechanism of ADRs, and many drug reactions may not result from allergic or non-allergic drug hypersensitivity. In addition, a drug reaction cannot be confirmed without further testing, such as rechallenge, which was not performed in our study. Moreover, histologic examination may not reveal changes specific to a drug eruption, although biopsies may be helpful in distinguishing particular subtypes of reactions. Furthermore, a more helpful study may compare the adverse event rate to exposure rate by gathering local data on dispensing of various etiologic agents to estimate the cutaneous adverse event rate.\n\nConclusion\nAccording to our results, adverse cutaneous drug reactions were mainly induced by beta-lactam antibiotics and NSAIDs. The most common forms of cutaneous ADRs in order of frequency were acute urticaria, fixed drug eruptions, and maculopapular rashes. In our study, the most common form of cutaneous ADR was found to be urticaria, while some studies conducted in other parts of the world have found maculopapular eruptions to be more common. The high consumption of beta-lactam antibiotics in the treatment of common viral upper respiratory infections in our area may contribute to our findings.\n\nDisclosure\n\nThe authors have no conflicts of interest to declare.\n\nFigure 1 A 25-year-old woman with the diagnosis of acute generalized exanthematous pustulosis following the use of cephalexin.\n\nFigure 2 A 37-year-old woman with clinical manifestation of DRESS syndrome due to phenytoin.\n\nAbbreviation: DRESS, Drug Reaction with Eosinophilia and Systemic Symptoms.\n\nFigure 3 Causative agents for the three most common types of cutaneous drug reactions: urticaria, fixed drug eruptions, and maculopapular eruptions.\n\nAbbreviation: NSAIDs, non-steroidal anti-inflammatory drugs.\n\nTable 1 Clinical manifestations of cutaneous adverse drug reactions\n\nClinical feature\tn\t%\tNumber of patients histologically confirmed\t\nAcute urticaria\t163\t52.9\t4\t\nFixed drug eruption\t57\t18.5\t30\t\nExanthematous eruption\t46\t14.9\t18\t\nErythema multiforme\t7\t2.3\t7\t\nAcute generalized exanthematous pustulosis\t7\t2.3\t7\t\nVasculitis\t7\t2.3\t7\t\nAngioedema\t7\t2.3\t–\t\nErythroderma\t4\t1.3\t4\t\nStevens–Johnson syndrome\t3\t1\t3\t\nSerum sickness\t3\t1\t0\t\nExfoliative dermatitis\t2\t0.6\t2\t\nDRESS syndrome\t1\t0.3\t1\t\nPhotosensitive dermatitis\t1\t0.3\t1\t\nTotal\t308\t100\t84\t\nAbbreviation: DRESS, Drug Reaction with Eosinophilia and Systemic Symptoms.\n==== Refs\nReferences\n1 Hunzicker T Kazia P Braunschweig S Comprehensive hospital drug monitoring (CHDM): Adverse skin reaction a 20 year survey Allergy 1997 52 4 388 393 9188919 \n2 Jean Revu Z Allanore LV Drug Reaction Bolognia Jean L Jorizzo Joseph L Julie Dermatology 3rd ed Elsevier 2012 335 \n3 Charli-Joseph Y Cruz-Fuentes C Orozco-Topete R Incidence of adverse cutaneous drug reaction in Mexican sample: an exploratory study on their association to tumour necrosis factor alpha TNF2 allele J Eur Acad Dermatol Venereol 2009 23 7 788 792 19309429 \n4 Wolf R Orion E Marcos B Matz H Life-threatening acute adverse cutaneous drug reactions Clin Dermatol 2005 23 2 171 181 15802211 \n5 Pichler WJ Yawalkar N Britschgi M Cellular and molecular pathophysiology of cutaneous drug reaction Am J Clin Dermatol 2002 3 4 299 238 \n6 Hamilton RG Adkinson NF Jr Clinical laboratory assessment of IgE-dependent hypersensitivity J Allergy Clin Immunol 2003 111 2 Suppl S687 S701 12592314 \n7 Kimyai-Asadi A Harris JC Nousari HC Critical overview: adverse cutaneous reactions to psychotropic medications J Clin Psychiatry 1999 60 10 714 725 10549695 \n8 Sushma M Noel MV Ritika MC James J Guido S Cutaneous adverse cutaneous drug: a 9 year study from a South Indian Hospital Pharmacoepidemiology Drug Saf 2005 14 8 567 570 \n9 Revuz J Valeyrie-Allanore L Drug reactions Bolognia JL Lorizzo JL Rapini RP Dermatology 2nd ed Spain Mosby-Elsevier 2008 301 320 \n10 Roujean JC Epidemiology of drug reaction, service de dermatologie, Universite Paris 2004 13 322 328 \n11 Kacalak-Rzepka A Klimowicz A Bielecka-Grzela S Załuga E Maleszka R Fabiańczyk H Retrospective analysis of adverse cutaneous drug reactions in patients Ann Acad Med Stetin 2008 54 2 52 58 19374232 \n12 Souissi A Fenniche S Benmously R Ben JS Marrak H Mokhtar I Study of the cutaneous drugs reactions in a teaching hospital in Tunis Tunis Med 2007 85 12 1011 1015 19170378 \n13 Fiszenson-Albala F Auzerie V Mahe E A 6 month prospective survey of cutaneous drug reaction Br J Dermatol 2003 149 5 1018 1022 14632808 \n14 Justiniano H Berlingeri-Ramos AC Sanchez JL Pattern analysis of drug-induced skin disease Am J Dermatopathol 2008 30 4 352 369 18645307\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-7015",
"issue": "8()",
"journal": "Clinical, cosmetic and investigational dermatology",
"keywords": "acute urticaria; adverse drug reaction; exanthematous eruption",
"medline_ta": "Clin Cosmet Investig Dermatol",
"mesh_terms": null,
"nlm_unique_id": "101543449",
"other_id": null,
"pages": "53-6",
"pmc": null,
"pmid": "25709487",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "10549695;14632808;19170378;15802211;12010068;19309429;19374232;18645307;15937869;9188919;12592314",
"title": "Drug-induced skin reactions: a 2-year study.",
"title_normalized": "drug induced skin reactions a 2 year study"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2015-02763",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEPHALEXIN"
},
"drugadditiona... |
{
"abstract": "BACKGROUND\nThe trigemino-cardiac reflex is defined as the sudden onset of parasympathetic dysrhythmia, sympathetic hypotension, apnea, or gastric hypermotility during stimulation of any of the sensory branches of the trigeminal nerve. Clinically, trigemino-cardiac reflex has been reported to occur during neurosurgical skull-base surgery. Apart from the few clinical reports, the physiological function of this brainstem reflex has not yet been fully explored. Little is known regarding any predisposing factors related to the intraoperative occurrence of this reflex.\n\n\nMETHODS\nWe report the case of a 70-year-old Caucasian man who demonstrated a clearly expressed form of trigemino-cardiac reflex with severe bradycardia requiring intervention that was recorded during surgical removal of a large subdural empyema.\n\n\nCONCLUSIONS\nTo the best of our knowledge, this is the first report of an intracranial infection leading to perioperative trigemino-cardiac reflex. We therefore add a new predisposing factor for trigemino-cardiac reflex to the existing literature. Possible mechanisms are discussed in the light of the relevant literature.",
"affiliations": "Department of Neurosurgery, Tokuda Hospital, Sofia, Bulgaria. spiriev@gmail.com.",
"authors": "Spiriev|Toma|T|;Sandu|Nora|N|;Arasho|Belachew|B|;Kondoff|Slavomir|S|;Tzekov|Christo|C|;Schaller|Bernhard|B|;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/1752-1947-4-391",
"fulltext": "\n==== Front\nJ Med Case ReportsJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-4-3912111853610.1186/1752-1947-4-391Case ReportA new predisposing factor for trigemino-cardiac reflex during subdural empyema drainage: a case report Spiriev Toma 12spiriev@gmail.comSandu Nora 23norasandu@yahoo.comArasho Belachew 24belachewda@yahoo.comKondoff Slavomir 1spiriev@gmail.comTzekov Christo 1spiriev@gmail.comSchaller Bernhard 24bernhard.schaller@yahoo.deTrigemino-Cardiac Reflex Examination Group (TCREG) 1 Department of Neurosurgery, Tokuda Hospital, Sofia, Bulgaria2 Department of Neurosurgery, University Hospital Lariboisiere, Paris, France3 Department of Neurosurgery, University of Lausanne, Switzerland4 Department of Neurology, University Addis Ababa, Ethiopia2010 30 11 2010 4 391 391 21 6 2010 30 11 2010 Copyright ©2010 Spiriev et al; licensee BioMed Central Ltd.2010Spiriev et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<url>http://creativecommons.org/licenses/by/2.0</url>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction\nThe trigemino-cardiac reflex is defined as the sudden onset of parasympathetic dysrhythmia, sympathetic hypotension, apnea, or gastric hypermotility during stimulation of any of the sensory branches of the trigeminal nerve. Clinically, trigemino-cardiac reflex has been reported to occur during neurosurgical skull-base surgery. Apart from the few clinical reports, the physiological function of this brainstem reflex has not yet been fully explored. Little is known regarding any predisposing factors related to the intraoperative occurrence of this reflex.\n\nCase presentation\nWe report the case of a 70-year-old Caucasian man who demonstrated a clearly expressed form of trigemino-cardiac reflex with severe bradycardia requiring intervention that was recorded during surgical removal of a large subdural empyema.\n\nConclusion\nTo the best of our knowledge, this is the first report of an intracranial infection leading to perioperative trigemino-cardiac reflex. We therefore add a new predisposing factor for trigemino-cardiac reflex to the existing literature. Possible mechanisms are discussed in the light of the relevant literature.\n==== Body\nIntroduction\nFor more than a century, it has been well known that electrical, chemical, or mechanical stimulation of the trigeminal nerve leads to trigemino-respiratory reflexes followed by cardiac arrhythmias [1]. In the early 20th century, this phenomenon gained increased clinical attention in the form of the oculocardiac reflex (OCR), which represents the cardiac response associated with stimulation of the ophthalmic division of the trigeminal nerve during ocular surgery [2]. In 1999, Schaller [3] demonstrated for the first time that a similar reflex occurs with stimulation of the intracranial (central) portion of the trigeminal nerve during skull-base surgery and subsummarized all these trigemino-depressor responses under the term \"trigemino-cardiac reflex (TCR)\" [4]. He also defined the TCR in a way that is now generally accepted. Later, his group also described the TCR for intraoperative stimulation of the peripheral portion [5].\n\nSince then, there has been increasing discussion about the TCR itself, its provoking factors, and its treatment during intracranial or extracranial neurosurgical procedures. Several predisposing factors for intraoperative occurrence of TCR have been described [6-8], but until now no case of intracranial infection in combination with intraoperative TCR has been reported.\n\nCase presentation\nPreoperative history\nA 70-year-old Caucasian man was admitted for the second time to the Department of Neurosurgery at our hospital. His personal history included symptomatic epilepsy and chronic anemia after nephrectomy because of kidney carcinoma two years before admission to our clinic.\n\nTwo months before the current admission, he underwent surgery for a giant left frontotemporal meningioma which was removed \"gross totally.\" One month after this intervention, there was seen a fistula with emission of pus in the middle third of the operative scar. After another neurosurgical consultation, he was admitted to our department for surgery. At this occasion, the patient presented afebrile, with a blood pressure (BP) of 150/70 mmHg and a heart rate (HR) of 82 beats per minute (beats/minute), complaining of headache as well as vomiting. In the neurological examination, there was seen a right-side horizontal nystagmus, a right-side hemiparesis (MRC grade 3) and complete motor aphasia. The only medication that he was taking was carbamazepine 2× 200 mg for epileptic prophylaxis. On the cranial computed tomography (CT) scan without contrast performed in our hospital, a partial osteolysis of the frontotemporal bone flap was demonstrated, the surrounding tissues (including the dura) were seen as thicker (due to the associated inflammation), and a subdural collection with capsule organization and peri-lesional brain edema on the side of the previous tumor was described (see Figures 1, 2, and 3). On cranial CT bone reconstruction, the osteolytic foci and fistula were clearly visible. The laboratory examination showed, besides the chronic anemia, normal C-reactive protein but a monocytosis of 1.04 10-9/L (normal value, 0.1 to 0.8). The patient was diagnosed with a subdural empyema and an indication for the operative treatment was set.\n\nFigure 1 Preoperative computed tomography (CT) scan. Subdural collection with capsule organization and collateral brain edema on the side of the previous tumor is clearly visible.\n\nFigure 2 Preoperative CT scan. The surrounding tissues (including the dura) are thicker, related to the associated inflammation.\n\nFigure 3 Preoperative CT scan. CT bone window shows partial osteolysis of the bone flap, due to osteomyelitic process.\n\nAnesthetic technique\nThe patient underwent surgery several days after this second hospitalization. No pre-operative antibiotics were given. The patient fasted for eight hours prior to surgery. Routine monitoring during surgery included electrocardiography (ECG), end-tidal (ET) concentration of CO2 and sevoflurane, and pulse oximetry. All hemodynamic parameters were monitored continuously and recorded throughout the neurosurgical procedure. Anesthesia was induced with midazolam (1 mg total dosage) and propofol (2 mg/kg) followed by suxamethonium chloride (1.1 mg/kg), atracurium (0.6 mg/kg), and fentanyl (100 μg total dosage). After the trachea was intubated, the lungs were mechanically ventilated (S/5 Aespire Config; Datex-Ohmeda Ins., Madison, WI, USA) with a mixture of air and O2. Anesthesia was maintained with sevoflurane (1%). An additional 50 mg of propofol and 1 mg of midazolam were applied during the intervention when necessary.\n\nSurgical technique and postoperative management\nA frontotemporal skin incision was made using the same method used in the first intervention. Between the bone flap and galea aponeurotica in the left frontotemporal region, a large quantity (approximately 7-12 ml) of pus was removed. Intraoperatively, the bone flap was found to be changed by the osteomyelitic process. It was eroded by the inflammation, with multiple pus-filled channels connecting the inner and outer bone tables. After opening the dura, a gray-white thick pus was removed. During the whole intervention, the patient's baseline mean arterial blood pressure (MABP) was 91.0 mmHg (range, 76.7-98.7 mmHg), and baseline mean heart rate (HR) was 82.5 bpm (range, 80-89 bpm). One hour and 20 minutes after skin incision during the removal of subdural pus and working around the dura, the patient's blood pressure dropped to 37/0 mmHg (MABP, 12.3 mmHg; a 86.49% drop from baseline) and concomitantly HR dropped to 61 bpm (a 26.07% drop from baseline). There was no significant blood loss at the time of the incident. The surgical procedure was discontinued, and the patient was given ephedrin (20 mg), atropin (0.5 mg), and methylprednisolone (60 mg) (see Figure 4). Two to three minutes after the administration of these drugs, the patient's hemodynamic parameters returned to normal, and the surgical intervention was continued. This phenomenon was reproducible. The skin fistulae were excised, and two subgaleal drainage systems (Dainobag Lock 300 V; B. Braun, Melsungen, Germany) with a diameter of 12 mm were left. The patient's postoperative period was uneventful, and he presented with no additional neurological deficit. On microbiological examination, actinomycosis was reported as the cause of the empyema that was treated with cefoperazone 2× 1 g for 12 days. The patient's C-reactive protein and leucocyte count remained normal. The postoperative period was uneventful. The patient was discharged from our hospital 13 days after the intervention.