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"abstract": "OBJECTIVE\nTo characterize adverse drug reactions (ADRs) reported by European (EU) consumer for antineoplastic and immunomodulating medications.\n\n\nMETHODS\nADRs reported by consumers of antineoplastic and immunomodulating medications (anatomical therapeutic chemical [ATC]) group L from 2007 to 2011 and located in the EU ADR database, EudraVigilance, were analyzed. Data were categorized with respect to age and sex, category, and seriousness of reported ADRs and medications. The unit of analysis was one ADR.\n\n\nRESULTS\nWe located 9649 ADRs reported for antineoplastic and immunomodulating medications, which approximately 15% of were serious, including 26 deaths. Less than 5% of ADRs were reported in children. Totally 73% of ADRs were reported for women and 27% for men. The majority of ADRs were of the type \"general disorders and administration site conditions\" (54% of total ADRs), followed by \"skin and subcutaneous disorders\" (7% of total ADRs), and \"infections and infestations\" (6% of total ADRs). Reports encompassed medicines from the therapeutic groups: Imunosupressants (ATC group L04) (90% of all ADRs), immunostimulants (ATC group L03) (6% of all ADRS), and antineoplastic agents (ATC group L01) (4% of all ADRs). Many ADRs were reported for etanercept (Enbrel(®)), Interferon beta (Betaferon(®)/Extavia(®)), and imatinib (Glivec(®)) with only few being serious.\n\n\nCONCLUSIONS\nIn general, consumers reported a high number of ADRs from the use of antineoplastic and immunostimulant medications and many of these were classified as non-serious. This indicates that consumers are interesting in reporting ADRs, but since the investigated substances potentially have the risk of causing many ADRs, we expected a higher number of serious ADRs.",
"affiliations": "Research Unit of Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, Odense, Denmark.;Department of Pharmacy, Section for Social and Clinical Pharmacy, University of Copenhagen, Denmark.",
"authors": "Aagaard|Lise|L|;Hansen|Ebba Holme|EH|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/2279-042X.114091",
"fulltext": "\n==== Front\nJ Res Pharm PractJ Res Pharm PractJRPPJournal of Research in Pharmacy Practice2319-96442279-042XMedknow Publications & Media Pvt Ltd India JRPP-2-4410.4103/2279-042X.114091Brief CommunicationSide effects of antineoplastic and immunomodulating medications reported by European consumers Aagaard Lise 1Hansen Ebba Holme 21 Research Unit of Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, Odense, Denmark2 Department of Pharmacy, Section for Social and Clinical Pharmacy, University of Copenhagen, DenmarkCorresponding author: Prof. Lise Aagaard, E-mail:laagaard@health.sdu.dkJan-Mar 2013 2 1 44 49 10 2012 1 2013 Copyright: © Journal of Research in Pharmacy Practice2013This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Objective:\nTo characterize adverse drug reactions (ADRs) reported by European (EU) consumer for antineoplastic and immunomodulating medications.\n\nMethods:\nADRs reported by consumers of antineoplastic and immunomodulating medications (anatomical therapeutic chemical [ATC]) group L from 2007 to 2011 and located in the EU ADR database, EudraVigilance, were analyzed. Data were categorized with respect to age and sex, category, and seriousness of reported ADRs and medications. The unit of analysis was one ADR.\n\nFindings:\nWe located 9649 ADRs reported for antineoplastic and immunomodulating medications, which approximately 15% of were serious, including 26 deaths. Less than 5% of ADRs were reported in children. Totally 73% of ADRs were reported for women and 27% for men. The majority of ADRs were of the type “general disorders and administration site conditions” (54% of total ADRs), followed by “skin and subcutaneous disorders” (7% of total ADRs), and “infections and infestations” (6% of total ADRs). Reports encompassed medicines from the therapeutic groups: Imunosupressants (ATC group L04) (90% of all ADRs), immunostimulants (ATC group L03) (6% of all ADRS), and antineoplastic agents (ATC group L01) (4% of all ADRs). Many ADRs were reported for etanercept (Enbrel®), Interferon beta (Betaferon®/Extavia®), and imatinib (Glivec®) with only few being serious.\n\nConclusion:\nIn general, consumers reported a high number of ADRs from the use of antineoplastic and immunostimulant medications and many of these were classified as non-serious. This indicates that consumers are interesting in reporting ADRs, but since the investigated substances potentially have the risk of causing many ADRs, we expected a higher number of serious ADRs.\n\nAdverse drug reactionsantineoplastic agentsconsumerseudravigilanceimmunomodulating agentspharmacovigilance\n==== Body\nINTRODUCTION\nAntineoplastic and immunomodulating medications are licensed for treatment of various types of cancer and immune diseases, and these medications have the potential to lead to serious adverse drug reactions (ADRs).[1] Many of the medicines, i.e., cancer medications, are tested under favorable conditions, meaning that the medications are tested in a few clinical trials of short duration, including fewer patients than clinical testing of conventional drugs.[2] Due to the favorable licensing conditions, knowledge about ADRs is limited at the time of marketing, and information of long-time safety issues is unknown.[2] Spontaneous reports are an important source of information about new and previously unrecognized ADRs occurring after the time of marketing.[3] Consumers can provide first-hand information about patients’ experiences with medicines and possible ADRs.[4] Studies of consumer ADR reports submitted to national pharmacovigilance databases in Denmark, the Netherlands, Sweden, and the United Kingdom, showed that patients are more likely to report ADRs from the nervous and psychiatric systems than health-care professionals. Studies also showed, that consumers submit information about ADRs not reported by physicians and that consumer reporting may be considered a supplement to traditional ADR reporting by health-care professionals.[56789] The published consumer studies, all conducted on small national datasets showed that consumers are willing to report ADRs, but we do not know to which, extent similar findings are applicable for other countries. Until June 2012, consumer reporting was officially accepted in 5 European (EU) countries: Denmark, the Netherlands, Norway, Sweden, and the United Kingdom.[10] The new EU pharmacovigilance legislation, which came into force in June 2012 has made it possible for consumers in all EU countries to report ADRs directly to the health authorities.[11] EudraVigilance (EV) is the central database containing reports of suspected ADRs for medicinal products authorized in the European Economic Area (EEA).[12] EV was set up in December 2001 to facilitate the electronic reporting of ADRs in the EEA countries between the pharmaceutical companies, regulatory agencies, and the European Medicines Agency (EMA).[12] Since 2012, researchers have been allowed to access information about ADR data in the database and this has laid the foundation for cross-national analyses based on a standardized reporting format.[13]\n\nThe objective of this study was to investigate ADR reports on antineoplastic and immunomodulating medications submitted by consumers to the EV ADR database in Europe during the 1st 5 years of electronic reporting.\n\nMETHODS\nThe study comprised all ADR reports located in the EV database and reported by consumers for antineoplastic and immunomodulating medications (ATC group L) occurring from 2007 to 2011. The content of the reports was analyzed with respect to seriousness, categories of ADRs classified by system organ class (SOC) and medications. The unit of analysis was one ADR. Patient age was grouped into: Children (0-17-year-olds) and adults (18 + year-olds). ADR information was provided for this study in anonymous form with encrypted person identification and extracted from the EV database in large Microsoft Excel files using the following criteria: Patient's sex and age, medicines (active substance), and type and seriousness of reported ADRs. In compliance with EU regulation (EC) no. 1049/2001, EMA ensures that the protection of privacy and integrity of individuals is guaranteed, and therefore, individual country-specific ADR information could not be disclosed.[13] The reported ADRs were coded with respect to type and seriousness by academic staff in the national regulatory agencies using the Council for International Organizations of Medical Sciences criteria.[14] Serious ADRs are divided into the following categories: Fatal, life-threatening, requiring hospitalization or prolongation of existing hospitalization, resulting in persistent or significant disability/incapacity, in a congenital anomaly/birth defect, and other medically important conditions. Other ADRs were classified as non-serious.[14] The different types of reported ADRs were classified according to the Medical Dictionary for Regulatory Activities SOC.[15] Medicines were classified according to the anatomical therapeutic chemical (ATC) classification system[16] in which medicinal products are classified at five levels. The medicinal products reported are referenced based on their active substance, and in this article we present ADR data at ATC level 1 and 5.[16]\n\nRESULTS\nDuring the study period, a total of 7434 consumer ADR reports containing information about 35349 ADRs were located in EV. Of these, 9644 ADRs were submitted for antineoplastic and immunomodulating medications (ATC group L). In total, 14% of these ADRs were classified as serious and of these, 26 fatal cases were reported. The characteristics of the fatal cases are displayed in Table 1. The largest number of fatal cases (n = 16) was reported for etanercept (ATC group L04AB01) followed by six fatal cases reported for adalimumab (ATC group L04AB04). Totally, 73% of ADRs were reported for women and 27% for men. Less than 1% of ADRs were reported in children. The majority, 54% of ADRs were of the type “general disorders and administration site conditions,” followed by “skin and subcutaneous disorders” (7% of total ADRs), and “infections and infestations” (6% of total ADRs) [Table 2]. Table 3 displays the number of ADRs reported by consumers distributed on therapeutic groups and seriousness. ADR reports encompassed medicines from the therapeutic groups: Immunosupressant (ATC group L04) (90% of all ADRs), immunostimulants (ATC group L03) (6% of all ADRs), and antineoplastic agents (ATC group L01) (4% of all ADRs). Except for immunostimulants, the majority of ADRs were serious. In particular, a large number of ADRs were reported for etanercept (Enbrel®) (n = 8462), interferon beta (Betaferon®/Extavia®) (n = 550), and imatinib (Glivec®) (n = 129). However, for interferon beta, the majority of reported ADRs were non-serious. Table 4 displays characteristics of serious ADRs reported for etanercept (Enbrel®). In total, 889 serious ADRs were reported; the most frequently reported ADR being abasia (n = 46), abdominal abscess (n = 43), abdominal adhesions/rigidity (n = 34), abdominal pain/discomfort (n = 17), and abnormal sensation in eye (n = 15). For imatinib, the largest numbers of reported ADRs were infection (n = 7), gastric disorder (n = 5), muscle spasm (n = 4), nausea (n = 4), and weight changes (n = 4).\n\nTable 1 Fatal cases reported by consumers for antineoplastic and immunomodulating agents in Europe, 2007 to 2011\n\nTable 2 Adverse drug reactions reported by European consumers for antineoplastic and immunomodulating agents by system organ class, 2007 to 2011\n\nTable 3 Distribution of adverse drug reactions reported by consumers for antineoplastic and immunomodulating agents by medication and seriousness (number of serious cases in parentheses), 2007 to 2011\n\nTable 4 Characteristics of serious adverse drug reactions for etanercept reported by European consumers, 2007 to 2011\n\nDISCUSSION\nThis is the first study to systematically analyze ADRs for cancer medications reported by consumers to the EV database. The majority of ADRs were reported for immunosuppressants, particularly etanercept (Enbrel®), interferon-beta (Betaferon®/Extavia®) and imatinib (Glivec®). More than one half of reported ADRs were of the type “general disorders and administration site conditions.” Few of the ADRs was rated as serious by the regulatory agencies, however fatal cases were found.\n\nThe largest number of ADRs was reported for etanercept (Enbrel®), and large shares of these were “injection site reactions.” This is not surprising since the medication is administered to the patients as injections. This study showed that this type of ADR from a patient perspective is viewed as serious and harmful because this ADR is easily assessed, and obvious compared to many other types of ADRs that the patients cannot easily detect. Approximately, 15% of ADRs were serious, and this share was lower than in other studies on consumer reports;[56789] we have no explanation for this reporting pattern.\n\nThe strength of our study is that the data comprised ADRs reported by consumers in Europe, which were forwarded to the EV database during a 5-year period. According to the EU regulation, we were not allowed to receive information about, the country of reporting. Therefore, we were unable to conduct further comparisons of consumer ADR reporting patterns between the EU countries, as well as compare the number of reports submitted to the EV database with ADR information presently stored in national pharmacovigilance databases. A major limitation to this study is that we do not know to which extent the causality of the reported ADRs can be confirmed, and this has implications for the interpretation of the findings.[4] In this study, we did not evaluate the validity of the consumer reports since we had access to the data entered into the EV database and not to the original reports. Spontaneous reporting systems suffer from various barriers such as incomplete recognition of ADRs, administrative barriers to reporting and low data quality, as well as lack of information about diagnosis, all of which may result in under-reporting of important serious and rare events.[4] ADRs that are classified as non-serious or already known may be over-reported; however, this study provides information about possible ADRs from the use of antineoplastic and immunomodulating medicines, and this information contributes to broadening the knowledge on medicine safety.\n\nIn general, consumers reported a high number of ADRs from antineoplastic and immunomodulating medications, and many of these were classified as non-serious. This indicates that consumers are interesting when it comes to reporting of ADRs, but since the investigated medications potentially have the risk of causing many ADRs, we expected a higher number of serious ADRs.\n\nAUTHORS’ CONTRIBUTION\nL. Aagaard and E.H. Hansen designed the study, analysed data and wrote the first version of the manuscript. L. Aagaard carried out the sampling. Both authors read and approved the final version of the manuscript. No sources of funding were used to assist in the preparation of this study.\n\nACKNOWLEDGMENTS\nThe authors wish to thank the European Medicines Agency for providing access to data and MSc Jesper Frederiksen for assistance with data handling.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Aagaard L Strandell J Melskens L Petersen PS Holme Hansen E Global patterns of adverse drug reactions over a decade: Analyses of spontaneous reports to VigiBase™ Drug Saf 2012 35 1171 82 23072620 \n2 Hansen EH Technology assessment in a user perspective–Experiences with drug technology Int J Technol Assess Health Care 1992 8 150 65 1601585 \n3 Aagaard L Hansen EH Information about ADRs explored by pharmacovigilance approaches: A qualitative review of studies on antibiotics, SSRIs and NSAIDs BMC Clin Pharmacol 2009 9 4 19254390 \n4 Blenkinsopp A Wilkie P Wang M Routledge PA Patient reporting of suspected adverse drug reactions: A review of published literature and international experience Br J Clin Pharmacol 2007 63 148 56 17274788 \n5 Medawar C Herxheimer A A comparison of adverse drug reaction reports from professionals and users, relating to risk of dependency and suicidal behaviour with paroxetine Int J Risk Saf Med 2003 16 5 19 \n6 Aagaard L Nielsen LH Hansen EH Consumer reporting of adverse drug reactions: A retrospective analysis of the Danish adverse drug reaction database from 2004 to 2006 Drug Saf 2009 32 1067 74 19810778 \n7 de Langen J van Hunsel F Passier A de Jong-van den Berg L van Grootheest K Adverse drug reaction reporting by patients in the Netherlands: Three years of experience Drug Saf 2008 31 515 24 18484785 \n8 Aagaard L Hansen EH Consumers’ reports of suspected adverse drug reactions volunteered to a consumer magazine Br J Clin Pharmacol 2010 69 317 8 20233206 \n9 Vilhelmsson A Svensson T Meeuwisse A Carlsten A What can we learn from consumer reports on psychiatric adverse drug reactions with antidepressant medication? Experiences from reports to a consumer association BMC Clin Pharmacol 2011 11 16 22026961 \n10 Van Hunsel F Härmark L Pal S Olsson S van Grootheest K Experiences with adverse drug reaction reporting by patients: An 11-country survey Drug Saf 2012 35 45 60 22149419 \n11 European Commission. The EU Pharmacovigilance System Last accessed 2012 Dec 14 Available from: http://www.ec.europa.eu/health/human-use/pharmacovigilance/index_en.htm \n12 European Medicines Agency. Note for guidance–Eudravigilance human – Processing of safety messages and individual case safety reports (ICSRs) EMA/H/20665/04/Final Rev. 2 Last accessed 2012 Dec 14 Available from: http://www.ema.europa.eu/./en_GB/document_library/Regulatory_and_procedural_guideline/2009/11/WC500015697.pdf \n13 Office Journal of the European Commission. Regulation (EC) no 1049/2001 of the European parliament and of the council of 30 May 2001 regarding public access to European Parliament, council and commission. L 145/43 Last accessed 2012 Dec 14 Available from: http://www.europarl.europa.eu/register/./r1049_en.pdf \n14 Pharmacovigilance: Medicinal products for human use and veterinary products Last accessed 2012 Dec 14 9 Available from: http://www.ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev9.htm \n15 MedDRA Last accessed 2012 Dec 14 Available from: http://www.meddramsso.com \n16 WHO Collaboration Centre for Drug Statistics Methodology 2007 Last accessed 2012 Dec 14 Available from: http://www.whocc.no/atc_ddd_index\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2279-042X",
"issue": "2(1)",
"journal": "Journal of research in pharmacy practice",
"keywords": "Adverse drug reactions; antineoplastic agents; consumers; eudravigilance; immunomodulating agents; pharmacovigilance",
"medline_ta": "J Res Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "101614023",
"other_id": null,
"pages": "44-9",
"pmc": null,
"pmid": "24991604",
"pubdate": "2013-01",
"publication_types": "D016428:Journal Article",
"references": "19810778;17274788;18484785;22149419;1601585;19254390;20233206;23072620;22026961",
"title": "Side effects of antineoplastic and immunomodulating medications reported by European consumers.",
"title_normalized": "side effects of antineoplastic and immunomodulating medications reported by european consumers"
} | [
{
"companynumb": "DK-AMGEN INC.-DNKCT2014054243",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
"drugadditional": null,
... |
{
"abstract": "This article discusses the anesthetic management and implications of 2 pediatric patients with a diagnosis of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis. Anti-NMDA receptor encephalitis has been described as an immune-meditated syndrome that triggers the production of antibodies to the NMDA receptor: a site of action for many commonly used anesthetic agents. Symptoms of this disease can be autonomic, neurologic, and psychological in nature. This disease process can pose a challenge to the anesthesia provider during all stages of the anesthetic. Thus, the anesthesia provider must incorporate an understanding of the administered anesthetic agent's potential pharmacologic effect on the affected NMDA receptor when formulating the patient's anesthetic plan.",
"affiliations": null,
"authors": "Simon|Robert W|RW|",
"chemical_list": "D000777:Anesthetics",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0094-6354",
"issue": "82(6)",
"journal": "AANA journal",
"keywords": null,
"medline_ta": "AANA J",
"mesh_terms": "D000293:Adolescent; D000758:Anesthesia; D000777:Anesthetics; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis; D005260:Female; D006801:Humans; D009871:Operating Room Nursing; D011183:Postoperative Complications; D017410:Practice Guidelines as Topic",
"nlm_unique_id": "0431420",
"other_id": null,
"pages": "431-6",
"pmc": null,
"pmid": "25842641",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anesthetic management and implications of pediatric patients with a diagnosis of anti-N-methyl-D-aspartate receptor encephalitis: two case reports.",
"title_normalized": "anesthetic management and implications of pediatric patients with a diagnosis of anti n methyl d aspartate receptor encephalitis two case reports"
} | [
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"companynumb": "US-BAXTER-2014BAX077659",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ONDANSETRON"
},
"drugadditional": null,
... |
{
"abstract": "Safe use of immune checkpoint blockade in patients with cancer and autoimmune disorders requires a better understanding of the pathophysiology of immunologic activation. We describe the immune correlates of reactivation of granulomatosis with polyangiitis (GPA)-an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis-in a patient with metastatic urothelial carcinoma treated with pembrolizumab. After PD-1 blockade, an inflammatory pulmonary nodule demonstrated a granulomatous, CD4+ T-cell infiltrate, correlating with increased CD4+ and CD8+ naïve memory cells in the peripheral blood without changes in other immune checkpoint receptors. Placed within the context of the existing literature on GPA and disease control, our findings suggest a key role for PD-1 in GPA self-tolerance and that selective strategies for immunotherapy may be needed in patients with certain autoimmune disorders. We further summarize the current literature regarding reactivation of autoimmune disorders in patients undergoing immune checkpoint blockade, as well as potential immunosuppressive strategies to minimize the risks of further vasculitic reactivation upon rechallenge with anti-PD-1 blockade. KEY POINTS: Nonspecific imaging findings in patients with cancer and rheumatological disorders may require biopsy to distinguish underlying pathology.Patients with rheumatologic disorders have increased risk of reactivation with PD-(L)1 immune checkpoint blockade, requiring assessment of disease status before starting treatment.Further study is needed to evaluate the efficacy of treatment regimens in preventing and controlling disease reactivation.",
"affiliations": "Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.;Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.;Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Division of Rheumatology, Department of Internal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.;Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.;Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.;Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.;Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.;Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.;Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.;Division of Rheumatology, Department of Internal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.;Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.;Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA laurenc_harshman@dfci.harvard.edu.",
"authors": "Nabel|Christopher S|CS|0000-0001-6515-8579;Severgnini|Mariano|M|;Hung|Yin P|YP|0000-0002-8568-1591;Cunningham-Bussel|Amy|A|0000-0001-7676-9244;Gjini|Evisa|E|;Kleinsteuber|Katja|K|0000-0001-5647-887X;Seymour|Lake J|LJ|;Holland|Martha K|MK|;Cunningham|Rachel|R|;Felt|Kristin D|KD|;Vivero|Marina|M|;Rodig|Scott J|SJ|;Massarotti|Elena M|EM|;Rahma|Osama E|OE|;Harshman|Lauren C|LC|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2018-0633",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "24(8)",
"journal": "The oncologist",
"keywords": null,
"medline_ta": "Oncologist",
"mesh_terms": "D000315:Adrenalectomy; D061067:Antibodies, Monoclonal, Humanized; D002295:Carcinoma, Transitional Cell; D059186:Chemoradiotherapy, Adjuvant; D015653:Cystectomy; D003937:Diagnosis, Differential; D014890:Granulomatosis with Polyangiitis; D006801:Humans; D008297:Male; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a; D009364:Neoplasm Recurrence, Local; D000074682:Nephroureterectomy; D061026:Programmed Cell Death 1 Receptor; D011468:Prostatectomy; D000067251:Symptom Flare Up; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "1013-1021",
"pmc": null,
"pmid": "31088979",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12130505;20525992;20647199;22367266;22447882;22554789;25372085;25739829;25992290;26633184;26765102;26927206;26952546;27069016;27256711;27595932;27687304;27717298;28131785;28198830;28212060;28214654;28551826;28588576;28817753;28855077;29262275;29268948;29297009;29320654;29366662;29443960;29746230;9704735",
"title": "Anti-PD-1 Immunotherapy-Induced Flare of a Known Underlying Relapsing Vasculitis Mimicking Recurrent Cancer.",
"title_normalized": "anti pd 1 immunotherapy induced flare of a known underlying relapsing vasculitis mimicking recurrent cancer"
} | [
{
"companynumb": "US-ACCORD-154729",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Despite its superior efficacy, clozapine is an underutilized agent, primarily owing to the \"Clozaphobia\"-fear of clozapine's adverse effects. Emergent cautions on metabolic side-effects have contributed to avoidance of clozapine prescription. Here, we describe our clinical experience with nine patients having schizophrenia/schizoaffective disorders with comorbid diabetes mellitus and treated with clozapine. Interestingly, all patients could be maintained on optimal glycemic control even after clozapine. In conclusion, a critique on the potential risks versus benefits of clozapine amidst our observations from this case series adds further supporting evidence to the emerging literature on the clinical utility of clozapine in treating schizophrenia patients with diabetes mellitus.",
"affiliations": "InSTAR Program, Schizophrenia & Metabolic Clinic, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India. Electronic address: vs8sreeraj@yahoo.com.;InSTAR Program, Schizophrenia & Metabolic Clinic, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India.;InSTAR Program, Schizophrenia & Metabolic Clinic, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India.;InSTAR Program, Schizophrenia & Metabolic Clinic, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India.;InSTAR Program, Schizophrenia & Metabolic Clinic, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India.;InSTAR Program, Schizophrenia & Metabolic Clinic, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India.;InSTAR Program, Schizophrenia & Metabolic Clinic, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, India.",
"authors": "Sreeraj|Vanteemar S|VS|;Dinakaran|Damodaran|D|;Nagendrappa|Sachin|S|;Rao|Naren P|NP|;Kesavan|Muralidaran|M|;Varambally|Shivarama|S|;Venkatasubramanian|Ganesan|G|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ajp.2017.04.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-2018",
"issue": "28()",
"journal": "Asian journal of psychiatry",
"keywords": "Clozapine; Diabetes mellitus; Metabolic syndrome; Treatment resistant schizophrenia",
"medline_ta": "Asian J Psychiatr",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003024:Clozapine; D015897:Comorbidity; D003920:Diabetes Mellitus; D005260:Female; D007722:Health Knowledge, Attitudes, Practice; D006801:Humans; D008297:Male; D008875:Middle Aged; D010698:Phobic Disorders; D011618:Psychotic Disorders; D012559:Schizophrenia",
"nlm_unique_id": "101517820",
"other_id": null,
"pages": "142-145",
"pmc": null,
"pmid": "28784368",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clozaphobia: Is avoidance of clozapine in diabetes warranted?",
"title_normalized": "clozaphobia is avoidance of clozapine in diabetes warranted"
} | [
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"abstract": "Aspergillus niger is usually considered to be a low virulence fungus, not commonly reported to cause invasive infections. Invasive pulmonary aspergillosis due to Aspergillus niger was diagnosed in a 43-year-old woman following bilateral lung transplantation. Intravenous voriconazole failed to control progression of the disease. Despite salvage therapy with a combination of voriconazole and caspofungin for 23 days, the patient developed massive hemoptysis leading to death. The authors report the clinical features and treatment of this case.",
"affiliations": "Réanimation chirurgicale, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, Paris 75018, France.;Réanimation chirurgicale, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, Paris 75018, France.;Laboratoire de Parasitologie-Mycologie, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, Paris 75018, France.;Pharmacologie et toxicologie, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, Paris 75018, France.;Pharmacologie et toxicologie, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, Paris 75018, France.;Chirurgie thoracique et vasculaire, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, Paris 75018, France.;Pneumologie B, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, Paris 75018, France.;Pneumologie B, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, Paris 75018, France.;Réanimation chirurgicale, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, Paris 75018, France.",
"authors": "Atchade|Enora|E|;Jean-Baptiste|Sylvain|S|;Houzé|Sandrine|S|;Chabut|Claire|C|;Massias|Laurent|L|;Castier|Yves|Y|;Brugière|Olivier|O|;Mal|Hervé|H|;Montravers|Philippe|P|",
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"fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(17)30019-210.1016/j.mmcr.2017.05.002Case ReportFatal invasive aspergillosis caused by Aspergillus niger after bilateral lung transplantation Atchade Enora enora.atchade@aphp.fra⁎Jean-Baptiste Sylvain aHouzé Sandrine bChabut Claire cMassias Laurent cCastier Yves dBrugière Olivier eMal Hervé eMontravers Philippe aa Réanimation chirurgicale, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, Paris 75018, Franceb Laboratoire de Parasitologie-Mycologie, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, Paris 75018, Francec Pharmacologie et toxicologie, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, Paris 75018, Franced Chirurgie thoracique et vasculaire, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, Paris 75018, Francee Pneumologie B, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, Paris 75018, France⁎ Corresponding author. enora.atchade@aphp.fr18 5 2017 9 2017 18 5 2017 17 4 7 26 4 2017 17 5 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Aspergillus niger is usually considered to be a low virulence fungus, not commonly reported to cause invasive infections. Invasive pulmonary aspergillosis due to Aspergillus niger was diagnosed in a 43-year-old woman following bilateral lung transplantation. Intravenous voriconazole failed to control progression of the disease. Despite salvage therapy with a combination of voriconazole and caspofungin for 23 days, the patient developed massive hemoptysis leading to death. The authors report the clinical features and treatment of this case.\n\nKeywords\nInvasive aspergillosisAspergillus nigerLung transplantationVoriconazoleMassive hemoptysis\n==== Body\n1 Introduction\nInvasive aspergillosis is a common complication after lung transplantation (LT) and is associated with high morbidity and mortality rates [1], [2]. Most cases of invasive aspergillosis are caused by Aspergillus fumigatus. Aspergillus niger is usually considered to be a low virulence fungus. We report a case of fatal invasive pulmonary aspergillosis caused by Aspergillus niger in a 43-year-old woman after LT.\n\n2 Case report\nA 43-year-old woman with α1-antitrypsin deficiency emphysema underwent bilateral LT. Sputum analysis performed prior to transplantation did not reveal any evidence of bacterial or fungal colonization. Surgery was performed according to the usual procedure [3]. According to our standard protocol, perioperative antibacterial prophylaxis by cefamandole was administered at induction of anesthesia, and continued for 48 h. No antifungal prophylaxis was administered to the patient. Immunosuppressive therapy was based on a combination of prednisolone, mycophenolate mofetil and tacrolimus. Cytomegalovirus prophylaxis with ganciclovir was administered, due to lung donor and recipient positive serologies.\n\nMultiple infectious complications occurred after the surgical procedure. Two days after LT, Candida albicans was isolated from a respiratory sample. Ischemic bronchitis and a small zone of bronchial necrosis were discovered on fiberoptic bronchoscopy at Day-6 and fluconazole (400 mg per day, IV route) was initiated according to our standard practice. On the same day, bacterial pneumonia was diagnosed, associated with multiple organ dysfunction syndrome, with hemodynamic failure, acute respiratory distress syndrome, and anuric acute renal failure, requiring continuous hemofiltration. Empiric antimicrobial therapy by cefepime was initiated and was deescalated to cefotaxime after identification of Klebsiella pneumoniae, for a total duration of 7 days. Pneumothorax was diagnosed on chest X-ray on Day-9. Chest CT scan performed on Day-14 confirmed the persistence of right anterior pneumothorax despite percutaneous pleural drainage and demonstrated the presence of a right posterior bronchial anastomosis fistula, and the presence of numerous bilateral cystic lesions in a large zone of consolidation of the right lower lobe (Fig. 1). Serum galactomannan assay, performed on Day-16, was negative. On the same day, Pseudomonas aeruginosa bacterial pneumonia was diagnosed, and treated by ceftazidime and amikacin for a total duration of 10 days.Fig. 1 Chest CT scan performed on Day-14.\n\nFig. 1\n\nOn Day-18, Aspergillus niger was cultured from bronchial aspirate, in combination with Candida albicans. The presence of Aspergillus niger was confirmed in BAL performed on Day-22, associated with a high galactomannan concentration in BAL (cutoff optical density (OD) index = 4.55; Platelia™ Aspergillus EIA, BioRad, Marnes la Coquette, France). Voriconazole (800 mg (13 mg/kg) on the first day, then 400 mg daily (6 mg/kg) intravenously) was initiated on Day-21. Despite voriconazole therapy, A.niger cultures were obtained on repeated BAL samples. A progressive extension of images was noted on chest CT scan, involving the right upper lobe on Day-21 (Fig. 2). Due to progression of the lung lesions, caspofungin (70 mg on the first day, and then 50 mg daily) was introduced on Day-23, in combination with voriconazole, as salvage therapy. However, subsequent BAL samples remained positive for A. niger. Susceptibility to voriconazole was confirmed by susceptibility testing on Day-22 (voriconazole MIC 0.19 mg/L; micafungin MIC 0.004 mg/L), and Day-38 (caspofungin MIC 0.004 mg/L). Serum and BAL galactomannan concentrations were monitored (Table 1). Serum voriconazole concentrations were also assayed by isocratic high-performance liquid chromatography with ultraviolet detection (255 nm) [4], with concentrations ranging between 0.9 and 1.2 mg/L (Table 2). The daily dose of voriconazole was increased to 500 mg per day on Day-34 (8 mg/kg/day), because of low serum concentrations. On Day-45, whole-body CT scan ruled out any extrapulmonary sites of invasive aspergillosis.Fig. 2 Evolution of pulmonary images (chest CT scan performed on Day-21 (Panel A), Day-29 (Panel B), Day-45 (Panel C)).\n\nFig. 2Table 1 Serum and BAL galactomannan levels expressed in cutoff optical density (OD) index.\n\nTable 1Day after LT\tBAL galactomannan\tSerum galactomannan\t\nDay 16\t\t0\t\nDay 22\t4.55\t\t\nDay 23\t\t1.89\t\nDay 31\t\t2.08\t\nDay 36\t\t3.17\t\nDay 38\t5.68\t\t\nTable 2 Serum voriconazole concentrations.\n\nTable 2\tSerum voriconazole concentrations (mg/L)\t\nDay 25\t0.9\t\nDay 35\t1.2\t\nDay 44\t0.9\t\n\n\nThe patient experienced hemoptysis on Day-37. Despite several interventional vascular radiology procedures designed to ensure occlusion of multiples pseudoaneurysms between Day-37 and Day-46, hemoptysis persisted. A recurrence of hemoptysis on Day-46 was complicated by hypoxic cardiac arrest. Arteriography revealed two pseudoaneurysms that were treated by occlusion. On the same day, massive hemoptysis led to refractory cardiorespiratory arrest and to the patient's death.\n\n3 Discussion\nInvasive fungal infections (IFI) are common complication after LT, responsible for high mortality and morbidity rates [1], [2]. Aspergillus species are responsible for 44% of all fungal infections after LT [5]. Several forms of infections have been described, including tracheobronchitis, anastomosis infection, pulmonary invasive aspergillosis, and disseminated aspergillosis. A great majority of these complications are caused by A. fumigatus\n[6]. Aspergillus niger is usually considered to be a low virulence fungus, and is not commonly reported to cause invasive infections. Its low virulence is explained by various physiological characteristics. The large size of A. niger conidia and the presence of strong interspore bridges make penetration into the lower respiratory tract more difficult [7]. The ideal temperature for growth is around 30 °C, making germination difficult at human body temperature [8]. The pathogenicity of A. niger is also limited by its acidophilic nature [9]. These characteristics explain why A. niger invasive infection only occurs in a context of severe immunosuppression. Only a few case reports of A. niger invasive infections have been published: a few cases of pulmonary aspergillosis [10], [11], two cases of tracheobronchitis [7], [12], and one case of peritonitis in a patient on peritoneal dialysis [13]. Among 194 documented cases of invasive aspergillosis in a cohort of patients with hematologic diseases over a 10-year period, only eight cases (4%) were due to Aspergillus niger\n[14].\n\nAn unusual feature of the present case report is the development of invasive aspergillosis during the early postoperative period. Invasive aspergillosis usually occurs later, a median of 271 days after lung transplantation [2]. This early onset could be explained by the absence of systematic antifungal prophylaxis in our center. Antifungal prophylaxis policies are heterogeneous worldwide, as no published guidelines were available until recently. In a previous study, a universal antifungal prophylaxis was used in 59% of LT centers after LT [15]. However, an earlier study performed in a non-cystic fibrosis population suggested that the incidence of invasive fungal infections was not increased in the absence of universal antifungal prophylaxis [2]. Our patient presented several risk factors for invasive aspergillosis: postoperative complications, recurrent bacterial infections or hemofiltration are usual risk factors for early invasive aspergillosis [1]. It is also noteworthy that this patient had no previous Aspergillus colonization prior to transplantation and did not present any CMV infection or acute rejection, while these conditions are commonly recognized to be risk factors for invasive aspergillosis. No other case was observed over the same period of time in our center.\n\nInterestingly, despite voriconazole antifungal therapy for 25 days, and salvage therapy by a combination of voriconazole and caspofungin for an additional 23 days, A. niger persisted in all BAL samples, despite its susceptibility to voriconazole and caspofungin confirmed by two tests. This unsuccessful outcome can be explained by several factors. Firstly, invasive aspergillosis is a severe complication after lung transplantation, responsible for high mortality rate, estimated to be about 55% [2]. Secondly, the modalities of our treatment may need to be reviewed. Since the study by Herbrecht et al. [16], voriconazole has become the first-line treatment for invasive aspergillosis, with successful outcome in 53% of patients. Caspofungin has been proposed as second-line treatment when conventional treatment is not tolerated, or in the case of refractory aspergillosis [17], leading to a favorable response in 40% of cases. Several non-randomized clinical trials have suggested the benefit of various combination therapies for invasive aspergillosis, especially caused by A. niger\n[18]. According to the Infectious Disease Society of America (IDSA) guidelines, combination therapy may be used as salvage therapy, but is not recommended as first-line treatment [19]. Finally, amphotericin-B could have been proposed, but renal replacement therapy is a major limitation to the use of this drug.\n\nIn this case, serum voriconazole assays revealed low serum levels, which could partly explain the unsuccessful outcome. Monitoring of serum voriconazole levels remains controversial, as marked variability of serum voriconazole concentrations has been reported in healthy hosts, due to variable host CYP450 enzyme activities. In a retrospective review [20], a pharmacokinetic-pharmacodynamic breakpoint was observed around 2.05 µg/mL. When the serum voriconazole concentration was below this breakpoint, 44% of patients experienced disease progression [20]. Finally, adjuvant treatments are also useful in invasive aspergillosis. In this case, the dosage of immunosuppressive therapy was reduced from Day-40 until the patient's death, as recommended by IDSA guidelines [19]. Surgical resections can also be useful when lesions are contiguous to great vessels or pericardium, when a single cavitary lesion is responsible for hemoptysis, or when infection involves the chest wall [19]. In the present case, surgical resection was not possible due to the presence of large, bilateral pulmonary lesions.\n\nThis case illustrates the value of serum and BAL galactomannan assays for diagnosis and evaluation of the efficacy of treatment, even in the case of Aspergillus niger infection. Galactommanan assay is not recommended by IDSA for screening in SOT recipients, however, as illustrated by this case, it could be useful to confirm the pathogenic role of Aspergillus spp. isolated from non-sterile samples and to confirm invasive aspergillosis in the presence of positive serum galactomannan.\n\nWe report an unusual case of early A. niger invasive aspergillosis after lung transplantation. Despite salvage combination therapy by voriconazole and caspofungin, and reduction of immunosuppressive therapy, invasive aspergillosis caused massive hemoptysis leading to the patient's death.\n\nConflict of interest\nThe author declares no conflicts of interests regarding publication of this paper.\n\nAcknowledgments\nAuthor contributions: E.A, S.J-B, and P.M: drafting of the manuscript; P.M., S.H., C.C., L.M., Y.C., H.M., O.B. and S.J-B: critical revision of the manuscript.\n==== Refs\nReferences\n1 Solé A. Salavert M. Fungal infections after lung transplantation Transplant. Rev. 22 2 2008 89 104 \n2 Pinney M.F. Rosenberg A.F. Hampp C. Schain D. Akindipe O. Baz M. Invasive fungal infections in lung transplant recipients not receiving routine systemic antifungal prophylaxis: 12-year experience at a university lung transplant center Pharmacotherapy 31 6 2011 537 545 21923437 \n3 Thabut G. Vinatier I. Brugière O. Lesèche G. Loirat P. Bisson A. Influence of preservation solution on early graft failure in clinical lung transplantation Am. J. Respir. Crit. Care Med. 164 7 2001 1204 1208 11673210 \n4 Khoschsorur G. Fruehwirth F. Zelzer S. Isocratic high-performance liquid chromatographic method with ultraviolet detection for simultaneous determination of levels of voriconazole and itraconazole and its hydroxy metabolite in human serum Antimicrob. Agents Chemother. 49 8 2005 3569 3571 16048987 \n5 Pappas P.G. Alexander B.D. Andes D.R. Hadley S. Kauffman C.A. Freifeld A. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET) Clin. Infect. Dis. Publ. Infect. Dis. Soc. Am. 50 8 2010 1101 1111 \n6 Solé A. Morant P. Salavert M. Pemán J. Morales P. Valencia lung transplant group. Aspergillus infections in lung transplant recipients: risk factors and outcome Clin. Microbiol Infect. Publ. Eur. Soc. Clin. Microbiol. Infect. Dis. 11 5 2005 359 365 \n7 Orzechowski Xavier M. Pasqualotto A.C. Uchoa Sales M.D.P. Bittencourt Severo C. Peixoto Camargo J.J. Severo L.C. Invasive pulmonary aspergillosis due to a mixed infection caused by Aspergillus flavus and Aspergillus fumigatus Rev. Iberoam. Micol. 25 3 2008 176 178 18785789 \n8 Abdel-Rahim A.M. Arbab H.A. Nutrient requirements in germination of conidiospores of Aspergillus niger V. Tieghen Mycopathologia 92 2 1985 111 113 4079968 \n9 Severo L.C. Geyer G.R. Porto N. da S. Wagner M.B. Londero A.T. Pulmonary Aspergillus niger intracavitary colonization. Report of 23 cases and a review of the literature Rev. Iberoam. Micol. 14 3 1997 104 110 17655384 \n10 Person A.K. Chudgar S.M. Norton B.L. Tong B.C. Stout J.E. Aspergillus niger: an unusual cause of invasive pulmonary aspergillosis J. Med Microbiol. 59 Pt 7 2010 834 838 20299503 \n11 Nakagawa Y. Shimazu K. Ebihara M. Nakagawa K. Aspergillus niger pneumonia with fatal pulmonary oxalosis J. Infect. Chemother. J. Jpn Soc. Chemother. 5 2 1999 97 100 \n12 Singhal P. Usuda K. Mehta A.C. Post-lung transplantation Aspergillus niger infection J. Heart Lung Transplant. Publ. Int Soc. Heart Transplant. 24 9 2005 1446 1447 \n13 Vellanki V.S. Bargman J.M. Aspergillus Niger peritonitis in a peritoneal dialysis patient treated with eculizumab Ren. Fail. 36 4 2014 631 633 24512095 \n14 Fianchi L. Picardi M. Cudillo L. Corvatta L. Mele L. Trapè G. Aspergillus niger infection in patients with haematological diseases: a report of eight cases Mycoses 47 3–4 2004 163 167 15078435 \n15 Neoh C.F. Snell G.I. Kotsimbos T. Levvey B. Morrissey C.O. Slavin M.A. Antifungal prophylaxis in lung transplantation--a world-wide survey Am. J. Transplant. J. Am. Soc. Transplant. Am. Soc. Transpl. Surg. 11 2 2011 361 366 \n16 Herbrecht R. Denning D.W. Patterson T.F. Bennett J.E. Greene R.E. Oestmann J.-W. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis N. Engl. J. Med. 347 6 2002 408 415 12167683 \n17 Maertens J. Raad I. Petrikkos G. Boogaerts M. Selleslag D. Petersen F.B. Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy Clin. Infect. Dis. Publ. Infect. Dis. Soc. Am. 39 11 2004 1563 1571 \n18 Zhang M. Sun W.-K. Wu T. Chen F. Xu X.-Y. Su X. Efficacy of combination therapy of triazole and echinocandin in treatment of invasive aspergillosis: a systematic review of animal and human studies J. Thorac. Dis. 6 2 2014 99 108 24605223 \n19 Walsh T.J. Anaissie E.J. Denning D.W. Herbrecht R. Kontoyiannis D.P. Marr K.A. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America Clin. Infect. Dis. Publ. Infect. Dis. Soc. Am. 46 3 2008 327 360 \n20 Smith J. Safdar N. Knasinski V. Simmons W. Bhavnani S.M. Ambrose P.G. Voriconazole therapeutic drug monitoring Antimicrob. Agents Chemother. 50 4 2006 1570 1572 16569888\n\n",
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"issn_linking": "2211-7539",
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"journal": "Medical mycology case reports",
"keywords": "Aspergillus niger; Invasive aspergillosis; Lung transplantation; Massive hemoptysis; Voriconazole",
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"title": "Fatal invasive aspergillosis caused by Aspergillus niger after bilateral lung transplantation.",
"title_normalized": "fatal invasive aspergillosis caused by aspergillus niger after bilateral lung transplantation"
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"abstract": "Thyroid stimulating hormone (TSH)-suppressive therapy with levothyroxine is a cornerstone of thyroid carcinoma follow-up therapy, but the achievement of therapeutic goals must be balanced against L-T4 side effects. We describe the case of a 64-year-old cardiopathic patient with papillary thyroid carcinoma and autoimmune thyroiditis, whose cardiac condition worsened during TSH-suppressive therapy. TSH concentrations also fluctuated widely because of changing intestinal absorption due to coeliac disease.\nTSH-suppressive therapy with levothyroxine (L-T4) to prevent thyroid carcinoma relapse can be a tricky problem in the presence of comorbidities.The recent American Thyroid Association guidelines are a useful reference for complex cases of thyroid carcinoma.When strict TSH control is crucial, the L-T4 liquid solution may be a valuable tool.",
"affiliations": "UOC Medicina Interna, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.;UOC Medicina Interna, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.;ICH Humanitas, EAS Pronto Soccorso, Rozzano (MI), Italy.;UOC Medicina Interna, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.",
"authors": "Baldini|Itala Marina|IM|;Cocino|Cristina|C|;Seghezzi|Sonia|S|;Cappellini|Maria Domenica|MD|",
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"fulltext": "\n==== Front\nEur J Case Rep Intern MedEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2016_000547547-1-3379-1-10-20161229ArticlesTSH-Suppressive Therapy: A Thorny Issue Baldini Itala Marina 1Cocino Cristina 1Seghezzi Sonia 2Cappellini Maria Domenica 1\n1 UOC Medicina Interna, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy\n2 ICH Humanitas, EAS Pronto Soccorso, Rozzano (MI), Italy2017 27 3 2017 4 2 00054702 12 2016 05 12 2016 © EFIM 20162016This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseThyroid stimulating hormone (TSH)-suppressive therapy with levothyroxine is a cornerstone of thyroid carcinoma follow-up therapy, but the achievement of therapeutic goals must be balanced against L-T4 side effects. We describe the case of a 64-year-old cardiopathic patient with papillary thyroid carcinoma and autoimmune thyroiditis, whose cardiac condition worsened during TSH-suppressive therapy. TSH concentrations also fluctuated widely because of changing intestinal absorption due to coeliac disease.\n\nLEARNING POINTS\nTSH-suppressive therapy with levothyroxine (L-T4) to prevent thyroid carcinoma relapse can be a tricky problem in the presence of comorbidities.\n\nThe recent American Thyroid Association guidelines are a useful reference for complex cases of thyroid carcinoma.\n\nWhen strict TSH control is crucial, the L-T4 liquid solution may be a valuable tool.\n\nThyroid carcinomaTSH-suppressive therapyintestinal malabsorption\n==== Body\nCASE PRESENTATION\nA 64-year-old woman with coeliac disease and autoimmune thyroiditis was examined 2 years after thyroidectomy with lymphadenectomy for carcinoma (January 2006). The histopathological report described multifocal papillary carcinoma, follicular variant, associated with lymphocytic thyroiditis; the main nodule (6 mm) had infiltrated the thyroid capsule without affecting the fat tissue, vascular or lymphatic vessels (TNM pT1 (G2) pN0 M0). Ten months after surgery, radioiodine remnant ablation had been performed. Subsequent whole body scintigraphy and periodic ultrasound scans were not suggestive of relapse; thyroglobulin concentrations were undetectable but anti-thyroglobulin antibody positivity persisted.\n\nThe patient also had ischaemic heart disease, diagnosed on the basis of myocardial scintigraphy as she refused coronarography.\n\nAt first examination at our clinic (March 2008), thyroid stimulating hormone (TSH) was suppressed on levothyroxine (L-T4) 3 μg/kg/day, but the treatment was not tolerated due to frequent angina and premature ventricular beats despite beta-blocking therapy. Consequently, L-T4 was tapered to the dose allowing satisfactory control of the side effects (2.4 μg/kg/day). The results of periodic tests are shown in Table 1.\n\nIn March 2009, the patient’s cardiac condition deteriorated and atrial fibrillation was noted; a CT scan revealed coronary artery disease that required angioplasty. At the same time, the periodic neck ultrasound showed a single 12×7 mm lymph node suspect for local relapse. As a result, TSH inhibition became more pressing even in the absence of significant changes in blood tests or pathological uptake areas at repeated whole body scintigraphy. However, we delayed any L-T4 increase in view of the patient’s unstable cardiac condition. Over the following observation period, the L-T4 dosage was frequently modified in response to wide TSH fluctuations, until January 2015 when TSH=12.7 mIU/l was registered. Although the patient declared good compliance with a gluten-free diet except on rare occasions, we suspected problems with absorption and switched from L-T4 tablets to the liquid formulation at the unchanged dose of 2.1 μg/kg/day, and recorded optimal TSH suppression after 6 weeks. Thereafter, follow-up was negative for relapse.\n\nDISCUSSION\nThe challenge we describe is not unusual for endocrinologists trying to minimize cancer recurrence risk while also limiting TSH-suppression side effects.\n\nOur patient had been classified as belonging to the high-risk category based on American Thyroid Association (ATA) guidelines[1]. Supra-physiological doses of L-T4 were therefore prescribed as it was mandatory to maintain TSH levels below 0.1 mU/l[1,2] to decrease the risk of recurrence[1–5]. However, the potential benefits of reaching the therapeutic goal must always be balanced against possible harm from subclinical thyrotoxicosis[1,2], a complex undertaking in this case due to the coexistence of cardiac ischaemic and arrhythmogenic disease. The recent ATA guidelines are particularly useful in situations like these, as they give strict indications for the thyrotropin targets, taking both L-T4 side effects and co-morbidities into consideration. According to these guidelines, the recommended TSH target is between 0.5 and 2 mU/l in the presence of specific conditions: an indeterminate response (anti-TG antibodies stable or declining without structural or functional disease), menopause, age >60, and in particular atrial fibrillation[6].\n\nOur patient had coeliac disease, which may mean L-T4 doses need to be increased to reach the target TSH[7–11]. In a retrospective study, Collins et al. demonstrated that the mean initial daily dose of L-T4 needed to reach euthyroidism was higher in patients with untreated coeliac disease and hypothyroidism than in those with hypothyroidism alone[12].\n\nIn our patient, switching from tablets to the liquid formulation overcame the negative effect of coeliac disease on drug absorption, producing more stable TSH concentrations with lower L-T4 doses; this effect is connected with the intrinsic characteristics of the drug. Levothyroxine is a lipophilic molecule that is absorbed in the upper intestinal tract. The tablet formulation contains a stable salt and excipients, which must be dissolved at the gastric acid pH to convert sodium L-T4 into a lipophilic molecule[13]; this will reach the duodenum and jejunum, where around 70% of the tablet L-T4 content will be absorbed[14–16]. The liquid formulation contains only L-T4 dissolved in a lipophilic solution of glycerine and ethanol; L-T4 also maintains its stability when added to breakfast beverages[17, 20].\n\nIn an in vivo study comparing the three available formulations of L-T4 (tablet, soft gel capsule, liquid solution), the liquid solution showed the best pharmacokinetics indices and the fastest blood peaks[18,19,21]. Brancato et al. reported a significant decrease in serum TSH levels in 68% of patients switched from tablets (taken according recommendations) to the liquid solution at the same dose. Interestingly, the patients in whom serum TSH decreased had a greater prevalence of factors known to interfere with L-T4 intestinal absorption (gastrointestinal diseases or drugs)[22].\n\nCONCLUSION\nAchieving a balance between therapeutic goals and the side effects of L-T4 is a thorny issue, especially when comorbidities are present. The oral solution is a valuable tool in complex cases where strict control of therapeutic goals is crucial.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nTable 1 Biochemical tests and L-T4 doses\n\nDate\tWeight, kg\tL-T4 dose\tTSH, mIU/l (nv 0.28–4.3)\tTg, μg/l\tAnti-Tg antibodies, IU/ml (nv <60)\t\n\t\tTablet\t\t\t\t\n05/03/2008\t75\t225 μg/day\n3 μg/kg/day\t0.04\t<0.2\t-\t\n18/12/2008\t76\t193 μg/day\n2.5 μg/kg/day\t0.01–0.02\t<0.2\t166–357\t\n28/05/2009\t77\t190 μg/day\n2.4 μg/kg/day\t0.02–0.34\t<0.2\t174–219\t\n23/09/2011\t80\t185 μg/day\n2.3 μg/kg/day\t0.3–2.3\t<0.2\t110–190\t\n21/03/2014\t81\t170 μg/day\n2.1 μg/kg/day\t0.17–5.7\t<0.2\t<60\t\n23/01/2015\t84\t165 μg/day\n2 μg/kg/day\t4.5–12.4\t<0.2\t<60\t\n\t\tLiquid solution\t\t\t\t\n03/07/2015\t84\t175 μg/day\n2.1 μg/kg/day\t0.05\t<0.2\t<60\t\nTg, thyroglobulin; TSH, thyroid stimulating hormone\n==== Refs\nREFERENCES\n1 Cooper DS Doherty GM Haugen BR Kloos RT Lee SL Mandel SJ The American Thyroid Association Guidelines Taskforce Management guidelines for patients with thyroid nodules and differentiated thyroid cancer Thyroid 2006 16 121 125 \n2 Cooper DS Doherty GM Haugen BR Kloos RT Lee SL Mandel SJ The American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer Thyroid 2009 19 1180 1187 \n3 Biondi B Wartofsky L Treatment with thyroid hormone Endocr Rev 2014 35 433 512 24433025 \n4 Pacini F Castagna MG Approach to and treatment of differentiated thyroid carcinoma Med Clin North Am 2012 96 369 383 22443981 \n5 Garber JR Cobin RH Gharib H American Association of Clinical Endocrinologists and American Thyroid Association Task Force on Hypothyroidism in Adults Clinical practice guidelines for hypothyroidism in adults: co-sponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association Endocr Pract 2012 18 988 1028 23246686 \n6 Haugen BR Alexander EK Bible KC Doherty GM Mandel SJ Nikiforov YE The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer Thyroid 2016 26 48 72 73 \n7 Jiskra J Limanova Z Vanickova Z Kocna P IgA and IgG antigliadin, IgA anti-tissue transglutaminase and antiendomysial antibodies in patients with autoimmune thyroid diseases and their relationship to thyroidal replacement therapy Physiol Res 2003 52 79 88 12625811 \n8 d’Esteve-Bonetti L Bennet AP Malet D Gluten-induced enteropathy (coeliac disease) revealed by resistance to treatment with levothyroxine and alfacalcidol in a sixty-eight-year old patient: a case report Thyroid 2002 12 633 636 12193310 \n9 McDermott JH Coss A Walsh CH Celiac disease presenting as resistant hypothyroidism Thyroid 2005 15 386 388 15876165 \n10 Chamberland D Weight C Rasmussen M Thyroxine malabsorption in a patient with type 1 diabetes and celiac disease Endocr Pract 2005 11 203 204 16239209 \n11 Caputo M Brizzolara R Schiavo M Occurrence of overt celiac disease in the elderly following total thyroidectomy J Endocrinol Invest 2006 29 831 833 17114916 \n12 Collins D Wilcox R Nathan M Zubarik R Celiac disease and hypothyroidism Am J Med 2012 125 278 282 22340926 \n13 Centanni M Gargano L Canettieri G Thyroxine in goiter, Helicobacter pylori infection, and chronic gastritis N Engl J Med 2006 354 1787 1795 16641395 \n14 Hays MT Nielsen RK Human thyroxine absorption: age effects and methodological analyses Thyroid 1994 4 55 64 8054862 \n15 Benvenga S Bartolone L Squadrito S Delayed intestinal absorption of levothyroxine Thyroid 1995 5 249 253 7488863 \n16 Hays MT Localization of human thyroxine absorption Thyroid 1991 1 241 248 1824339 \n17 Vita R Saraceno G Trimarchi F Benvenga S A novel formulation of L-thyroxine (L-T4) reduces the problem of L-T4 malabsorption by coffee observed with traditional tablet formulations Endocrine 2013 43 154 160 22932947 \n18 Colucci P D’Angelo P Mautone G Pharmacokinetic equivalence of a levothyroxine sodium soft capsule manufactured using the new Food and Drug Administration potency guidelines in healthy volunteers under fasting conditions Ther Drug Monit 2011 33 355 361 21516059 \n19 Santaguida M Virili C Gatto I A novel therapeutic approach for patients with gastric disorders and T4 malabsorption: thyroxine softgel preparation Thyroid 2013 23 S1 A53 \n20 Bernareggi A Grata E Pinorini MT Oral liquid formulation of levothyroxine is stable in breakfast and may improve thyroid patient compliance Pharmaceutics 2013 5 621 633 24351573 \n21 Yue CS Scarsi C Ducharme MP Pharmacokinetics and potential advantages of a new oral solution of levothyroxine vs. other available dosage forms Arzneimittelforschung 2012 62 631 636 23154888 \n22 Brancato D Scorsone A Saura G Comparison of TSH levels with liquid formulation versus tablet formulations of levothyroxine in the treatment of adult hypothyroidism Endocr Pract 2014 20 657 662 24449674\n\n",
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"title": "TSH-Suppressive Therapy: A Thorny Issue.",
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"abstract": "BACKGROUND\nFahr's disease is rare a neurodegenerative idiopathic condition characterized by symmetric and bilateral calcifications of basal ganglia, usually associated with progressive neuropsychiatric dysfunctions and movement disorders. The term \"Fahr's syndrome\" is used in presence of calcifications secondary to a specific cause, but the variability of etiology, pathogenesis, and clinical picture underlying this condition have raised the question of the real existence of a syndrome. Several classifications based on the etiology, the location of brain calcifications and the clinical presentation have been proposed. Here we describe seven clinical cases of basal ganglia calcifications, in order to search for pathognomonic features and correlations between clinical picture and imaging findings.\n\n\nMETHODS\nThe patients came to our attention for different reasons (most of them for memory/behavior disturbances); all underwent neuro-psychologic evaluation and neuro-imaging. All patients showed variable degrees of deterioration in cognitive function; anxiety and depression were frequent too, and resistant to treatment in all cases. Less frequent, but severe if present, were psychotic symptoms, with different grade of structure and emotional involvement, and always resistant to treatment. We observed only few cases of extrapyramidal disorders related to the disease itself; anyway, mild extrapyramidal syndrome occurred quite frequently after treatment with antipsychotics.\n\n\nCONCLUSIONS\nBased on these findings we discourage the use of the term \"Fahr's syndrome\", and suggest to refer to Idiopathic or Secondary basal ganglia calcification. Unlike early onset forms (idiopathic or inherited), the clinical presentation of late onset form and Secondary basal ganglia calcification seems to be really heterogeneous. Case-control studies are necessary to determine the actual significance of basal ganglia calcification in the adult population and in the elderly, in cognitive, physical and emotional terms.",