\n\nFigure 4 Anesthesiology chart. Before the occurrence of trigemino-cardiac reflex (TCR), mean arterial blood pressure (MABP) was 91.0 mmHg and heart rate (HR) was 82.5 beats/minute. At the time of the TCR record, the patient's blood pressure dropped to 37/0 mmHg (MABP, 12.3 mmHg; 86.49% drop from baseline), and concomitantly HR dropped to 61 beats/minute (26.07% drop from baseline). No significant blood loss at the time of the incident was recorded. The applied medications were ephedrin (20 mg), atropin (0.5 mg) and methylprednisolone (60 mg). After drug administration, the patient's hemodynamic parameters returned to normal and the intervention was reinitiated.\n\nDiscussion\nThe presented case report is unique and adds a new and important risk factor for the intraoperative occurrence of TCR to the existing literature. It seems that infected intracranial tissue may be a new predisposing factor in combination with surgical manipulation on the meninges, a routine surgical operative technique that has never been described before to be associated with TCR occurrence.\n\nIt has already been shown that mechanical stimulation of the cerebral falx results in hyperactivity of trigeminal ganglion, thereby triggering the TCR [9]. The neural supply of the cranial dura mater involves mainly the three divisions of the trigeminal nerve, the first three cervical spinal nerves, and the cervical sympathetic trunk. A case of immediate, reproducible, and reflexive response of asystole upon stimulation of the cerebral falx during operative resection of a parafalcine meningioma was previously reported [9], being most likely related to bilateral trigeminal stimulation of the falx. According to the studies of Penfield and McNaughton [10], the nervus tentorii, a recurrent branch of the ophthalmic branch of the trigeminal nerve bilaterally innervates the tentorium cerebelli, the dura of the parieto-occipital region, the posterior third of the falx, and the adjacent sinuses. In our present case, however, the subdural empyema was located in the middle cranial fossa that is predominantly innervated by the V2 and V3 branches of trigeminal nerve [11]. However, it has been previously shown by us and others that surgical procedures at the anterior, middle, and posterior skull base (any branch of the central part of trigeminal nerve) may elicit the TCR.\n\nIn this special case, one may suggest that the patient had simply a (physiological) Cushing reflex with consecutive elevated MABP before operation that only normalized after elevation of the mass lesion. But the Cushing reflex is not a possible explanation of the MABP and HF drop as seen in our case. In our case, the intraoperative phenomenon was reproducible, which would be not the case if there were a Cushing reflex. Our case shows, therefore, a clear cause-and-effect relationship necessary for the TCR and as described earlier in detail [3].\n\nDifferent retrospective studies have shown an incidence of TCR ranging from 8% [12] to 18% [13] using all the same inclusion criteria as defined earlier by us [3]. However, it seems that TCR is often unrecognized intraoperatively, so the identification of possible provoking factors is important but often elusive. There are several reports for the provoking factor for the peripheral initiation and central initiation of the TCR. To date, several risk factors for the intraoperative occurrence of TCR have been identified, such as light general anesthesia, childhood, and the nature of the provoking stimulus (strength and duration of stimulus) [3,8]. In addition, there are several known provoking drugs such as potent narcotic agents (sufentanil and alfentanil), β-blockers, and calcium channel blockers [3,8]. Until now, no report for intracranial infections as a provoking factor for intraoperative TCR occurrence has been identified.\n\nIntracranial infections, as in the current case of subdural empyema, could lead to a pathological process called sensitization of trigeminal afferents in the dura mater [14]. It was demonstrated that chemical stimulation of dural receptive fields with inflammatory mediators such as prostaglandin E2, bradykinin, or histamine directly excite the neurons and enhance their mechanical sensitivity [1,5], such that they can be easily activated by mechanical stimuli that initially had evoked little or no response [14,15]. It seems that meningeal sensory innervation is not known to subserve multiple sensory modalities [10,14]. Meningeal afferents are thought to become activated only under potentially harmful or pathological conditions [10]. However, although the dural afferent population does not appear to mediate distinct sensory modalities, it shows a pattern of variation in mechanosensitivity as a function of conduction velocities [10,16]. Mechanical response properties of dura are attributed to A and C primary afferent neurons. Such exaggerated mechanical sensitivity and manipulation of the dura mater could play a role in the initiation of TCR in our case.\n\nConclusion\nTo the best of our knowledge, this is the first report of an intracranial infection with the intra-operative occurrence of TCR during a routine neurosurgical maneuver. Infected (intracranial) tissue may be a new and important predisposing factor for the occurrence of TCR, a phenomenon that is different from the falcine TCR caused by bilateral stimulation of tentorial nerve that was described earlier. Further laboratory and clinical investigations are needed to clarify this new information about TCR.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent\nWritten informed consent was obtained form the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-chief of this journal.\n\nAuthors' contributions\nTS and BS wrote the article. TS collected the data. BS interpreted and analyzed the data. SK and CK performed the operation and the patient's treatment and provided substantial information regarding the patient's case and were therefore major contributors to writing the manuscripts. NS and BA provided some specific and general ideas that initiated the work and helped to finish the work. Without both contributions, this report would not have been possible. NS made substantial corrections to the manuscript. All authors read and approved the final manuscript.\n==== Refs\nAngell-James JE Daly MB Nasal reflexes Proc R Soc Med 1969 62 1287 1293 5363117 \nAshner B Über einen bisher noch nicht beschriebenen Reflex, vom Auge auf Kreislauf und Atmung. Verschwinden des Radialispulses bei Druck auf das Auge Wien Klin Wochenschr 1908 21 1529 1530 \nSchaller B Probst R Strebel S Gratzl O Trigeminocardiac reflex during surgery in the cerebellopontine angle J Neurosurg 1999 90 215 220 10.3171/jns.1999.90.2.0215 9950491 \nSchaller B Trigeminocardiac reflex: a clinical phenomenon or a new physiological entity? J Neurol 2004 251 658 665 10.1007/s00415-004-0458-4 15311339 \nSchaller BJ Filis A Buchfelder M Trigemino-cardiac reflex in humans initiated by peripheral stimulation during neurosurgical skull-base operations: its first description Acta Neurochir (Wien) 2008 150 715 717 10.1007/s00701-008-1602-1 18536994 \nBlanc VF Hardy JF Milot J Jacob JL The oculocardiac reflex: a graphic and statistical analysis in infants and children Can Anaesthet Soc J 1983 30 360 369 10.1007/BF03007858 \nSchaller B Cornelius JF Prabhakar H Koerbel A Gnanalingham K Sandu N Ottaviani G Filis A Buchfelder M Trigemino-Cardiac Reflex Examination Group (TCREG) The trigemino-cardiac reflex: An update of the current knowledge J Neurosurg Anesthesiol 2009 21 187 195 10.1097/ANA.0b013e3181a2bf22 19542994 \nBauer DF Youkilis A Schenck C Turner CR Thompson BG The falcine trigeminocardiac reflex: case report and review of the literature Surg Neurol 2005 63 143 148 10.1016/j.surneu.2004.03.022 15680656 \nPenfield W McNaughton F Dural headache and innervation of the dura mater Arch Neurol Psychiatr 1940 44 43 75 \nStrassman AM Raymond SA Burstein R Sensitization of meningeal sensory neurons and the origin of headaches Nature 1996 384 560 564 10.1038/384560a0 8955268 \nJeker A Martins C Rhoton AL JrPamir MN, Black MP, Fahlbusch R Meningeal Anatomy Meningiomas 2010 Amsterdam: Elsevier \nKoerbel A Gharabaghi A Samii A Gerganov V von Gösseln H Tatagiba M Samii M Trigeminocardiac reflex during skull base surgery: mechanism and management Acta Neurochir (Wien) 2005 147 727 733 10.1007/s00701-005-0535-1 15889318 \nSchaller B Trigemino-cardiac reflex during microvascular trigeminal decompression in cases of trigeminal neuralgia J Neurosurg Anesthesiol 2005 17 45 48 15632542 \nStrassman AM Levy D Response properties of dural nociceptors in relation to headache J Neurophysiol 2006 95 1298 1306 10.1152/jn.01293.2005 16492942 \nHarriott AM Gold MS Electrophysiological properties of dural afferents in the absence and presence of inflammatory mediators J Neurophysiol 2009 101 3126 3134 10.1152/jn.91339.2008 19339455 \nStrassman AM Levy D Mechanical response properties of A and C primary afferent neurons innervating the rat intracranial dura J Neurophysiol 2002 88 3021 3031 10.1152/jn.00029.2002 12466427\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "4()",
"journal": "Journal of medical case reports",
"keywords": null,
"medline_ta": "J Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "391",
"pmc": null,
"pmid": "21118536",
"pubdate": "2010-11-30",
"publication_types": "D016428:Journal Article",
"references": "8955268;19542994;12466427;19339455;6871777;15889318;5363117;9950491;16492942;15680656;15632542;18536994;15311339",
"title": "A new predisposing factor for trigemino-cardiac reflex during subdural empyema drainage: a case report.",
"title_normalized": "a new predisposing factor for trigemino cardiac reflex during subdural empyema drainage a case report"
} | [
{
"companynumb": "BG-MYLANLABS-2018M1007853",
"fulfillexpeditecriteria": "1",
"occurcountry": "BG",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SEVOFLURANE"
},
"drugadditional": null,
... |
{
"abstract": "Hospitalized patients with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) are at risk for developing secondary fungal infections due to greater incidence of preexisting comorbidities and exposure to iatrogenic factors such as corticosteroid use. We present the case of a 44-year-old Hispanic female discovered unresponsive in her home that was found to have severe hyperglycemia with comorbid COVID-19 (coronavirus disease 2019) associated pneumonia. The patient was intubated and treated with several broad-spectrum antibiotics, remdesivir, and corticosteroids but had little improvement in her clinical status. Bronchoscopy was performed and revealed multiple necrotic lesions in the lungs. Endobronchial biopsy and bronchoalveolar lavage samples revealed pauciseptated hyphae consistent with zygomycetes. The patient was treated with multiple antifungals including voriconazole, micafungin, and amphotericin B. However, despite maximal medical therapy, the patient perished. This case highlights that clinicians must carry a high degree of suspicion and a low threshold to begin treatment for Mucor in diabetics and other immunosuppressed patients.",
"affiliations": "UT Health San Antonio, Joe R. and Terry Lozano Long School of Medicine, Department of Internal Medicine, San Antonio, Texas, USA.;University Health System, Pharmacotherapy and Pharmacy Services, San Antonio, Texas, USA.;UT Health San Antonio, Joe R. and Terry Lozano Long School of Medicine, Department of Medicine, Division of Pulmonary Diseases and Critical Care Medicine, San Antonio, Texas, USA.;UT Health San Antonio, Joe R. and Terry Lozano Long School of Medicine, Department of Internal Medicine, San Antonio, Texas, USA.",
"authors": "Khan|Nariman|N|;Gutierrez|Christina G|CG|;Martinez|David Villafuerte|DV|;Proud|Kevin C|KC|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": "10.22551/2020.28.0703.10172",
"fulltext": "\n==== Front\nArch Clin Cases\nArch Clin Cases\nACC\nArchive of Clinical Cases\n2360-6975\nUMF “Gr. T. Popa” Iasi Publishing House Iași, Romania\n\n10.22551/2020.28.0703.10172\nCase Report\nA case report of COVID-19 associated pulmonary mucormycosis\nKhan Nariman 1*\nGutierrez Christina G. 23\nMartinez David Villafuerte 4\nProud Kevin C 145\n1 UT Health San Antonio, Joe R. and Terry Lozano Long School of Medicine, Department of Internal Medicine, San Antonio, Texas, USA\n2 University Health System, Pharmacotherapy and Pharmacy Services, San Antonio, Texas, USA\n3 UT Health San Antonio, Pharmacotherapy Education and Research Center, San Antonio, Texas, USA\n4 UT Health San Antonio, Joe R. and Terry Lozano Long School of Medicine, Department of Medicine, Division of Pulmonary Diseases and Critical Care Medicine, San Antonio, Texas, USA\n5 South Texas Veterans Health Care System, Texas, USA\n* Corresponding author: Nariman Khan, UT Health San Antonio, Joe R. and Terry Lozano Long School of Medicine, Department of Internal Medicine, 7703 Floyd Curl Dr, San Antonio, TX 78229, USA. Email: khan_nariman@yahoo.com\n2020\n27 10 2021\n7 3 4651\n11 2020\n12 2020\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nAbstract\n\nHospitalized patients with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) are at risk for developing secondary fungal infections due to greater incidence of preexisting comorbidities and exposure to iatrogenic factors such as corticosteroid use. We present the case of a 44-year-old Hispanic female discovered unresponsive in her home that was found to have severe hyperglycemia with comorbid COVID-19 (coronavirus disease 2019) associated pneumonia. The patient was intubated and treated with several broad-spectrum antibiotics, remdesivir, and corticosteroids but had little improvement in her clinical status. Bronchoscopy was performed and revealed multiple necrotic lesions in the lungs. Endobronchial biopsy and bronchoalveolar lavage samples revealed pauciseptated hyphae consistent with zygomycetes. The patient was treated with multiple antifungals including voriconazole, micafungin, and amphotericin B. However, despite maximal medical therapy, the patient perished. This case highlights that clinicians must carry a high degree of suspicion and a low threshold to begin treatment for Mucor in diabetics and other immunosuppressed patients.\n\nSARS-CoV-2\nCOVID-19\nmucormycisis\ndiabetes melitus\nthoracic CT\nremdesivir\n==== Body\npmcIntroduction\n\nMucormycosis is a rare infection seen primarily in patients with immunocompromise including uncontrolled diabetes, hematologic malignancies, and systemic corticosteroid use [1]. Patients diagnosed with severe COVID-19 pneumonia are at high risk for developing secondary fungal infections due to their hospitalized status, preexisting comorbidities, and treatment regimens consisting of steroids and oftentimes antibiotics.\n\nCOVID-19 pneumonia with superimposed Aspergillus infection has been well-documented in literature since the dawn of the pandemic [2, 3]. However, there is limited data on co-infection with Mucor in critically-ill COVID-19 patients. Here we present a rare case of severe COVID-19 associated pneumonia complicated by invasive pulmonary mucormycosis.