"affiliations": "Department of Medical Sciences, Section of Internal and Cardiopulmonary Medicine, University of Ferrara, Via Savonarola n°9, 44100, Ferrara, Italy.;Department of Medical Sciences, Section of Internal and Cardiopulmonary Medicine, University of Ferrara, Via Savonarola n°9, 44100, Ferrara, Italy. cecilia.soavi@gmail.com.;Department of Medical Sciences, Section of Internal and Cardiopulmonary Medicine, University of Ferrara, Via Savonarola n°9, 44100, Ferrara, Italy.;Azienda Ospedaliero-Universitaria S. Anna Ferrara, Ferrara, Italy.;Azienda Ospedaliero-Universitaria S. Anna Ferrara, Ferrara, Italy.;Department of Medical Sciences, Section of Internal and Cardiopulmonary Medicine, University of Ferrara, Via Savonarola n°9, 44100, Ferrara, Italy.;Department of Medical Sciences, Section of Internal and Cardiopulmonary Medicine, University of Ferrara, Via Savonarola n°9, 44100, Ferrara, Italy.",
"authors": "Savino|Elisabetta|E|;Soavi|Cecilia|C|;Capatti|Eleonora|E|;Borrelli|Massimo|M|;Vigna|Giovanni B|GB|;Passaro|Angelina|A|;Zuliani|Giovanni|G|",
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"doi": "10.1186/s12883-016-0693-1",
"fulltext": "\n==== Front\nBMC NeurolBMC NeurolBMC Neurology1471-2377BioMed Central London 69310.1186/s12883-016-0693-1Case ReportBilateral strio-pallido-dentate calcinosis (Fahr’s disease): report of seven cases and revision of literature Savino Elisabetta svnlbt@unife.it 1Soavi Cecilia 39-0532-247409cecilia.soavi@gmail.com 1Capatti Eleonora cptlnr@unife.it 1Borrelli Massimo brm@ospfe.it 2Vigna Giovanni B. vgg@unife.it 2Passaro Angelina psn@unife.it 1Zuliani Giovanni zlngnn@unife.it 121 Department of Medical Sciences, Section of Internal and Cardiopulmonary Medicine, University of Ferrara, Via Savonarola n°9, 44100 Ferrara, Italy 2 Azienda Ospedaliero-Universitaria S. Anna Ferrara, Ferrara, Italy 8 9 2016 8 9 2016 2016 16 1 16528 4 2016 1 9 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\nFahr’s disease is rare a neurodegenerative idiopathic condition characterized by symmetric and bilateral calcifications of basal ganglia, usually associated with progressive neuropsychiatric dysfunctions and movement disorders. The term “Fahr’s syndrome” is used in presence of calcifications secondary to a specific cause, but the variability of etiology, pathogenesis, and clinical picture underlying this condition have raised the question of the real existence of a syndrome. Several classifications based on the etiology, the location of brain calcifications and the clinical presentation have been proposed. Here we describe seven clinical cases of basal ganglia calcifications, in order to search for pathognomonic features and correlations between clinical picture and imaging findings.\n\nCases presentation\nThe patients came to our attention for different reasons (most of them for memory/behavior disturbances); all underwent neuro-psychologic evaluation and neuro-imaging. All patients showed variable degrees of deterioration in cognitive function; anxiety and depression were frequent too, and resistant to treatment in all cases. Less frequent, but severe if present, were psychotic symptoms, with different grade of structure and emotional involvement, and always resistant to treatment. We observed only few cases of extrapyramidal disorders related to the disease itself; anyway, mild extrapyramidal syndrome occurred quite frequently after treatment with antipsychotics.\n\nConclusion\nBased on these findings we discourage the use of the term “Fahr’s syndrome”, and suggest to refer to Idiopathic or Secondary basal ganglia calcification. Unlike early onset forms (idiopathic or inherited), the clinical presentation of late onset form and Secondary basal ganglia calcification seems to be really heterogeneous. Case–control studies are necessary to determine the actual significance of basal ganglia calcification in the adult population and in the elderly, in cognitive, physical and emotional terms.\n\nKeywords\nCase reportFahr’s diseaseBasal ganglia calcificationNeurodegenerationissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nFahr’s disease, Bilateral striopallidodentate calcinosis [1], and Idiopathic basal ganglia calcification [2] are three of the more than 30 names used to identify a rare neurodegenerative condition characterized by the presence of bilateral calcification of the basal ganglia and other parts of the brain [3]. This condition has a wide range of possible clinical manifestations, usually marked by neuropsychiatric symptoms (i.e. dementia, schizophrenia-like psychosis, mood disorders), and extrapiramidal movement disorders [3]. Fahr was the first author who, despite a few previous case-reports by others [4, 5], described in 1930 the case of a demented patient with movement disturbances, whose autopsy revealed vascular non atherosclerotic calcifications in centrum semiovale and striatum [6].\n\nFor years, the terms Fahr’s disease and Fahr’s syndrome have been used indistinctly to identify different clinical conditions characterized by basal ganglia calcification. Nowadays, several authors use the term syndrome referring to clinical cases, symptomatic or not, in which a specific cause can be identified at the basis of brain calcification [7]. Nevertheless, there is no agreement about the use of the term “Fahr’s syndrome”, since, under this name, are grouped a very wide range of conditions, with different etiologies, pathogeneses, and different clinical phenotypes, raising the question of the real existence of such a syndrome. In fact, a study conducted in 2007 found that among 1569 healthy subjects, 0.8 % presented basal ganglia calcifications at CT scan, apparently without any symptoms, thus inducing the authors to consider them intracranial “physiological” calcifications [8]. More recently, irrespective of the etiology, Manyam proposed a classification based on the anatomical site in which calcium and other minerals depose, including 1. striopallidodentate calcinosis, 2. bilateral striopallidal (basal ganglia) calcinosis, and 3. bilateral cerebellar calcification [3]. In this paper we report seven consecutive cases of patients with basal ganglia calcification detected from a series of 750 patients referring to our Clinic for the study of Cognitive Diseases or to our Internal Medicine Ward from January 2003 to December 2013. Our purpose was, in a group of patients with non-genetic forms of basal ganglia calcinosis, to evaluate whether a clinical picture corresponding to neuroimaging could be detected and, consequently, whether the use of the term “syndrome” may be correct.\n\nCase presentation\nCase 1\nM.G., a 73 year old man, came to our attention after the instruction of mandatory medical treatment, disposed to the police after reports of inadequate behavior. After repulsing his wife and daughter, five years before, he had been living alone, in a state of total neglect. His medical history was positive for type 2 diabetes, and a previous transient ischemic attack. No family history of neurologic nor psychiatric disturbances was reported. The physical examination revealed only poor self-care and bradykinesia. The findings at neuropsychological testing are summarized in Table 1.Table 1 Principal characteristics of the seven subjects with Fahr’s disease\n\nCase\tGender\tAge\tDiagnosis\tRisk factors\tClassification by Manyam (and other neuroimaging findings)\tPsychotic symptoms\tCognitive impaiment\tOther Psychiatric disorders\tExtrapyramidal disorders\tOther neurologic abnormalities\tResponse to neuroleptics\t\n1\tMale\t73\tPrimary\nLate onset\t(cerebrovascular disease ?)\tSPD calcinosis (+ left, frontal malacic area, leukoaraiosis, cortical atrophy)\tSevere: well-structured paranoid delusions of robbery and conspirancy, with strong emotional involvment\tSevere, progressive: memory, language, orientation, calculation, attention (MMSE: 19/30; MODA: 88/100)\tApathia,\tBradykinesia\nLater, secondary hypertonia, diskinesias, tremor, gait disturbances\t\tPoor\t\n2\tMale\t37\tSecondary\nEarly onset\tHead injury\tSP calcinosis\tSevere: poorly structured paranoid delusions of body transformation and greatness, auditory hallucinations, aggressiveness\tMild: language, comprehension, abstract reasoning, visual-motor ability.\n(WAIS: below lower limit)\tFlattening of affectivity\tLate, secondary (facial and limb diskinesias)\tAmimia, fatuous expression\tPoor\t\n3\tMale\t54\tPrimary\nLate onset\t\tSP calcinosis (+ mild cerebellar atrophy)\tAbsent\tMild: memory\tAnxious-depressive syndrome focused on health problems\tAbsent\t-\t-\t\n4\tFemale\t48\tSecondary\nEarly onset\tHead injuries, Hyperparathyroidism\tSP calcinosis (+ mild cerebellar atrophy)\tAbsent\tMild: attention, memory, logical reasoning, language, visual-spatial skills.\tAnxious-depressive syndrome\tAbsent\tInexhaustible glabellar reflex\t-\t\n5\tFemale\t63\tPrimary\nLate onset\t\tSPD + occipital calcinosis (+ frontal leukoaraiosis; left ponto-cerebellar cistern meningioma)\tAbsent\tVery mild: sustained and divided attention\tMild focus on health condition\tAbsent\t-\t-\t\n6\tFemale\t73\tSecondary\nLate onset\tHyperparathyroidism\tSP calcinosis (worsened at follow-up with development of moderate atrophy, leukoaraiosis and left parietal cortical infarction)\tProgressive: visual hallucinations, then aggressiveness, paranoid delusions\tProgressive: memory, orientation. (initial MMSE: 24.7/30, then progressive worsening).\tMajor depression\tEarly, progressive (worsening tremor of superior limbs, then gait disturbances)\tPalmo-mental reflex\tPartial\t\n7\tFemale\t82\tSecondary\nLate onset\tHyperparathyroidism, previous stroke?\tSPD calcinosis (+ diffuse atrophy)\tProgressive: visual and auditory hallucinations, then aggressiveness\tProgressive, severe: memory, orientation, attention (MMSE 19.5/30)\tDepression\tEarly (diffuse hypertonia, resting and intentional tremor, gait disturbances)\tInexhaustible glabellar reflex, bilateral Babinski reflex\tGood\t\nLegend: MMSE mini mental state examination, MODA Milan overall dementia assessment, SP strio-pallidal, SPD strio-pallido-dentate, WAIS Wechsler Adult Intelligence Scale\n\n\n\nBlood tests, comprehensive of calcium and phosphate, were normal. Computed Tomography (CT) scan (Fig. 1-a) and Magnetic Resonance Imaging (MRI) findings are summarized in Table 1. An antipsychotic treatment was started (quetiapine up to 200 mg/day) with poor response; after discharge behavior disorders recurred, inducing forced hospitalization in a nursing home. He displayed extrapyramidal symptoms, strong structured delusions, and worsening of dementia.Fig. 1 CT scan imaging of Cases 1,3,4 and 5. a Case 1. CT scans: extensive bilateral calcification of pallidus nuclei of basal ganglia and dentate nuclei of cerebellum; Hypodense malacic aspect in left frontal lobe. b Case 3. CT scans: mineral hyperdense deposits in bilateral pallidus nuclei without other area of altered density. Small enlargement, age-related, of frontal cerebral sulci due to atrophy. c Case 4. CT scans: hyperdense simmetric calcific deposits in pallidus nuclei and caudate nuclei of both sides. d Case 5. CT scans: hyperdense bilateral calcific deposits in the head of caudate nuclei, putamen and pallidus nuclei\n\n\n\nCase 2\nD.C., a 37 years old man, came to our attention for psychiatric evaluation to assess his capacity of discernment and his social dangerousness, after receiving a complaint for theft. The only anamnestic element was a head injury occurred 11 years before. After this trauma, his personality had changed with aggressiveness, recurrent migraine with auditory/olfactory hallucinations. A treatment with haloperidol had been tried, suspended because of scarce effect on psychotic disturbances and appearance of extrapyramidal symptoms. An extensive bilateral calcification of globus pallidus was revealed by CT scan. The findings of psychiatric examination are summarized in Table 1.\n\nCase 3\nE.F., a 54 years old man, came to our observation for weight loss, weakness, and hyporexia. He had a psychiatric history of “somatoform autonomic dysfunction”, and had been followed by local Psychiatric Service during the previous years, and treated with selective serotonin reuptake inhibitors (SSRI) at maximum dose with inadequate results. His anamnesis was positive for coronary heart disease, hypertension, dyslipidemia, hyper-omocysteinemia, and monoclonal gammopathy of undetermined significance. Except for the rapid decrease in body weight, the physical and neurologic examination was unremarkable, as well as blood exams, abdominal ultrasound, and chest X-rays. Gastroscopy showed the presence of bulbar erosive duodenitis. The results of his psychiatric evaluation are summarized in Table 1. A CT scan revealed the presence of bilateral hyperdense calcium deposits in globus pallidus, and slight dilatation of the pericerebellar fluid space because of atrophy (Fig. 1-b-). A treatment with sertraline up to 150 mg/day, together with aripiprazole (15 mg/day) was started, with slight improvement in mood and clinical conditions.\n\nCase 4\nB.S., a 48 years old woman, came to our attention sent by her psychiatrist for a neuro-psycological evaluation. She had a family history of vascular dementia, and her medical history was positive for hypothyroidism, obesity, dyslipidemia, and hypertensive cardiopathy. After a car accident with brain injury occurred 10 years before, she had suffered from anxious-depressive syndrome; some years later, a second car accident with brain trauma occurred. She was treated with venlafaxine and quetiapine, with poor response. Physical and neurologic examination were unremarkable, except for mild frontal liberation signs. Blood test showed hyperparathyroidism (Parathyroid hormone: 83 pg/ml; normal range: 12–65 pg/ml) associated with hypovitaminosis D (vitamin D: 10.8 ng/ml; normal range: 20–120 ng/ml); serum calcium was within normal values (2.55 mmol/l; normal range: 2.15–2.55 mmol/l). A thyroid ultrasound examination was unremarkable, parathyroids were not visible. Brain CT scan (Fig. 1-c) and neuropsychological evaluation results are shown in Table 1.\n\nCase 5\nB.M., a 63 years old woman, was admitted to our Day Hospital after two episodes of syncope. She denied seizures, bite, and sphincter relaxation, but reported tinnitus and gait instability lasting two months. For this reason she had already undergone several examinations showing mild atherosclerotic carotid disease, a phenotype II-b dyslipidemia, and a deficit of Vitamin D without calcium, phosphorus or parathyroid hormone alterations. Her anamnesis was positive for hypertension, thyroid nodules, smoking habit. She had an high level of education (university degree) and a family history of depression and dementia. Physical and neurological examinations were normal except for orthostatic hypotension. The findings at cerebral MRI and CT scan, and results from neuropsychological tests are summarized in Table 1 and shown in Fig. 1-d.\n\nCase 6\nM.M., a 73 years old woman was referred to our clinic for memory complaints, episodes of time/space disorientation, visual hallucinations, and sleep disorders. At the time of first visit she was still totally independent in basic, and partially in instrumental activities of daily living (score 18/19). Her anamnesis was positive for hypertension, COPD (Chronic Obstructive Pulmonary Disease), and major depression. Her physical examination showed mild frontal liberation and extrapyramidal signs (see Table 1). Blood tests revealed increased parathyroid hormone with normal calcium levels. Brain CT scan showed important bilateral calcification of globus pallidus. Citalopram (20 mg/day), risperidone (2 mg/day), and oxazepam were prescribed. On follow-up her memory and movement disturbances gradually worsened with development of psychotic symptoms (see Table 1), and a second CT scan revealed the worsening of known calcifications and development of degenerative/vascular encephalopathy (see Table 1). Quetiapine (100 mg/day) and promazine (200 mg/day) were prescribed in place of risperidone, with partial response. She progressively lost her independence until refusing of feeding on, and died at the age of 81.\n\nCase 7\nC.L., a 82 years old woman was admitted to our ward for a lipothymia. Her anamnesis was positive for hypertension, carotid atherosclerosis, previous stroke, and frequent falls in the last 5 years. Her familiar history was positive for dementia. Neurological examination revealed both pyramidal and extrapyramidal signs (see Table 1). At neurologic evaluations cognitive impairment, depressive symptoms, and hallucinations emerged. Blood test revealed vitamin D deficiency, with increased parathyroid hormone and hypercalcemia, and a brain CT scan showed diffuse atrophy, and basal ganglia calcification. Sertraline, nimodipine, and vitamin D supplementation were started, with poor response. The progressive worsening of hypertonia, resistant to L-dopa treatment, caused several further falls, with many bone fractures. She progressively loss independency, was institutionalized, and developed aggressive behaviour responsive to promazine.\n\nRevision of literature\nEpidemiology\nThe frequency of incidental finding of basal ganglia calcification during CT scan raised from an incidence of 0.24–0.75 % during the eighties [9–12], until 12.5 % in two thousands [13, 14]. The reason of this increase depends on one side on the wide spread of CT-scan, and, on the other side, on larger new diagnostic criterions (from minimal monolateral calcification isolated to globus pallidus to massive bilateral calcification [3]. Fahr’s disease is considered a rare disorder, even if its real prevalence is still unknown. The epidemiology of this disease is so hard to be obtained for several reasons: firstly for the plethora of names used indistinctly to identify different conditions, secondly for the complexity of diagnosis with a wide spectrum of clinical manifestations (from asymptomatic people, to severe cognitive and movement disturbances), finally because the clinical manifestations are reported in literature mainly as case reports or small series. For example, applying uniform criteria to 61 cases of literature and 38 cases seen in a registry, Manyam found that less than 70 % of subjects were symptomatic [15]. There are no data indicating the mean age of onset of the disease, nor suggesting a gender prevalence, even if in the cited work by Manyam the male–female ratio was 2:1 [15].\n\nEtiology and histopathology\nConsidering the etiology, bilateral striopallidodentate calcinosis can be subdivided into four forms, with first to third belonging to Fahr’s disease, that means lacking of secondary causes [1]: 1. Autosomal dominant; 2. Familial; 3. Sporadic; 4. Secondary. The autosomal dominant form involves different people in the same parental line (parents or offsprings of the proband), and seems associated mainly to chromosome locus 14q48 mutation (IBCG1) [16–19]. Familial form is diagnosed when many members of the same family are affected, but this can be accounted for by chance, and there are not the characteristics to consider it a genetic form [3]. Fahr’s disease is sporadic when only one person of a family is affected; of course, the lack of symptoms in other family members is not enough to consider sporadic a case, but adequate neuroimaging studies should rule out brain calcifications. It must be underlined that a certain degree of calcification of basal ganglia can be considered “physiological” with aging, over 50 years [20].\n\nSecondary forms, called Fahr’s syndrome by some authors, have been associated with several diseases, including: A) Abnormalities in calcium and phosphate metabolism, mainly hyper- [21, 22], hypo- [23, 24] and pseudo-hypoparathyroidism [25, 26]; B) Brain infections, such as Acquired Immune Deficiency Syndrome (AIDS) [27], Epstein–Barr virus [28], and other meningoencephalitis [29]; C) tumors (mainly angiomas and cerebral gliomas) [30, 31]; D) systemic lupus erythematosus [32, 33]; E) previous head injuries [34]. Calcium deposition involves basal ganglia, thalami, dentate nuclei of cerebellum, and occasionally cortical and sub-cortical frontal, parietal and occipital regions connecting associative cortex to basal ganglia and thalami [35]. The involvement of such a complex system explains the possible presence of movement, cognitive, and behavioral/emotional disorders in affected patients [35]. Histological and chemical studied demonstrated that several minerals are involved in the disease, like iron, magnesium, aluminum, and zinc [3], but the exact pathophysiological pathway is still unknown. We can argue, firstly, that the anatomy of the local arterial system could determine a low blood flow, leading to a reduction of glucose metabolism [36]. Secondly, there could be a slowly progressive metabolic and inflammatory modifications that lead to calcium deposition [37]. Differently from atherosclerotic lesions, the intima is spared [38] and the deposits mainly affect adventitia and basal membrane of the small vessels and the perivascular spaces [39]. Neuronal degeneration and gliosis in the surrounding areas firstly involve astrocytes [40], initially causing hypertrophy and hyperplasia, and finely leading to necrosis [41]. The affected areas are characterized by the deposition of muchopolysaccharides and proteins, followed by calcium and phosphorus in form of hydroxyapatite [42]. The extravascular deposition of an acid mucopolysaccharide-alkalic protein complex was suggested as a mechanism for the secondary accumulation of calcium, with vascular membrane abnormalities responsible for the leakage of plasma-derived fluid as suggested by MRI studies [38]. Furthermore, calcium phosphate deposition would be facilitated by the high concentration of iron and alkaline phosphatase in these areas [43]. Finally, basal ganglia are known to be the target for many other mineral and non-mineral deposits, such as bilirubin in the newborn, methyl-phenyl-tetrahydropyridine (MPTP) and carbon monoxide in poisoning [3], maybe indicating an intrinsic vulnerability of this system.\n\nClinical features\nThe clinical presentation of the disease is really variable with a wide range of clinical presentations, from the completely asymptomatic subject to the patient with severe extrapyramidal and neuropsychiatric disorders. As already said, Manyam reported symptomatic subjects as being about 68 % in a series of 99 patients [15]; in symptomatic patients, the most commonly reported symptoms were movement disorders (55 %), like Parkinsonism, chorea, tremors, dystonia, athetosis, oro-facial diskinesia), followed by cognitive impairment (39 %), speech disorder (36 %), cerebellar impairment (36 %), and psychiatric symptoms (31 %). Relatively rare were pyramidal signs, gait disorders, sensory changes, and pain [15]. No differences in clinical presentation were found comparing secondary forms and Fahr’s disease. Similarly, no specific clinical patterns were found to be associated with the localization of calcium deposits, with similar clinical features in striopallidodentate, striopallidal, and dentate calcinosis. The only aspect significantly influencing the clinical features of Fahr’s disease seems to be the age of onset (probably because of a different and yet completely unknown etiology). Based on this, three different clinical patterns are distinguished [44]: 1) a very rare infantile form; 2) an early onset type, developing symptoms in the thirties, and mainly characterized by schizophrenia-like psychosis, with a lower role of movement disorders; 3) a late onset type, with symptoms onset in the fifties, whose typical features are dementia and movement disorders (Table 2). Movement disorders usually present early in the late onset form (even if sometimes late development of movement disorders have been reported), while they appear late in the early onset form, probably when progressive neurodegeneration exceeds a certain threshold. Dementia, with the classical characteristics of the primary sub-cortical types [45–47], is typical of the late onset type, but in younger patients a secondary evolution to dementia has been reported too. The pathogenesis of cognitive impairment is related to the destruction of connection between basal ganglia and cortex, also leading to fronto-temporal atrophy, formation of cortical neurofibrillar aggregates and loss of neurons, both in cortex and basal ganglia [45]. Psychotic symptoms are characteristic of the early onset form, and an association was hypothesized between the severity of clinical expression and the extension of calcifications [48]. This form was considered by DSM-IV (fourth version of the Diagnostic and Statistical Manual of Mental Disorders) one of the “psychotic disorders due to a general medical condition”, and as other organic psychosis is characterized mainly by hallucinations and delirium, but also mood and attention may be affected. Psychotic symptoms include auditory, visual and olfactory hallucinations, ideas of reference and persecutory delusions [45, 46, 49, 50]. Typically, psychiatric symptoms poorly respond to antipsychotic treatment, and an increase in susceptibility to adverse reactions to these therapies was documented [44]. Finally, in both clinical forms of the disease, other neuropsychiatric symptoms may occur, such as mood disorders (mainly depressive symptoms) and anxiety disorders.Table 2 Principal clinical features of Fahr’s disease\n\n\tFahr’s disease\t\n\tEarly onset\tLate onset\t\nCognitive impairment/dementia\tA cortical dementia may develop in advanced stages\tUsually starts with a subcortical dementia\t\nPsychotic disorders\tOrganic psychosis (basal ganglia calcification); delusion has syndromic pervasiveness behavioral, is moderately structured and organized, has low emotional participation, varied content. Abnormalities of perception are rare.\tOrganic psychosis (dementia): delusion is poorly structured and organized, override the contents of jealousy, poisoning, and persecution. Abnormalities of perception are frequent.\t\nMood disorders\tMay be associated to psychotic symptoms. Depressive disorders are prevalent towards maniacal ones.\tAlways associated with cognitive impairment, may precede symptoms as prodromes. Prevailing depression, irritability, hyper-emotionality, apathy\t\nAnxiety disorders\tPossible association between Fahr’s disease and obsessive-compulsive disorder.\tPossible association between Fahr’s disease and obsessive-compulsive disorder. They can also be associated to cognitive impairment\t\nOther neuro psychiatric/cognitive disorders\tPossible attention’s disorders.\tProgressive alteration of cognitive functions (attention, language, memory, constructive abilities, etc.)\t\nExtrapyramidal movement disorders\tIn advanced stages of the disease.\tMay be present since the onset.\t\nResponse to therapy\tPoor sensibility to neuroleptic treatment; high susceptibility to side effects.\tPoor response to any type of symptomatic therapy. Frequent side effects.\t\n\n\nPrognosis\nFahr’s disease is characterized by a progressive and extremely variable course; for this reason, the prognosis is really variable and hard to predict. The neurodegenerative evolution of the disease was confirmed in two recent studies, in which brain CT scans demonstrated the development of cerebral atrophy in some affected patients [15, 51].\n\nDiagnosis\nThe diagnosis of Fahr’s disease is based on the presence of brain calcification on CT scan, together with the clinical manifestations, in absence of demonstrated alterations in calcium and phosphate serum levels and metabolism. However, because of the frequency of asymptomatic patients, the incidental diagnosis in patients undergoing brain CT scan for other reasons is possible. When parkinsonism is associated to dementia and cerebellar signs, obtaining a CT scan might be helpful [3]; when brain imaging is positive for bilateral striopallidodentate calcification, obtaining serum calcium and parathormone levels should help differentiating Fahr’s disease from hypoparathiroidism, which is the major differential diagnosis [3], leading to the diagnosis of secondary basal ganglia calcification. As regards secondary forms, the diagnosis is made, independently of the presence of symptoms, when cerebral calcifications are present at brain imaging, and a specific factor able to cause them is demonstrated. Among the neuroradiologic exams, brain CT is more sensitive than traditional MRI in the detection of calcium deposits [52], but the recently introduced SWI (Susceptibility-weighted imaging) MRI seems to be more sensitive for early changes [53, 54]; another useful tool is the 99mTehexamethyl-propylenamine oxime (99mTc-HMPAO) single proton emission computed tomography (SPECT)[55], revealing markedly decreased perfusion involving the basal ganglia bilaterally and cerebral cortices [56].\n\nNo marked alterations are found at neurophysiologic studies in Fahr’s disease patients: excluding the possible finding of minor abnormalities at brainstem auditory-evoked potentials, all other neurophysiologic exams give completely normal results [3]. Finally, decreased cerebrospinal fluid levels of calcium were detected in one study [57], but a confirmation is needed yet.\n\nTherapy\nThere is no therapy able to limit the progression of basal ganglia calcification in patients with Fahr’s disease. Moreover, despite a specific approach to all etiological identified factors, no improvement was demonstrated in secondary forms. In this context, at present time management and treatment strategies mainly focus on symptomatic relief, and are strictly related with the clinical features.\n\nConclusions\nIn the present work we describe the clinical presentation of seven subjects with basal ganglia calcification. By comparing these clinical cases with current Literature we observed that actual studies don’t allow conclusions about real clinical features of basal ganglia calcification, in relation to qualitative and methodological limitations. The only exception is represented by inherited Fahr’s disease, in which the early calcium deposition in nucleus pallidus and striatum is inevitably related to severe, although heterogeneous, clinical manifestations. Moreover, it must be pointed out that the very few anatomical pathology studies show a late neuronal involvement; therefore, it is not possible to relate in any way the morphological findings obtained by CT scan with the real impairment of the anatomic pathways concerned. Several observations can be made considering the seven, heterogeneous, presented cases.\n\nPatient of Case 1, was affected by strio-pallido-dentate calcinosis. This is probably a case of Fahr’s disease with severe primitive calcifications, even if a form secondary to cerebrovascular disease cannot be excluded. However, the clinical picture favors the hypothesis of Late onset Fahr’s disease, since well-structured delusions with emotional involvement are very rare in vascular dementia [58]. Extrapiramidal disorders developed two years after the first observation: they might represent late symptoms of the disease or side effect of antipsychotic treatment. The disappointing response to this treatment, and the possible development of side effects, are in favour of Fahr’s disease [44].