\n\nCase report\n\nA 44-year-old Hispanic woman with type II diabetes mellitus and no prior history of tobacco use was admitted to the hospital after being found unresponsive in her home. On arrival she had a temperature of 36.6 C degrees, heart rate of 126 bpm, respiratory rate of 26, blood pressure of 160/90, and an oxygen saturation of 78% on room air. Her physical exam was remarkable for a Glasgow coma score of 3, dry mucous membranes, and clear lung sounds to auscultation bilaterally. She was intubated upon arrival. Laboratory studies revealed a white blood cell count of 13000, CRP 412, blood glucose 997 mg/dl, serum sodium 160 mmol/L, serum creatinine of 3.72 mg/dL, and serum bicarbonate 11. Her arterial blood gas showed pH of 7.08, PaCO2 37.1, and PaO2 of 96 on 60% fraction of inspired O2 (FiO2) and she tested positive for SARS-CoV-2 by RT-PCR. COVID-19 specific labs were drawn and revealed elevated D-dimer to 1393 and normal values for troponin, BNP, procalcitonin, INR, AST/ALT, and ferritin. The patient was started on an insulin drip for her hyperglycemic syndrome. Her COVID-19 pneumonia was treated with 5 days of both remdesivir 100 mg IV daily and methylprednisolone 30 mg IV twice a day. Due to the critical presentation of the patient, empiric treatment for a possible superimposed bacterial pneumonia was also initiated on hospital day 1 with the broad-spectrum antibiotics cefepime and vancomycin.\n\nThe patient’s metabolic derangements improved during the first 3 days of her ICU stay, however her respiratory status worsened and she developed acute respiratory distress syndrome associated with her COVID-19 pneumonia. She required optimization of her ventilatory parameters along with rescue therapies including neuromuscular blockade and prone positioning by hospital day 4. Tracheal aspirate cultures were drawn at this time and revealed Pseudomonas aeruginosa and Aspergillus flavus. The patient was started on voriconazole 250 mg IV twice daily and switched to piperacillin/tazobactam 4.5 g IV every eight hours based on susceptibilities.\n\nComputed tomography of the chest was obtained on hospital day 8 due to worsening hypoxemia and revealed diffuse ground glass opacities (GGO) and multiple cavitary lesions measuring up to 2.1 cm in the right middle and upper lobes (Figures 1 and 2). Micafungin 150 mg IV daily was added to the patient’s treatment regimen on hospital day 9 for invasive pulmonary aspergillosis given her poor response to treatment.\n\nFig. 1 Computer tomography of the chest, axial view: diffuse GGO (arrows) throughout both lung fields.\n\nFig. 2 Computer tomography of the chest, sagittal view: approximately 2 cm cavitary lesion in right middle lobe\n\nBronchoscopy was performed on hospital day 13 due to worsening ventilation/perfusion ratio to less than 100 and lack of response to treatment. Multiple gray necrotic-appearing mucosal lesions were visualized bilaterally with near complete destruction of the left upper lobe and lingula. The lesions could be easily detached from the endobronchial wall and were non-friable. Endobronchial biopsy and bronchoalveolar lavage (BAL) were performed on the necrotic appearing lingula and Grocott’s methenamine silver stain on the sample revealed pauciseptated hyphae consistent with zygomycetes. Culture results were significant for isolated Candida albicans, glabrata, and krusei along with Aspergillus flavus and niger. The patient’s hemoglobin A1c was then checked and found to be 13. Given the endobronchial destruction on bronchoscopy, the histopathologic findings, and evidence of poorly controlled diabetes, a clinical diagnosis of pulmonary mucormycosis was made and the patient was then started on treatment with liposomal amphotericin B 5 mg/kg/day.\n\nDespite aggressive therapy, the patient’s condition continued to decline. She required continuous renal replacement therapy and was deemed not to be a candidate for extracorporeal membrane oxygenation given her devastating pulmonary disease and multi-organ dysfunction. The patient expired on hospital day seventeen.\n\nDiscussion\n\nSecondary infections with invasive pulmonary aspergillosis are well documented in critically ill patients with COVID-19 [2, 3]. However, there have only been isolated case reports of Mucor in COVID-19 patients, including one by Mehta et al. of a 60-year-old diabetic patient with rhino-orbital mucor confirmed by nasal biopsy culture. The patient eventually developed a severe cytokine storm and died from shock [4]. Another example presented by Werthman-Ehrenreich documents the case of a 33-year-old diabetic woman in ketoacidosis with concomitant COVID-19 and biopsy culture proven rhino-orbital-cerebral mucormycosis. The patient was eventually transitioned to comfort care due to extensive fungal neurological involvement and poor prognosis [1]. Finally, Placik et al. document the case of a healthy 49-year-old man with COVID-19 that eventually developed a tension pneumothorax with a bronchopleural fistula. Cardiothoracic surgery performed a thoracotomy for fistula repair and intraoperatively found an empyema that grew Rhizopus species on culture. This patient also succumbed to his illness [5]. Mucormycosis without concomitant COVID-19 infection has a mortality rate ranging from 40-80% [6]. This mortality rate appears to reach 100% when these two infections co-occur based on documented cases in literature thus far.\n\nDiabetes remains the greatest risk factor for mucormycosis, but more recently there has been a rise in cases among patients with immunosuppressive conditions. Diabetic patients typically present with rhino-cerebral disease whereas pulmonary mucormycosis is better documented in immunosuppressed patients such as transplant recipients [7]. Our patient was at very high risk for developing an invasive fungal infection due to her uncontrolled diabetes, hospitalized status, and systemic corticosteroid use as part of her treatment regimen. Mucorales infections are characterized by rapid progression and angioinvasion resulting in thrombosis and extensive tissue necrosis. Pulmonary mucormycosis manifests with persistent fever, cough, and dyspnea, while rhino-cerebral mucormycosis presents with fever, unilateral facial swelling, headache, sinus congestion, and dark lesions on the nasal bridge and inner mouth [8]. Our patient exhibited persistent fever that prompted further diagnostic workup yielding diagnosis.\n\nImaging findings of mucormycosis are nonspecific as they can present as a solitary nodule, lobar consolidation, or a cavitary lesion depending on the severity of the infection [9]. Hammer et al. researched the CT features of pulmonary mucormycosis in 30 patients with definite or probable disease. They found that the reverse halo sign, which is a GGO surrounded by a denser consolidation of crescentic shape was found in 67 percent of their patients at some point in their disease course. They also found that 53 percent of patients had a large perilesional halo and 87 percent had peripheral distribution of their lung lesions [10]. However, CT findings alone cannot diagnose pulmonary mucormycosis as some findings such as the reverse halo sign may also be found in invasive aspergillosis and COVID-19 pneumonia. Our patient’s CT chest showed diffuse GGO and multiple cavitary lesions which were nonspecific and likely due to her multi-organism infection with COVID-19, mucormycosis, and aspergillosis. Similarly, laboratory testing such as the beta-D-glucan assay and serum galactomannan antigen can aid in determining the presence of a fungal infection, but neither are associated with Mucorales. Thus, diagnosis of mucormycosis requires a multifaceted approach consisting of clinical observations, radiographic and histopathologic findings, and fungal culture analysis. It is important to note that cultures of mucormycosis often produce no growth and in these situations proper clinical context is necessary to establish a diagnosis [11].\n\nOur patient was treated with voriconazole, micafungin, and liposomal amphotericin B due to her multi organism culture growth. Aggressive source control with surgical debridement is the cornerstone of management. When surgical debridement is not an option due to high surgical mortality risk, as was the case for our patient, systemic treatment with high dose liposomal amphotericin B is the standard of care. Our patient was placed on liposomal amphotericin B 5 mg/kg/day, however higher doses of up to 10 mg/kg/daily have been associated with increased response to treatment and our patient may have benefited from rapid dose escalation [12]. However, she had significant acute kidney injury throughout her hospitalization and likely would not have tolerated maximal dosing.\n\nCombination of amphotericin B with either posaconazole or echinocandins is not currently recommended by any major treatment guidelines. However, there are studies that show improved survival in mice and human subjects with mucormycosis treated with a combination of echinocandin and amphotericin therapy. Ibrahim et al. induced neutropenia or DKA in mice then infected them with mucormycosis. They found that mice treated with micafungin or anidulafungin with liposomal amphotericin B had improved survival compared to monotherapy with any agent alone [13]. Additionally, a retrospective study on 41 patients with rhino-orbital-cerebral mucormycosis compared the effects of polyene (amphotericin B lipid complex, liposomal amphotericin B, or amphotericin B deoxycholate) plus caspofungin therapy versus polyene monotherapy on survival time. The authors found that combination therapy was associated with greater survival time and improved outcomes at 30 days post discharge [14]. Combination therapy was utilized in this patient with the hope of improving her outcome given that she was not a surgical candidate.\n\nConclusion\n\nAs COVID-19 cases continue to rise, increased surveillance for co-infections with unique organisms should be continued. Diagnosis of mucormycosis is difficult because it frequently requires invasive measures such as bronchoscopy. Clinicians should be aware of this risk in COVID pneumonia patients with persistent fever and hypoxemia. They must have a high degree of suspicion and a low threshold to begin treatment for Mucor, particularly in diabetics and immunosuppressed patients.\n\nConsent\n\nWritten informed consent was obtained from the patient’s relatives for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n\n1 Werthman-Ehrenreich A Mucormycosis with orbital compartment syndrome in a patient with COVID-19 Am J Emerg Med 2020 10.1016/j.ajem.2020.09.032\n2 Mohamed A Rogers TR Talento AF COVID-19 associated invasive pulmonary aspergillosis: Diagnostic and therapeutic challenges J Fungi (Basel) 2020 6 3 115 10.3390/jof6030115 32707965\n3 Koehler P Cornely OA Böttiger BW COVID-19 associated pulmonary aspergillosis Mycoses 2020 63 6 528 534 10.1111/myc.13096 32339350\n4 Mehta S Pandey A Rhino-orbital mucormycosis associated with COVID-19 Cureus 2020 12 9 e10726 10.7759/cureus.10726 33145132\n5 Placik DA Wesley TL Nathan WM Bronchopleural fistula development in the setting of novel therapies for acute respiratory distress syndrome in SARS-CoV-2 pneumonia Radiol Case Rep 2020 15 11 2378 2381 10.1016/j.radcr.2020.09.026 32983308\n6 Cornely OA Alastruey-Izquierdo A Arenz D Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium Lancet 2019 19 12 e405 e421 10.1016/S1473-3099(19)30312-3\n7 Jeong W Keighley C Wolfe R The Epidemiology and Clinical Manifestations of Mucormycosis: A Systematic Review and Meta-Analysis of Case Reports Clin Microbiol Infect 2019 25 1 26 34 10.1016/j.cmi.2018.07.011 30036666\n8 Symptoms of Mucormycosis 2020 https://www.cdc.gov/fungal/diseases/mucormycosis/symptoms.html Accessed: December 30, 2020\n9 Pulmonary Mucormycosis 2020 https://radiopaedia.org/articles/pulmonary-mucormycosis?lang=us Accessed: December 30, 2020\n10 Hammer MM Madan R Hatabu H: Pulmonary mucormycosis: radiologic features at presentation and over time AJR Am J Roentgenology 2018 210 4 742 747 10.2214/AJR.17.18792\n11 Mucormycosis (zygomycosis) 2020 https://www.uptodate.com/contents/mucormycosis-zygomycosis/print Accessed: December 30, 2020\n12 Lanternier F Poiree S Elie C Prospective pilot study of high-dose (10 mg/kg/day) liposomal amphotericin B (L-AMB) for the initial treatment of mucormycosis J Antimicrob Chemother 2015 70 11 3116 3123 10.1093/jac/dkv236 26316385\n13 Ibrahim AS Gebremariam T Fu Y Edwards JE Jr Spellberg B Combination echinocandin-polyene treatment of murine mucormycosis Antimicrob Agents Chemother 2008 52 4 1556 1558 10.1128/AAC.01458-07 18212099\n14 Reed C Bryant R Ibrahim AS Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis Clin Infect Disease 2008 47 3 364 371 10.1086/589857 18558882\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2360-6975",
"issue": "7(3)",
"journal": "Archive of clinical cases",
"keywords": "COVID-19; SARS-CoV-2; diabetes melitus; mucormycisis; remdesivir; thoracic CT",
"medline_ta": "Arch Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101727313",
"other_id": null,
"pages": "46-51",
"pmc": null,
"pmid": "34754927",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "26316385;32707965;33145132;32972795;32983308;29470162;31699664;32339350;18558882;18212099;30036666",
"title": "A case report of COVID-19 associated pulmonary mucormycosis.",
"title_normalized": "a case report of covid 19 associated pulmonary mucormycosis"
} | [
{
"companynumb": "US-GILEAD-2021-0556899",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nInflammatory breast cancer is a complex pathological entity associated with poor outcomes. This loco-regional disease is characterised by a rapid clinical course in the presence breast erythema and infiltration of dermal lymphatics by tumours cells. Herein we describe a case of inflammatory breast cancer with a rare presentation and disease course defined by a profound systemic inflammatory response in the absence of an infective cause.\n\n\nMETHODS\nThe patient presented with pyrexia and malaise following a recent tissue diagnosis of inflammatory breast cancer. At the time of admission the patient demonstrated clinical features of the systemic inflammatory response syndrome (SIRS) in the presence of a negative septic screen. Her condition deteriorated despite systemic broad spectrum intravenous antibiotics and she underwent surgical debulking of a 180 × 135 × 100 mm (821 g) primary tumour composed of oedematous, friable and haemorrhagic tissue (pT4,N1a,M0; oestrogen/progesterone/HER-2 receptor negative). Following surgery, the clinical picture dramatically improved with cessation of SIRS and normalisation of inflammatory markers. After 4 weeks the patient required readmission to hospital due to recurrent SIRS and negative septic screen. The patient received treatment with systemic chemotherapy showing transient clinical improvement and suppression of SIRS. Despite on going chemotherapy, systemic antibiotics and a trial of steroid therapy the patient died 5 months after her initial presentation to hospital. At the time of death she demonstrated persistent SIRS with elevated inflammatory markers.\n\n\nCONCLUSIONS\nThis is the first case report of inflammatory breath cancer associated with SIRS in the absence of clinically confirmed infection. Important learning points highlighted by this case are: (a) recognition of the diagnostic and therapeutic uncertainties that still exist in the context of inflammatory breast cancer; (b) appreciation of the potential paraneoplastic systemic inflammatory manifestations of this disease, and finally; (c) the importance a multidisciplinary and multimodal approach to treatment.",
"affiliations": "Department of Surgery and Cancer, Imperial College London, London, UK.;Department of Breast Surgery, Imperial College NHS Healthcare Trust, Charing Cross Hospital, London, UK.;Department of Breast Surgery, Imperial College NHS Healthcare Trust, Charing Cross Hospital, London, UK.;Department of Rheumatology, Imperial College NHS Healthcare Trust, Charing Cross Hospital, London, UK.;Department of Oncology, Imperial College NHS Healthcare Trust, Charing Cross Hospital, London, UK.;Department of Surgery and Cancer, Imperial College London, London, UK.",