\n\nCase 2 was affected by strio-pallidal calcinosis [3], probably this was a case of Secondary BGC (Basal Ganglia Calcification) due to the previous brain injury. As reported for early onset forms, the predominant symptom was the psychotic disorder. Also mild cognitive impairment is a typical symptom of BGC, even if in early onset type it usually appears later. Unfortunately, no information about the neurologic examination before starting antipsychotic therapy was available; however at the time of evaluation the patient was amimic: in lack of other elements this could suggest a Parkinsonism. Finally, the unsuccessful response and hypersensitivity to antipsychotic therapy supports SBCG diagnosis [44].\n\nCase 3 presented with a strio-pallidal calcinosis [3] too, but the later beginning of the symptoms configures a late onset idiopathic form, although we don’t actually know the duration of the psychiatric disturbance before the patient was taken in charge. The preponderant symptom was the anxious-depressive syndrome resistant to drugs. The observation of memory deficit suggests the presence of cognitive impairment, even if a complete neuropsychological evaluation was not available. However, the relatively lower impact of cognitive deficit compared with mood disorder is typical of the early onset forms. Besides basal ganglia calcification, the mild atrophy showed at CT scan could explain, at least in part, the cognitive deficits.\n\nCase 4 presented a strio-pallidal calcinosis [3], in this case due to a probable secondary BGC. A mood disorder was the prevalent symptom, even if a mild cognitive impairment was also detected. Two probable etiologic elements must be considered: severe hypovitaminosis D with secondary hyperparathyroidism and brain injury. Alteration in calcium/D vitamin metabolism can be at the basis of BGC [21, 22], but symptoms develop only after the brain injury, which seems to act as a trigger in this case. Probably, the brain injuries accelerated the evolution of the pathology that otherwise would have manifested as a late onset form. Again, the depressive syndrome was resistant to antipsychotic/antidepressant therapy at maximum dose, suggesting that BGC may induce resistance to antidepressant treatment, in addition to cognitive decline (cases 3–4), and head trauma (case 4).\n\nCase 5 presents a strio-pallido-dentate and occipital calcinosis [3], probably of idiopathic origin (Fahr’s disease). Despite a quite extensive calcification, symptoms were really mild, and the diagnosis was incidental. At neuropsychologic evaluation very mild cognitive deficits emerged: this could represent the outset of a late onset form, commonly characterized by dementia [46, 47], even if vascular dementia could not be excluded. Finally, BGC can be secondary to the small brain tumor [30, 31]; usually, gliomas and angiomas are involved, while no association with meningiomas have been reported in literature.\n\nCase 6 presented a strio-pallidal calcinosis [3] probably secondary to hyperparathyroidism. On the opposite of case 5, this patient initially had a mild-moderate burden of calcification, but symptoms were quite severe from the beginning. This late onset form was characterized by progressively worsening cognitive deficits associated with psychotic disturbances partially responsive to therapy. Movement disorders were present from the beginning and continued after suspension and change of treatment. Cognitive impairment was attributable to brain calcifications since it progressed to severe dementia before the appearance of vascular lesions and atrophy.\n\nFinally, case 7 presented a strio-pallido-dentate calcinosis [3] probably due to secondary hyperparathyroidism. The patient showed a late onset form with early cognitive and motor dysfunction and later appearance of behavior disturbances. The brain atrophy and the responsiveness of behavioral disturbances to treatment may suggest the disturbances were secondary to degenerative encephalopathy, rather than to BGC. Another possibility is to consider the brain atrophy itself as a consequence of BCG, as neurodegeneration has been reported to occur later in the course of the disease in some cases [15, 51]. The hypertonia unresponsive to L-dopa could be due to BGC or to cerebrovascular disease, suggested by the anamnestic presence of previous stroke.\n\nThe conclusions of our report are limited by the lack of anatomical pathology studies evaluating the real burden of calcification, and by the incomplete information we obtained about some of our cases. However, Fahr’s disease is a quite rare disorder, and by comparing 7 cases (one with each other and with literature) we could suggest some interesting conclusions:Cognitive impairment\n\n\n\nEven with a variable severity, it seems to be a constant finding in patients with basal ganglia calcification; in particular, the two domains most commonly involved in our experience seem to be memory and attention. This observation might result from the fact that basal ganglia play a role in maintaining the integrity of cognitive functions. Alternatively, the calcification of basal ganglia may be a marker of other alterations related to cognitive impairment, such as reduction of cerebral blood flow, atrophy, ischemic sub-cortical lesions. Anyway, our findings strongly argue against the lack of cognitive symptoms in these type of patients.2. Anxiety and depression\n\n\n\nThey are common in patients with basal ganglia calcification, but less than the cognitive decline. In our experience, depression in BGC is resistant to pharmacologic therapy. Anxiety and depression might be secondary to the impairment of the serotonin and dopamine pathways involved in the limbic system. Depression, frequently associated to cognitive impairment, might also represent a phenomenon preceding the onset of dementia, as often happens in the natural history of this disease [59].3. Psychotic disorders\n\n\n\nThey may be associated to basal ganglia calcification. When present, they are usually severe, with different grade of structure and emotional involvement; nevertheless, we didn’t observe a clear pattern of presentation of psychotic symptoms (different organic background?). Moreover, in agreement with literature, psychosis poorly responds to specific treatment.4. Extrapyramidal disorders\n\n\n\nWe observed only few cases (4/7) of extra pyramidal disorders probably related to the disease; in particular, significant gait disturbances and tremor were developed by the three older individuals. Anyway, a mild extra pyramidal syndrome might have developed also as a side effect of antipsychotic drugs.\n\nIn conclusion, while Fahr's disease with early onset seems to present fairly homogeneously, the clinical presentation of late-onset forms of Idiopathic/Secondary BGC seems to be much more heterogeneous, as evidenced by the presented clinical cases and the data from literature.\n\nBased on these results, we discourage the use of the term “Fahr’s syndrome” to describe secondary causes, and prefer referring to them as “Secondary Basal Ganglia Calicification”.\n\nOur data don’t allow to address the border phenotype between physiological calcinosis and putative pathological calcinosis of basal ganglia, since in our case series all of seven cases present some pathological aspects. This result might come from a “selection bias”: working in a Clinic for the study of Cognitive Impairment, most of the patients we evaluate come to our attention because of cognitive/behavioural/mood disturbances. However, we found basal ganglia calcifications in about 0.9 % of our patients, and this result is not different from the 0.8 % found in the general population by Daghighi et al. [8]. In our case series, basal ganglia calcification never seems to be an isolated and clinically insignificant finding, but always underlies cognitive/psychiatric/motor disturbances. Of consequence, although in some cases basal ganglia calcification might be an occasional finding, some cases (unknown percentage) present with overt clinical symptoms, and the degree of calcification at neuroimaging does not necessary correlate with the severity of clinical picture. Of consequence, we suggest that all subjects with the finding of BGC undergo a screening of cognitive performance and mood state. It could be correct to consider affected by “Fahr’s disease” only people in which BGC have a pivotal role in determining the symptoms, while all conditions in which calcifications are the marginal consequence of different insults to basal ganglia should be labelled as BGC.\n\nAbbreviations\n99mTc-HMPAO99mTehexamethyl-propylenamine oxime\n\nAIDSAcquaired Immune Deficiency Syndrome\n\nBGCBasal ganglia calcification\n\nCOPDChronic Obstructive Pulmonary Disease\n\nCTComputed Tomography\n\nDSM-IVFourth version of the Diagnostic and Statistical Manual of Mental Disorders\n\nMMSEMini Mental State Examination\n\nMODAMilan Overall Dementia Assessment\n\nMPTPMethyl-phenyl-tetrahydropyridine\n\nMRIMagnetic Resonance Imaging\n\nSPECTSingle Proton Emission Computed Tomography\n\nSSRISelective Serotonin Reuptake Inhibitors\n\nWAIS-RWechsler Adult Intelligence Scale\n\nAcknowledgements\nNothing to be acknowledged.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nNot appliable.\n\nAuthors’ contributions\nES and CS participated to the design of the study, acquired data and drafted and revised the manuscript. EC acquired data and participated in drafting the manuscript. GBV participated to the conception of the study, and revised the manuscript. MB participated to the conception of the study, interpreted the imaging and revised the manuscript. AP and GZ participated to the design of the study and revised the manuscript. All authors read and approved the final version of the manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent for publication (including details, images, or videos relating to individual participants) was obtained from all participants (or their parent or legal guardian).\n\nEthics approval and consent to participate\nAll subjects and their caregivers were informed in detail about the research and gave their written consent to participate to the study. The study was carried out accordingly to the Declaration of Helsinki (World Medical Association, http://www.wma.net), the guidelines for Good Clinical Practice (European Medicines Agency, http://www.ema.europa.eu), and the guidelines of the local ethic committee (S. Anna University Hospital, Ferrara, Italy). All personal data were blinded so that it was not possible to go back to patients’ identity. Since the study did not deviate from current normal clinical practice, and had no additional burden or additional risks imposed on the patients, the study was not proposed for the ethic committee approval.\n==== Refs\nReferences\n1. Manyam BV Bilateral striopallidodentate calcinosis: a proposed classification of genetic and secondary causes Mov Disord 1990 5 1 94 10.1002/mds.870050112 \n2. Klein C Vieregge P The confusing history of ‘Fahr’s disease’ Neurology 1998 50 4 A59 \n3. 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"fulltext_license": "CC BY",
"issn_linking": "1471-2377",
"issue": "16()",
"journal": "BMC neurology",
"keywords": "Basal ganglia calcification; Case report; Fahr’s disease; Neurodegeneration",
"medline_ta": "BMC Neurol",
"mesh_terms": "D000328:Adult; D000368:Aged; D001480:Basal Ganglia Diseases; D002114:Calcinosis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases; D013577:Syndrome",
"nlm_unique_id": "100968555",
"other_id": null,
"pages": "165",
"pmc": null,
"pmid": "27608765",
"pubdate": "2016-09-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "571978;13357333;7312741;15733784;9596016;17925363;20951361;21891938;11352376;14325917;17594669;12611239;16288137;7231643;23879399;7931433;1586138;13302894;15258221;24286000;11295778;17277397;6508450;11784818;10441584;18332839;7191528;14618548;7699451;9706533;11253108;857589;8509774;8493595;15734663;8743125;7334414;6860732;18600421;77318;533249;7163797;17917073;7350641;678079;1695401;26280254;3748385;19757205;3950660",
"title": "Bilateral strio-pallido-dentate calcinosis (Fahr's disease): report of seven cases and revision of literature.",
"title_normalized": "bilateral strio pallido dentate calcinosis fahr s disease report of seven cases and revision of literature"
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"abstract": "BACKGROUND\nHigh-risk acute leukemia (AL) and myelodysplastic syndrome (MDS) remain a therapeutic challenge. Unmanipulated haploidentical-related donor transplantation based on a myeloablative conditioning regimen (HAPLO-MAC) and post-transplant cyclophosphamide (PT-Cy) as prophylaxis against graft vs host disease (GvHD) is now a promising rescue strategy that could become universally available.\n\n\nOBJECTIVE\nTo evaluate the results of HAPLO-MAC with PT-Cy in patients with AL and MDS reported to the Haploidentical Transplantation Subcommittee of the Spanish Group for Hematopoietic Transplantation (GETH).\n\n\nMETHODS\nWe report our multicenter experience using an IV busulfan-based HAPLO-MAC regimen and PT-Cy for treatment of 65 adults with high-risk AL and MDS.\n\n\nRESULTS\nEngraftment was recorded in 64 patients (98.5%), with a median time to neutrophil and platelet recovery of 16 and 27 days, respectively. The cumulative incidence of grade II-IV acute GvHD and chronic GvHD was 28.6% and 27.5%, respectively. After a median follow-up of 31 months for survivors, the cumulative incidence of non-relapse mortality and relapse at 2 years was 18.8% and 25%, respectively. Estimated 30-month event-free survival and overall survival were 56% and 54.5%, respectively.\n\n\nCONCLUSIONS\nHAPLO-MAC comprising an IV busulfan-based conditioning regimen enabled long-term disease control with acceptable toxicity in high-risk AL and MDS.",
"affiliations": "Facultad de Medicina Universidad Complutense, HGU Gregorio Marañón, Madrid, Spain.;Facultad de Medicina Universidad Complutense, HGU Gregorio Marañón, Madrid, Spain.;Facultad de Medicina Universidad Complutense, HGU Gregorio Marañón, Madrid, Spain.;Hospital Universitario Ramón y Cajal, Madrid, Spain.;Hospital Universitario Marqués de Valdecilla, Santander, Spain.;Hospital Universitario Son Espases, Palma de Mallorca, Spain.;Hospital Universitario Doctor Negrín, Las Palmas de Gran Canaria, Spain.;Hospital Clínico Universitario, Salamanca, Spain.;Facultad de Medicina Universidad Complutense, HGU Gregorio Marañón, Madrid, Spain.;Hospital Universitario La Fé, Valencia, Spain.;Hospital Regional Universitario, Málaga, Spain.;HGU Morales Meseguer, Murcia, Spain.;Hospital Universitario Son Espases, Palma de Mallorca, Spain.;Hospital Universitario de A Coruña, A Coruña, Spain.;Hospital Universitario La Paz, Madrid, Spain.;Complejo Hospitalario de Navarra, Pamplona, Spain.;Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.;Facultad de Medicina Universidad Complutense, HGU Gregorio Marañón, Madrid, Spain.;Facultad de Medicina Universidad Complutense, HGU Gregorio Marañón, Madrid, Spain.;Facultad de Medicina Universidad Complutense, HGU Gregorio Marañón, Madrid, Spain.;Facultad de Medicina Universidad Complutense, HGU Gregorio Marañón, Madrid, Spain.;Facultad de Medicina Universidad Complutense, HGU Gregorio Marañón, Madrid, Spain.",
"authors": "Gayoso|Jorge|J|http://orcid.org/0000-0002-6057-6672;Balsalobre|Pascual|P|;Kwon|Mi|M|;Herrera|Pilar|P|;Bermúdez|Arancha|A|;Sampol|Antonia|A|;Jiménez|Santiago|S|;López-Corral|Lucía|L|;Serrano|David|D|;Piñana|Jose Luis|JL|;Pascual|María J|MJ|;Heras|Inmaculada|I|;Bento|Leyre|L|;Varela|Rosario|R|;Humala|Karem|K|;Zabalza|Amaya|A|;Laiglesia|Almudena|A|;Bastos-Oreiro|Mariana|M|;Pérez-Corral|Ana|A|;Martínez-Laperche|Carolina|C|;Buño|Ismael|I|;Díez-Martín|José L|JL|;|||",
"chemical_list": "D002066:Busulfan",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.13103",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "101(3)",
"journal": "European journal of haematology",
"keywords": "acute leukemia; haploidentical transplantation; myeloablative conditioning; myelodysplastic syndromes; post-transplant cyclophosphamide",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002066:Busulfan; D003131:Combined Modality Therapy; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007938:Leukemia; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D012008:Recurrence; D019233:Retreatment; D016019:Survival Analysis; D019172:Transplantation Conditioning; D000075442:Transplantation, Haploidentical; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "332-339",
"pmc": null,
"pmid": "29846964",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Busulfan-based myeloablative conditioning regimens for haploidentical transplantation in high-risk acute leukemias and myelodysplastic syndromes.",
"title_normalized": "busulfan based myeloablative conditioning regimens for haploidentical transplantation in high risk acute leukemias and myelodysplastic syndromes"
} | [
{
"companynumb": "PHHY2018ES067924",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nGall bladder carcinoma is one of the most common cancers in India. Gall bladder cancer with metastasis to the breast is very rare. Herein we intend to report a case of carcinoma gall bladder with breast metastasis and a short review of the literature.\n\n\nMETHODS\nThis report describes an interesting and unusual case of gall bladder carcinoma presenting with breast metastasis.\n\n\nMETHODS\nA 38-year lady presented with complaints of right abdominal pain. Bilateral breast examination showed 2×2cm palpable lump in the upper outer quadrant of the left breast. Contrast-enhanced CT of the abdomen and pelvis showed circumferential thickening of gall bladder with the loss of fat plane with the adjacent liver parenchyma. Biopsy from the breast lump was reported as metastatic adenocarcinoma compatible with primary in the gall bladder. Whole body PET-CT showed gall bladder mass with abdominal and pelvic nodes with metastasis to liver, left breast, C7 vertebral body and left supra-clavicular node. She was diagnosed to have disseminated carcinoma gall bladder with liver, breast and supraclavicular nodal metastasis. She received palliative chemotherapy with gemcitabine and carboplatin and radiotherapy to C7 vertebra. After receiving 3 cycles of chemotherapy, chemotherapy was changed to the second line with single agent capecitabine. In spite of two lines of chemotherapy, she succumbed to disease progression and expired.\n\n\nCONCLUSIONS\nThere are limited examples of gall bladder adenocarcinoma with simultaneous metastasis to breast in the English literature. Our case showed an unusual dissemination of gall bladder cancer.",
"affiliations": "Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India. Electronic address: damodar.dr@gmail.com.;Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India.;Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India.;Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.;Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Kumaran|Damodara|D|;Anamalai|Manikandan|M|;Velu|Umesh|U|;Nambirajan|Aruna|A|;Julka|Pramod Kumar|PK|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D016190:Carboplatin",
"country": "England",
"delete": false,
"doi": "10.1016/j.jnci.2016.06.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1110-0362",
"issue": "28(4)",
"journal": "Journal of the Egyptian National Cancer Institute",
"keywords": "Breast metastasis; Case series; Gall bladder carcinoma",
"medline_ta": "J Egypt Natl Canc Inst",
"mesh_terms": "D000328:Adult; D001943:Breast Neoplasms; D016190:Carboplatin; D002277:Carcinoma; D003841:Deoxycytidine; D005260:Female; D005706:Gallbladder Neoplasms; D006801:Humans; D009362:Neoplasm Metastasis; D065126:Palliative Medicine",
"nlm_unique_id": "9424566",
"other_id": null,
"pages": "263-266",
"pmc": null,
"pmid": "27381065",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Carcinoma of Gall bladder with distant metastasis to breast parenchyma. Report of a case and review of literature.",
"title_normalized": "carcinoma of gall bladder with distant metastasis to breast parenchyma report of a case and review of literature"
} | [
{
"companynumb": "IN-CIPLA LTD.-2016IN09759",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"d... |
{
"abstract": "BACKGROUND\nHormone therapies, particularly those targeting estrogen and its receptors, are a key treatment modality for patients with estrogen receptor (ER)-positive breast or ovarian cancer. Some gastric cancers (GCs) express ERs, and preclinical studies suggest the potential of estrogen-targeting hormone therapy on GC; however, the clinical relevance of this hormone therapy on GC treatment has not been well elucidated.\nAn 80-year-old female was admitted to our department with hypogastric pain and vomiting. Computed tomography demonstrated small bowel obstruction, and laparotomy after bowel decompression revealed peritoneal dissemination consisting of a poorly-differentiated adenocarcinoma. Intestinal bypass between the ileum and transverse colon was performed.\nThe tumor was ER- and mammaglobin-positive, indicating that it originated from a breast cancer. Diagnostic imaging revealed no evidence of breast cancer; however, right axillary ER- and mammaglobin-positive lymphadenopathy was found.\n\n\nMETHODS\nThe patient received hormone therapy using letrozole based on a clinical diagnosis of occult breast cancer with peritoneal dissemination and right axillary lymph node metastasis.\n\n\nRESULTS\nThe patient remained disease free until 37 months but deceased at 53 months from the onset of disease. An autopsy revealed no tumor cells in the right breast tissue; however, there was a massive invasion of cancer cells in the stomach.\n\n\nCONCLUSIONS\nA patient with ER positive GC with peritoneal dissemination and right axillary lymph node metastasis presented remarkable response to letrozole. The long-term survival obtained using letrozole for a patient with GC with distant metastasis suggests the potential of estrogen targeting hormone therapies for GC.",
"affiliations": "Department of Surgery, Yaizu City Hospital.;Department of Surgery, Yaizu City Hospital.;Department of Surgery, Yaizu City Hospital.;Department of Surgery, Yaizu City Hospital.;Department of Surgery, Yaizu City Hospital.;Department of Surgery, Yaizu City Hospital.;Department of Surgery, Yaizu City Hospital.;Department of Pathology, Yaizu City Hospital 1000 Dobara, Yaizu city, Shizuoka, Japan.;Department of Surgery, Yaizu City Hospital.",
"authors": "Iida|Yuuki|Y|0000-0003-2929-9619;Hongo|Kumiko|K|;Onoda|Takanobu|T|;Kita|Yusuke|Y|;Ishihara|Yukio|Y|;Takabayashi|Naoki|N|;Kobayashi|Ryo|R|;Kuriki|Ken|K|;Hiramatsu|Takeyuki|T|",
"chemical_list": "D000970:Antineoplastic Agents; D011960:Receptors, Estrogen; D000077289:Letrozole",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000026146",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\n34032767\nMD-D-21-01893\n10.1097/MD.0000000000026146\n26146\n4500\nResearch Article\nClinical Case Report\nLong-term response on letrozole for gastric cancer\nA case report\nIida Yuuki MD, PhD a∗\nHongo Kumiko MD, PhD a\nOnoda Takanobu MD a\nKita Yusuke MD, PhD a\nIshihara Yukio MD, PhD a\nTakabayashi Naoki MD a\nKobayashi Ryo MD a\nKuriki Ken MD, PhD b\nHiramatsu Takeyuki MD, PhD a\nSaranathan. Maya\na Department of Surgery, Yaizu City Hospital\nb Department of Pathology, Yaizu City Hospital 1000 Dobara, Yaizu city, Shizuoka, Japan.\n∗ Correspondence: Yuuki Iida, Department of Surgery, Yaizu City Hospital, 1000 Dobara, Yaizu city 425-8505, Shizuoka, Japan (e-mail: yiida-tky@umin.ac.jp).\n28 5 2021\n28 5 2021\n100 21 e2614615 3 2021\n28 4 2021\n11 5 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nRationale:\n\nHormone therapies, particularly those targeting estrogen and its receptors, are a key treatment modality for patients with estrogen receptor (ER)-positive breast or ovarian cancer. Some gastric cancers (GCs) express ERs, and preclinical studies suggest the potential of estrogen-targeting hormone therapy on GC; however, the clinical relevance of this hormone therapy on GC treatment has not been well elucidated.\n\nPatient concerns:\n\nAn 80-year-old female was admitted to our department with hypogastric pain and vomiting. Computed tomography demonstrated small bowel obstruction, and laparotomy after bowel decompression revealed peritoneal dissemination consisting of a poorly-differentiated adenocarcinoma. Intestinal bypass between the ileum and transverse colon was performed.\n\nDiagnoses:\n\nThe tumor was ER- and mammaglobin-positive, indicating that it originated from a breast cancer. Diagnostic imaging revealed no evidence of breast cancer; however, right axillary ER- and mammaglobin-positive lymphadenopathy was found.\n\nInterventions:\n\nThe patient received hormone therapy using letrozole based on a clinical diagnosis of occult breast cancer with peritoneal dissemination and right axillary lymph node metastasis.\n\nOutcomes:\n\nThe patient remained disease free until 37 months but deceased at 53 months from the onset of disease. An autopsy revealed no tumor cells in the right breast tissue; however, there was a massive invasion of cancer cells in the stomach.\n\nLessons:\n\nA patient with ER positive GC with peritoneal dissemination and right axillary lymph node metastasis presented remarkable response to letrozole. The long-term survival obtained using letrozole for a patient with GC with distant metastasis suggests the potential of estrogen targeting hormone therapies for GC.\n\nKeywords\n\ncase report\nestrogen receptor\ngastric cancer\nhormone therapy\nletrozole\nOPEN-ACCESSTRUE\n==== Body\n1 Introduction\n\nCurrently, systemic therapies for unresectable locally advanced, recurrent or metastatic gastric cancer (GC) include chemotherapies and a limited variation of molecular targeted therapies.[1] Preferred regimens for first-line therapy are a combination of fluoropyrimidines (e.g., fluorouracil or capecitabine) and platinum-based agents (e.g., cisplatin or oxaliplatin). ECF (epirubicin, cisplatin, and fluorouracil), DCF (docetaxel, cisplatin, and fluorouracil) and their modifications are also applicable for the first-line therapy.[1] Preferred second-line therapy is a combination of taxanes (paclitaxel or nab-paclitaxel) and ramucirumab.[1–3] Other chemotherapeutic agents, such as irinotecan, docetaxel, or trifluridine/tipiracil, are also candidates for second- or later-line treatment.[1,4] Besides these chemotherapies, molecular targeted therapies have been recently applied in clinical practice; trastuzumab for HER2-positive GC, ramucirumab targeting VEGF2R used in second-line treatment with taxanes, and nivolumab, a monoclonal anti-programed death-1 antibody, known as immune checkpoint inhibitor.[1,5] Despite these advances in chemotherapies and molecular targeted therapies for GC treatment, many of the clinical trials demonstrated median overall survival less than 18 months for unresectable locally advanced, recurrent, or metastatic GC; thus, alternative therapies need to be investigated to improve the prognosis of this disease.\n\nRecently, many investigators have explored the potential of applying hormone therapy on GC, particularly targeting estrogen and estrogen receptor (ER).[6–9] Hormone therapy targeting estrogen consists of an aromatase inhibitor, an ER inhibitor (tamoxifen), and a selective ER degrader (fulvestrant).[10] Aromatase inhibitor, such as letrozole, exemestane, or anastrozole, are applied for the treatment of breast cancer in postmenopausal women. On the contrary, tamoxifen is mainly selected for premenopausal women with breast cancer.[10] Although several reports have documented the effect of hormonal replacement therapy (HRT) or tamoxifen use on GC development,[11–16] studies investigating the potential of estrogen targeting hormone therapy on GC treatment are currently very limited, and there are no recent reviews on this topic. Herein, we report a case of GC that presented with a long-term response on letrozole and reviewed recent progress in estrogen targeting hormone therapy for GC.\n\n2 Case report\n\nAn 80-year-old female, who underwent right hemicolectomy with lymph node dissection for ascending colon cancer one and half year ago (moderately-differentiated adenocarcinoma, Stage IIIa, UICC eighth edition), was admitted to our department with hypogastric pain and vomiting. The patient had slight anemia (Hb 10.3 g/dL) and high CA125 (902 U/mL), but CEA (3.1 ng/mL), CA19-9 (20.2 U/mL), CA72-4 (0.9 U/mL), and CA15-3 (11.4 U/mL) were within normal range. Computed tomography (CT) demonstrated small bowel obstruction and ascites in the pelvis and on the liver surface (Fig. 1A). After decompression of the small bowel with long-tube insertion, injection of contrast medium through the tube demonstrated a stenosed segment in the small bowel (Fig. 1B). The patient underwent laparotomy, which revealed peritoneal dissemination of a poorly differentiated adenocarcinoma diagnosed by intraoperative rapid diagnosis. For relieving the small bowel obstruction due to dissemination, intestinal bypass between the ileum and transverse colon was performed. The patient experienced no postoperative complication and started oral intake 4 days after the surgery.\n\nFigure 1 ER-positive poorly-differentiated adenocarcinoma from peritoneal dissemination. (A). Contrast-enhanced CT scan of the abdomen showing dilated small bowel (arrows) and ascites on the liver surface (arrowhead). (B). Gastrografin contrast radiography through long-tube showing a stenosed segment in the small bowel. Histopathological findings showing the proliferation of poorly-differentiated adenocarcinoma in the disseminated tissue (C, ×200) and proliferation of moderately-differentiated adenocarcinoma in the ascending colon cancer (D, ×200). Immunohistochemical examination showing positive results for ER (E, ×200) and mammaglobin (F, ×200) from the disseminated tissue.\n\nHistopathological examination confirmed proliferation of a poorly-differentiated adenocarcinoma in the resected specimen from the dissemination. Its feature was distinct from moderately-differentiated adenocarcinoma observed in the previous ascending colon cancer (Fig. 1C and 1D), suggesting the presence of an independent primary tumor. Immunohistochemical examination demonstrated positive results for cytokeratin (CK) 7, CK19, ER, progesterone receptor, and mammaglobin, whereas negative for CK20, GCDFP15, TTF1, or CDX-2 (Fig. 1E and 1F). The presence of ER, progesterone receptor, and mammaglobin expression indicated that the tumor originated from breast cancer. Ultrasonography, CT, and magnetic resonance imaging revealed lymphadenopathy in the right axilla (Fig. 2A and 2B); however, there was no evidence of breast cancer. The patient underwent surgical removal of the lymph node under local anesthesia, and histopathological and immunohistochemical examination demonstrated a similar pattern from the peritoneal dissemination (ER and mammaglobin-positive, Figures 2C and 2D). Based on these findings, we made a diagnosis of occult breast cancer with peritoneal dissemination and right axillary lymph node metastasis. Additionally, 18F-fluorodeoxyglucose positron emission tomography (PET)/CT, esophagogastroduodenoscopy, and colonoscopy revealed no evidence of other primary tumors. The patient and her family declined intensive chemotherapy for breast cancer to avoid severe adverse effects and decided to receive hormone therapy using letrozole for ER-positive breast cancer. Ascites diminished and CA125 rapidly decreased (Fig. 3A), and the patient remained free of disease until 37 months after the treatment without experiencing severe adverse effects. CT scan revealed ascites, pleural effusion, and multiple bone metastasis at 48 months (Fig. 3B and 3C), and she deceased from the cancer at 53 months.