"authors": "Boshier|Piers R|PR|;Sayers|Rosie|R|;Hadjiminas|Dimitri J|DJ|;Mackworth-Young|Charles|C|;Cleator|Susan|S|;Leff|Daniel R|DR|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40164-016-0045-2",
"fulltext": "\n==== Front\nExp Hematol OncolExp Hematol OncolExperimental Hematology & Oncology2162-3619BioMed Central London 273406094510.1186/s40164-016-0045-2Case ReportSystemic inflammatory response syndrome in a patient diagnosed with high grade inflammatory triple negative breast cancer: a case report of a potentially rare paraneoplastic syndrome Boshier Piers R. prb03@ic.ac.uk 1Sayers Rosie rs7644@my.bristol.ac.uk 2Hadjiminas Dimitri J. d.hadjiminas@imperial.ac.uk 2Mackworth-Young Charles c.mackworth-young@imperial.ac.uk 3Cleator Susan s.cleator@imperial.ac.uk 4Leff Daniel R. d.leff@imperial.ac.uk 11 Department of Surgery and Cancer, Imperial College London, London, UK 2 Department of Breast Surgery, Imperial College NHS Healthcare Trust, Charing Cross Hospital, London, UK 3 Department of Rheumatology, Imperial College NHS Healthcare Trust, Charing Cross Hospital, London, UK 4 Department of Oncology, Imperial College NHS Healthcare Trust, Charing Cross Hospital, London, UK 22 6 2016 22 6 2016 2016 5 1619 3 2016 9 6 2016 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nInflammatory breast cancer is a complex pathological entity associated with poor outcomes. This loco-regional disease is characterised by a rapid clinical course in the presence breast erythema and infiltration of dermal lymphatics by tumours cells. Herein we describe a case of inflammatory breast cancer with a rare presentation and disease course defined by a profound systemic inflammatory response in the absence of an infective cause.\n\nCase presentation\nThe patient presented with pyrexia and malaise following a recent tissue diagnosis of inflammatory breast cancer. At the time of admission the patient demonstrated clinical features of the systemic inflammatory response syndrome (SIRS) in the presence of a negative septic screen. Her condition deteriorated despite systemic broad spectrum intravenous antibiotics and she underwent surgical debulking of a 180 × 135 × 100 mm (821 g) primary tumour composed of oedematous, friable and haemorrhagic tissue (pT4,N1a,M0; oestrogen/progesterone/HER-2 receptor negative). Following surgery, the clinical picture dramatically improved with cessation of SIRS and normalisation of inflammatory markers. After 4 weeks the patient required readmission to hospital due to recurrent SIRS and negative septic screen. The patient received treatment with systemic chemotherapy showing transient clinical improvement and suppression of SIRS. Despite on going chemotherapy, systemic antibiotics and a trial of steroid therapy the patient died 5 months after her initial presentation to hospital. At the time of death she demonstrated persistent SIRS with elevated inflammatory markers.\n\nConclusion\nThis is the first case report of inflammatory breath cancer associated with SIRS in the absence of clinically confirmed infection. Important learning points highlighted by this case are: (a) recognition of the diagnostic and therapeutic uncertainties that still exist in the context of inflammatory breast cancer; (b) appreciation of the potential paraneoplastic systemic inflammatory manifestations of this disease, and finally; (c) the importance a multidisciplinary and multimodal approach to treatment.\n\nKeywords\nInflammatory breast cancerSystemic inflammatory response syndromeParaneoplastic syndromeCase reportissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nInflammatory breast cancer (IBC) is a complex clinicopathological entity that is associated with a poor prognosis [1]. Consensus guidelines for the diagnosis of IBC describe a locoregional disease characterised by rapid onset breast erythema, oedema and/or peau d’orange with or without an underlying palpable mass [1]. Whilst localised skin warmth may be present, a systemic inflammatory response is not a recognised feature of this disease and if present is likely to suggest an alternative diagnosis.\n\nThe systemic inflammatory response syndrome (SIRS) is a multifaceted pathophysiological response to a range of noxious stimuli, whose characteristics were first defined in 1992 [2]. The link between inflammation and cancer has long been established [3] and is associated with readily detectable clinical and biochemical changes [4]. The mechanism by which cancer induces both local and systemic inflammatory responses is yet to be fully elucidated, although it is thought to involve complex interactions between cancerous cells and adjacent stroma leading to tissue damage and initiation of an acute phase response [3].\n\nTraditionally the ‘inflammatory’ response observed in IBC is attributed to the infiltration of dermal lymphatics by tumour cells, which in turn causes congestion. A potent inflammatory milieu has nevertheless been observed in the context of IBC [5, 6]. Furthermore, raised serum inflammatory markers are recognised in the serum of up to one-third of patients with grade I-III breast cancer [7]. The underlying mechanism clinical significance of SIRS in the context of a cancer diagnosis is however yet to be determined.\n\nHerein, we present an unusual case of inflammatory breast cancer associated with a systemic inflammatory response in the absence of clinical evidence of infection.\n\nCase presentation\nA 48 year old pre-menopausal Jamaican female, recently diagnosed with IBC affecting the left breast, was admitted with a 5 day history of pyrexia and general malaise. Her co-morbidities included hypertension and sarcoidosis treated with antihypertensives and low dose oral prednisolone respectively. There was no relevant family or travel history and no history of recent illness.\n\nAn ultrasound scan performed at the time of diagnosis, 6 weeks prior to admission, showed a 41 mm ill-defined mass in the upper outer quadrant of the left breast with bilateral axillary nodal enlargement. Computed tomography (CT) imaging at the time of diagnosis revealed no evidence of solid organ metastasis within the chest, abdomen or pelvis. Core biopsy of the lesion confirmed a pleomorphic, poorly differentiated triple negative (estrogen/progesterone/human epidermal growth factor (HER2) receptor) grade III invasive ductal carcinoma.\n\nAt the time of admission, clinical examination revealed a large (~5 × 10 cm) left upper outer quadrant breast mass with associated erythema and induration of the surrounding tissue and palpable lymphadenopathy of within the axilla. The diagnostic criteria for systemic inflammatory response syndrome (SIRS) were fulfilled [heart rate 120; respiratory rate 26; temperature 38.7 °C; white blood cell count 16.9 × 109/L (neutrophils 14.9 × 109/L)] [2]. Biochemical markers of acute inflammation were observed to be markedly deranged (C-reactive protein (CRP) 385 mg/L; erythrocyte sedimentation rate >100 mm/h; ferritin 1044 μg/L; transferrin 0.6 g/L; albumin 16 g/L). Blood cultures at the time of admission, before initiation of antibiotic therapy, demonstrated no bacterial growth. Likewise an ultrasound guided aspirate of tissue fluid contained within the mass yielded no evidence of bacterial infection.\n\nDespite treatment with antibiotics (Cefuroxime and Metronidazole), 48 h after admission worsening SIRS was observed (heart rate 114; respiratory rate 24; Temperature 39.0 °C; White blood cell count 20.0 × 109). A CT scan 72 h after admission demonstrated an increase in size of the primary breast lesion (75 × 94 vs. 38 × 80 mm), features in keeping with pectoralis major muscle invasion and associated ipsilateral lymphadenopathy and cervical chain adenopathy. A left upper lobe pulmonary nodule (9 mm) and para-aortic lymph node (8 mm) suspicious of metastatic spread were also noted in addition to small bilateral pleural and pericardial effusions. Subsequent transthoracic echocardiogram and CT head revealed no additional abnormalities or likely source of infection. Serum virology and autoimmune screens were negative as were repeat blood and urine cultures.\n\nOver the subsequent week she experienced continued clinical deterioration with anaemia (haemoglobin; 87–65 g/L) and coagulopathy (fibrinogen 5.65 g/L; prothrombin time 17.2 s; activate partial thromboplastin time 40.6 s) that required transfusion of packed red cells (6 units) and fresh frozen plasma (3 units). There was no evidence of active bleeding and haemoglobin electrophoresis was normal. A blood film showed signs of anaemia with significant red cell hypochromia, anisopoikilocytosis, hypersegmentated neutrophils and thrombocytosis with platelet clumping.\n\nThe patients condition deteriorated over the course of 9 days with no evidence of a response to broad spectrum antibiotic therapy (including: Vancomycin; Ciprofloxacin; Tazocin, and; Meropenem) (Fig. 1) and persistently worsening SIRS and episodic hypotension without objective evidence of an infective source. Formal nutritional assessment revealed good nutritional intake and no specific deficiency. Consequently the multidisciplinary team advised emergency excision of the left breast tumour mass on the assumption that the SIRS might represent a response to necrotic inflammatory cancer. At the time of surgery a 180 × 135 × 100 mm (821 g) diffusely oedematous, friable and haemorrhagic tissue mass was excised (Fig. 2). A delayed primary closure of the wound was performed on the seventh postoperative day with Yates drain left in situ. Histology of the resected specimen confirmed grade III pleomorphic carcinoma (>100 mm) with adjacent high grade ductal carcinoma in situ, lymphovascular invasion and extracapsular spread and significant necrosis (pT4,N1a,Mx; oestrogen/progesterone/HER-2 receptor negative, E-cadherin/cytokeratin-7/p53/p63 positive) (Fig. 2). Radial margins were clear (>2 mm) but the deep resection margin was involved.Fig. 1 C-reactive protein CRP and white blood cell WBC trends from time of acute admission to hospital\n\n\nFig. 2 Macro- and microscopic tumour appearance. a Macroscopic image of excised breath tissue with section through tumour (white arrow). Microscopic images demonstrating: b tumour cells and lymphovascular invasion of the superficial epidermis; c high magnification image of tumour cells, and; d tumour involvement of the deep excision margin (black arrow)\n\n\n\n\nFollowing surgery the patient’s clinical picture dramatically improved with a cessation of SIRS and normalisation of inflammatory markers. At the time of hospital discharge on (postoperative day 8), the patient was clinically well. A multidisciplinary team decision for the continuation of therapy as an outpatient had been agreed. Approximately 4 weeks later she represented with recurrent SIRS and a left breast seroma which was formally drained (1.5L haemoserous fluid) and which was negative on culture. Critically, no infective source could be identified (blood, urine, seroma aspirate culture were negative). Positron emission tomography–CT performed soon after readmission demonstrated a recurrent mass (32 × 77 mm) at the site of the original tumour. In addition there was progressive bilateral lymphadenopathy including mediastinal nodes and bilateral intrapulmonary masses with the largest present in the superior segment of the lingual measuring (22 × 40 mm). There was heterogeneity of the hepatic fludeoxyglucose uptake with increase skeletal activity, indicative of metastatic disease. Chemotherapy (FEC regimen; fluorouracil, epirubicin and cyclophosphamide) was started 6 weeks after her initial emergency presentation. The first cycle of chemotherapy was well tolerated and associated with resolution of SIRS and improvement in inflammatory markers. Whilst receiving the second cycle of chemotherapy as an outpatient, she developed neutropenia and pyrexias (culture negative) for which she received a further course of broad spectrum antibiotics and epidermal growth factor.\n\nShe received a third cycle of FEC chemotherapy following which a repeat CT scan showed an increase in size of the primary tumour, multiple pulmonary metastasis with extensive nodal disease.\n\nA subsequent aspiration of the breast cavity grew staphylococcus aureus, pseudomonas and enterococcus for which she was prescribed Linezolid and Meropenem but without a clinical response.\n\nThe Oncology team discussed whether second line taxane chemotherapy was appropriate, but this was withheld because the patient’s condition deteriorated rapidly. The albumin at this point was 13 g/L.\n\nDespite no impedance to the investigation, diagnosis and management of this patient during her care she died 5 months after her initial presentation to hospital. At the time of death she demonstrated persistent SIRS with elevated markers of inflammation (white blood cell count 47.6 × 109/L (Neutrophils 44.5 × 109/L); CRP 332 mg/L).\n\nDiscussion\nThis is the first case report of IBC associated with SIRS in the absence of clinically defined infection in the English medical literature. Important learning points highlighted by this case are as follows: (a) recognition of the diagnostic and therapeutic uncertainties that still exist in the context of IBC; (b) appreciation of the potential para-neoplastic systemic inflammatory manifestations of this disease, and; (c) the importance a multidisciplinary and multimodal approach to treatment.\n\nOne feature of this case that is particularly remarkable was the magnitude of the observed systemic inflammatory response. A systematic review of the literature revealed no previously published report of an equivalent systematic inflammatory response to IBC. Several case reports have described: fever [8]; elevated erythrocyte sedimentation rate [9]; elevated CRP, and; raised white blood cell count and in the presence of a negative septic screen as well as pure red cell aplasia [10] in patients diagnosed with IBC. Molecular profiling has sought to provide further insight into the pathogenesis of IBC [5]. Studies have found evidence for the up-regulation of several genes associated with inflammatory signalling pathways in IBC cells compared to non-IBC cells. Biѐche et al., reported up regulation of interleukin (IL) 6 and genes encoding the CCL3/MIP1A and CCL5/RANTES [5]. Likewise NF-κB, cyclooxygenase family of enzymes and JAK/STAT signalling, all responsible for a range of effects including propagation of the inflammatory and immune response, are constitutively active in IBC [6]. Of note, the genetic expression of other important inflammatory mediators, tumour necrosis factor alpha (TNFα), Interferon, IL-1, IL-8 and IL-10 was similar in IBC and non-IBC cells [5]. Significantly increased inflammatory cytokine (TNFα, IL-8, IL-10 and CCL2/MCP-1) secretion was however observed in CD14+ monocytes isolated from IBC compared to non-IBC patients [11]. Finally, the acute phase protein CRP has been correlated to a more aggressive disease phonotype and poorer prognosis in breast cancers patients [12]. Sphingosine-1-phosphate, a potent inflammatory mediator, has recently been reported to up-regulate the expression of CRP in breast cells [13]. Whilst these findings support the premise of an inflammatory basis for IBC their wider implications for a systemic inflammatory response are yet to be fully elucidated.\n\nThe patient fulfilled all of the clinical criteria for the diagnosis of SIRS as defined by the American College of Chest Physicians/Society of Critical Care Medicine [2]. An additional feature of this case was observed derangement of red blood cell count and clotting function that required treatment with blood products. The Third International Consensus Definitions for Sepsis and Septic Shock defines sepsis as a “life-threatening organ dysfunction caused by a dysregulated host response to infection” [14]. Critically after extensive and repeated investigation at the time of presentation and during the initial period of treatment no evidence was found for an infective origin for this response. Whilst positive bacterial cultures were eventually grown from the surgical wound cavity, isolated organisms are reported amongst the most common causes of hospital acquired wound infection [15, 16]. As such the eventual presence of these bacteria in the wound is most in keeping with nosocomial infection. Numerous factors, including previous surgery, chemotherapy and general cachexia would strongly predispose this patient to such infection.\n\nThe unusual clinical course exhibited by this patient proved challenging both in terms of establishing an underlying mechanism and determination of appropriate management. Existing criteria for a diagnosis of neoplastic fever are not met in this specific case [17, 18]. Measurement of plasma procalcitonin is an alternative method of differentiating sepsis from paraneoplastic fever that may have help direct this patients management. Procalcitonin, a pre-cursor of the hormone calcitonin, is found in significantly higher levels in patients with sepsis compared to febrile patients with no documented evidence of infection [18]. This investigation is however not widely available and the merits of use are still debated. Lymph node biopsy at the time of presentation may also have help determine if another cause of lymphadenopathy, other than tumour metastasis, was responsible for the patients clinical picture.\n\nA second remarkable characteristic of this case was the dramatic effects of surgical excision and subsequent chemotherapy on suppression of the systemic inflammatory response, albeit only temporary. Furthermore, the transient nature of the response to surgical excision only served to emphasise the extremely aggressive nature of the underlying disease process. Consensus guidelines for the management of IBC published by Dawood et al. and the National Comprehensive Cancer Network, recommend primary systemic chemotherapy as the first line treatment with aim of down-staging the disease allowing the possibility for definitive surgery [1, 19]. In this specific case, however, due to the profound clinical deterioration and in the absence of a confirmed source of sepsis a multidisciplinary team decision was taken to excise the tumour mass for fear that the patient may not survive without surgical resection. Ultimately the observed SIRS response was only transiently suppressed by surgical resection and cycles of systemic chemotherapy.\n\nThe presence of a prior diagnosis of sarcoidosis, an immunologically mediated disease, may have contributed to the observed systemic inflammatory response. Whilst the pathophysiology of sarcoidosis is itself incompletely understood, it is recognised that a low activation threshold and dysregulation of the immune system are important for its development and progression [20]. A systematic review of the literature reveals no previous published reports of IBC in the presence of sarcoidosis. Notwithstanding, it may be hypothesised that in the context of existing immune dysfunction, the local and systemic inflammatory effects of IBC can be significantly augmented.\n\nConclusion\nThis case report represents the first description of a potential paraneoplastic systemic inflammatory response in the context of inflammatory breast cancer. This report contributes to the existing published literature that seeks to characterise and define the underlying link between the inflammatory process and IBC. It also serves as a reminder of the aggressive and unpredictable nature of this disease and offers new insight into the challenges faced by clinicians charged with its management.\n\nAbbreviations\nCCL2/MCP-1chemokine (C–C motif) ligand 2/monocyte chemotactic protein 1\n\nCCL3/MIP1Achemokine (C–C motif) ligand 3/macrophage inflammatory protein 1-alpha\n\nCCL5/RANTESchemokine (C–C motif) ligand 5/regulated on activation, normal T cell expressed and secreted\n\nCD14+cluster of differentiation 14+\n\nCRPC-reactive protein\n\nCTcomputer tomography\n\nFECfluorouracil, epirubicin and cyclophosphamide\n\nHER2human epidermal growth factor receptor 2\n\nIBCinflammatory breast cancer\n\nILinterleukin\n\nJAK/STATjanus kinase/signal transducer and activator of transcription\n\nNF-κBnuclear factor kappa-light-chain-enhancer of activated B cells\n\nSIRSsystemic inflammatory response syndrome\n\nTNFαtumour necrosis factor alpha\n\nAuthors’ contributions\nPB, RS, DH, CM-Y, SC and DL were involved in the care of this patient and together proposed this a suitable case for reporting in the literature. PB and RS were responsible retrieval of clinical case notes and drafting the manuscript. PB, RS, DH, CM-Y, SC and DL were responsible for reviewing and amending the manuscript. All authors have given final approval to the version of the manuscript to be published. All authors read and approved the final manuscript.\n\nAcknowledgements\nThe authors acknowledge the work of the Breast Cancer Multidisciplinary Team of Imperial College Healthcare NHS Trust who were responsible for coordinating this patients management. The authors are grateful to Kevin Lessey from the department of histopathology at Charing Cross Hospital for providing macro- and microscopic images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAvailability of data and materials\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nEthics\nFormal ethic committee approval was not applicable to this case report.\n==== Refs\nReferences\n1. Dawood S Merajver SD Viens P Vermeulen PB Swain SM Buchholz TA International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment Ann Oncol 2011 22 3 515 523 10.1093/annonc/mdq345 20603440 \n2. Bone RC Balk RA Cerra FB Dellinger RP Fein AM Knaus WA Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine Chest 1992 101 6 1644 1655 10.1378/chest.101.6.1644 1303622 \n3. Balkwill F Mantovani A Inflammation and cancer: back to Virchow? Lancet 2001 357 9255 539 545 10.1016/S0140-6736(00)04046-0 11229684 \n4. Proctor MJ Talwar D Balmar SM O’Reilly DS Foulis AK Horgan PG The relationship between the presence and site of cancer, an inflammation-based prognostic score and biochemical parameters. Initial results of the Glasgow inflammation outcome study Br J Cancer 2010 103 6 870 876 10.1038/sj.bjc.6605855 20717110 \n5. Bieche I Lerebours F Tozlu S Espie M Marty M Lidereau R Molecular profiling of inflammatory breast cancer: identification of a poor-prognosis gene expression signature Clin Cancer Res 2004 10 20 6789 6795 10.1158/1078-0432.CCR-04-0306 15501955 \n6. Fouad TM Kogawa T Reuben JM Ueno NT The role of inflammation in inflammatory breast cancer Adv Exp Med Biol 2014 816 53 73 10.1007/978-3-0348-0837-8_3 24818719 \n7. Petekkaya I Aksoy S Roach EC Okoh AK Gecmez G Gezgen G Impact of inflammatory markers on the prognosis of patients with operable breast cancer J BUON 2014 19 3 673 680 25261651 \n8. Harrison AM Zendejas B Ali SM Scow JS Farley DR Lessons learned from an unusual case of inflammatory breast cancer J Surg Educ 2012 69 3 350 354 10.1016/j.jsurg.2011.10.016 22483137 \n9. Choueiri MB Otrock ZK Tawil AN El H II El Saghir NS Inflammatory breast cancer in a male N Z Med J 2005 118 1218 U1566 16027755 \n10. Harris SJ Seah JA Barnett F White SC Inflammatory breast cancer and secondary pure red cell aplasia Acta Oncol 2011 50 5 727 728 10.3109/0284186X.2011.562917 21574834 \n11. Mohamed MM El-Ghonaimy EA Nouh MA Schneider RJ Sloane BF El-Shinawi M Cytokines secreted by macrophages isolated from tumor microenvironment of inflammatory breast cancer patients possess chemotactic properties Int J Biochem Cell Biol 2014 46 138 147 10.1016/j.biocel.2013.11.015 24291763 \n12. Ravishankaran P Karunanithi R Clinical significance of preoperative serum interleukin-6 and C-reactive protein level in breast cancer patients World J Surg Oncol 2011 9 18 10.1186/1477-7819-9-18 21294915 \n13. Kim ES Cha Y Ham M Jung J Kim SG Hwang S Inflammatory lipid sphingosine-1-phosphate upregulates C-reactive protein via C/EBPbeta and potentiates breast cancer progression Oncogene 2014 33 27 3583 3593 10.1038/onc.2013.319 23955082 \n14. Singer M Deutschman CS Seymour CW Shankar-Hari M Annane D Bauer M The third international consensus definitions for sepsis and septic shock (Sepsis-3) JAMA 2016 315 8 801 810 10.1001/jama.2016.0287 26903338 \n15. Giacometti A Cirioni O Schimizzi AM Del Prete MS Barchiesi F D’Errico MM Epidemiology and microbiology of surgical wound infections J Clin Microbiol 2000 38 2 918 922 10655417 \n16. Surucuoglu S Gazi H Kurutepe S Ozkutuk N Ozbakkaloglu B Bacteriology of surgical wound infections in a tertiary care hospital in Turkey East Afr Med J 2005 82 7 331 336 16167704 \n17. Zell JA Chang JC Neoplastic fever: a neglected paraneoplastic syndrome Support Care Cancer 2005 13 11 870 877 10.1007/s00520-005-0825-4 15864658 \n18. Shomali W Hachem R Chaftari AM Jiang Y Bahu R Jabbour J Can procalcitonin distinguish infectious fever from tumor-related fever in non-neutropenic cancer patients? Cancer 2012 118 23 5823 5829 10.1002/cncr.27602 22605389 \n19. National Comprehensive Cancer Network. Breast cancer (Version 2.2016). https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf Accessed June 5 2016.\n20. Blank N Lorenz HM Ho AD Witzens-Harig M Sarcoidosis and the occurrence of malignant diseases Rheumatol Int 2014 34 10 1433 1439 10.1007/s00296-014-2983-5 24658811\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2162-3619",
"issue": "5()",
"journal": "Experimental hematology & oncology",
"keywords": "Case report; Inflammatory breast cancer; Paraneoplastic syndrome; Systemic inflammatory response syndrome",
"medline_ta": "Exp Hematol Oncol",
"mesh_terms": null,
"nlm_unique_id": "101590676",
"other_id": null,
"pages": "16",
"pmc": null,
"pmid": "27340609",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "21574834;20717110;24818719;23955082;22605389;20603440;22483137;16027755;24658811;10655417;15501955;16167704;24291763;15864658;1303622;11229684;26903338;25261651;21294915",
"title": "Systemic inflammatory response syndrome in a patient diagnosed with high grade inflammatory triple negative breast cancer: a case report of a potentially rare paraneoplastic syndrome.",
"title_normalized": "systemic inflammatory response syndrome in a patient diagnosed with high grade inflammatory triple negative breast cancer a case report of a potentially rare paraneoplastic syndrome"
} | [
{
"companynumb": "GB-BAUSCH-BL-2017-001283",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe chronic inflammation of the intestinal mucosa, the extra-intestinal manifestations of the disease and the immunosuppressive treatment of inflammatory bowel disease may increase cancer risk.\n\n\nOBJECTIVE\nTo report the demographic and clinical features of patients with IBD who developed a malignant tumor.\n\n\nMETHODS\nRetrospective analysis of an IBD patient registry of a private clinic, diagnosed between 1976 and 2014.\n\n\nRESULTS\n437 subjects were included, aged 15-88 years (58% women). Seventy two percent of patients had ulcerative colitis. The median time of follow up was 6 years. Ten patients (2.3%) developed a malignant tumor. In four, the tumor could be related to IBD (two colorectal cancers, one cholangiocarcinoma and one chronic myeloid leukemia (CML)). Two of 45 patients treated with biological therapy developed a tumor (CML and hypernephroma). Three of 170 patients on immunosuppressive treatment developed tumors. Only one had a tumor possibly related with the use of azathioprine (non-melanoma skin cancer). In only two patients, the treatment was changed at the time of their cancer diagnosis, from immunosuppressive medications to mesalamine.\n\n\nCONCLUSIONS\nOnly a small proportion of these patients with IBD developed a malignant tumor. The treatment of IBD has to be determined by the severity of the disease and not by the fear of developing a neoplasia. Following recommendations is fundamental to decrease the possibility of developing this complication.",
"affiliations": null,
"authors": "Meyer|Lital|L|;Simian|Daniela|D|;Kronberg|Udo|U|;Estay|Camila|C|;Lubascher|Jaime|J|;Figueroa|Carolina|C|;Quera|Rodrigo|R|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Chile",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0034-9887",
"issue": "143(7)",
"journal": "Revista medica de Chile",
"keywords": null,
"medline_ta": "Rev Med Chil",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001691:Biological Therapy; D002677:Chile; D015331:Cohort Studies; D003093:Colitis, Ulcerative; D015179:Colorectal Neoplasms; D003424:Crohn Disease; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D015212:Inflammatory Bowel Diseases; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "0404312",
"other_id": null,
"pages": "834-40",
"pmc": null,
"pmid": "26361018",
"pubdate": "2015-07",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Development of malignant tumors in patients with inflammatory bowel disease.",
"title_normalized": "development of malignant tumors in patients with inflammatory bowel disease"
} | [
{
"companynumb": "CL-MYLANLABS-2015M1047879",
"fulfillexpeditecriteria": "1",
"occurcountry": "CL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
... |
{
"abstract": "A 73-year-old man presented with right lower back pain and dysuria. Right hydronephrosis and a large pelvic large mass were seen on computed tomography (CT). Although his prostate-specific antigen (PSA) was 0.5 ng/mL, an irregularly enlarged, stony, hard prostate was palpable on digital rectal examination. A prostate tumor was suspected, and a transrectal prostate biopsy and right transurethral ureteral stent placement were performed. Histological and immunohistochemical studies revealed diffuse large B-cell lymphoma. Positron emission tomography-computed tomography showed abnormal uptake in the stomach, cecum, right obturator lymph nodes, para-aortic lymph nodes, and dorsal left kidney. No abnormal findings were seen on bone marrow histology. Clinical stage IVA was confirmed according to Ann Arbor criteria. The patient achieved a complete response after 8 cycles of combination chemotherapy with rituximab, pirarubicin, cyclophosphamide, vincristine, and prednisolone.",
"affiliations": "Department of Urology, Nippon Medical School Hospital.;Department of Urology, Nippon Medical School Hospital.;Department of Urology, Nippon Medical School Hospital.;Department of Hematology, Nippon Medical School Hospital.;Department of Urology, Nippon Medical School Hospital.;Department of Urology, Nippon Medical School Hospital.;Department of Urology, Nippon Medical School Hospital.;Department of Urology, Nippon Medical School Hospital.;Department of Urology, Nippon Medical School Hospital.;Department of Urology, Nippon Medical School Hospital.;Department of Urology, Nippon Medical School Hospital.;Department of Urology, Nippon Medical School Hospital.;Department of Urology, Nippon Medical School Hospital.;Department of Urology, Nippon Medical School Hospital.;Department of Urology, Nippon Medical School Hospital.;Department of Urology, Nippon Medical School Hospital.;Department of Hematology, Nippon Medical School Hospital.;Department of Urology, Nippon Medical School Hospital.",
"authors": "Yasuoka|Shotaro|S|;Kimura|Go|G|;Toyama|Yuka|Y|;Moriya|Keichi|K|;Takahashi|Keigo|K|;Matsuoka|Ryo|R|;Shibayama|Keita|K|;Obayashi|Kotaro|K|;Inoue|Yasushi|Y|;Shindo|Takao|T|;Iigaya|Shigeki|S|;Endo|Yuki|Y|;Akatsuka|Jun|J|;Hayashi|Tatsuro|T|;Nakayama|Satoko|S|;Hamasaki|Tsutomu|T|;Inokuchi|Koiti|K|;Kondo|Yukihiro|Y|",