\n\nFigure 2 Proliferation of ER-positive poorly-differentiated adenocarcinoma in the right axilla. Ultrasonography (A) and CT (B) images showing lymphadenopathy in the right axilla. (C). Histopathological examination showing proliferation of the poorly-differentiated adenocarcinoma in the right axilla (×150). (D). Immunohistochemical examination showing positive result for ER (×150).\n\nFigure 3 Clinical course with letrozole treatment. (A). Chronological change in serum CA125 level after laparotomy. CT scan showing pleural effusion (B) and ascites (C) at 48 months.\n\nAn autopsy was performed to confirm the clinical diagnosis and treatment. The autopsy revealed no tumor cells in the right breast tissue; however, massive invasion and proliferation of poorly-differentiated adenocarcinoma was observed in the stomach (Fig. 4A and 4B), indicating that the tumor originated from GC. Interestingly, the tumor cells presented positive mammaglobin expression (Fig. 4C); however, no cells expressed ER, suggesting that the tumor cells acquired resistance during hormone therapy under drug pressure. The final diagnosis was ER-positive GC with peritoneal dissemination and right axillary lymph node metastasis; therefore, we concluded that GC presented remarkable response to letrozole.\n\nFigure 4 ER-positive gastric cancer specified by an autopsy. (A). Macroscopic image of the stomach obtained from an autopsy showing stiffness and thickening of the gastric wall. (B). Histopathological examination showing proliferation of poorly differentiated adenocarcinoma in the stomach (×400). (C). Immunohistochemical examination showing positive results for ER (×400).\n\n3 Discussion\n\n3.1 ER expression in GC\n\nThe prevalence of ER-positive GC varies between literatures and differs between ER subtypes, namely ERα and ERβ.[17,18] Both ERs are members of a superfamily of nucleus receptors and exert their functions through a genomic pathway; estrogen binding promotes ER dimerization, the complex translocates into the nucleus, binds to estrogen response elements on the genomic DNA with transcriptional co-activators or co-repressors, and regulates DNA transcription of specific genes. There also exists a non-genomic pathway; ERs interact with other signaling molecules involved in MAPK or PI3K/Akt pathways.[17,18] Interestingly, at sub-saturating hormone levels, ERβ functions as an inhibitor/competitor of ERα transcriptional activity, suggesting the relative expression level of the ER subtypes determine cellular responses to ER agonists and antagonists.[17,19] Accordingly, the association between ER expression and clinicopathological features of GC differs between ERα and ERβ. There exist 3 isoforms for ERα, namely ERα66, ERα46, and ERα36, and their difference lies in their distinct transcriptional activation factors (AF-1 and AF-2). Of clinical relevance, ERα66 expression is associated with diffuse type GC, shorter DFS, or poor OS,[8,17,20,21] whereas ERα36 expression is correlated with lymph node metastasis in clinical samples.[22] Five different isoforms, ERβ1- ERβ5, have been identified for ERβ. Contrary to ERα, ERβ expression is associated with lower tumor stage, intestinal type, and free of recurrence.[17,23] Another study demonstrated the absence of ERβ as an independent factor for poor OS, indicating the suppressive effect of ERβ on GC progression.[21] These results suggest that ERα and ERβ have distinct effects on GC progression and that distinguishing ER subtype is essential. A recent meta-analysis also demonstrated that high ERα predicted poor OS and lower tumor differentiation, while high ERβ suggested favorable OS and higher tumor differentiation,[24] further supporting the distinct function between ER subtypes in GC.\n\nThe prevalence of ER-positive GC ranges between 4.3% to 49.6% for ERα[8,25,26] and 32% to 93.5% for ERβ.[25–27] The positivity rates vary between studies, probably due to the difference in clinical background and evaluation (e.g., staining procedures and threshold for positive ER staining). As a considerable number of GC cases are ER positive, preclinical and clinical studies investigating the interaction between estrogen, ER, and GC potentially provides us additional strategies to overcome GC with metastasis.\n\n3.2 Effect of HRT and tamoxifen use on GC development\n\nIn contrast to a limited number of investigations on hormone therapy in the treatment of GC, more reports have referred to the risk of GC development after HRT or tamoxifen use (an inhibitor of ER).[11–16] Epidemiologic studies demonstrating male dominance of GC suggest a possible role of sex hormones on the oncologic risk of GC.[28] A population-based study from Shanghai indicated that female hormones play a protective role in GC risk.[12] Another population-based study from Sweden also demonstrated that the incidence of esophageal cancer and GC decreased with HRT.[13] These results indicate the protective role of estrogen on GC risk. Conversely, tamoxifen use might accelerate GC progression or increase the GC risk based on population-based studies[14,15]; however, a recent meta-analysis demonstrated that there was no substantial GC risk with tamoxifen use in female patients.[16] These studies refer to the preventive effect of HRT or potential risk of tamoxifen use on the development of GC; the effect of long-term exposure to estrogen or tamoxifen on the oncogenesis or progression of GC.\n\n3.3 Potential of hormone therapy for GC treatment\n\nSeveral preclinical studies using GC cell lines suggest the potential of applying estrogen-targeting hormone therapy on GC. One of the ER-targeting agents, tamoxifen, has an anti-proliferative effect on GC cell lines.[9] Stimulation of GC cell lines with 17β-estradiol (E2) promoted proliferation, up-regulated ER-α36 mRNA expression, and repressed cell apoptosis. Conversely, tamoxifen treatment repressed proliferation, downregulated ER-α36 mRNA expression, and induced apoptosis, indicating the suppressive effect of tamoxifen on GC growth. Exemestane, an inhibitor of aromatase enzymatic function, also demonstrated a similar effect on GC cells.[7] Aromatase is a key enzyme that catalyzes the conversion of androstenedione or testosterone to estradiol or estrone, and a high expression of aromatase was associated with poor overall survival in patients with GC. Exemestane inhibited aromatase and suppressed colony formation both in GC cell lines and a xenograft mouse model. Interestingly, the addition of 5-FU facilitated the suppressive effect of exemestane.[7] Another agent, fulvestrant, an analog of E2 that downregulates and degrades ERα, also demonstrated anti-neoplastic efficacy on GC cells.[8] E2 enhanced the proliferation of ER-positive GC cell lines, while the administration of fulvestrant repressed the proliferative effect of E2. Furthermore, fulvestrant presented synergistic anti-proliferative effect with paclitaxel.[8] These results from preclinical studies provide a rationale for estrogen-targeting hormone therapy for GC treatment. Of clinical importance, the above-mentioned agents are already applied in clinical practice for patients with ER-positive breast cancer, thus these therapies are well characterized and managed for their adverse effects.[10]\n\nClinically, there is only 1 report demonstrating the clinical effect of hormone therapy on GC.[6] They reported a case with ER-positive breast cancer treated with letrozole. The patient also suffered from independent primary GC with no ER expression and decided to initially start with letrozole treatment to regulate the breast cancer. Following the letrozole treatment, the patient underwent a staging laparoscopy followed by a subtotal D2 gastrectomy. Surprisingly, histopathological examination demonstrated no evidence of malignancy from the resected stomach and lymph nodes. Their report suggests the possibility of applying letrozole for GC treatment in clinical practice, although the mechanisms by which letrozole exerted its suppressive effect on ER-negative GC is unclear. In our case, metastatic GC showed positive ER expression, providing stronger rationale for the application of hormone therapy in GC. Patients with GC with peritoneal metastasis demonstrates poor OS for less than 18 months even with intensive surgery and chemotherapy.[29,30] However, our case demonstrated remarkable response to hormone therapy and long-term survival for more than 50 months. To the best of our knowledge, we report the first case demonstrating long-term repression of ER positive GC using letrozole.\n\n3.4 Applying hormone therapy on cancer of unknown primary with positive ER expression\n\nThe initial diagnosis in our case was occult breast cancer with peritoneal dissemination and right axillary lymph node metastasis; however, the origin of the tumor was GC at the final diagnosis. Immunohistochemical examination is indispensable to precisely specify the origin of the tumor for patients presenting a non-stereotypical clinical course as in this case or those with cancer of unknown primary (CUP).[31] Breast cancer has multiple specific immunohistochemical markers, such as GATA3, mammaglobin, and GCDFP-15[32–34]; however, there are no specific markers strongly recommended or commonly used for GC, making it difficult to specify the origin in GC cases.[31] Five percent of CUP cases are originating from GC based on autopsy,[35] and they are potential candidates for hormone therapy when ER expression is positive. Currently, estrogen-targeting hormone therapy for ER-positive CUP is not recommended unless breast cancer is expected as an origin[10,31]; however, exploring GC specific markers as well as investigating estrogen-targeting hormone therapy for GC potentially improves the prognosis of CUP that are actually originated from GC.\n\n4 Conclusions\n\nWe report a case of ER-positive GC with peritoneal dissemination and right axillary lymph node metastasis that displayed remarkable response on letrozole and long-term survival. Accumulation of GC case series treated with hormone therapy and further preclinical studies are encouraged for the wide application of hormone therapy on GC, and eventually, to facilitate clinical trials.\n\nAuthor contributions\n\nConceptualization: Yuuki Iida, Kumiko Hongo, Takanobu Onoda, Ryo Kobayashi.\n\nData curation: Yuuki Iida, Kumiko Hongo, Yusuke Kita, Naoki Takabayashi, Ken Kuriki.\n\nSupervision: Yukio Ishihara, Ken Kuriki, Takeyuki Hiramatsu.\n\nWriting – original draft: Yuuki Iida, Kumiko Hongo, Yusuke Kita, Yukio Ishihara, Naoki Takabayashi.\n\nWriting – review & editing: Yuuki Iida, Kumiko Hongo, Takanobu Onoda, Yusuke Kita, Ryo Kobayashi, Ken Kuriki, Takeyuki Hiramatsu.\n\nAbbreviations: CK = cytokeratin, CT = computed tomography, CUP = cancer of unknown primary, ER = estrogen receptor, GC = gastric cancer.\n\nHow to cite this article: Iida Y, Hongo K, Onoda T, Kita Y, Ishihara Y, Takabayashi N, Kobayashi R, Kuriki K, Hiramatsu T. Long-term response on letrozole for gastric cancer: a case report. Medicine. 2021;100:21(e26146).\n\nPatient has provided informed consent for performing the treatment and publication of the case. Institutional review board in Yaizu City Hospital approved publication of current study.\n\nThe authors have no funding and conflicts of interests to disclose.\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n\n[1] Ajani JA D’Amico TA Almhanna K . Gastric cancer, version 3.2016; clinical practice guidelines in oncology. JNCCN J Natl Compr Cancer Netw 2016;doi:10.6004/jnccn.2016.0137.\n[2] Koizumi W Morita S Sakata Y . A randomized Phase III trial of weekly or 3-weekly doses of nab-paclitaxel versus weekly doses of Cremophor-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE Trial). Jpn J Clin Oncol 2015;doi:10.1093/jjco/hyu205.\n[3] Bando H Shimodaira H Fujitani K . A phase II study of nab-paclitaxel in combination with ramucirumab in patients with previously treated advanced gastric cancer. Eur J Cancer 2018;doi:10.1016/j.ejca.2017.11.032.\n[4] Shitara K Doi T Dvorkin M . Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2018;doi:10.1016/S1470-2045(18)30739-3.\n[5] Kang YK Boku N Satoh T . Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;doi:10.1016/S0140-6736(17)31827-5.\n[6] Hadi AEL AL-Momani H Edwards P . An effect of letrozole on gastric cancer? J Gastric Cancer 2011;doi:10.5230/jgc.2011.11.3.180.\n[7] Yang JC Chang N Wu DC . Preclinical evaluation of exemestane as a novel chemotherapy for gastric cancer. J Cell Mol Med 2019;doi:10.1111/jcmm.14605.\n[8] Yi JH Do IG Jang J . Anti-tumor efficacy of fulvestrant in estrogen receptor positive gastric cancer. Sci Rep 2014;doi:10.1038/srep07592.\n[9] Wang X Chen Q Huang X . Effects of 17β-estradiol and tamoxifen on gastric cancer cell proliferation and apoptosis and ER-(36 expression. Oncol Lett 2017;doi:10.3892/ol.2016.5424.\n[10] Gradishar WJ Anderson BO Balassanian R . NCCN guidelines insights: breast cancer, version 1.2017. J Natl Compr Cancer Netw 2017;doi:10.6004/jnccn.2017.0044.\n[11] Lindblad M García Rodríguez LA Chandanos E . Hormone replacement therapy and risks of oesophageal and gastric adenocarcinomas. Br J Cancer 2006;doi:10.1038/sj.bjc.6602906.\n[12] Freedman ND Chow WH Gao YT . Menstrual and reproductive factors and gastric cancer risk in a large prospective study of women. Gut 2007;doi:10.1136/gut.2007.129411.\n[13] Brusselaers N Maret-Ouda J Konings P . Menopausal hormone therapy and the risk of esophageal and gastric cancer. Int J Cancer 2017;doi:10.1002/ijc.30588.\n[14] Chandanos E Lindblad M Rubio CA . Tamoxifen exposure in relation to gastric adenocarcinoma development. Eur J Cancer 2008;doi:10.1016/j.ejca.2008.02.049.\n[15] Chandanos E Lindblad M Jia C . Tamoxifen exposure and risk of oesophageal and gastric adenocarcinoma: a population-based cohort study of breast cancer patients in Sweden. Br J Cancer 2006;doi:10.1038/sj.bjc.6603214.\n[16] Chen S Liu H Li J . Risk of gastric and colorectal cancer after tamoxifen use for breast cancer: a systematic review and meta-analysis. J Clin Gastroenterol 2015;doi:10.1097/MCG.0000000000000262.\n[17] Rahman MSU Cao J . Estrogen receptors in gastric cancer: advances and perspectives. World J Gastroenterol 2016;doi:10.3748/wjg.v22.i8.2475.\n[18] Chen C Gong X Yang X . The roles of estrogen and estrogen receptors in gastrointestinal disease (Review). Oncol Lett 2019;doi:10.3892/ol.2019.10983.\n[19] Kousteni S Bellido T Plotkin LI . Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 2001;doi:10.1016/s0092-8674(02)08100-x.\n[20] Yokozaki H Takekura N Takanashi A . Estrogen receptors in gastric adenocarcinoma: a retrospective immunohistochemical analysis. Virchows Arch A Pathol Anat Histopathol 1988;doi:10.1007/BF00783021.\n[21] Xu CY Guo JL Jiang ZN . Prognostic role of estrogen receptor α and estrogen receptor β in gastric cancer. Ann Surg Oncol 2010;doi:10.1245/s10434-010-1031-2.\n[22] Deng H Huang X Fan J . A variant of estrogen receptor-α, ER-α36 is expressed in human gastric cancer and is highly correlated with lymph node metastasis. Oncol Rep 2010;doi:10.3892/or-00000842.\n[23] Ryu WS Kim JH Jang YJ . Expression of estrogen receptors in gastric cancer and their clinical significance. J Surg Oncol 2012;doi:10.1002/jso.23097.\n[24] Zhang D Ku J Yi Y . The prognostic values of estrogen receptor alpha and beta in patients with gastroesophageal cancer: a meta-analysis. Medicine (Baltimore) 2019;doi:10.1097/MD.0000000000017954.\n[25] Tang W Liu R Yan Y . Expression of estrogen receptors and androgen receptor and their clinical significance in gastric cancer. Oncotarget 2017;doi:10.18632/oncotarget.16582.\n[26] Zhou F Xu Y Shi J . Expression profile of E-cadherin, estrogen receptors, and P53 in early-onset gastric cancers. Cancer Med 2016;doi:10.1002/cam4.931.\n[27] Matsui M Kojima O Kawakami S . The prognosis of patients with gastric cancer possessing sex hormone receptors. Surg Today 1992;doi:10.1007/BF00308791.\n[28] Torre LA Bray F Siegel RL . Global cancer statistics, 2012. CA Cancer J Clin 2015;doi:10.3322/caac.21262.\n[29] Ishigami H Fujiwara Y Fukushima R . Phase III trial comparing intraperitoneal and intravenous paclitaxel Plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIXGC trial. J Clin Oncol 2018;doi:10.1200/JCO.2018.77.8613.\n[30] Glehen O Gilly FN Arvieux C . Peritoneal carcinomatosis from gastric cancer: a multi-institutional study of 159 patients treated by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy. Ann Surg Oncol 2010;doi:10.1245/s10434-010-1039-7.\n[31] Ettinger DS Agulnik M Cristea M . Occult Primary. J Natl Compr Cancer Netw 2008;doi:10.6004/jnccn.2008.0078.\n[32] Kaufmann O Deidesheimer T Muehlenberg M . Immunochemical differentiation of metastatic breast carcinomas from metastatic adenocarcinomas of other common primary sites. Histopathology 1996;doi:10.1111/j.1365-2559.1996.tb01396.x.\n[33] De Lara S Parris TZ Werner Rönnerman E . GATA3 as a putative marker of breast cancer metastasis—A retrospective immunohistochemical study. Breast J 2018;doi:10.1111/tbj.12863.\n[34] Chia SY Thike AA Cheok PY . Utility of mammaglobin and gross cystic disease fluid protein-15 (GCDFP-15) in confirming a breast origin for recurrent tumors. Breast 2010;doi:10.1016/j.breast.2010.02.007.\n[35] Pentheroudakis G Golfinopoulos V Pavlidis N . Switching benchmarks in cancer of unknown primary: from autopsy to microarray. Eur J Cancer 2007;doi:10.1016/j.ejca.2007.06.023.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "100(21)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000230:Adenocarcinoma; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D000077289:Letrozole; D008207:Lymphatic Metastasis; D011960:Receptors, Estrogen; D013274:Stomach Neoplasms",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e26146",
"pmc": null,
"pmid": "34032767",
"pubdate": "2021-05-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Long-term response on letrozole for gastric cancer: A case report.",
"title_normalized": "long term response on letrozole for gastric cancer a case report"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1940301",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LETROZOLE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe objective of this study was to assess whether a lower dose than the currently used one of darunavir/ritonavir might achieve good CSF concentrations and contribute to inhibition of CNS viral replication.\n\n\nMETHODS\nThis was a substudy of a randomized, open, multicentre study (eudraCT 2011-006272-39), comparing the efficacy and safety of 800/100 mg of darunavir/ritonavir (darunavir 800) versus 600/100 mg of darunavir/ritonavir (darunavir 600) once daily plus tenofovir/emtricitabine or abacavir/lamivudine in 100 virologically suppressed patients. Paired blood and CSF samples were obtained. Total plasma darunavir concentrations were determined by HPLC, and CSF concentrations by liquid chromatography-tandem MS. Viral load (VL) was determined in plasma and CSF (limit of detection = 40 copies/mL) by PCR.\n\n\nRESULTS\nSixteen patients were enrolled. The median (range) of darunavir CSF concentrations in darunavir 600 (n = 8) and darunavir 800 (n = 8) patients was 17.08 (5.79-30.19) and 13.23 (3.47-32.98) ng/mL, respectively (P = 0.916). The median (range) darunavir CSF:plasma ratio was 0.010 (0.005-0.022) in darunavir 600 patients and 0.008 (0.004-0.017) in the darunavir 800 arm (P = 0.370). All 16 patients had a VL < 40 copies/mL in plasma and 14 had a VL < 40 copies/mL in CSF. Of the two patients with detectable CSF VL (280 copies/mL and 159 copies/mL), one was receiving darunavir 600 and the other darunavir 800 plus tenofovir/emtricitabine. Of note, these patients had the lowest CSF darunavir concentrations in their respective groups: 5.79 ng/mL (802 ng/mL in plasma) and 3.47 ng/mL (958 ng/mL in plasma).\n\n\nCONCLUSIONS\nDarunavir CSF and plasma concentrations were comparable between the two arms. However, one patient from each group (with the lowest CSF darunavir concentrations in their respective groups) had detectable CSF VL despite undetectable plasma VL.",
"affiliations": "Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.;Fundació Lluita Contra la Sida, Hospital Universitari Germans Trias i Pujol, Badalona, Spain Universitat Autònoma de Barcelona, Barcelona, Spain.;Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.;Hospital Vall d'Hebrón, Barcelona, Spain.;Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.;Department of Infectious Diseases, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.;Fundació Lluita Contra la Sida, Hospital Universitari Germans Trias i Pujol, Badalona, Spain Universitat Autònoma de Barcelona, Barcelona, Spain Fundació IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Badalona, Spain Universitat de Vic, Vic, Spain.;Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.;Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.;Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.;Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.;Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.;Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain dpodzamczer@bellvitgehospital.cat.",
"authors": "Di Yacovo|Maria S|MS|;Moltó|José|J|;Ferrer|Elena|E|;Curran|Adrian|A|;Else|Laura|L|;Gisslén|Magnus|M|;Clotet|Bonaventura|B|;Tiraboschi|Juan M|JM|;Niubò|Jordi|J|;Vila|Antonia|A|;Zetterberg|H|H|;Back|David|D|;Podzamczer|Daniel|D|",
"chemical_list": "D019380:Anti-HIV Agents; D019438:Ritonavir; D000069454:Darunavir",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dku558",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": "70(5)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": "ART; CSF; HIV/AIDS; antiretroviral therapy",
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents; D002555:Cerebrospinal Fluid; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D000069454:Darunavir; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D010949:Plasma; D019438:Ritonavir; D053719:Tandem Mass Spectrometry; D019562:Viral Load; D014766:Viremia; D055815:Young Adult",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "1513-6",
"pmc": null,
"pmid": "25608583",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Antiviral activity and CSF concentrations of 600/100 mg of darunavir/ritonavir once daily in HIV-1 patients with plasma viral suppression.",
"title_normalized": "antiviral activity and csf concentrations of 600 100 mg of darunavir ritonavir once daily in hiv 1 patients with plasma viral suppression"
} | [
{
"companynumb": "ES-CIPLA LTD.-2015ES00960",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EMTRICITABINE\\TENOFOVIR"
},
"drugadditional"... |
{
"abstract": "OBJECTIVE\nProgressive multifocal leukoencephalopathy (PML) is a very rare and opportunistic encephalitis caused by JC polyomavirus that is linked to profound immunosuppression and is usually fatal unless immune function can be restored. Immune checkpoint inhibitors (ICI) are monoclonal antibodies (mAbs) that block either CTLA-4 or PD-1 inhibitor receptors, thus enhancing antiviral T-cell activity. Successful treatment of PML by ICI has recently generated some enthusiasm in case reports/small series of patients. However, the initial enthusiasm was mitigated by some individual case reports that did not show any benefit. More data are thus warranted about efficacy of immune checkpoint inhibitors in the specific context of PML.\n\n\nRESULTS\nWe report here the outcomes of six PML patients treated by ICI between 2017 and 2019. Underlying causes of immunosuppression consisted in hematologic malignancies (n = 4), primary immune deficiency (n = 1) and use of immunosuppressive therapies for myasthenia gravis (n = 1). Three patients were alive with a mean follow-up of 21 months (14-33) after first ICI infusion, including one patient with frank clinical response, one with stabilization, and one with initial worsening and further stabilization of PML. The three other patients rapidly died from PML.\n\n\nCONCLUSIONS\nOur data suggest that ICI may be effective for PML treatment but were less impressive than the ones previously reported. Larger studies are thus warranted to confirm this efficacy and to identify the predictive factors of response.",
"affiliations": "Sorbonne Université, Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, APHP, 47-83 Bd de l'Hôpital, 75651, Paris Cedex, France. damien.roosweil@aphp.fr.;Sorbonne Université, AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Neurologie, Unité de Médecine Intensive Réanimation Neurologique, and Institut du Cerveau et de la Moelle Épinière, ICM, F-75013, Paris, France.;Sorbonne UniversitéAssistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-SalpêtrièreInserm U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Département d'Immunologie, Paris, France.;Sorbonne Université, Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, APHP, 47-83 Bd de l'Hôpital, 75651, Paris Cedex, France.;Pharmacie à Usage Intérieur, Sorbonne Université, AP-HP, Hôpital Pitié-Salpêtrière, APHP, Paris, France.;Nord-Est/Ile-de-France Neuromuscular Reference Center, Myology Institute, Pitié-Salpêtrière Hospital, Paris, France.;Department of Internal Medicine and Clinical Immunology, Centre National de Références Maladies Autoimmunes Systémiques Rares, Centre National de Références Maladies Autoinflammatoires Rares et Amyloses Inflammatoires, Sorbonne Université, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.;CNRS, UMR S 1127, Institut du Cerveau et de la Moelle Épinière, ICM, Sorbonne Université, Inserm, AP-HPHôpitaux Universitaires la Pitié Salpêtrière, Charles Foix, Service de Neurologie 2-Mazarin, F-75013, Paris, France.;CNRS, UMR S 1127, Institut du Cerveau et de la Moelle Épinière, ICM, Sorbonne Université, Inserm, AP-HPHôpitaux Universitaires la Pitié Salpêtrière, Charles Foix, Service de Neurologie 2-Mazarin, F-75013, Paris, France.;Sorbonne Université, AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Neurologie, Unité de Médecine Intensive Réanimation Neurologique, and Institut du Cerveau et de la Moelle Épinière, ICM, F-75013, Paris, France.;Laboratoire de Virologie, AP-HP, Hôpitaux Universitaires Paris Sud Saclay, Hôpital Paul Brousse, Villejuif, France.;Sorbonne Université, Service d'Hématologie Clinique, Hôpital Pitié-Salpêtrière, APHP, 47-83 Bd de l'Hôpital, 75651, Paris Cedex, France.;Department of Neuroradiology, Sorbonne Université, Pitié Salpêtrière Hospital, APHP, Paris, France.;Department of Neuroradiology, Sorbonne Université, Pitié Salpêtrière Hospital, APHP, Paris, France.;Sorbonne Université, AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière Charles Foix, Institut Pierre Louis d'Épidémiologie et de Santé Publique, Service de Maladies Infectieuses et Tropicales, INSERM 1136, 47-83 Bd de l'Hôpital, 75651, Paris Cedex, France. valerie.martinez@aphp.fr.",
"authors": "Roos-Weil|Damien|D|http://orcid.org/0000-0002-7767-755X;Weiss|Nicolas|N|;Guihot|Amélie|A|;Uzunov|Madalina|M|;Bellanger|Agnès|A|;Eymard|Bruno|B|;Saadoun|David|D|;Houillier|Caroline|C|;Idbaih|Ahmed|A|;Demeret|Sophie|S|;Deback|Claire|C|;Leblond|Véronique|V|;Galanaud|Damien|D|;Shor|Natalia|N|;Pourcher|Valérie|V|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D000082082:Immune Checkpoint Inhibitors",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00415-021-10414-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-5354",
"issue": "268(7)",
"journal": "Journal of neurology",
"keywords": "Immune checkpoint inhibitor; Immunosuppression; JCV; PD-1; Progressive multifocal leukoencephalopathy",
"medline_ta": "J Neurol",
"mesh_terms": "D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007577:JC Virus; D007968:Leukoencephalopathy, Progressive Multifocal",
"nlm_unique_id": "0423161",
"other_id": null,
"pages": "2458-2465",
"pmc": null,
"pmid": "33515299",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Immune checkpoint inhibitors for progressive multifocal leukoencephalopathy: a new gold standard?",
"title_normalized": "immune checkpoint inhibitors for progressive multifocal leukoencephalopathy a new gold standard"
} | [
{
"companynumb": "FR-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-015495",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "TA-TMA is a described complication of aHCT in children with neuroblastoma. Outcomes are poor with mortality rates approaching 60%. Described late effects in survivors include chronic kidney disease and persistent pulmonary hypertension.\n\n\n\nWe report a case of a 2-year-old with neuroblastoma who developed severe TA-TMA 35 days after high dose chemotherapy and autologous stem cell rescue. He presented with respiratory failure, pericardial and pleural effusions, hemolysis, hypertension, and mild altered mental status. He was mechanically ventilated for 3 weeks and after sedation was lifted, he was minimally responsive. He was treated with eculizumab with resolution of hemolysis, kidney injury and polyserositis. Initially he was more responsive; however, after almost a year of intensive therapy he remained nonverbal and had persistent irritability and behavioral changes. He had an extensive negative evaluation. On day +345, he presented with severe, refractory epilepsy. Three years after TA-TMA, he continues to have severe neurologic disabilities.\n\n\n\nTo our knowledge, persistent neurologic toxicity has not been reported in TA-TMA. However, deficits and seizures are reported in other TMAs, particularly in children with atypical HUS who present with significant neurologic changes at diagnosis. Our patient's persistent neurologic disability despite eculizumab response in all other involved organs may reflect irreversible damage. This case describes a new long-term sequela of TA-TMA and highlights the need for further studies to understand both acute and long-term neurologic complications of this disease.",
"affiliations": "Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.;Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.;Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.",
"authors": "Schoettler|Michelle|M|0000-0003-4565-6399;Duncan|Christine|C|;Lehmann|Leslie|L|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C481642:eculizumab",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13381",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "23(3)",
"journal": "Pediatric transplantation",
"keywords": "TA-TMA; autologous transplant; eculizumab; epilepsy; neuroblastoma; neurotoxicity",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D002675:Child, Preschool; D018450:Disease Progression; D004827:Epilepsy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015994:Incidence; D008297:Male; D009422:Nervous System Diseases; D009447:Neuroblastoma; D057049:Thrombotic Microangiopathies; D014182:Transplantation, Autologous",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13381",
"pmc": null,
"pmid": "30828947",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports",
"references": "25705530;22670043;16041306;20981675;28039081;20717073;24370861;26259912;25483393;22960385;11328282;20498239;23294015;26456258;20697372;16184183;27156964;16275594;29674658;20153836;24820211;17229640;14962323",
"title": "Severe, persistent neurotoxicity after transplant-associated thrombotic microangiopathy in a pediatric patient despite treatment with eculizumab.",
"title_normalized": "severe persistent neurotoxicity after transplant associated thrombotic microangiopathy in a pediatric patient despite treatment with eculizumab"
} | [
{
"companynumb": "US-UCBSA-2019036355",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nA case of mild symptomatic hypotension after treatment with menaquinone (vitamin K(2)) is reported.\n\n\nCONCLUSIONS\nA 62-year-old white man with a medical history of hyperlipidemia, coronary artery disease, and benign prostatic hyperplasia was started on a regimen of menaquinone 100 μg daily as a supplement to his medications for coronary artery disease. Approximately two hours after taking the first dose of menaquinone, the patient experienced sudden weakness and dizziness. At that time, his blood pressure was 110/55 mm Hg. On day 2 of treatment, his blood pressure was 105/50 mm Hg two hours after taking menaquinone; however the patient was asymptomatic. On day 3, the patient's blood pressure was 100/50 mm Hg two hours after menaquinone ingestion, with symptoms of generalized weakness and dizziness, at which point menaquinone was discontinued. All of the patient's heart rate measurements were within normal limits during this time. The day after discontinuing menaquinone, the patient's blood pressure was 115/65 mm Hg, after which his readings were within normal limits on subsequent days. After a 10-day menaquinone-free period, the patient was rechallenged. On rechallenge day 1, the patient's blood pressure was 115/60 mm Hg two hours after menaquinone ingestion; on rechallenge day 2, his blood pressure was 100/55 mm Hg. The patient was asymptomatic on both days of the rechallenge. The Naranjo et al. adverse drug reaction probability scale score was 7, indicating a probable adverse reaction to menaquinone. The drug interaction probability scale score for this case was 6, indicating that a drug interaction was probable.\n\n\nCONCLUSIONS\nA 62-year-old white man developed mild symptomatic hypotension while receiving menaquinone therapy.",
"affiliations": "Drug Information Center, Synapse, Hellenic Pharmaceuticals and Services, Drug Information Division, Egnatias 117, Thessaloniki, 54635, Greece. lefteris@shps.gr",
"authors": "Teperikidis|Eleftherios|E|",
"chemical_list": "D024482:Vitamin K 2",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp110235",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "69(15)",
"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": "D003324:Coronary Artery Disease; D006801:Humans; D007022:Hypotension; D008297:Male; D008875:Middle Aged; D024482:Vitamin K 2",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "1307-9",
"pmc": null,
"pmid": "22821789",
"pubdate": "2012-08-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypotension associated with menaquinone.",
"title_normalized": "hypotension associated with menaquinone"
} | [
{
"companynumb": "GR-TEVA-369202ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALFUZOSIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "The challenges of managing relapsed ovarian cancer increase as more advanced lines of chemotherapy are achieved.\n\n\n\nA case study is presented to illustrate the complexities of selecting treatment in a patient with platinum-sensitive relapsed ovarian cancer and exposure to two previous lines of platinum-based chemotherapy.\n\n\n\nIn this clinical scenario, options include re-treatment with platinum-based chemotherapy or treatment with a nonplatinum single-agent or a nonplatinum combination. In this case, the nonplatinum combination of trabectedin + pegylated liposomal doxorubicin (PLD) was selected as the patient had limited platinum sensitivity (progression-free interval of 9 months), no BRCA mutation, and taking into account evidence that the regimen is effective and safe in the third line and beyond and may restore platinum sensitivity. After nine cycles of trabectedin + PLD, there was no evidence of disease. The patient was able to resume normal activities during therapy. Progression-free interval (PFI) was 17 months before disease progression. Subsequent platinum rechallenge produced a partial response.\n\n\n\nTrabectedin + PLD may be an option for patients with platinum-sensitive relapsed ovarian cancer, including those who have received two or more previous lines of platinum.",
"affiliations": "a Department of Obstetrics and Gynecology , Medical University of Innsbruck , Innsbruck , Austria.",
"authors": "Marth|Christian|C|",
"chemical_list": "D017671:Platinum Compounds; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D000077606:Trabectedin",
"country": "England",
"delete": false,
"doi": "10.1080/14737140.2018.1513793",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1473-7140",
"issue": "18(sup1)",
"journal": "Expert review of anticancer therapy",
"keywords": "Platinum-sensitive relapsed ovarian cancer; peglyated liposomal doxorubicin; trabectedin",
"medline_ta": "Expert Rev Anticancer Ther",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D018572:Disease-Free Survival; D004317:Doxorubicin; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms; D017671:Platinum Compounds; D011092:Polyethylene Glycols; D000077606:Trabectedin; D016896:Treatment Outcome",
"nlm_unique_id": "101123358",
"other_id": null,
"pages": "19-22",
"pmc": null,
"pmid": "30223697",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Trabectedin + pegylated liposomal doxorubicin in third-line treatment of platinum-sensitive relapsed ovarian cancer: a case study.",
"title_normalized": "trabectedin pegylated liposomal doxorubicin in third line treatment of platinum sensitive relapsed ovarian cancer a case study"
} | [
{
"companynumb": "AT-PFIZER INC-2018402229",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThis 52-week open-label extension (OLE) to a double-blind placebo-controlled recurrence prevention study examined the long-term safety and efficacy of flexibly-dosed paliperidone extended-release (ER) tablets in patients with schizophrenia.\n\n\nMETHODS\nPatients entering the OLE either entered from the double-blind phase (placebo or paliperidone ER treatment) or entered directly from the run-in or stabilization phase (paliperidone ER) of the earlier study. During the OLE, patients were treated with flexibly-dosed paliperidone ER (3-15 mg/day; 9 mg starting dose). Safety and tolerability assessments included incidence of adverse events and extrapyramidal symptoms. Efficacy was also assessed.\n\n\nRESULTS\nThe study population (n=235) was predominantly men (66%), 18-58 years of age. Twelve patients (5%) experienced an adverse event requiring treatment discontinuation. One or more serious treatment-emergent adverse events were reported in 13 patients (6%). There was one death. The mean Positive and Negative Syndrome Scale total score decreased from open-label baseline to endpoint for all groups, regardless of previous double-blind treatment (placebo or paliperidone ER).\n\n\nCONCLUSIONS\nThis year-long OLE provides information on the long-term safety and tolerability of paliperidone ER in patients with schizophrenia. The resulting safety and tolerability profile was similar to that seen in earlier short-term studies.",
"affiliations": "Johnson & Johnson Pharmaceutical Research & Development; L.L.C. Raritan, USA.",
"authors": "Kramer|Michelle|M|;Simpson|George|G|;Maciulis|Valentinas|V|;Kushner|Stuart|S|;Liu|Yanning|Y|;Lim|Pilar|P|;Hough|David|D|;Palumbo|Joseph|J|;Eerdekens|Mariëlle|M|",
"chemical_list": "D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D007555:Isoxazoles; D013607:Tablets; D000068882:Paliperidone Palmitate",
"country": "United States",
"delete": false,
"doi": "10.1017/s1092852900000456",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1092-8529",
"issue": "15(8)",
"journal": "CNS spectrums",
"keywords": null,
"medline_ta": "CNS Spectr",
"mesh_terms": "D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D006801:Humans; D007555:Isoxazoles; D000068882:Paliperidone Palmitate; D012559:Schizophrenia; D013607:Tablets",
"nlm_unique_id": "9702877",
"other_id": null,
"pages": "506-14",
"pmc": null,
"pmid": "20703197",
"pubdate": "2010-08",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "One-year open-label safety and efficacy study of paliperidone extended-release tablets in patients with schizophrenia.",
"title_normalized": "one year open label safety and efficacy study of paliperidone extended release tablets in patients with schizophrenia"
} | [
{
"companynumb": "US-MYLANLABS-2016M1020364",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PALIPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo elucidate the main latent classes of substances detected among overdose decedents, and latent class associations with age, sex, race, and jurisdiction of death in Maryland.\n\n\nMETHODS\nWe used toxicology data from the Office of the Chief Medical Examiner of Maryland for all decedents. We analyzed all cases of drug overdose deaths that occurred from 2016 to 2018 (N = 6566) using latent class analysis and regression.\n\n\nRESULTS\nDrug overdose deaths were concentrated in 2 of 24 counties in Maryland (Baltimore City and County). Fentanyl was involved in 71% of all drug overdose deaths, and the majority (76%) of these deaths included multiple substances. Three latent classes emerged: (1) fentanyl/heroin/cocaine (64%); (2) fentanyl/alcohol (18%); and (3) prescription drugs including opioids, benzodiazepines and antidepressants (18.0%). The fentanyl/heroin/cocaine class members were significantly younger (<30 years), female and White compared to the fentanyl/alcohol class, but more male and non-White than the prescription drugs class (all P < 0.05). Deaths in Baltimore City/County were more likely than in other locations to involve fentanyl/alcohol (P < 0.05).\n\n\nCONCLUSIONS\nThe majority of fentanyl-involved overdose deaths in Maryland involved multiple substances, and several demographic and geographic differences in these patterns emerged. Geographically-targeted interventions that are tailored to reduce the harms associated with polysubstance use (including cocaine, alcohol, and prescription drugs) for different demographic groups are warranted.",
"affiliations": "Department of Health, Behavior and Society, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (JNP, SGS); Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (KES, RM, PSN); Office of the Chief Medical Examiner, Baltimore, MD (DF); Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (SGS); Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD (PSN).",
"authors": "Park|Ju Nyeong|JN|;Schneider|Kristin E|KE|;Fowler|David|D|;Sherman|Susan G|SG|;Mojtabai|Ramin|R|;Nestadt|Paul S|PS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ADM.0000000000000823",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1932-0620",
"issue": null,
"journal": "Journal of addiction medicine",
"keywords": null,
"medline_ta": "J Addict Med",
"mesh_terms": null,
"nlm_unique_id": "101306759",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33675604",
"pubdate": "2021-03-04",
"publication_types": "D016428:Journal Article",
"references": "18956528;29035705;29715347;31951925;29976195;27228510;31586804;31168735;29314075;24852056;29211971;32264789;28801014;28735776;31393864;31465320;31048676;16298837;15555812;32191688;28640680;31706248;32808709;31216059;11684613;23961726;30292493;28817331;31195347;12780362;26653341;32487285",
"title": "Polysubstance Overdose Deaths in the Fentanyl Era: A Latent Class Analysis.",
"title_normalized": "polysubstance overdose deaths in the fentanyl era a latent class analysis"
} | [
{
"companynumb": "US-JNJFOC-20210332939",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "We present a case of acute dystonia in an adolescent, with features that fit the description of the Pisa syndrome. The symptoms developed postoperatively, in a non-psychiatric setting, following administration of antiemetic medication, and the phenomenon was misdiagnosed as a conversion disorder. This case reinforces previous reports cautioning against misinterpretation of dystonic reactions as functional disorders, especially in children and adolescents.",
"affiliations": "Loyola University Stritch School of Medicine, Illinois 60141.",
"authors": "Fichtner|C G|CG|;Pechter|B M|BM|;Jobe|T H|TH|",
"chemical_list": "D000932:Antiemetics",
"country": "England",
"delete": false,
"doi": "10.1192/bjp.161.6.849",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1250",
"issue": "161()",
"journal": "The British journal of psychiatry : the journal of mental science",
"keywords": null,
"medline_ta": "Br J Psychiatry",
"mesh_terms": "D000293:Adolescent; D000932:Antiemetics; D003291:Conversion Disorder; D003937:Diagnosis, Differential; D004421:Dystonia; D005260:Female; D006801:Humans; D011183:Postoperative Complications",
"nlm_unique_id": "0342367",
"other_id": null,
"pages": "849-52",
"pmc": null,
"pmid": "1483175",
"pubdate": "1992-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pisa syndrome mistaken for conversion in an adolescent.",
"title_normalized": "pisa syndrome mistaken for conversion in an adolescent"
} | [
{
"companynumb": "US-PFIZER INC-2020398002",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DROPERIDOL"
},
"drugadditional": "3",
... |
{
"abstract": "Bedaquiline (Bdq), a novel TB drug, is referred to the most effective drugs and used for the management of multidrug-resistant tuberculosis (MDR-TB). The drug produces a cardiotoxic effect, and its use is limited to six months. We describe a clinical observation of prolonged bedaquiline use in the treatment for MDR-TB using a restricted number of drugs, to which susceptibility was preserved, in a 12-year-old child. The previous treatment course had failed; the patient remained sputum-positive after eight months of the treatment. We used a personalized approach to chemotherapy correction based on repeat drug susceptibility testing. The treatment regimen only contained those drugs, to which susceptibility was preserved: amikacin, cycloserine, linezolid, bedaquiline (AmCsLzdBdq). Amikacin was withdrawn after three months due to the development of sensorineural hearing loss. The treatment was continued with CsLzdBdq. The total chemotherapy course took 18 months. Sputum conversion was observed after one month, cavity closure - by 18 months of treatment. We did not observe cardiotoxic effects due to prolonged bedaquiline use. The administration of prolonged bedaquiline use was based on life-saving considerations. We achieved favourable treatment outcome and demonstrated safety of prolonged bedaquiline use for a child.",
"affiliations": "Central TB Research Institute, 2 Yauzskaya Alley, Moscow, Russia.;Central TB Research Institute, 2 Yauzskaya Alley, Moscow, Russia.;Central TB Research Institute, 2 Yauzskaya Alley, Moscow, Russia.;Central TB Research Institute, 2 Yauzskaya Alley, Moscow, Russia.",
"authors": "Gubkina|Marina F|MF|;Khokhlova|Julia Yu|JY|;Yukhimenko|Natalia V|NV|;Petrakova|Irina Yu|IY|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2021.e01311",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(21)00267-5\n10.1016/j.idcr.2021.e01311\ne01311\nCase Report\nProlonged use of bedaquiline in the treatment for MDR-TB in a child\nGubkina Marina F. gubkinamf@mail.ru\n\nKhokhlova Julia Yu. anhh@rambler.ru\n\nYukhimenko Natalia V. disstub@gmail.com\n⁎\nPetrakova Irina Yu. irina71petrakova@yandex.ru\n\nCentral TB Research Institute, 2 Yauzskaya Alley, Moscow, Russia\n⁎ Corresponding author. disstub@gmail.com\n20 10 2021\n2021\n20 10 2021\n26 e0131114 5 2021\n14 10 2021\n14 10 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nBedaquiline (Bdq), a novel TB drug, is referred to the most effective drugs and used for the management of multidrug-resistant tuberculosis (MDR-TB). The drug produces a cardiotoxic effect, and its use is limited to six months. We describe a clinical observation of prolonged bedaquiline use in the treatment for MDR-TB using a restricted number of drugs, to which susceptibility was preserved, in a 12-year-old child. The previous treatment course had failed; the patient remained sputum-positive after eight months of the treatment. We used a personalized approach to chemotherapy correction based on repeat drug susceptibility testing. The treatment regimen only contained those drugs, to which susceptibility was preserved: amikacin, cycloserine, linezolid, bedaquiline (AmCsLzdBdq). Amikacin was withdrawn after three months due to the development of sensorineural hearing loss. The treatment was continued with CsLzdBdq. The total chemotherapy course took 18 months. Sputum conversion was observed after one month, cavity closure – by 18 months of treatment. We did not observe cardiotoxic effects due to prolonged bedaquiline use. The administration of prolonged bedaquiline use was based on life-saving considerations. We achieved favourable treatment outcome and demonstrated safety of prolonged bedaquiline use for a child.\n\nKeywords\n\nPulmonary TB\nMDR-TB\nTreatment\nBedaquiline\nChildren\n==== Body\npmcIntroduction\n\nMDR-TB patients is the most challenging group of patients with low treatment effectiveness due to resistance to two major TB drugs – isoniazid and rifampin. The new TB drug, bedaquiline, improves treatment effectiveness in these patients; it has been recommended for the treatment of MDR-TB since 2013 [1]. Bedaquiline produces a cardiotoxic effect, which limits its use to six months. In 2018 WHO revised its classification of TB drugs by priority in the treatment for MDR-TB; Bdq was referred to the most effective drugs [2]. Since 2019 Bdq has been allowed for the use in children aged 6 years or above [3]. WHO has affirmed that the risk–benefit assessment of the use of Bdq in patients aged 6–17 is incomplete due to scarce information; the same situation is with the use of Bdq beyond six months [3]. WHO refers the use of Bdq in adults and children to research priorities related to MDR-TB treatment [3].\n\nThe objective of our publication is to share the experience of prolonged bedaquiline use in the treatment for MDR-TB with a restricted number of drugs, to which susceptibility was preserved, in a child.\n\nCase report\n\nA girl aged 12 years was hospitalized after eight months of unsuccessful treatment for disseminated pulmonary rifampin resistant tuberculosis (RR-TB) to determine further treatment tactics. A household contact with the father, who was ill with TB since 2016, was established; drug susceptibility data were absent. The girl was diagnosed with TB in December 2018 at the referral to a health facility with complaints of high temperature (39 °С), expectoration, and weakness. Plain chest X-ray revealed infiltrative changes with cavities in the upper lobe of the left lung with multiple dissemination foci into both lungs. Ziehl-Neelsen sputum smear microscopy result was positive. The Xpert® MTB/RIF assay determined resistance to rifampin. Chemotherapy was administered as follows: AmZELfx – three months; ZELfxEto – five months. The treatment outcome: a positive sputum smear result by microscopy, lack of positive X-ray dynamics. The BACTEC MGIT-960 detected growth of mycobacteria in culture.\n\nMultidrug resistance (MDR) of M. tuberculosis was established with the following spectrum: isoniazid, rifampin, ethambutol, pyrazinamide, ethionamide, levofloxacin, moxifloxacin, para-aminosalicylic acid (HREZEtoLfxMfxPAS). Susceptibility to amikacin, capreomycin, cycloserine, linezolid, bedaquiline (AmCmCsLzdBdq) was preserved. Chest computed tomography (CT) showed the presentations of disseminated pulmonary TB (Fig. 1). Considering the prior treatment failure due to drug resistance and severity of the disease, we used a personalized chemotherapy regimen (AmCsLzdBdq) adapted to the specific case. The chemotherapy regimen contained bedaquiline, which was a new drug with age restrictions for that moment: age 18 years or above. We obtained an informed consent for bedaquiline use from the patient’s father. Amikacin was withdrawn after three months due to the toxic reaction (sensorineural hearing loss), and the treatment was continued with CsLzdBdq. We used three courses of bedaquiline due to life-saving considerations. Sputum conversion was observed after one month. Chest CT after 18 months of treatment showed significant resolution of infiltrates and dissemination foci in S 1, 2 of the left lung, cavity closure (Fig. 2). We did not observe cardiotoxic effects of the prolonged use of bedaquiline (the QTс interval did not change during the whole treatment course).Fig. 1 A fragment of the chest CT image before bedaquiline-containing chemotherapy: the areas of lung tissue consolidation with cavities in the upper lobe of the left lung. Multiple centrilobular foci, blending in some parts, in both lungs.\n\nFig. 1\n\nFig. 2 A fragment of the chest CT image after 18-month bedaquiline-containing chemotherapy: residual changes after disseminated pulmonary TB in the form of single small solid foci in both lungs.\n\nFig. 2\n\nDiscussion\n\nPersistent sputum positivity during the management of RR-TB requires extended microbiological testing for the subsequent correction of chemotherapy. The personalized approach to the selection of drugs with the inclusion of bedaquiline and its prolonged administration was preconditioned by the disease severity and the limited choice of TB drugs according to drug susceptibility testing. This observation demonstrates effectiveness and safety of the prolonged administration of bedaquiline for children.\n\nConsent\n\nConsent to publish this case report was obtained from the patient’s family and the copy of the consent is available for the journal on request.\n\nEthics approval and consent to participate\n\nNo ethical approval was obtained for this case report.\n\nFunding\n\nThis study received no grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nCRediT authorship contribution statement\n\nMarina F. Gubkina: Conceptualization, Analysis and interpretation of data, Writing – original draft preparation. Julia Yu. Khokhlova: Acquisition of data, Patient care, Analysis and interpretation of data. Natalia V.Yukhimenko: Analysis and interpretation of data, Supervision, Writing – review & editing. Irina Yu. Petrakova: Acquisition of data, Patient care, Analysis and interpretation of data, Description of CT images. All the authors participated in the patient management. All the authors read and agreed with the final version of the manuscript.\n\nDeclaration of Competing Interest\n\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n==== Refs\nReferences\n\n1 The use of bedaquiline in the treatment of multidrug-resistant tuberculosis. Interim guidance. Geneva, World Health Organization, 2013 (WHO/HTM/TB/2013.6).\n2 Rapid communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). License: CC BY-NC-SA 3.0 IGO.\n3 WHO consolidated guidelines on drug-resistant tuberculosis treatment. Copenhagen, WHO Regional Office for Europe, 2019. License: CC BY-NC-SA 3.0 IGO.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "26()",
"journal": "IDCases",
"keywords": "Bedaquiline; Children; MDR-TB; Pulmonary TB; Treatment",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e01311",
"pmc": null,
"pmid": "34745886",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Prolonged use of bedaquiline in the treatment for MDR-TB in a child.",
"title_normalized": "prolonged use of bedaquiline in the treatment for mdr tb in a child"
} | [
{
"companynumb": "RU-TEVA-2021-RU-1979920",
"fulfillexpeditecriteria": "1",
"occurcountry": "RU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": "4",
... |
{
"abstract": "Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy has emerged as an aggressive treatment option with intent to either cure or extend disease-free survival of selected patients with peritoneal carcinomatosis. However, postoperative complications are common. We describe the cases of 2 men who underwent CRS with hyperthermic intraperitoneal oxaliplatin and developed scrotal pain, which was consistent with noninfectious epididymitis.",
"affiliations": "Hospital São José, São Paulo, Brazil.;Hospital São José, São Paulo, Brazil.;Hospital São José, São Paulo, Brazil.",
"authors": "Barbosa|Luiza Damian Ribeiro|LD|;Belotto|Marcos|M|;Peixoto|Renata D'Alpino|RD|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000443726",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000443726cro-0009-0138Published online: February, 2016Epididymitis following Cytoreductive Surgery with Intraperitoneal Oxaliplatin Chemotherapy: Two Case Reports Barbosa Luiza Damian Ribeiro *Belotto Marcos Peixoto Renata D'Alpino Hospital São José, São Paulo, Brazil*Luiza Damian Ribeiro Barbosa Hospital São José R. Martiniano de Carvalho, 965 São Paulo, SP 01321-001 (Brazil) E-Mail luizabarb@hotmail.comJan-Apr 2016 19 2 2016 19 2 2016 9 1 138 142 Copyright © 2016 by S. Karger AG, Basel2016This 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.Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy has emerged as an aggressive treatment option with intent to either cure or extend disease-free survival of selected patients with peritoneal carcinomatosis. However, postoperative complications are common. We describe the cases of 2 men who underwent CRS with hyperthermic intraperitoneal oxaliplatin and developed scrotal pain, which was consistent with noninfectious epididymitis.\n\nKey Words\nEpididymitisHyperthermic intraperitoneal chemotherapyCytoreductive surgeryOxaliplatin\n==== Body\nIntroduction\nPeritoneal carcinomatosis associated with gastrointestinal malignancies was once considered a very poor prognostic condition [1, 2]. However, in the last decades, cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has gained popularity and emerged as an aggressive treatment option with intent to either cure or extend disease-free survival of selected patients with peritoneal carcinomatosis [3, 4].\n\nThis complex multimodal surgical procedure involves extensive stripping of the peritoneal surface and multiple visceral organ resections in order to achieve maximal cytoreduction with no macroscopic residual disease within the abdomen [5]. Following resection of all visible tumor, a heated chemotherapy perfusate is administered intraoperatively into the abdominal cavity with the aim of annihilating viable microscopic residual disease. The peritoneal route of chemotherapy is based on the peritoneal-plasma division concept, whereby a tenfold higher concentration of the chemotherapy is reached in the abdominal cavity in direct contact with residual cancerous cells, while minimal systemic absorption and adverse effects are expected.\n\nDespite all those potential benefits, the morbidity and mortality rates associated with CRS and HIPEC are elevated. Large series of patients undergoing CRS with HIPEC report mortality rates varying from 1 to 8% [6, 7, 8, 9, 10]. In the only prospective randomized study, 105 patients were randomly assigned to receive either standard treatment consisting of systemic chemotherapy (fluorouracil-leucovorin) with or without palliative surgery, or experimental therapy consisting of aggressive CRS with HIPEC, followed by the same systemic chemotherapy regime. The treatment-related mortality in CRS with the HIPEC group was 8% [11]. Surgical morbidity, such as postoperative ileus, anastomotic fistula, and wound infection, as well as medical morbidity, including pharmacological toxicity, cytopenia, bone marrow aplasia, renal toxicity, and hydroelectrolytic disorders are also frequent following CRS with HIPEC [6, 11], with a morbidity rate of approximately 25%. The most common described complications include enteric fistula, intraabdominal abscess, pneumonia, small-bowel obstruction, pancreatitis, and neutropenia which often prolong the hospital stay.\n\nTo the best of our knowledge, there are no reported cases of epididymitis after CRS with HIPEC. Here, we describe the cases of 2 men who underwent CRS with hyperthermic intraperitoneal oxaliplatin and developed scrotal pain, which was consistent with noninfectious epididymitis.\n\nCase Reports\nCase 1\nA 23-year-old man presented in 2011 with increasing abdominal pain. In October 2011, he developed obstructive symptoms and underwent exploratory laparotomy. He was found to have a poorly differentiated adenocarcinoma of the transverse colon with multiple peritoneal implants. It was consistent with a pT4 pN2 (4/28) pM1 adenocarcinoma, K-RAS wild type. From January to July 2012, he received 12 cycles of FOLFIRI plus bevacizumab at another institution and had complete clinical response. Therefore, it was decided to stop his chemotherapy completely. In September 2013, he again developed abdominal pain. A PET-CT scan revealed FDG-uptaking lesions in the peritoneum as well as in the colonic anastomosis. From June 2014 to June 2015, he received 24 cycles of FOLFIRI and cetuximab with initial response followed by stable disease. In September 2015, he was first seen at our institution, and during a multidisciplinary meeting, it was decided to pursue CRS with HIPEC (oxali-platin 300 mg/m2), which occurred on October 5, 2015. He stayed at the ICU for only 72 h, and had the first bowel movement 6 days after surgery. On the 7th postoperative day, he developed fever with no identified origin, and was started on piperacillin-tazobactam and vancomycin. At this time, the patient was also complaining of left scrotal pain and swelling. An ultrasound of the testis was performed on October 17th and showed normal testicles and increased volume of the left epididymis with heterogeneous echogenicity. In addition, analysis of the epididymal waveform revealed a low-resistance pattern suggestive of acute epididymitis (fig. 1). Although all cultures remained negative, it was decided to switch antibiotics to amikacin for 10 days and doxycycline for 14 days and treat as infectious epididymitis. The patient was discharged home on October 22, 2015, to complete antibiotics at the outpatient unit. As of November 23, the patient was still facing left scrotal discomfort, although less in intensity.\n\nCase 2\nA 57-year-old man presented in August 2014 with epigastralgia. An upper endoscopy was requested and revealed a 3-cm infiltrative ulcer in the posterior wall of the stomach. Biopsy confirmed a well-differentiated adenocarcinoma, HER-2 3+. A staging CT scan showed peritoneal carcinomatosis, and the CEA was 256 ng/ml. In October 2014, he was started on FLOT plus trastuzumab and achieved an excellent response. In June 2015, his CEA was 2.2, and he was completely asymptomatic. On August 17, 2015, the patient underwent CRS with hyperthermic intraperitoneal oxaliplatin at a dose of 300 mg/m2 as well as gastrectomy and lymphadenectomy. The patient stayed at the ICU for 72 h and had no major adverse event. He had a bowel movement 5 days after surgery. His only complaint was fatigue and moderate right scrotal pain with no inflammatory signs. The scrotal pain subsequently improved over the course of 3 months.