"chemical_list": "D014408:Biomarkers, Tumor; D017430:Prostate-Specific Antigen",
"country": "Japan",
"delete": false,
"doi": "10.1272/jnms.JNMS.2018_85-37",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1345-4676",
"issue": "85(4)",
"journal": "Journal of Nippon Medical School = Nippon Ika Daigaku zasshi",
"keywords": "International Prognostic Index (IPI); dysuria; hydronephrosis; malignant lymphoma; prostate",
"medline_ta": "J Nippon Med Sch",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001416:Back Pain; D014408:Biomarkers, Tumor; D051517:Digital Rectal Examination; D053159:Dysuria; D006801:Humans; D008223:Lymphoma; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D000072078:Positron Emission Tomography Computed Tomography; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms; D015607:Stents; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "100935589",
"other_id": null,
"pages": "236-240",
"pmc": null,
"pmid": "30259894",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Primary Malignant Lymphoma of the Prostate Gland Presenting as Right Lower Back Pain and Dysuria.",
"title_normalized": "a case of primary malignant lymphoma of the prostate gland presenting as right lower back pain and dysuria"
} | [
{
"companynumb": "JP-TEVA-2018-JP-980129",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"... |
{
"abstract": "The aims were to determine the incidence rate, predictive factors and severity of liver injury that develops during MTX treatment for RA and to evaluate the role of pretreatment hepatic fat deposition.\nWe used an ongoing real-life registry containing RA patients who had started MTX between August 2007 and April 2018 at participating institutions. The liver-to-spleen attenuation ratio on CT scans at enrolment was used to evaluate pretreatment fat deposition quantitatively. Patients were followed until persistent transaminitis developed or until the end of the study. Liver biopsy was performed for patients who presented with persistent transaminitis.\nWe followed 289 new MTX users without pretreatment elevations of transaminases (mean follow-up time, 58.3 months). Hepatic fat deposition was detected in half of the patients at enrolment. During follow-up, persistent transaminitis occurred at a crude incidence rate of 3.13 per 100 person-years, and the cumulative incidence at 5 years was estimated to be 13%. A multivariate Fine-Gray regression analysis showed that the most important predictive factors were pre-existing moderate to severe fat deposition (adjusted hazard ratio, 7.69; 95% CI: 3.10, 19.10) and obesity (adjusted hazard ratio, 2.68; 95% CI: 1.37, 5.25). Non-alcoholic steatohepatitis (NASH) was the most predominant pattern in liver biopsy samples. Hepatic fibrosis was found in 90% of samples, but most cases were not advanced.\nAggravation of underlying fatty liver to NASH with fibrosis seems to be an important mechanism of liver injury that occurs in MTX-treated RA patients.",
"affiliations": "Department of Rheumatology, Clinical Research Center for Rheumatic Diseases, National Hospital Organization Kumamoto Saishun Medical Center, Kohshi, Kumamoto.;Department of Pathology, Kumamoto Shinto General Hospital, Kumamoto.;Department of Pathology, Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Omura, Nagasaki.;Rheumatic and Collagen Disease Center, Sasebo Chuo Hospital, Sasebo, Nagasaki.;Department of Public Health, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki.;Department of Public Health, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki.;Department of Gastroenterology and Hepatology, Kumamoto Shinto General Hospital, Kumamoto, Japan.",
"authors": "Mori|Shunsuke|S|0000-0001-7972-4252;Arima|Nobuyuki|N|;Ito|Masahiro|M|;Ueki|Yukitaka|Y|;Abe|Yasuyo|Y|;Aoyagi|Kiyoshi|K|;Fujiyama|Shigetoshi|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/rap/rkaa020",
"fulltext": "\n==== Front\nRheumatol Adv Pract\nRheumatol Adv Pract\nrheumap\nRheumatology Advances in Practice\n2514-1775 Oxford University Press \n\n10.1093/rap/rkaa020\nrkaa020\nOriginal Article\nAcademicSubjects/MED00010\nIncidence, predictive factors and severity of methotrexate-related liver injury in rheumatoid arthritis: a longitudinal cohort study\nhttp://orcid.org/0000-0001-7972-4252Mori Shunsuke r1 Arima Nobuyuki r2 Ito Masahiro r3 Ueki Yukitaka r4 Abe Yasuyo r5 Aoyagi Kiyoshi r5 Fujiyama Shigetoshi r6 r1 \nDepartment of Rheumatology, Clinical Research Center for Rheumatic Diseases, National Hospital Organization Kumamoto Saishun Medical Center, Kohshi, Kumamoto\nr2 \nDepartment of Pathology, Kumamoto Shinto General Hospital, Kumamoto\nr3 \nDepartment of Pathology, Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Omura, Nagasaki\nr4 \nRheumatic and Collagen Disease Center, Sasebo Chuo Hospital, Sasebo, Nagasaki\nr5 \nDepartment of Public Health, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki\nr6 \nDepartment of Gastroenterology and Hepatology, Kumamoto Shinto General Hospital, Kumamoto, Japan\nCorrespondence to: Shunsuke Mori, Department of Rheumatology, Clinical Research Center for Rheumatic Diseases, National Hospital Organization Kumamoto Saishun Medical Center, 2659 Suya, Kohshi, Kumamoto 861-1196, Japan. E-mail: mori.shunsuke.ra@mail.hosp.go.jp\n2020 \n05 6 2020 \n05 6 2020 \n4 2 rkaa02020 2 2020 27 5 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.2020This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract\nObjectives\nThe aims were to determine the incidence rate, predictive factors and severity of liver injury that develops during MTX treatment for RA and to evaluate the role of pretreatment hepatic fat deposition.\n\nMethods\nWe used an ongoing real-life registry containing RA patients who had started MTX between August 2007 and April 2018 at participating institutions. The liver-to-spleen attenuation ratio on CT scans at enrolment was used to evaluate pretreatment fat deposition quantitatively. Patients were followed until persistent transaminitis developed or until the end of the study. Liver biopsy was performed for patients who presented with persistent transaminitis.\n\nResults\nWe followed 289 new MTX users without pretreatment elevations of transaminases (mean follow-up time, 58.3 months). Hepatic fat deposition was detected in half of the patients at enrolment. During follow-up, persistent transaminitis occurred at a crude incidence rate of 3.13 per 100 person-years, and the cumulative incidence at 5 years was estimated to be 13%. A multivariate Fine–Gray regression analysis showed that the most important predictive factors were pre-existing moderate to severe fat deposition (adjusted hazard ratio, 7.69; 95% CI: 3.10, 19.10) and obesity (adjusted hazard ratio, 2.68; 95% CI: 1.37, 5.25). Non-alcoholic steatohepatitis (NASH) was the most predominant pattern in liver biopsy samples. Hepatic fibrosis was found in 90% of samples, but most cases were not advanced.\n\nConclusion\nAggravation of underlying fatty liver to NASH with fibrosis seems to be an important mechanism of liver injury that occurs in MTX-treated RA patients.\n\nrheumatoid arthritismethotrexateliver injurypretreatment fat depositionnon-alcoholic steatohepatitisNational Hospital Organization\n==== Body\nKey messages\nThe crude incidence rate of persistent transaminitis after MTX treatment is 3.13 per 100 person-years.\n\nThe most important predictive factors are pretreatment moderate to severe fat deposition and obesity.\n\nMTX use can favour the aggravation of pre-existing fatty liver to non-alcoholic steatohepatitis with fibrosis.\n\nIntroduction\nMTX is widely used as the conventional systemic DMARD (csDMARD) of first choice to treat patients with RA, psoriatic disease and other autoimmune diseases [1–3]. With chronic MTX use, liver injury has been recognized as an important adverse event in these patients [4, 5]. Recently, the role of non-alcoholic fatty liver disease (NAFLD) as a risk factor for drug-induced liver injury has received a lot of attention [6, 7]. NAFLD is characterized by excessive hepatic fat accumulation, without significant alcohol consumption, competing aetiologies for hepatic steatosis, or coexisting causes for chronic liver disease [8–11]. Several studies reported a significant association of NAFLD risk factors, especially obesity and type 2 diabetes, with the development of histologically advanced grades of liver injury and severe fibrosis in psoriasis patients receiving MTX treatment [12–15]. In addition, the similarity of pathological features between MTX-related liver injury and a more progressive form of NAFLD, namely non-alcoholic steatohepatitis (NASH), was reported in psoriasis patients [13].\n\nFor RA patients, several studies identified obesity, type 2 diabetes and hypercholesterolaemia as risk factors for the increase in alanine and/or aspartate aminotransferase (ALT and/or AST) levels that is observed during MTX treatment [16–19]. A NASH-like pattern was reported to be a common histological abnormality in MTX-treated RA patients who had persistent transaminitis [19]. These findings suggest that use of MTX could favour aggravation of pre-existing NAFLD and progression to NASH. However, this assumption has not been proved because there is a lack of information regarding the extent of hepatic fat deposition before the start of MTX use and its effect on the development of liver injury during treatment.\n\nTo address this issue, we used an ongoing real-life registry including RA patients with no increases in transaminase levels who had commenced MTX treatment at our institution since August 2007. The liver-to-spleen attenuation ratio (L/S ratio) on high-resolution CT scans at enrolment was used to evaluate fat deposition quantitatively before the start of MTX treatment. We determined the incidence rate, predictive factors and severity of liver injury developing during MTX treatment and explored the role of pre-existing hepatic fat deposition.\n\nMethods\nPatients\nThe MET-START registry (the METhotrexate-new STARTer registry) is an ongoing real-life cohort consisting of all patients with RA who have commenced low-dose MTX treatment since August 2007 at the outpatient clinic for rheumatic diseases of National Hospital Organization (NHO) Kumamoto Saishun Medical Center in Japan. The main objective of this registry is to study the long-term safety of MTX use and to identify predictive factors for adverse events that are associated with this drug. Registrants are required to be ≥18 years of age and MTX-naïve at enrolment. They are also required to fulfil the 1987 ACR criteria or the 2010 ACR/EULAR criteria for diagnosis of RA [20, 21]. In this cohort, MTX is prescribed at 4–14 mg weekly for RA patients (a median of 8 mg/week), and 5 mg/week of folic acid is prescribed concomitantly during MTX treatment [22]. For non-elderly patients with high disease activity who are at low risk for adverse events, MTX can be started at an initial dose of 10 mg/week or more. Data from each patient at baseline and during follow-up have been deposited regularly in the Data Management Center for the MET-START registry at NHO Kumamoto Saishun Medical Center.\n\nAll participants in the present study came from the MET-START registry. We followed patients who had been enrolled in this registry during the period between 1 August 2007 and 30 April 2018. The exclusion criteria for this study were the presence of chronic liver disease, including viral hepatitis (hepatitis B and hepatitis C), autoimmune liver disease (autoimmune hepatitis and primary biliary cholangitis), hereditary liver disease and significant ethanol intake (>30 g/day for males and >20 g/day for females) at the time of starting MTX treatment. In addition, eligible patients were required to have normal serum ALT and AST levels at MTX initiation.\n\nStudy design\nTo identify patients who had developed persistent transaminitis, we monitored participant serum ALT and AST levels at each visit (i.e. every 4–8 weeks) during MTX treatment. Persistent transaminitis was defined as elevations in ALT and/or AST levels above the upper limit of normal in five of nine determinations within a given 12 month interval (6 of 12 determinations if tests are performed monthly) [23]. The upper limit of normal value for ALT and AST that was used in this study was 30 IU/l. Follow-up started on the first day of MTX treatment and ended with the development of persistent transaminitis, MTX discontinuation, loss to follow-up, death or the last follow-up visit before 30 April 2019, whichever was first. MTX discontinuation was defined as no use of this drug for >3 months. The reasons for MTX discontinuation included adverse events, inefficacy and other reasons (e.g. hospital transfer, surgery). Patients who missed at least two scheduled visits without any contact were classified as lost to follow-up.\n\nPatient characteristics at the start of MTX use\nFor each patient, demographic characteristics and RA-related factors, such as RA duration, Steinbrocker’s radiological stage, serum CRP levels, ESR values, positivity of anti-CCP antibodies and RF, together with the presence of NAFLD risk factors and co-morbidities, including hypertension, type 2 diabetes, chronic kidney disease (CKD), smoking history and BMI, were examined at enrolment in the MET-START registry. The definitions of hypertension, type 2 diabetes and CKD were given elsewhere [24]. Concurrent use of prednisolone, NSAIDs and other DMARDs was recorded at the same time. In addition, the use of hepatotoxic drugs apart from RA medications was examined.\n\nIn the NHO Kumamoto Saishun Medical Center, a high-resolution CT examination extending from the lung apices to the diaphragm is performed on RA patients who are scheduled to receive MTX, because it is essential to evaluate pulmonary conditions carefully. This policy makes it possible to evaluate quantitatively the fat infiltration in the liver of unselected RA patients before starting MTX treatment. The L/S ratio on high-resolution CT imaging was calculated on a SYNAPSE EX workstation (Fujifilm, Tokyo, Japan). Hepatic and splenic attenuation values were measured on unenhanced high-resolution CT scans using four circular region-of-interest cursors in the liver (two in the right lobe and two in the left lobe) and three in the spleen. Average attenuation values of the liver and spleen were calculated and used to determine the L/S ratio. Based on L/S ratio data from previous studies with Japanese individuals, we interpreted an L/S ratio of ≥1.3 to indicate no steatosis. To differentiate between mild (<30%) and moderate to severe (≥30%) steatosis, we set a cut-off level for the L/S ratio of 1.1, as follows: L/S ratio of ≥1.1 and <1.3 was defined as mild steatosis and L/S ratio of <1.1 as moderate to severe steatosis [25, 26].\n\nAssessment of patients who developed persistent transaminitis after the start of MTX use\nFor radiological evaluation of the liver in patients who developed persistent transaminitis during MTX treatment, we performed abdominal US and high-resolution CT without reference to any of the patients’ clinical data. A radiological diagnosis of fatty liver was made based on the following four abnormal findings on US scan: bright liver, hepatorenal echo contrast, vascular blurring and deep attenuation [27]. Hepatic fibrosis was identified based on the following morphological abnormalities: irregular or nodular liver surface, coarse or non-homogeneous liver parenchymal echotexture and blunted or rounded liver edge [28]. We also measured autoantibodies [ANA and anti-mitochondrial M2 antibody (AMA-M2)] and serological markers for hepatitis B and C.\n\nFor assessment of the type and severity of liver injury, US-guided liver biopsy was performed for patients who developed persistent transaminitis. Patients who had contraindications to liver biopsy and those who refused to undergo this procedure were excluded. Histological assessment of the type and severity of fatty liver were performed in accordance with the following two pathological criteria: the NASH Clinical Research Network pathological criteria (NAS; NAFLD activity score) [29] and the Younossi criteria (revised version of the Matteoni criteria) [30, 31]. Histological parameters were evaluated for each liver biopsy specimen independently by two board-certified experts in liver pathology (N.A. and M.I.). Both observers were blinded to the patients’ clinical status, and the final diagnosis was determined by consensus. NASH was diagnosed based on the following criteria: (a) any degree of steatosis along with centrilobular ballooning of hepatocytes and/or Mallory–Denk bodies; or (b) any degree of steatosis along with centrilobular pericellular/perisinusoidal fibrosis or bridging fibrosis, if patients had no identifiable secondary causes of hepatic fat accumulation [31]. Steatosis alone or steatosis with lobular inflammation was considered to be non-NASH NAFLD (non-alcoholic fatty liver: NAFL) [30]. Staging of fibrosis was based on the NAS system. Advanced fibrosis was defined as NAS staging 3 and 4.\n\nThis study was conducted in accordance with the principles of the Declaration of Helsinki (2008). The protocol of this study also meets the requirements of the Ethical Guidelines for Medical and Health Research Involving Human Subjects, Japan (2014) and has been approved by the Human Research Ethics Committee of NHO Kumamoto Saishun Medical Center (no. 28-06). Informed written consent was obtained from all participants.\n\nStatistical analysis\nCrude incidence rates of persistent transaminitis and the 95% CI were calculated by dividing the number of incidence cases by the number of corresponding follow-up person-years overall and for each patient group.\n\nThe probability of persistent transaminitis over time was computed using the cumulative incidence function (CIF), because we considered the presence of competing risks. Gray’s test was used to compare the estimates between each patient group.\n\nFine–Gray competing risks regression analysis was used to evaluate the effect of each patient characteristic on the development of persistent transaminitis during MTX treatment and to calculate adjusted hazard ratios (HRs), treating MTX discontinuation, death and loss to follow-up as competing events. As predictor variables, we used baseline patient characteristics that were considered to be clinically relevant variables. We first performed univariate Fine–Gray regression analysis for each of the predictor variables. Thereafter, all variables with P-values <0.20 in univariate models were introduced into a multivariate Fine–Gray regression analysis. The proportional hazards assumption was checked using log-minus-log plots of log cumulative hazard curve function and scaled Schoenfeld residual plots for exposure variables over time. By calculating the variance inflation factor, we confirmed that there was no multicollinearity among predictor variables.\n\nFor all tests, the probability values (P-values) <0.05 were considered to indicate statistical significance. All calculations were performed using PASW Statistics v.22 (SPSS Japan Inc., Tokyo, Japan) and Easy R (Saitama Medical Center, Jichi Medical University, Saitama Japan) [32].\n\nResults\nBaseline patient characteristics\nThere were 289 patients who commenced MTX treatment (a median of 8 mg/week) for RA and were enrolled into this study. Baseline characteristics are shown in Table 1. Most cases were early RA (disease duration <2 years, 79.9%). NSAIDs and prednisolone were prescribed in 32.3 and 28.0% of patients, respectively. Sixty-four patients (22.1%) were obese (BMI ≥25 kg/m2), and 6.2% had type 2 diabetes. Approximately half of the patients had fat deposition, as evidenced by the L/S ratio on high-resolution CT scans (42.6% with mild fat deposition and 5.9% with moderate to severe fat deposition). No patients used acetaminophen or other hepatotoxic drugs except RA medications.\n\n\nTable 1 Patient characteristics at the time of first starting MTX use for RA (n = 289)\n\n Characteristic\tEntire cohort\t\nAge, years, mean (95% CI)\t60.4 (59.0, 61.7)\t\nMale/female, n\t70/219\t\nMTX weekly dose, mg, median (95% CI)\t8.4 (8.2, 8.6)\t\nRA duration, months, mean (95% CI)\t23.2 (15.7, 30.7)\t\n <2 years (early RA), n (%)\t231 (79.9)\t\nAnti-CCP positive, n (%)\t263 (91.0)\t\nRF positive, n (%)\t238 (82.4)\t\nSteinbrocker’s stages III/IV, n (%)\t52 (18.0)\t\nCRP, mg/dl, mean (95% CI)\t1.71 (1.42, 2.00)\t\n ≥1.5 mg/dla, n (%)\t95 (32.9)\t\nESR, mm/h, mean (95% CI)\t37.7 (34.6, 40.9)\t\n ≥28 mm/ha, n (%)\t169 (58.5)\t\nL/S ratio on high-resolution CT, mean (95% CI)\t1.29 (1.27, 1.30)\t\n ≥1.3 (no fat deposition), n (%)\t149 (51.6)\t\n ≥1.1 and <1.3 (mild fat liver), n (%)\t123 (42.6)\t\n <1.1 (moderate to severe fat liver), n (%)\t17 (5.9)\t\nBMI, kg/m2, mean (95% CI)\t22.6 (22.2, 23.1)\t\n ≥25 (obesity), n (%)\t64 (22.1)\t\nHypertension, n (%)\t88 (30.4)\t\nType 2 diabetes, n (%)\t18 (6.2)\t\nChronic kidney disease, n (%)\t41 (14.2)\t\nCurrent/ex-smokersb, n (%)\t96 (33.2)\t\nConcurrent use of other RA medications\t\t\n NSAIDs, n (%)\t93 (32.2)\t\n Prednisolone, n (%)\t81 (28.0)\t\n bDMARDs, n (%)\t12 (4.2)\t\n csDMARDc, n (%)\t5 (1.7)\t\n tsDMARDc, n (%)\t0\t\nData were obtained at the time of enrolment in the MET-START registry.\n\na Cut-off values were set based on the inclusion criteria often used for clinical trials of new DMARDs.\n\nb Defined as current or former smokers with a smoking history ≥10 pack-years.\n\nc Tacrolimus was used as a csDMARD, and no tsDMARD was used concurrently with MTX. bDMARDs: biological DMARDs; csDMARD: conventional systemic DMARD; L/S ratio: liver-to-spleen attenuation ratio; tsDMARD: targeted synthetic DMARD.\n\nIncidence of persistent transaminitis during MTX treatment\nSerum ALT and AST levels were monitored over follow-up periods, with a mean follow-up time of 58.3 months (95% CI: 54.2, 62.5). Persistent transaminitis was found in 44 patients (15.2%) over 1405 person-years at risk. The crude incidence rate was 3.13 per 100 person-years (95% CI: 2.33, 4.21). During follow-up, 70 patients discontinued MTX because of adverse events (7 patients), inefficacy (36 patients) and hospital transfer (27 patients). Adverse events included aggravation of interstitial pneumonia (three patients), cholangiocarcinoma (one patient), oesophageal carcinoma (one patient), Pneumocystis jirovecii pneumonia (one patient) and myocardial infarction (one patient). Among the adverse event cases, three patients with cholangiocarcinoma, Pneumocystis jirovecii pneumonia or myocardial infarction eventually died. No other patients died. Fifteen patients (5.0%) were categorized as lost to follow-up. According to CIF analysis based on a competing risks model, the cumulative incidence (95% CI) of persistent transaminitis at 2, 5 and 7 years was 0.10 (0.07, 0.14), 0.13 (0.09, 0.17) and 0.16 (0.11, 0.21), respectively (Fig. 1).\n\n\nFig. 1 Cumulative incidence of persistent transaminitis during MTX treatment for RA\n\nUsing the CIF, the cumulative incidence of persistent transaminitis occurring in RA patients who initially started MTX treatment is shown. Numbers below these figures represent the number of patients remaining on MTX treatment. CIF: cumulative incidence function; IR: incidence rate; PYs: person-years\n\nPredictive factors for the development of persistent transaminitis during MTX treatment\nResults of univariate and multivariate Fine–Gray competing risks regression analyses are shown in Table 2. Based on the results of univariate analyses, all variables with P-values <0.20 were included in multivariate analysis. Through multivariate modelling, moderate to severe fat deposition (L/S ratio <1.1), obesity, type 2 diabetes and prednisolone use at baseline were identified as significant predictive factors for persistent transaminitis. There was no multicollinearity among these variables. Among them, a baseline L/S ratio <1.1 and obesity were particularly important predictive factors for persistent transaminitis; the adjusted HR (95% CI) was 7.69 (3.10, 19.10) for L/S ratio <1.1 vs L/S ratio ≥1.3 (P < 0.001) and 2.68 (1.37, 5.25) for obesity vs non-obesity (P = 0.004). Other RA-related factors or co-morbid conditions did not remain in the final multivariate regression model.\n\n\nTable 2 Predictive factors for developing persistent transaminitis during MTX treatment for RA\n\n Variables at baseline\tUnadjusted HR (95% CI)\t\nP-value\tAdjusted HR (95% CI)\t\nP-value\t\nAge per 1 year more\t1.00 (0.98, 1.02)\t0.98\t–\t–\t\nMale vs female\t0.68 (0.32, 1.44)\t0.31\t–\t–\t\nWeekly dose of MTX per 1.0 mg more\t1.11 (0.96, 1.29)\t0.16\t–\t–\t\nRA duration per 1 month more\t1.00 (1.00, 1.00)\t0.38\t–\t–\t\nAnti-CCP positive\t2.04 (0.50, 8.39)\t0.32\t–\t–\t\nRF positive\t0.80 (0.38, 1.67)\t0.55\t–\t–\t\nSteinbrocker’s stages III/IV vs I/II\t1.39 (0.72, 2.68)\t0.33\t–\t–\t\nCRP ≥1.5 mg/dl\t1.33 (0.73, 2.42)\t0.36\t–\t–\t\nESR ≥28 mm/h\t1.96 (1.00, 3.89)\t0.051\t–\t–\t\nL/S ratio on high-resolution CT\t\t\t\t\t\n ≥1.3 (no fat deposition)\tReference\t–\tReference\t–\t\n ≥1.1 and <1.3 (mild fat deposition)\t1.88 (0.95, 3.74)\t0.072\t1.85 (0.94, 3.67)\t0.070\t\n <1.1 (moderate to severe fat deposition)\t10.76 (4.75, 24.37)\t<0.001\t7.69 (3.10, 19.10)\t<0.001\t\nObesity (BMI ≥25 kg/m2)\t3.50 (1.94, 6.33)\t<0.001\t2.68 (1.37, 5.25)\t0.004\t\nHypertension\t1.49 (0.83, 2.67)\t0.18\t–\t–\t\nType 2 diabetes\t2.25 (0.87, 5.81)\t0.10\t2.76 (1.02, 7.48)\t0.046\t\nChronic kidney disease\t0.55 (0.20, 1.51)\t0.24\t–\t–\t\nCurrent/ex-smokers\t0.65 (0.33, 1.28)\t0.21\t–\t–\t\nNSAID use\t1.51 (0.84, 2.72)\t0.17\t–\t–\t\nPrednisolone use\t2.01 (1.11, 3.64)\t0.020\t1.96 (1.09, 3.51)\t0.030\t\nbDMARD use\t0.38 (0.05, 2.86)\t0.34\t–\t–\t\nUnivariate and multivariate Fine–Gray competing risks regression analyses were conducted to evaluate baseline patient-specific factors that predict the development of persistent transaminitis during MTX treatment. All variables with P-values <0.20 in the univariate Fine–Gray models were introduced into multivariate analysis. Variables that remained in the final multivariate model are shown as significant predictive factors for persistent transaminitis.\n\nbDMARDs: biological DMARDs; HR: hazard ratio; L/S ratio: liver-to-spleen attenuation ratio.\n\nUsing CIF analysis with Gray’s test, the cumulative incidence of persistent transaminitis during MTX treatment was compared between patients with and without the presence of hepatic fat deposition at baseline (L/S ratio <1.3 vs L/S ratio ≥1.3; Fig. 2A) and between those with and without obesity (BMI ≥25 vs BMI <25 kg/m2; Fig. 2B). The cumulative incidence of persistent transaminitis in patients with fat deposition at baseline was significantly higher over time compared with those without this condition (P = 0.003). Likewise, obese patients had a higher cumulative incidence than non-obese patients (P < 0.001).\n\n\nFig. 2 Cumulative incidence of persistent transaminitis grouped by predictive factors\n\nUsing the CIF, the cumulative incidence of persistent transaminitis occurring in RA patients who initially started MTX treatment are shown grouped according to predictive factors for persistent transaminitis. Predictive factors included (A) the pre-existence of fat deposition (L/S ratio <1.3) and (B) obesity (BMI ≥25 kg/m2). Numbers below these figures represent the number of patients remaining on MTX treatment. Provability of survival without persistent transaminitis between the groups with and without predictive factors was compared using Gray’s test. CIF: cumulative incidence function; L/S ratio: liver-to-spleen attenuation ratio.\n\nThe crude incidence rate in patients with and without hepatic fat deposition at baseline was 4.50 per 100 person-years (95% CI: 3.20, 6.41) and 1.81 per 100 person-years (95% CI: 1.10, 3.10), respectively. The crude incidence rate was 8.20 per 100 person-years (95% CI: 5.20, 12.91) in obese patients and 2.10 per 100 person-years (1.40, 3.21) in non-obese patients.\n\nAssessment of patients who developed persistent transaminitis during MTX treatment\nAs shown in Table 3, the median time of MTX use to the diagnosis of persistent transaminitis was 29.0 months (a median cumulative MTX dose of 1113 mg). According to the L/S ratio, moderate to severe fat deposition had already existed in 22.7% of patients at the start of MTX treatment. At the development of persistent transaminitis, the rate of patients with moderate to severe fat deposition was 45.5%. According to US examinations, 31 out of 44 patients (70.5%) showed fatty liver (43.2% with fatty liver alone and 27.3% with fatty liver plus fibrosis). These patients had no secondary causes of steatosis, including alcoholic fatty liver, chronic viral hepatitis, autoimmune liver disease or hereditary liver disease. Seven patients were diagnosed with hepatic fibrosis and six patients had no abdominal US findings. One patient without abnormal US findings was ultimately diagnosed with primary biliary cholangitis.\n\n\nTable 3 Assessment of patients who developed persistent transaminitis during MTX treatment for RA (n = 44)\n\n Characteristic\tAt baseline\tAt development\t\nAge, years, mean (95% CI)\t60.5 (57.8, 61.7)\t63.0 (60.2, 65.8)\t\nMale/female, n\t8/36\t‒\t\nMTX use\t\t\t\n Weekly dose, mg, median (95% CI)\t8.7 (8.1, 9.2)\t8.7 (8.1, 9.3)\t\n Duration, months, median (95% CI)\t0\t29.0 (20.5, 37.6)\t\n Cumulative dose, mg, median (95% CI)\t0\t1113 (750, 1476)\t\nUS findings\t\t\t\n Fatty liver\t‒\t19 (43.2)\t\n Fatty liver + hepatic fibrosis\t–\t12 (27.3)\t\n Hepatic fibrosis\t‒\t7 (15.9)\t\n No abnormal findings\t‒\t6 (13.6)\t\nL/S ratio on high-resolution CT, mean (95% CI)\t1.20 (1.14, 1.25)\t1.14 (1.09, 1.20)\t\n ≥1.3 (no fat deposition), n (%)\t13 (29.5)\t9 (20.5)\t\n ≥1.1 and <1.3 (mild fat deposition), n (%)\t21 (47.7)\t15 (34.1)\t\n <1.1 (moderate to severe fat deposition), n (%)\t10 (22.7)\t20 (45.5)\t\nBMI, kg/m2, mean (95% CI)\t24.8 (23.5, 26.1)\t24.7 (23.4, 26.1)\t\n ≥25 (obesity), n (%)\t19 (43.2)\t18 (40.9)\t\nHypertension, n (%)\t18 (40.9)\t20 (45.5)\t\nType 2 diabetes, n (%)\t5 (11.4)\t7 (15.9)\t\nChronic kidney disease, n (%)\t4 (9.1)\t5 (11.4)\t\nConcurrent use of other RA medications\t\t\t\n NSAIDs, n (%)\t19 (43.2)\t10 (22.7)\t\n Prednisolone, n (%)\t19 (43.2)\t5 (11.4)\t\nAutoantibodies\t\t\t\n ANA titres ≥1:160, n (%)\t–\t2 (4.5)\t\n AMA-M2 positive, n (%)\t–\t1 (2.3)\t\nData were obtained when MTX use began (at baseline) and when persistent transaminitis developed (at development).\n\nAMA-M2: anti-mitochondrial M2 antibody; L/S ratio: liver-to-spleen attenuation ratio.\n\nLiver biopsy\nOut of 44 patients who presented with persistent transaminitis, 24 underwent liver biopsy (Table 4). Among them, 19 (79.2%) and three (12.5%) were classified as having NASH and NAFL, respectively. They included 19 cases of US-diagnosed fatty liver (7 with fatty liver alone and 12 with fatty liver plus hepatic fibrosis), one case of hepatic fibrosis and two cases without abnormal US findings. Interface hepatitis was observed in the two other patients, who were also diagnosed radiologically with hepatic fibrosis. The remaining 20 patients did not receive liver biopsy (8 owing to advanced age, one with a diagnosis of primary biliary cholangitis and 11 who refused to undergo the procedure). This group consisted of 12 patients with US-diagnosed fatty liver alone, 4 with hepatic fibrosis and 4 without abnormal US findings. There were no significant differences in ALT or AST levels between patients receiving biopsy and those who did not [mean ALT: 20.1 (95% CI: 16.0, 24.2) vs 23.5 IU/l (95% CI: 18.9, 28); mean AST: 20.2 (95% CI: 18.2, 22.3) vs 21.8 IU/l (18.8, 24.8)].