\n\nDiscussion\nCRS with HIPEC has proven to be an effective treatment modality for selected patients with peritoneal surface malignancies. However, postoperative complications are very common, such as anastomotic leakage, intestinal obstruction, and pancreatitis [12]. To the best of our knowledge, no previous reports exist in the literature regarding epididymitis following CRS with HIPEC. Both of our case reports describe men who underwent CRS with hyperthermic intraperitoneal oxaliplatin and developed scrotal pain, which was consistent with noninfectious epididymitis.\n\nEpididymitis is the most common cause of scrotal pain in adults [13], and its most common etiology is infectious, although it can also be due to noninfectious causes, such as trauma and autoimmune disease [14]. Noninfectious epididymitis is generally a chronic condition. Other noninfectious causes of epididymitis include vasculitis and certain medications, such as amiodarone [15]. However, no etiology is found in many cases.\n\nRisk factors for epididymitis in all men include sexual activity, strenuous physical activity, bicycle or motorcycle riding, and prolonged periods of sitting (e.g., during travel, with a sedentary job) [13]. Risk factors in men older than 35 years and in prepubertal boys include recent urinary tract surgery or instrumentation and anatomic abnormalities, such as prostatic obstruction in older men and posterior urethral valves or meatal stenosis in prepubertal boys [13, 14]. Our patients had none of the risk factors described previously.\n\nUnlike patients with infectious epididymitis, patients with noninfectious epididymitis have less epididymal inflammation, such as pain and swelling [13, 14, 15, 16]. The diagnosis is usually made after the exclusion of other etiologies, particularly infectious epididymitis. No further evaluation is necessary for noninfectious epididymitis [14]. In the first case, signs and symptoms were more intense, and the ultrasound of the testis was helpful in defining the diagnosis. In the second case, the pain was only mild and no imaging tests were requested. Interestingly, in both cases pain was still present a few months after surgery, suggesting a more chronic condition.\n\nThe physiopathology behind noninfectious epididymitis following CRS with HIPEC remains unknown. Usually, the testes descend spontaneously into the scrotum by 4 months of age. The mechanisms responsible for normal testicular descent are not well understood. The intraabdominal phase of descent is thought to be androgen-independent. Passage through the inguinal canal, which begins in the 28th week of gestation, is believed to result from interaction between mechanical, hormonal, and neurotransmitter effects [17]. One of our hypotheses for epididymitis following HIPEC is that maybe both patients had patency of the processus vaginalis. Therefore, during intraperitoneal oxaliplatin administration, a small amount of oxaliplatin could have gained access to the scrotum through the processus vaginalis, leading to testis inflammation and epididymitis.\n\nIt remains unknown whether other intraperitoneal chemotherapeutic agents could also cause epididymitis or it is an oxaliplatin-related effect. Also, we have not found any report in the literature regarding epididymitis as a side effect of intravenous oxaliplatin, which is very frequently used in clinical practice. In conclusion, although rare, epididymitis should be noted as one of the potential complications following CRS with intraperitoneal oxaliplatin.\n\nStatement of Ethics\nThe corresponding author acknowledges that she is responsible for complying with ethical requirements and declares that the patients were correctly informed and written informed consent was obtained; the confidentiality of the patients was strictly preserved; the patients were informed about the submission of the manuscript and will be acquainted when the article is published.\n\nDisclosure Statement\nThe authors declare that they have nothing to disclose.\n\nFig. 1 Ultrasound showing increased volume of the left epididymis with heterogeneous echogenicity.\n==== Refs\nReferences\n1 Lang NP Thompson C Chu DZ Peritoneal carcinomatosis in nongynecologic malignancy: A prospective study of prognostic factors. Cancer 1989 63 364 367 2910444 \n2 Sadeghi B Arvieux C Glehen O Carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE-1 multicentric prospective study Cancer 2000 88 358 363 10640968 \n3 Levine EA Stewart JH Russell GB Cytoreductive surgery and intraperitoneal hyperthermic chemotherapy for peritoneal surface malignancy: experience with 501 procedures J Am Coll Surg 2007 204 943 953 17481516 \n4 Sugarbaker PH Cunliffe WJ Belliveau J Rationale for integrating early postoperative intraperitoneal chemotherapy into the surgical treatment of gastrointestinal cancer Semin Oncol 1989 16 suppl 6 83 97 2669141 \n5 Verwaal VJ Bruin S Boot H 8-year follow-up of randomized trial: cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer. Ann Surg Oncol 2008 15 754 763 18080166 \n6 Stephens AD Alderman R Chang D Morbidity and mortality analysis of 200 treatments with cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy using the coliseum technique Ann Surg Oncol 1999 6 790 796 10622509 \n7 Glehen O Osinsky D Cotte E Intraperitoneal chemohyperthermia using a closed abdominal procedure and cytoreductive surgery for the treatment of peritoneal carcinomatosis: morbidity and mortality analysis of 216 consecutive procedures Ann Surg Oncol 2003 10 863 869 14527903 \n8 Kusamura S Younan R Baratti D Cytoreductive surgery followed by intraperitoneal hyperthermic perfusion: Analysis of morbidity and mortality in 209 peritoneal surface malignancies treated with closed abdomen technique. Cancer 2006 106 1144 1153 16456817 \n9 Nadler A McCart JA Govindarajan A Peritoneal carcinomatosis from colon cancer: a systematic review of the data for cytoreduction and intraperitoneal chemotherapy Clin Colon Rectal Surg 2015 28 234 246 26648794 \n10 Desantis M Bernard JL Casanova V Morbidity, mortality, and oncological outcomes of 401 consecutive cytoreductive procedures with hyperthermic intraperitoneal chemotherapy (HIPEC) Langenbecks Arch Surg 2015 400 37 48 25319432 \n11 Verwaal VJ Ruth SV Bree E Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer J Clin Oncol 2003 21 3737 3743 14551293 \n12 Lampl B Leebmann H Mayr M Rare diaphragmatic complications following cytoreductive surgery and HIPEC: report of two cases Surg Today 2014 44 383 386 23224234 \n13 Trojian TH Lishnak TS Heiman D Epididymitis and orchitis: an overview Am Fam Physician 2009 79 583 19378875 \n14 Tracy CR Steers WD Costabile R Diagnosis and management of epididymitis Urol Clin North Am 2008 35 101 18061028 \n15 Nikolaou M Ikonomidis I Lekakis I Amiodarone-induced epididymitis: a case report and review of the literature Int J Cardiol 2007 121 e15 e16 17692943 \n16 Walker NA Challacombe B Managing epididymo-orchitis in general practice Practitioner 2013 257 21 25 2–3 23724748 \n17 Wensing CJ The embryology of testicular descent Horm Res 1988 30 144 2907890\n\n",
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"journal": "Case reports in oncology",
"keywords": "Cytoreductive surgery; Epididymitis; Hyperthermic intraperitoneal chemotherapy; Oxaliplatin",
"medline_ta": "Case Rep Oncol",
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"title": "Epididymitis following Cytoreductive Surgery with Intraperitoneal Oxaliplatin Chemotherapy: Two Case Reports.",
"title_normalized": "epididymitis following cytoreductive surgery with intraperitoneal oxaliplatin chemotherapy two case reports"
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"abstract": "BACKGROUND\nThe association between acute kidney injury (AKI) and use of non-steroidal anti-inflammatory drugs (NSAIDs) is well established. However, little is known about the comparative risk of individual NSAIDs, including specific COX-2 inhibitors.\n\n\nMETHODS\nWe conducted a systematic review and meta-analysis of cohort studies that reported relative risk, hazard ratio or standardized incidence ratio with 95% confidence comparing AKI risk in NSAID users versus non-users. Pooled risk ratios and 95% confidence intervals for individual NSAIDs were calculated using random-effect, generic inverse variance methods.\n\n\nRESULTS\nFive studies were identified and included in our data analysis. Pooled risk ratios were calculated for seven traditional NSAIDs and two specific COX-2 inhibitors, including indomethacin, piroxicam, ibuprofen, naproxen, sulindac, diclofenac, meloxicam, rofecoxib and celecoxib that were evaluated in at least two studies. Our meta-analysis was able to demonstrate a statistically significant elevated AKI risk among most of the included traditional NSAIDs. The pooled risk ratios were fairly consistent among individual traditional NSAIDs, ranging from 1.58 to 2.11. Differences between pooled risk ratios did not reach statistical significance (p≥0.19 for each comparison). Elevated AKI risk was also observed in diclofenac, meloxicam, rofecoxib and celecoxib users, although did not achieve a statistical significance.\n\n\nCONCLUSIONS\nA statistically significant elevated AKI risk among traditional NSAID users has been demonstrated in this meta-analysis. The pooled risk ratios among individual traditional NSAIDs were not significantly different. The pooled risk ratios of specific COX-2 inhibitors and the two traditional NSAIDs with the most COX-2 selectivity (diclofenac and meloxicam) were also comparable with other traditional NSAIDs even though they did not achieve a statistical significance.",
"affiliations": "Division of Rheumatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA; Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Electronic address: Ungprasert.Patompong@mayo.edu.;Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Rheumatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA; Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.;Division of Rheumatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA; Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.",
"authors": "Ungprasert|Patompong|P|;Cheungpasitporn|Wisit|W|;Crowson|Cynthia S|CS|;Matteson|Eric L|EL|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors",
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"mesh_terms": "D058186:Acute Kidney Injury; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D006801:Humans; D064887:Observational Studies as Topic; D016017:Odds Ratio; D012307:Risk Factors",
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"references": null,
"title": "Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A systematic review and meta-analysis of observational studies.",
"title_normalized": "individual non steroidal anti inflammatory drugs and risk of acute kidney injury a systematic review and meta analysis of observational studies"
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"abstract": "BACKGROUND\nPatients with severe motor and intellectual disabilities (SMID) are those who have both severe intellectual disabilities and severe physical disabilities. Intractable epilepsy is often associated with SMID. The purpose of this study was to elucidate the relationship between epilepsy associated with SMID and oxidative stress, and to clarify the safety and efficacy of the newer antiepileptic drugs (newer AEDs), lamotrigine and levetiracetam.\n\n\nMETHODS\nThis study was conducted in 27 SMID patients with epilepsy who were treated with the newer AEDs. The patient characteristics and the safety and efficacy of the newer AEDs were investigated. The reactive oxygen metabolite (d-ROM) and biological antioxidant potential (BAP) levels were measured as indicators of the degree of oxidative stress. The relationship between the investigation results (the patient characteristics, and the safety and efficacy of the newer AEDs) and the results of measurements of the d-ROMs/BAP were analyzed.\n\n\nRESULTS\nAll the patients who discontinued the newer AEDs had abnormal plasma d-ROM levels. In addition, all the patients who developed adverse events also had abnormal d-ROM levels. Furthermore, there was a trend toward a lower response rate in patients with higher plasma d-ROM levels.\n\n\nCONCLUSIONS\nThe results of this study suggested that d-ROM levels are useful for predicting the safety and efficacy of the newer AEDs (lamotrigine, levetiracetam) in SMID patients with intractable epilepsy. Therefore, d-ROMs could be important biomarkers for determining the safety and efficacy of drug therapy in SMID patients with epilepsy.",
"affiliations": "Tokushima Bunri University, Graduate School of Pharmaceutical Sciences, Tokushima, Japan; Japanese Red Cross Tokushima Hinomine Rehabilitation Center for People with Disabilities, Tokushima, Japan. Electronic address: morimoto@hinomine-mrc.jp.;Japanese Red Cross Tokushima Hinomine Rehabilitation Center for People with Disabilities, Tokushima, Japan.;Japanese Red Cross Tokushima Hinomine Rehabilitation Center for People with Disabilities, Tokushima, Japan.;Tokushima Bunri University, Graduate School of Pharmaceutical Sciences, Tokushima, Japan.",
"authors": "Morimoto|Masahito|M|;Satomura|Shigeko|S|;Hashimoto|Toshiaki|T|;Kyotani|Shojiro|S|",
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"keywords": "antiepileptic drugs; children with disabilities; epilepsy; oxidative stress",
"medline_ta": "J Chin Med Assoc",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants; D002648:Child; D004827:Epilepsy; D005260:Female; D006801:Humans; D008607:Intellectual Disability; D008297:Male; D016472:Motor Neuron Disease; D018384:Oxidative Stress; D017382:Reactive Oxygen Species",
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"title": "A study of oxidative stress and the newer antiepileptic drugs in epilepsy associated with severe motor and intellectual disabilities.",
"title_normalized": "a study of oxidative stress and the newer antiepileptic drugs in epilepsy associated with severe motor and intellectual disabilities"
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"abstract": "The place of bevacizumab (BEV) in salvage re-irradiation (Re-RT) settings of malignant glioma is poorly defined. In the current study risk/benefit profiles of two BEV-based Re-RT protocols were analyzed and compared with that of salvage BEV plus irinotecan (BEV/IRI). According to interdisciplinary tumor board recommendations, patients were assigned to one of three BEV-based treatment protocols: (1) BEV/IRI, (2) Re-RT (36 Gy/18 fx) with concomitant BEV (Re-RT/BEV), and (3) Re-RT with concomitant/maintenance BEV (Re-RT/BEV→BEV). Prognostic factors were obtained from proportional hazards models. Adverse events were classified according to the NCI CTCAE, v4.0. 105 consecutive patients were enrolled from 08/2008 to 05/2014. Patients undergoing Re-RT experienced longer time intervals from initial diagnosis to BEV treatment (median: 22.0 months vs. 13.7 months, p = 0.001); those assigned to Re-RT/BEV→BEV rated better on the performance scale (median KPSREC: 90 vs. 70, p = 0.013). Post-recurrence survival after BEV-based treatment (PRS) was longest after Re-RT/BEV→BEV (median: 13.1 months vs. 8 months, p = 0.006). PRS after Re-RT/BEV and BEV/IRI was similar. Multivariately, higher KPSREC and Re-RT/BEV→BEV were associated with longer PRS. Treatment toxicity did not differ among groups. Re-RT/BEV→BEV is safe, feasible and effective and deserves further prospective evaluation.",
"affiliations": "Department of Neurosurgery, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.;Department of Neurosurgery, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.;Department of Radiation Oncology, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.;Department of Neurosurgery, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.;MVZ Onkologie im Elisenhof, Prielmayerstr. 1, 80335, Munich, Germany.;Center for Neuropathology and Prion Research, LMU Munich, Feodor-Lynen-Str. 20, 81377, Munich, Germany.;Department of Neurosurgery, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.;Department of Radiation Oncology, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.;Department of Neurosurgery, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.;Department of Radiation Oncology, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany. maximilian.niyazi@med.uni-muenchen.de.",
"authors": "Schnell|Oliver|O|;Thorsteinsdottir|Jun|J|;Fleischmann|Daniel Felix|DF|;Lenski|Markus|M|;Abenhardt|Wolfgang|W|;Giese|Armin|A|;Tonn|Jörg-Christian|JC|;Belka|Claus|C|;Kreth|Friedrich Wilhelm|FW|;Niyazi|Maximilian|M|",
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"medline_ta": "J Neurooncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001932:Brain Neoplasms; D018572:Disease-Free Survival; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D000069475:Re-Irradiation; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8309335",
"other_id": null,
"pages": "591-599",
"pmc": null,
"pmid": "27599828",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": "16314646;24552317;23400732;26376163;19031176;26328938;24504501;25529015;25054664;17947719;2358840;25263092;20167811;21986722;26575171;23314822;20231676;18784279;26777122;19167838;17618441;19720927;22312554;19567589;25035291;24293233;17236958;24813092;18327820;17317837;24469853;21030162;19593660;21792866;25702193",
"title": "Re-irradiation strategies in combination with bevacizumab for recurrent malignant glioma.",
"title_normalized": "re irradiation strategies in combination with bevacizumab for recurrent malignant glioma"
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"abstract": "Spondylodiscitis is a rare complication after facet joint steroid injection. This article presents a 78-y-old male with chronic back pain and facet joint arthritis who developed Pseudomonas aeruginosa L2-L3 and L3-L4 spondylodiscitis after computed tomography-guided facet joint steroid injection. Magnetic resonance imaging, fine needle aspiration and cultures confirmed the diagnosis. The patient was treated with intravenous administration of amikacin, and imipenem plus cilastatin for 4 weeks, followed by oral administration of ciprofloxacin for another 10 weeks. Sterile preparation prior to facet joint steroid injection should be stressed. To the best of our knowledge, this is the only reported case of iatrogenic spondylodiscitis after facet joint steroid injection. This iatrogenic complication should be considered in the risk-benefit analysis of facet joint diagnostic or therapeutic injections.",
"affiliations": "Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece. matthew.falagas@tufts.edu",
"authors": "Falagas|Matthew E|ME|;Bliziotis|Ioannis A|IA|;Mavrogenis|Andreas F|AF|;Papagelopoulos|Panayiotis J|PJ|",
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"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D015299:Discitis; D006801:Humans; D007278:Injections, Spinal; D008279:Magnetic Resonance Imaging; D008297:Male; D011552:Pseudomonas Infections; D011859:Radiography; D021801:Zygapophyseal Joint",
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"abstract": "Drug-induced immune thrombocytopaenia (DITP) is a type of thrombocytopaenia caused by medications. It is one of the common causes of unexplained thrombocytopaenia. It is caused by the formation of autoantibodies against a particular drug and is commonly observed with medications like heparin and beta-lactam antibiotics. One of the rare causes of DITP is eptifibatide, a widely used antiplatelet agent for pretreatment in cardiac catheterisation. These patients can be asymptomatic or develop complications like skin bruising, epistaxis and even intracranial haemorrhage. We present a case of a 64-year-old man who developed eptifibatide-induced profound thrombocytopaenia leading to extensive skin bruising. He was treated with platelet transfusions followed by prompt improvement in platelet count.",
"affiliations": "Internal Medicine, Carle Foundation Hospital, Urbana, Illinois, USA pranav71293@gmail.com.;Internal Medicine, Carle Foundation Hospital, Urbana, Illinois, USA.;Carle Illiinois College of Medicine, University of Illinois, Champaign, Illinois, USA.;Interventional Cardiology, Cardiology, Carle Foundation Hospital, Urbana, Illinois, USA.",
"authors": "Mahajan|Pranav|P|http://orcid.org/0000-0001-7779-7810;Ayub|Fatima|F|;Azimi|Roxana|R|;Adoni|Naveed|N|",
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"title": "Eptifibatide-induced profound thrombocytopaenia: a rare complication.",
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"abstract": "Vitamin B12 (B12) deficiency is known to be associated with various neurological manifestations. Although central manifestations such as dementia or subacute combined degeneration are the most classic, neurological manifestations also include sensory neuropathies. However, B12 deficiency is still rarely integrated as a potential cause of sensory neuronopathy. Moreover, as many medical conditions can falsely normalize serum B12 levels even in the context of a real B12 deficiency, some cases may easily remain underdiagnosed. We report the illustrating case of an anorexic patient with sensory neuronopathy and consistently normal serum B12 levels. After all classical causes of sensory neuronopathy were ruled out, her clinical and electrophysiological conditions first worsened after folate administration, but finally improved dramatically after B12 administration. B12 deficiency should be systematically part of the etiologic workup of sensory neuronopathy, especially in a high risk context such as anorexia nervosa.",
"affiliations": "Hôpital de La Casamance, 13400 Aubagne, France. j.franques@hp-lacasamance.fr.;Service de Médecine Interne, Hôpital Européen, 13003 Marseille, France. l.chiche@hopital-europeen.fr.;Service de Neurologie, CHU Bordeaux 33000 Bordeaux, France. stephane.mathis@chu-bordeaux.fr.",
"authors": "Franques|Jérôme|J|;Chiche|Laurent|L|;Mathis|Stéphane|S|",
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"fulltext": "\n==== Front\nNutrientsNutrientsnutrientsNutrients2072-6643MDPI 10.3390/nu9030281nutrients-09-00281Case ReportSensory Neuronopathy Revealing Severe Vitamin B12 Deficiency in a Patient with Anorexia Nervosa: An Often-Forgotten Reversible Cause Franques Jérôme 12Chiche Laurent 2*Mathis Stéphane 31 Hôpital de La Casamance, 13400 Aubagne, France; j.franques@hp-lacasamance.fr2 Service de Médecine Interne, Hôpital Européen, 13003 Marseille, France3 Service de Neurologie, CHU Bordeaux 33000 Bordeaux, France; stephane.mathis@chu-bordeaux.fr* Correspondence: l.chiche@hopital-europeen.fr; Tel.: +33-616-834-430; Fax: +33-413-427-71215 3 2017 3 2017 9 3 28117 2 2017 13 3 2017 © 2017 by the authors.2017Licensee 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/).Vitamin B12 (B12) deficiency is known to be associated with various neurological manifestations. Although central manifestations such as dementia or subacute combined degeneration are the most classic, neurological manifestations also include sensory neuropathies. However, B12 deficiency is still rarely integrated as a potential cause of sensory neuronopathy. Moreover, as many medical conditions can falsely normalize serum B12 levels even in the context of a real B12 deficiency, some cases may easily remain underdiagnosed. We report the illustrating case of an anorexic patient with sensory neuronopathy and consistently normal serum B12 levels. After all classical causes of sensory neuronopathy were ruled out, her clinical and electrophysiological conditions first worsened after folate administration, but finally improved dramatically after B12 administration. B12 deficiency should be systematically part of the etiologic workup of sensory neuronopathy, especially in a high risk context such as anorexia nervosa.\n\nsensory neuropathycobalamin deficiencyvitamin B12anorexia nervosa\n==== Body\n1. Introduction\nVitamin B12 (B12) or cobalamin deficiency is a real public health issue, since it has been reported to occur in up to 20% of the elderly and up to 30% in specific subgroups of patients above 70 years [1,2]. The most characteristic manifestations of severe deficiency are haematological (i.e., macrocytic anemia) and central neurological manifestations such as reversible dementia or subacute combined degeneration [3]. However, peripheral neuropathies account for 30% to 50% of the neurological symptoms associated with B12 deficiency [4]. They are mostly symmetrical, length-dependent axonal sensory and sometimes sensorimotor neuropathies [5]. To date, B12 deficiency has not been included among the classical causes of sensory neuronopathies, which usually have an acute onset, are sometimes asymmetrical, or have a non-length-dependent distribution [6]. Importantly, the fact that B12 serum levels assessment can be falsely normalized by various medical conditions (including acute and chronic liver diseases, often of alcoholic origin, various neoplasias, malignant hemopathies such as myeloproliferative diseases, and renal insufficiency), a situation often termed as “functional B12 deficiency”, may have participated to the underdiagnosis of this association [7,8]. Indeed, in the cases where the serum levels are in the normal range but the index of suspicion for a B12 deficiency remains strong, the diagnosis should rely on either surrogate biomarkers for B12 deficiency (high homocysteine or methylmalonic acid (MMA) levels, medullary aspiration findings) and/or on the improvement under B12 supplementation. However, in practice, these additional investigations are rarely performed [8].\n\nWe report here an illustrating case of sensory neuronopathy in the context of chronic anorexia with dramatic improvement after vitamin B12 treatment.\n\n2. Case Presentation\nA 30 year-old female patient, with no past medical history, presented with painful paresthesia in the feet, which extended within two weeks to the hands and lips. She had lost 10 kg during the last four months in a context of anorexia nervosa. Clinical examination revealed only skin hyperpigmentation. The neurological examination showed the existence of diffuse areflexia and hypoesthesia in all four limbs. No proprioceptive ataxia or weakness was detected. The biological tests showed low plasma folate level (vitamin B9) (4.5 nmol/L for normal value > 7 nmol/L) with normal serum B12 or vitamin E levels. The electrophysiological study was in favor of a severe non-symmetrical, non-length-dependent sensory neuropathy involving all four limbs, with an electro-clinical pattern of sensory neuronopathy (Table 1). The motor nerve conduction study was normal, without slowing of nerve conduction velocities or any conduction block, and the evoked motor potentials (studied in all four limbs using transcranial magnetic stimulation) were also normal. \n\nThe cerebrospinal fluid analysis (cytology, protein and glucose levels, immunoelectrophoresis) and brain/spinal cord MRI findings were normal. The whole-body CT-scan was normal. The immunological tests including anti-neuronal, anti-ganglioside, anti-SSA/SSB were negative. The salivary gland biopsy was normal. No monoclonal gammopathy or immunoglobulin light chain was found. The HIV blood test was negative, as other usual serologies (EBV, CMV, hepatitis, Lyme disease); Treponema pallidum particle agglutination assay (TP-PA) and venereal disease research laboratory test (VDRL) turned out to be negative. \n\nThe patient was given vitamins B1, B6, and B9 at usual doses. Cutaneous symptoms responded well to this treatment, but she was admitted to hospital three months later because of a subacute proprioceptive ataxia causing frequent falls. Owing to her persistent state of anorexia, she had then lost 10 more kg. She was still suffering from painful paresthesia in wrists and ankles despite continuous treatment with vitamins B1, B6, and B9. She was only able to walk a few meters unaided. At physical examination, no pallesthesia was observed at levels of the knees. No motor symptoms or pyramidal sign were detected. She presented no orthostatic hypotension nor other signs of dysautonomia. The folate serum level was then normalized (34 nmol/L) and B12 level still in the normal range (314 pmol/L, normal value > 220 pmol/L), but hyperhomocysteinemia (25 µmol/L; normal value < 15 µmol/L) was observed (without renal insufficiency), as well as macrocytosis (mean corpuscular volume (MCV): 102 fl, normal value < 100 fl) without anemia (complete blood count was strictly normal), suggestive of B12 deficiency. Anti-transglutaminase, anti-endomysium, and intrinsic factor/gastric parietal cell antibodies were negative and oesogastroduodenal fibroscopy was normal. \n\nThe patient was therefore given daily 1000 µg intramuscular injections of B12 for two months. Although anorexia persisted, this treatment significantly decreased painful paresthesia within three months in parallel of a normalization of homocysteinemia and MCV. Five months later, her ability to walk was no longer restricted. At last examination, nine months after B12 administration, there was no more symptom in the upper limbs, and pallesthesia was quite normal in the feet with normal walking. Electrophysiological tests confirmed a progressive increase of the amplitude of sensory nerve action potential (SNAP) with time (Table 1). \n\n3. Discussion and Conclusions\nVitamin B12 deficiency is usually associated with various hematological, gastrointestinal and neurological/neuropsychiatric disorders [3]. Hematological manifestations may include anemia with a macrocytic blood picture and megaloblastic bone marrow, as well as isolated macrocytosis, as in our patient, and even in the complete absence of hematological manifestations in some patients with clear neurological manifestations [5,9]. Indeed, neurological manifestations may be the earliest and often the only manifestation of B12 deficiency [9]. \n\nWhile the main neurological complication is peripheral neuropathy, subacute combined degeneration, and optic nerve neuropathy can occur. Other rare manifestations include dementia, cerebellar ataxia, leukoencephalopathy, orthostatic tremor, myoclonus, ophthalmoplegia, catatonia, vocal cord paralysis, syringomyelia-like distribution of motor and sensory deficits, and autonomic dysfunction. Clinical and pathological involvement of the peripheral nervous system has been well described with B12 deficiency, usually with electrophysiological abnormalities suggestive of a length-dependent sensorimotor axonopathy [5].