\n\n\nTable 4 Type and severity of fatty liver: data from liver biopsy (n = 24)\n\n Fatty liver\tAt development\t\nHistological classification, n (%)\t\t\n NASH\t19 (79.2)\t\n NAFL\t3 (12.5)\t\n Interface hepatitis\t2 (8.3)\t\nNAS fibrosis staging, n (%)\t\t\n Stage 0 (no fibrosis)\t3 (12.5)\t\n Stage 1 (perisinusoidal or periportal fibrosis)\t11 (45.8)\t\n 1A (mild, zone 3, perisinusoidal fibrosis)\t8 (33.3)\t\n 1B (moderate, zone 3, perisinusoidal fibrosis)\t1 (4.2)\t\n 1C (portal/periportal fibrosis)\t2 (8.3)\t\n Stage 2 (perisinusoidal plus periportal fibrosis)\t5 (20.8)\t\n Stage 3 (bridging fibrosis)\t5 (20.8)\t\n Stage 4 (cirrhosis)\t0\t\nData were obtained when persistent transaminitis developed (at development).\n\nNAFL: non-alcoholic fatty liver; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; NAS: NAFLD activity score.\n\nHepatic fibrosis was observed in 21 patients (87.5%), comprising 19 cases of NASH and 2 cases of interface hepatitis. Among them, only five patients (four cases of NASH and one case of interface hepatitis) had bridging fibrosis. No cirrhosis was observed.\n\nDiscussion\nIn this register-based RA cohort study, persistent transaminitis occurred at a crude incidence rate of 3.13 per 100 person-years in new MTX users who did not have increased pretreatment transaminase levels. The cumulative incidence at 5 years was estimated to be 13%. The most important predictive factors were the pre-existence of moderate to severe fat deposition and obesity at baseline. Approximately 70% of patients who had developed persistent transaminitis had fatty liver without competing aetiologies for chronic liver disease. NASH was the most predominant histological pattern in liver biopsy samples. Hepatic fibrosis was found in nearly 90% of biopsy samples, but most cases were not advanced.\n\nAlthough the association between NAFLD risk factors and liver injury during MTX treatment for inflammatory rheumatic diseases has been reported [12–19], information about the extent of pretreatment fat deposition in the liver and its effect on the development of liver injury is lacking. In the present study, 5.9% of MTX-naïve RA patients without pretreatment elevations of transaminases had moderate to severe fat deposition. Given that all participants in this study had no competing aetiologies for hepatic steatosis at enrolment, these patients were considered to have NAFLD before starting MTX treatment. We showed that the pre-existence of moderate to severe fat deposition was a significant predictive factor for the development of liver injury during MTX treatment for RA. In liver biopsies for patients who had developed persistent transaminitis, the NASH pattern was the most prevalent histological pattern, and all patients with the NASH pattern had hepatic fibrosis. These findings support the notion that the aggravation of pre-existing NAFLD lesions is an important mechanism of liver injury that occurs after MTX treatment for RA. Continuous use of MTX can favour the worsening of underlying NAFLD to NASH with fibrosis.\n\nIn the present study, hepatic fibrosis was commonly observed in biopsy samples, but advanced fibrosis (NAS fibrosis scores ≥3) was found in only one-fifth of the specimens. No patients showed cirrhosis in liver biopsies. This might be explained by the fact that liver biopsy was performed at the time of first development of persistent transaminitis (a mean cumulative MTX dose of 1.1 g). Aithal et al. [33] reported that the cumulative amount of MTX influences the severity of liver fibrosis in psoriasis patients. In that study, the frequency of advanced fibrosis (Ishak scores ≥4) in MTX-treated patients increased from 0% at a cumulative MTX dose of 1.5 g to 2.6% at 3 g, 2.6% at 4.5 g and 8.2% at 5 g. Conversely, Rosenberg et al. [15] showed that psoriasis patients with risk factors, especially obesity or type 2 diabetes, are at higher risk of developing advanced liver fibrosis (NAS scores ≥3) than those without any pre-existing risk factors, even when lower cumulative MTX doses are given. In that study, 38% of patients with risk factors had advanced fibrosis at a median cumulative dose of 1.6 g compared with 9% without any risk factors at a median dose of 1.9 g. A study of liver transplant recipients in the USA showed that end-stage MTX-related liver disease is very rare among these patients [34].\n\nThere are several limitations to this study. First, we could not perform liver biopsy for all patients who had developed persistent transaminitis during MTX treatment, because there is no strong recommendation for a liver biopsy for MTX-treated RA patients [35]. Non-invasive methods for the diagnosis of hepatic fibrosis and cirrhosis, such as transient elastography and shear wave elastography, might be considered in future studies that assess the severity of hepatic fibrosis in MTX-treated RA patients [36, 37]. Second, we did not include MTX-untreated patients as controls. A follow-up study including such controls would be helpful in exploring a causal relationship between MTX use and worsening of underlying NAFLD lesions. However, it is ethically unacceptable, because the current guidelines recommend that DMARD therapy be started as soon as the diagnosis of RA is made and that MTX is the first choice for RA treatment [3]. The present study was performed using an inception cohort of MTX, and all patients had no increases in hepatic enzymes at baseline. In addition to information on NAFLD risk factors, the quantitative data on pretreatment fat deposition in the liver were available in all patients. The present study, therefore, provides important information to answer the question of whether persistent transaminitis in MTX-treated patients might be related to a new occurrence of steatohepatitis or aggravation of pre-existing NAFLD lesions.\n\nIn conclusion, pre-existing moderate to severe fat deposition in the liver and obesity are the most potent predictive factors for persistent transaminitis during MTX treatment for RA. The aggravation of underlying fatty liver to NASH with fibrosis seems to be the important mechanism in the development of liver injury in MTX-treated patients. Considering that fat deposition was detected in half of MTX-naïve RA patients at enrolment in this registry, careful and regular monitoring of transaminases is required during MTX treatment. Quantitative evaluation of pretreatment fat deposition in the liver is useful to identify patients who are at high risk for developing a liver injury during MTX treatment.\n\nAcknowledgements\nS.M. and S.F. contributed to the study conception and design; data acquisition, analysis and interpretation; and drafting the manuscript. N.A. and M.I. participated in the histological data analysis and interpretation and drafting the manuscript. Y.U. contributed to the study conception and design as well as drafting the manuscript. Y.A. and K.Y. contributed to the statistical analysis and data interpretation as well as drafting the manuscript. All authors read and approved the final version of the manuscript.\n\n\nFunding: This study was supported by research funds from the National Hospital Organization, Japan. The funding body was not involved in any aspects of the study.\n\n\nDisclosure statement: S.M. has received research grants from Eisai Co., Ltd and Pfizer Japan Inc. Y.U. has received lecture fees from Pfizer Japan Inc. The other authors have declared no conflicts of interest.\n==== Refs\nReferences\n1 \nSingh JA Saag KG Bridges SLJ et al 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis\n. Arthritis Rheumatol 2016 ;68 :1 –26\n.\n2 \nAmerican Academy of Dermatology Work Group ; Menter A Korman NJ et al Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions\n. J Am Acad Dermatol 2011 ;65 :137 –74\n.21306785 \n3 \nSmolen JS , Landewe RBW , Bijlsma JWJ et al\nEULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update\n. Ann Rheum Dis 2020 ;79 :685 –99\n.31969328 \n4 \nCurtis JR Beukelman T Onofrei A et al Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide\n. Ann Rheum Dis 2010 ;69 :43 –7\n.19147616 \n5 \nSalliot C van der Heijde D. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research\n. Ann Rheum Dis 2009 ;68 :1100 –4\n.19060002 \n6 \nFromenty B. Drug-induced liver injury in obesity\n. J Hepatol 2013 ;58 :824 –6\n.23298629 \n7 \nShetty A Cho W Alazawi W Syn WK. Methotrexate hepatotoxicity and the impact of nonalcoholic fatty liver disease\n. Am J Med Sci 2017 ;354 :172 –81\n.28864376 \n8 \nWatanabe S Hashimoto E Ikejima K et al Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis\n. J Gastroenterol 2015 ;50 :364 –77\n.25708290 \n9 \nEuropean Association for the Study of Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO) . EASL–EASD–EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease\n. J Hepatol 2016 ;64 :1388 –402\n.27062661 \n10 \nWong VW-S Chan W-K Chitturi S et al Asia–Pacific Working Party on Non-alcoholic Fatty Liver Disease guidelines 2017—Part 1: definition, risk factors and assessment\n. J Gastroenterol Hepatol 2018 ;33 :70 –85\n.28670712 \n11 \nChalasani N Younossi Z Lavine JE et al The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases\n. Hepatology 2018 ;67 :328 –57\n.28714183 \n12 \nMalatjalian DA Ross JB Williams CN Colwell SJ Eastwood BJ. Methotrexate hepatotoxicity in psoriatics: report of 104 patients from Nova Scotia, with analysis of risks from obesity, diabetes and alcohol consumption during long term follow-up\n. Can J Gastroenterol 1996 ;10 :369 –75\n.9193771 \n13 \nLangman G Hall PM Todd G. Role of non-alcoholic steatohepatitis in methotrexate-induced liver injury\n. J Gastroenterol Hepatol 2001 ;16 :1395 –401\n.11851839 \n14 \nBerends MA Snoek J de Jong EM et al Liver injury in long-term methotrexate treatment in psoriasis is relatively infrequent\n. Aliment Pharmacol Ther 2006 ;24 :805 –11\n.16918884 \n15 \nRosenberg P Urwitz H Johannesson A et al Psoriasis patients with diabetes type 2 are at high risk of developing liver fibrosis during methotrexate treatment\n. J Hepatol 2007 ;46 :1111 –8\n.17399848 \n16 \nSuzuki Y Uehara R Tajima C et al Elevation of serum hepatic aminotransferases during treatment of rheumatoid arthritis with low-dose methotrexate. Risk factors and response to folic acid\n. Scand J Rheumatol 1999 ;28 :273 –81\n.10568423 \n17 \nKent PD Luthra HS Michet C Jr. Risk factors for methotrexate-induced abnormal laboratory monitoring results in patients with rheumatoid arthritis\n. J Rheumatol 2004 ;31 :1727 –31\n.15338491 \n18 \nSchmajuk G Miao Y Yazdany J et al Identification of risk factors for elevated transaminases in methotrexate users through an electronic health record\n. Arthritis Care Res (Hoboken) 2014 ;66 :1159 –66\n.24470205 \n19 \nMori S Arima N Ito M et al Non-alcoholic steatohepatitis-like pattern in liver biopsy of rheumatoid arthritis patients with persistent transaminitis during low-dose methotrexate treatment\n. PLoS One 2018 ;13 :e0203084 .30142184 \n20 \nArnett FC Edworthy SM Bloch DA et al The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis\n. Arthritis Rheum 1988 ;31 :315 –24\n.3358796 \n21 \nAletaha D Neogi T Silman AJ et al 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative\n. Ann Rheum Dis 2010 ;69 :1580 –8\n.20699241 \n22 \nKameda H Fujii T Nakajima A et al Japan College of Rheumatology guideline for the use of methotrexate in patients with rheumatoid arthritis\n. Mod Rheumatol 2019 ;29 :31 –40\n.29718746 \n23 \nKremer JM Alarcón GS Lightfoot RW Jr et al Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology\n. Arthritis Rheum 1994 ;37 :316 –28\n.8129787 \n24 \nMori S Yoshitama T Hirakata N Ueki Y. Prevalence of and factors associated with renal dysfunction in rheumatoid arthritis patients: a cross-sectional study in community hospitals\n. Clin Rheumatol 2017 ;36 :2673 –82\n.28884373 \n25 \nIwasaki M Takada Y Hayashi M et al Noninvasive evaluation of graft steatosis in living donor liver transplantation\n. Transplantation 2004 ;78 :1501 –5\n.15599315 \n26 \nKan H Kimura Y Hyogo H et al Non-invasive assessment of liver steatosis in non-alcoholic fatty liver disease\n. Hepatol Res 2014 ;44 :E420 –7\n.24636073 \n27 \nDasarathy S Dasarathy J Khiyami A Joseph R et al Validity of real time ultrasound in the diagnosis of hepatic steatosis: a prospective study\n. J Hepatol 2009 ;51 :1061 –7\n.19846234 \n28 \nGerstenmaier JF Gibson RN. Ultrasound in chronic liver disease\n. Insights Imaging 2014 ;5 :441 –55\n.24859758 \n29 \nKleiner DE Brunt EM Van Natta M et al Design and validation of a histological scoring system for nonalcoholic fatty liver disease\n. Hepatology 2005 ;41 :1313 –21\n.15915461 \n30 \nMatteoni CA Younossi ZM Gramlich T et al Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity\n. Gastroenterology 1999 ;116 :1413 –9\n.10348825 \n31 \nYounossi ZM Stepanova M Rafiq N et al Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality\n. Hepatology 2011 ;53 :1874 –82\n.21360720 \n32 \nKanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics\n. Bone Marrow Transplant 2013 ;48 :452 –8\n.23208313 \n33 \nAithal GP Haugk B Das S et al Monitoring methotrexate-induced hepatic fibrosis in patients with psoriasis: are serial liver biopsies justified?\n Aliment Pharmacol Ther 2004 ;19 :391 –9\n.14871278 \n34 \nDawwas MF Aithal GP. End-stage methotrexate-related liver disease is rare and associated with features of the metabolic syndrome\n. Aliment Pharmacol Ther 2014 ;40 :938 –48\n.25185870 \n35 \nVisser K Katchamart W Loza E et al Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative\n. Ann Rheum Dis 2009 ;68 :1086 –93\n.19033291 \n36 \nLaharie D Seneschal J Schaeverbeke T et al Assessment of liver fibrosis with transient elastography and FibroTest in patients treated with methotrexate for chronic inflammatory diseases: a case–control study\n. J Hepatol 2010 ;53 :1035 –40\n.20801541 \n37 \nKim TY Kim JY Sohn JH et al Assessment of substantial liver fibrosis by real-time shear wave elastography in methotrexate-treated patients with rheumatoid arthritis\n. J Ultrasound Med 2015 ;34 : 1621 –30\n.26269292\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2514-1775",
"issue": "4(2)",
"journal": "Rheumatology advances in practice",
"keywords": "liver injury; methotrexate; non-alcoholic steatohepatitis; pretreatment fat deposition; rheumatoid arthritis",
"medline_ta": "Rheumatol Adv Pract",
"mesh_terms": null,
"nlm_unique_id": "101736676",
"other_id": null,
"pages": "rkaa020",
"pmc": null,
"pmid": "33134809",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "28670712;28884373;28864376;19033291;24636073;19846234;24470205;3358796;11851839;21306785;25832328;8129787;29718746;19060002;10568423;9193771;26269292;23298629;15915461;14871278;27062661;16918884;20801541;28714183;15599315;10348825;19147616;23208313;24859758;26545940;15338491;21360720;17399848;31969328;20699241;25185870;30142184",
"title": "Incidence, predictive factors and severity of methotrexate-related liver injury in rheumatoid arthritis: a longitudinal cohort study.",
"title_normalized": "incidence predictive factors and severity of methotrexate related liver injury in rheumatoid arthritis a longitudinal cohort study"
} | [
{
"companynumb": "JP-ACCORD-208378",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FOLIC ACID"
},
"drugadditional": null,
"dru... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.