\n\nWe describe here a severe case of ataxia due to a sensory neuronopathy that was dramatically improved after B12 administration in a patient suffering severe anorexia nervosa. Because of the known poor sensitivity of the radio-immunological methods to detect it, a functional B12 deficiency was suspected because of the clinical context and in spite of repeated normal blood serum B12 levels [7]. Indeed, from measured total serum B12, only a small and variable proportion of B12 is active, so that metabolic B12 deficiency is common in patients with a serum B12 in the reference range [10]. To be reasonably sure that total serum B12 is adequate, some have proposed to consider as correct only levels above ~400 pmol/L [11,12]. Especially below that cut-off, as in our case, confirmatory tests are needed to assess adequacy of functional B12: measurement of methylmalonic acid, or in folate-replete patients, total homocysteine [8]. The worsening under folate therapy was also evocative of the process termed the ‘folate trap’ [13]. Indeed, folates and B12 both act as cofactors in the process of DNA synthesis. Giving folates to patients with B12 deficiency may mobilize the remaining stocks of B12 required to synthesize the nucleic acids on which fast cell replacement processes depend. This mobilization of the last remaining B12 supplies may occur to the detriment of other biochemical reactions involving B12, such as those resulting in the formation of methionine and hence that of myelin. Ultimately, a therapeutic test with B12 supplementation may be mandatory to confirm that B12 deficiency is the cause of the observed neurological manifestations. Importantly, this test may be worthwhile even in patients with an alternative cause of peripheral neuropathies. In a recent study, Solomon observed that 83% of 78 patients with neuropathy (including 35 patients with other known causes of neuropathy) improved after having been treated with oral or parenteral B12 [14]. Although patients with severe B12 deficiency with severe clinical complications first need parenteral B12, oral B12 is usually adequate to achieve target levels [15], so that as long as anorexia persists, patients should be given oral B12 supplements in the long term.\n\nSensory neuronopathies are characterized by the primary involvement of sensory neurons in the dorsal root ganglia [16]. New diagnostic criteria for sensory neuronopathies have been published [5,17]. Using these criteria, our patient was classified in the ‘possible sensory neuronopathy’ group. Indeed, the electrophysiological study including 14 sensory nerves showed an asymmetrical and a more pronounced involvement of the proximal sensory nerves (cutaneous median and lateral forearm from both upper limb) compared to distal nerves (medial, radial and ulnar nerves) in favor of a non-length-dependent neuropathy. Finally, paresthesia in the lips is not a classical sensory localisation of length-dependent axonopathy. The known etiological causes of sensory neuronopathies are paraneoplastic, toxic, dysimmune, nutritional (lack of vitamin E, nicotinic acid, and riboflavin), infectious, and genetic causes. Approximately 50% of the cases of sensory neuronopathy are said to be ‘idiopathic’ [16], but B12 deficiency has not been included so far among the definite causes. Pathological findings on totally gastrectomized rats (a murine model for B12 deficiency) also support this causality. Indeed, it was reported that non-vasogenic edema present in endoneurium of the dorsal root ganglia disappeared in response to B12 administration [18]. \n\nIn the case of our patient, there seems to have been a link between B12 deficiency and sensory neuronopathy: (a) the classical etiological patterns were ruled out; (b) the neurological symptoms worsened after folate administration (‘folate trap’); and (c) the clinical and electrophysiological findings improved dramatically in response to B12 treatment concomitantly with the normalisation of homocysteinemia and MCV. \n\nVitamin B12 deficiency has not yet been recognized as one of the causes of sensory neuronopathy, mainly because of the poor sensitivity of radio-immunological methods of determination and/or by the absence of systematic screening in the presence of alternative concomitant causes. In patients at high risk such as those with anorexia nervosa, it is therefore essential to identify as quickly as possible this deficiency, even if B12 serum levels are normal or paradoxically high [19], since a specific treatment is available, the time elapsing before its introduction being the main prognostic factor.\n\nAuthor Contributions\nJ.F., L.C. and S.M. analyzed and interpreted the patient data and contributed in writing the manuscript. All authors read and approved the final manuscript.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nAbbreviations\nB12\tvitamin B12\t\nCMV\tcytomegalovirus\t\nCT-scan\tcomputerized tomography scanner\t\nDNA\tdeoxyribonucleic acid\t\nEBV\tEpstein-Barr virus\t\nHIV\thuman immunodeficiency virus\t\nMRI\tmagnetic resonance imaging\t\nSNAP\tsensory nerve action potential\t\nTP-PA\tTreponema pallidum particle agglutination assay\t\nVDRL\tvenereal disease research laboratory test\t\nnutrients-09-00281-t001_Table 1Table 1 Evolution of amplitude of sensory nerve action potential (SNAP) on three successive electrophysiological studies of sensory nerves: initial study (M0) before treatment, second study five months after (M5), then third study nine months after the vitamin B12 treatment initiation (M9).\n\n\n\t\n\tM0\tM5\tM9\t\nright side\tmedian nerve\t4.4 µV\t8.6 µV\t11 µV\t\nulnar nerve\t6 µV\t9.3 µV\t10 µV\t\nradial nerve\t5 µV\t10 µV\t11 µV\t\ncutaneous median forearm nerve\t0 µV\t7.5 µV\t8 µV\t\ncutaneous lateral forearm nerve\t0 µV\t0 µV\t4.3 µV\t\nsural nerve\t0 µV\t0 µV\t3 µV\t\nfibular nerve\t0 µV\t0 µV\t0 µV\t\nleft side\tmedian nerve\t4.6 µV\t5.6 µV\t9 µV\t\nulnar nerve\tNO\t2.5 µV\t6 µV\t\nradial nerve\t5.3 µV\t5.9 µV\t11.4 µV\t\ncutaneous median forearm nerve\t0 µV\t0 µV\t8 µV\t\ncutaneous lateral forearm nerve\t0 µV\t0 µV\t1.4 µV\t\nsural nerve\t0 µV\t1.2 µV\t6.4 µV\t\nfibular nerve\t0 µV\t0 µV\t0 µV\n==== Refs\nReferences\n1. Andrès E. Loukili N.H. Noel E. Kaltenbach G. Abdelgheni M.B. Perrin A.E. Noblet-Dick M. Maloisel F. Schlienger J.L. Blicklé J.F. Vitamin B12 (cobalamin) deficiency in elderly patients CMAJ 2004 171 251 259 10.1503/cmaj.1031155 15289425 \n2. Spence J.D. Nutrition and stroke prevention Stroke 2006 37 2430 2435 10.17925/USN.2013.09.01.45 16873712 \n3. Kumar N. Neurologic aspects of cobalamin (B12) deficiency Handb. Clin. Neurol. 2014 120 915 926 24365360 \n4. Franques J. Gazzola S. Neuropathies métaboliques et carentielles: Mise au point sur le diabète, les carences en vitamine B12 et les carences en cuivre Rev. Neurol. (Paris) 2013 169 991 996 10.1016/j.neurol.2013.09.004 24269115 \n5. Saperstein D.S. Wolfe G.I. Gronseth G.S. Nations S.P. Herbelin L.L. Bryan W.W. Barohn R.J. Challenges in the identification of cobalamin-deficiency polyneuropathy Arch. Neurol. 2003 60 1296 1301 10.1001/archneur.60.9.1296 12975298 \n6. Camdessanché J.P. Jousserand G. Ferraud K. Vial C. Petiot P. Honnorat J. Antoine J.C. The pattern and diagnostic criteria of sensory neuronopathy: A case-control study Brain 2009 132 1723 1733 10.1093/brain/awp136 19506068 \n7. Solomon L.R. Cobalamin-responsive disorders in the ambulatory care setting: Unreliability of cobalamin, methylmalonic acid, and homocysteine testing Blood 2005 105 978 985 10.1182/blood-2004-04-1641 15466926 \n8. Chiche L. Mancini J. Arlet J.B. BDOSE Study Investigators. Indications for cobalamin level assessment in departments of internal medicine: A prospective practice survey Postgrad. Med. J. 2013 89 560 565 10.1136/postgradmedj-2012-131024 23708236 \n9. Ralapanawa D.M. Jayawickreme K.P. Ekanayake E.M. Jayalath W.A. B12 deficiency with neurological manifestations in the absence of anaemia BMC Res. Notes 2015 8 458 10.1186/s13104-015-1437-9 26385097 \n10. Spence J.D. Metabolic vitamin B12 deficiency: A missed opportunity to prevent dementia and stroke Nutr. Res. 2016 36 109 116 10.1016/j.nutres.2015.10.003 26597770 \n11. Vogiatzoglou A. Oulhaj A. Smith A.D. Nurk E. Drevon C.A. Ueland P.M. Vollset S.E. Tell G.S. Refsum H. Determinants of plasma methylmalonic acid in a large population: Implications for assessment of vitamin B12 status Clin. Chem. 2009 55 2198 2206 10.1373/clinchem.2009.128678 19833840 \n12. Bang H. Mazumdar M. Spence J.D. Tutorial in biostatistics: Analyzing associations between total plasma homocysteine and B vitamins using optimal categorization and segmented regression Neuroepidemiology 2006 27 188 200 10.1159/000096149 17035715 \n13. Gutierrez M. Franques J. Faivre A. Koric L. Chiche L. Attarian S. Pouget J. Diagnostic d’une carence en vitamine B12 ou le signe de l’ordonnance Rev. Neurol. (Paris) 2010 166 242 247 10.1016/j.neurol.2009.05.002 19520408 \n14. Solomon L.R. Vitamin B12-responsive neuropathies: A case series Nutr. Neurosci. 2016 19 162 168 10.1179/1476830515Y.0000000006 25710280 \n15. Van Walraven C.G. Austin P. Naylor C.D. Use of vitamin B12 injections among elderly patients by primary care CMAJ 1999 161 146 149 10439823 \n16. Sghirlanzoni A. Pareyson D. Lauria G. Sensory neuron diseases Lancet Neurol. 2005 4 349 361 10.1016/S1474-4422(05)70096-X 15907739 \n17. Antoine J.C. Robert-Varvat F. Maisonobe T. Créange A. Franques J. Mathis S. Delmont E. Kuntzer T. Lefaucheur J.P. Pouget J. Testing the validity of a set of diagnostic criteria for sensory neuronopathies: A francophone collaborative study J. Neurol. 2014 261 2093 2100 10.1007/s00415-014-7423-7 25108558 \n18. Tredici G. Buccellato F.R. Cavaletti G. Scalabrino G. Subacute combined degeneration in totally gastrectomized rats: An ultrastructural study J. Submicrosc. Cytol. Pathol. 1998 30 165 173 9530864 \n19. Corbetta F. Tremolizzo L. Conti E. Ferrarese C. Neri F. Bomba M. Nacinovich R. Paradoxical increase of plasma vitamin B12 and folates with disease severity in anorexia nervosa Int. J. Eat. Disord. 2015 48 317 322 10.1002/eat.22371 25446249\n\n",
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"title": "Sensory Neuronopathy Revealing Severe Vitamin B12 Deficiency in a Patient with Anorexia Nervosa: An Often-Forgotten Reversible Cause.",
"title_normalized": "sensory neuronopathy revealing severe vitamin b12 deficiency in a patient with anorexia nervosa an often forgotten reversible cause"
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"abstract": "We previously reported that oral low-dose acyclovir (200 mg/day) for the prevention of herpes simplex virus (HSV) infections after allogenic hematopoietic stem cell transplantation (HSCT) is effective without the emergence of acyclovir-resistant HSV infections. However, HSV infections are of significant concern because the number of allogeneic HSCT with T-cell depletion, which is a risk factor of the emergence of drug-resistant HSV infections, has been increasing. We experienced a 25-year-old female who received allogenic HSCT from an unrelated donor with 1-antigen mismatch using anti-thymocyte globulin. Despite acyclovir prophylaxis (200 mg/day), she developed the right palatal ulcer that was positive for HSV-1 specific antigen by fluorescent antibody on day 20 and developed new hypoglossal and tongue ulcers on day 33. Replacement of acyclovir with foscarnet improved her ulcers. We isolated 2 acyclovir-resistant and foscarnet-sensitive strains from the right palatal and hypoglossal ulcers, which had the same frame shift mutation in the thymidine kinase genes. The rate of proliferation of the isolate from the hypoglossal ulcer was faster than that from the right palatal ulcer in the plaque reduction assay. HSV strains that acquired acyclovir-resistant mutations at the right palatal ulcer with larger plaque might spread to the hypoglossal ulcer as the secondary site of infection because of better growth property. Second-line antiviral agents should be considered when we suspect treatment failure of HSV infection, especially in HSCT with T-cell depletion. Further studies are required whether low-dose acyclovir prophylaxis leads to the emergence of virological resistance.",
"affiliations": "Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan.;Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan.;Department of Virology, University of Toyama, Toyama 930-0194, Japan.;Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan.;Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan.;Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan.;Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan.;Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan.;Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan.;Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan.;Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan.;Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan.;Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan.;Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan.;Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan.;Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan.;Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan.;Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan.;Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan.;Department of Virology, University of Toyama, Toyama 930-0194, Japan.;Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Omiya-ku, Saitama, Saitama 330-8503, Japan. Electronic address: ycanda-tky@umin.ac.jp.",
"authors": "Akahoshi|Yu|Y|;Kanda|Junya|J|;Ohno|Ayumu|A|;Komiya|Yusuke|Y|;Gomyo|Ayumi|A|;Hayakawa|Jin|J|;Harada|Naonori|N|;Kameda|Kazuaki|K|;Ugai|Tomotaka|T|;Wada|Hidenori|H|;Ishihara|Yuko|Y|;Kawamura|Koji|K|;Sakamoto|Kana|K|;Sato|Miki|M|;Terasako-Saito|Kiriko|K|;Kimura|Shun-Ichi|SI|;Kikuchi|Misato|M|;Nakasone|Hideki|H|;Kako|Shinichi|S|;Shiraki|Kimiyasu|K|;Kanda|Yoshinobu|Y|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
"country": "Netherlands",
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"doi": "10.1016/j.jiac.2017.02.001",
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"issn_linking": "1341-321X",
"issue": "23(7)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Allogeneic hematopoietic stem cell transplantation; Herpes simplex virus; In vivo T-cell depletion; Virological resistance",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000212:Acyclovir; D000328:Adult; D000998:Antiviral Agents; D024882:Drug Resistance, Viral; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006561:Herpes Simplex; D018259:Herpesvirus 1, Human; D006801:Humans; D016867:Immunocompromised Host; D013601:T-Lymphocytes; D014059:Tongue; D014184:Transplantation, Homologous",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "485-487",
"pmc": null,
"pmid": "28262533",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acyclovir-resistant herpes simplex virus 1 infection early after allogeneic hematopoietic stem cell transplantation with T-cell depletion.",
"title_normalized": "acyclovir resistant herpes simplex virus 1 infection early after allogeneic hematopoietic stem cell transplantation with t cell depletion"
} | [
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"companynumb": "JP-TEVA-797260ROM",
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"abstract": "L-asparaginase (L-Asp) is an essential component of acute lymphoblastic leukemia (ALL) treatment protocols and its use has been associated with many adverse effects. We report a case of a 15-year-old boy with ALL who developed L-Asp induced hypoglycemia. To the best of our knowledge, only one such case has been reported previously.",
"affiliations": null,
"authors": "Misgar|Raiz Ahmad|RA|;Laway|Bashir Ahmad|BA|;Rahaman|Sk Hammadur|SH|;Wani|Arshad Iqbal|AI|;Bashir|Mir Iftikhar|MI|;Bhat|Javeed Rasool|JR|",
"chemical_list": "D000970:Antineoplastic Agents; D001215:Asparaginase",
"country": "Germany",
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"issn_linking": "0334-018X",
"issue": "28(3-4)",
"journal": "Journal of pediatric endocrinology & metabolism : JPEM",
"keywords": null,
"medline_ta": "J Pediatr Endocrinol Metab",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D001215:Asparaginase; D006801:Humans; D007003:Hypoglycemia; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "9508900",
"other_id": null,
"pages": "439-41",
"pmc": null,
"pmid": "25210761",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "L-asparaginase induced hypoglycemia in a case of acute lymphoblastic leukemia: a patient report.",
"title_normalized": "l asparaginase induced hypoglycemia in a case of acute lymphoblastic leukemia a patient report"
} | [
{
"companynumb": "IN-JAZZ-2016-IN-021878",
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"activesubstance": {
"activesubstancename": "ASPARAGINASE"
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{
"abstract": "BACKGROUND\nLeptospirosis is the most widespread zoonosis in the world. Cardiac involvement is a frequent complication of leptospirosis although significant left ventricular dysfunction is rare. We report a case of fatal leptospira myocarditis leading to cardiogenic shock on the second day of illness. This early occurrence of myocarditis is not previously reported.\n\n\nMETHODS\nA 36-yr-old previously healthy Sri Lankan male who takes care of a horse presented to the medical casualty ward with a one day history of fever, arthralgia and severe myalgia. He developed hypotension on the second day of illness. Electrocardiogram showed sinus tachycardia with ST segment depression in lateral leads which evolved in to rapid atrial fibrillation in the subsequent days. 2D echocardiogram showed dilated cardiac chambers with severe global hypokinesia and an ejection fraction of 20%. His renal and liver functions were within normal limits. He developed multi organ dysfunction syndrome and refractory shock, later in the course of illness. Leptospirosis was confirmed by positive leptospira IgM and negative IgG. Patient died on the fifth day of illness despite optimal medical treatment with intravenous penicillin, meropenem, levofloxacin, inotropes and supportive care in the intensive care unit.\n\n\nCONCLUSIONS\nWe describe a rare and unusual early complication of leptospirosis which has not been reported before. It is important to bear in mind that leptospirosis could present as myocarditis during the early phase of illness.",
"affiliations": "Ward 01, Colombo South Teaching Hospital, Kalubowila, Sri Lanka. jagathsltt@yahoo.com.;Ward 01, Colombo South Teaching Hospital, Kalubowila, Sri Lanka. thushanthy.prasath@gmail.com.;Ward 01, Colombo South Teaching Hospital, Kalubowila, Sri Lanka. ganaja007@yahoo.co.uk.;Ward 01, Colombo South Teaching Hospital, Kalubowila, Sri Lanka. sugandika23@gmail.com.;Department of Medicine, Faculty of Medical Sciences, University of Sri Jayewardenepura, Kalubowila, Sri Lanka. nilanka.dushani@gmail.com.;Department of Medicine, Faculty of Medical Sciences, University of Sri Jayewardenepura, Kalubowila, Sri Lanka. indrak2004@gmail.com.",
"authors": "Pushpakumara|Jagath|J|;Prasath|Thushanthy|T|;Samarajiwa|Ganaja|G|;Priyadarshani|Sugandika|S|;Perera|Nilanka|N|;Indrakumar|Jegarajah|J|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": "10.1186/s13104-015-1031-1",
"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central London 103110.1186/s13104-015-1031-1Case ReportMyocarditis causing severe heart failure - an unusual early manifestation of leptospirosis: a case report Pushpakumara Jagath jagathsltt@yahoo.com Prasath Thushanthy thushanthy.prasath@gmail.com Samarajiwa Ganaja ganaja007@yahoo.co.uk Priyadarshani Sugandika sugandika23@gmail.com Perera Nilanka nilanka.dushani@gmail.com Indrakumar Jegarajah indrak2004@gmail.com Ward 01, Colombo South Teaching Hospital, Kalubowila, Sri Lanka Department of Medicine, Faculty of Medical Sciences, University of Sri Jayewardenepura, Kalubowila, Sri Lanka University Medical Unit, CSTH, Kalubowila, Sri Lanka Department of Medicine, Faculty of Medical Sciences, USJP, Nugegoda, Sri Lanka 13 3 2015 13 3 2015 2015 8 808 10 2014 23 2 2015 © Pushpakumara 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\nLeptospirosis is the most widespread zoonosis in the world. Cardiac involvement is a frequent complication of leptospirosis although significant left ventricular dysfunction is rare. We report a case of fatal leptospira myocarditis leading to cardiogenic shock on the second day of illness. This early occurrence of myocarditis is not previously reported.\n\nCase presentation\nA 36-yr-old previously healthy Sri Lankan male who takes care of a horse presented to the medical casualty ward with a one day history of fever, arthralgia and severe myalgia. He developed hypotension on the second day of illness. Electrocardiogram showed sinus tachycardia with ST segment depression in lateral leads which evolved in to rapid atrial fibrillation in the subsequent days. 2D echocardiogram showed dilated cardiac chambers with severe global hypokinesia and an ejection fraction of 20%. His renal and liver functions were within normal limits. He developed multi organ dysfunction syndrome and refractory shock, later in the course of illness.\n\nLeptospirosis was confirmed by positive leptospira IgM and negative IgG. Patient died on the fifth day of illness despite optimal medical treatment with intravenous penicillin, meropenem, levofloxacin, inotropes and supportive care in the intensive care unit.\n\nConclusions\nWe describe a rare and unusual early complication of leptospirosis which has not been reported before. It is important to bear in mind that leptospirosis could present as myocarditis during the early phase of illness.\n\nKeywords\nLeptospirosisMyocarditisLeft ventricular dysfunctionissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nLeptospirosis is an infectious disease of animals and humans caused by the pathogenic spirochetes of the genus Leptospira. It is the most widespread zoonosis in the world [1] and is re-emerging globally [2]. Leptospirosis is found commonly in the tropical countries and Sri Lanka reports an annual incidence rate of 31–164 per 100,000 populations [3]. Anicteric leptospirosis resembles a simple febrile illness causing diagnostic difficulty. The mortality in leptospirosis is mainly due to more serious manifestations such as myocarditis, acute renal failure, hepatitis, pulmonary hemorrhage and multi-organ failure.\n\nLeptospirosis is a biphasic illness characterized by an early septicaemic phase lasting about a week and a delayed immune phase [1]. Most complications occur during the immune phase which has raised the possible pathogenic mechanisms described up to now. However, pathophysiology of cardiac involvement in leptospirosis is poorly understood [4]. Most studies reveal that cardiac involvement in the form of ECG (electrocardiogram) abnormalities or trans thoracic echo abnormalities are frequent and probably underestimated [1,3,5,6]. Autopsy studies also report a significant cardiac involvement in fatal leptospirosis [7]. But data reveal that severe cardiac dysfunction in these patients are rare [3,6,8] and all published literature report the occurrence of myocarditis beyond the first 5 days – 1 week of illness [5,9,10].\n\nWe report a case of fatal leptospira myocarditis leading to cardiogenic shock on the second day of illness. Patient rapidly deteriorated due to severe myocarditis leading to refractory shock and passed away on the fifth day of illness despite optimal medical care. This case is unusual for the development of early myocarditis in anicteric leptospirosis.\n\nCase presentation\nA 36-yr-old previously healthy Sri Lankan male who takes care of a horse presented to the medical casualty ward with fever, arthralgia and myalgia for one day. He complained of mild dysuria but had normal urine output. He did not have chest pain or shortness of breath. Further inquiry revealed that he was treated for leptospirosis during a febrile illness in the past. On examination, patient was afebrile, anicteric. His blood pressure was 90/60 mmHg and pulse rate 76 bpm. Rest of the examination was unremarkable. Initial investigations performed on the day of admission revealed neutrophil leukocytosis, mild thrombocytopaenia and microscopic haematuria (Table 1). Renal function and liver enzymes were within normal limits. Urine analysis revealed pus cells 05 – 06 /hpf, red cells 30 – 35 /hpf. CRP (C-reactive protein) was 75 mg/dl. A clinical diagnosis of leptospirosis was made and he was started on intravenous penicillin in addition to adequate hydration.Table 1 \nDemonstrating the serial investigations\n\n\n\nFBC\n\t\nD\n1\n\t\nD\n2\n\t\nD\n3\n\t\nD\n4\n\t\nD\n5\n\t\nWBC\t10.5 × 103/mic L\t10.5 × 103/mic L\t1.6 × 103/mic L\t3.5 × 103/micL\t3.1 × 103/micL\t\nN\t95%\t91%\t59%\t62%\t58%\t\nL\t4%\t5.7%\t32%\t36%\t38%\t\nHb\t12.9 g/dl\t11.3 g/dl\t9.1 g/dl\t9.8 g/dl\t10.1 g/dl\t\nPCV\t40%\t33%\t28%\t32%\t34%\t\nPlatelet\t102 × 103/mic L\t55 ×103/mic L\t10 × 103/mic L\t46 × 103/micL\t36 × 103/micL\t\n\nS. Creatinine\n\t70 micmol/L\t103 micmol/L\t234 micmol/L\t269 micmol/L\t362 micmol/L\t\n\nALT\n\t\t48 IU/L\t80 IU/L\t188 IU/L\t2726 IU/L\t\n\nAST\n\t\t42 IU/L\t197 IU/L\t235 IU/L\t7438 IU/L\t\n\n\nOn the second day of illness, he developed hypotension with tachycardia and dyspnoea. ECG revealed sinus tachycardia with ST depression in leads V4 – V6 [Figure 1]. His CXR (chest x ray) showed gross cardiomegaly and bilateral pulmonary shadows [Figure 2]. CVP (central venous pressure) was 16 cmH2O and 2D echocardiogram revealed dilatation of all four chambers, severe global hypokinesia and ejection fraction of 20%. Troponin I was 12.77 ng/ml (normal range < 0.40). He was diagnosed to have early and severe myocarditis. Patient was transferred to ICU (intensive care unit) as he needed inotropic support. Intravenous antibiotics including penicillin, meropenem and levofloxacin were continued. Patient was electively ventilated on the 3rd day of illness due to severe respiratory distress. On the same day, he developed rapid atrial fibrillation [Figure 3] unresponsive to digoxin and intravenous amiodarone. Platelet count dropped to 10 × 103 μ/L and he was given platelet transfusions to prevent bleeding [Table 1]. We started intravenous methylprednisolone based on previous studies showing a mortality benefit in severe leptospirosis complicated with myocarditis [11]. His serum creatinine increased to 362 μ mol/L by the 5th day of illness and ALT (alanine transaminase) and AST (aspartate transaminase) were markedly elevated up to 2726 U/l and 7438 U/l respectively. Dengue and Mycoplasma infections were excluded. Blood cultures were negative. Leptospira IgM antibody performed on the 5th day of illness was positive (IgG negative). Patient developed refractory shock and died of persistent ventricular tachycardia despite optimal treatment in the ICU.Figure 1 \nECG ,demonstrating sinus tachycardia, ST depressions and T inversions in leads V\n4\n– V\n6\non 2nd day of illness.\n\n\nFigure 2 \nCXR showed gross cardiomegaly and bilateral pulmonary shadows on the 3rd day of illness.\n\n\nFigure 3 \nECG showing rapid atrial fibrillation, developed on the 3rd day.\n\n\n\n\nDiscussion\nLeptospirosis is a life threatening disease that can present as a mild anicteric illness (90% of cases) or as a severe icteric disease [6]. Our patient presented with early myocarditis leading to severe left ventricular dysfunction. Myocarditis in this patient was characterized by persistent hypotension, tachycardia leading to atrial fibrillation, ST segment depression in ECG, elevated cardiac markers and dilated cardiac chambers with LV (left ventricular) dysfunction. Apart from myocarditis, leptospirosis can be complicated with pulmonary hemorrhage, hepatitis causing fulminant hepatic failure, acute kidney injury and ocular manifestations. However, most patients with leptospirosis recover completely without permanent residual effects [5,9].\n\nPrevious studies reveal that cardiac involvement is common in leptospirosis [3,6,8]. A study conducted in India found that 56% of leptospirosis patients had cardiac involvement and 52% of them had ECG abnormalities [6]. Commonest ECG changes were conduction defects followed by ST/T wave changes and atrial arrhythmias [3,6,8]. But significant LV dysfunction was not seen. A study conducted in Sri Lanka during the 2011 outbreak found 15.6% of patients to have myocarditis [3]. The degree of LV dysfunction was not documented. However, there were no fatalities. Prevalence of myocarditis in leptospirosis increased from 10.3% in 2008 to 15.6% in 2011 according to this study. This data reveal that despite the more frequent occurrence of myocarditis in leptospirosis, severe LV dysfunction and mortality is still rare.\n\nPathophysiology of cardiac involvement in leptospirosis is largely unknown. Autopsy studies show an interstitial myocarditis with infiltration of predominantly lymphocytes and plasma cells, petechial hemorrhages (particularly in the epicardium), mononuclear infiltration in the epicardium, pericardial effusions, and coronary arteritis [1] vasculitis was proposed as the principal pathogenic mechanism [8]. Recent literature reports that activation of Toll-like receptor (TLR) 2 is responsible for renal and pulmonary manifestations in leptospirosis [9]. This immunological basis explains the development of myocarditis after the initial one week of illness. There are no reported cases of leptospirosis causing myocarditis presenting as early as day two of illness.\n\nOur patient probably developed an unusually early immune phase as evidenced by early and severe myocarditis on the second day of illness. It is possible that immune reaction may have been triggered early by the presence of low levels of preformed antibodies resulting from the first episode of leptospirosis which occurred 15 years before.\n\nThis case illustrates that in endemic areas of leptospirosis, a possible second episode of this common illness may cause early and severe manifestations leading to diagnostic difficulty and high mortality.\n\nConclusion\nMyocarditis in leptospirosis can rarely lead to fatal cardiac dysfunction and could manifest during the early part of anicteric leptospirosis despite normal renal, hepatic functions. A high degree of suspicion is needed to diagnose and treat this life threatening complication early.\n\nConsent\nWritten informed consent was obtained from the patient’s next of kin for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nLVLeft Ventricle\n\nECGElectrocardiogram\n\nCXRChest X ray\n\nCRPC reactive protein\n\nCVPCentral Venous Pressure\n\nICUIntensive Care Unit\n\nTLRToll like Receptors\n\nALTAlanine Transaminase\n\nASTAspartate Transaminase\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nAll authors were involved in the management of the patient. JP researched the background literature on the case and wrote the first draft. JI and NP contributed towards the discussions and analysis of the case. All authors read and approved the final manuscript.\n\nAuthors’ information\n\nJP (MBBS) and TP (MBBS) are registrars in internal medicine, GS (MBBS) is a registrar in Emergency Medicine, SP (MBBS) is a intern medical officer in the University Medical Unit, Colombo South Teaching Hospital, Kalubowila, Sri Lanka. NP (MBBS, MD) Lecturer in Medicine, JI (MBBS, MD, FRCP) is a Professor in Medicine and Consultant Physician, in the Department of Medicine, Faculty of Medical Sciences, and University of Sri Jayewardenepura, Sri Lanka.\n==== Refs\nReferences\n1. Levett PN Leptospirosis Clin Microbiol Rev 2001 14 2 296 10.1128/CMR.14.2.296-326.2001 11292640 \n2. Hartskeerl RA Collares-Pereira M Ellis WA Emergence, control and re-emerging leptospirosis: dynamics of infection in the changing world Clin Microbiol Infect 2011 17 494 501 10.1111/j.1469-0691.2011.03474.x 21414083 \n3. Agampodi SB Dahanayaka NJ Bandaranayaka AK Perera M Priyankara S Weerawansa P Regional Differences of Leptospirosis in Sri Lanka: Observations from a Flood-Associated Outbreak in 2011 PLoS Negl Trop Dis 2014 8 1 e2626 10.1371/journal.pntd.0002626 24454971 \n4. Navinan MR Rajapakse S Cardiac involvement in Leptospirosis Trans R Soc Trop Med Hyg 2012 106 9 515 520 10.1016/j.trstmh.2012.06.007 22818758 \n5. Turhan V Ozmen N Ulusoy E Aparcl M Gur M Cardiac Leptospirosis, a case report and review Anatol J Clin Investig 2008 3 1 54 56 \n6. Trivedi SV Bhattacharya A Amichandwala K Jakkamsetti V Evaluation of cardiovascular status in severe Leptospirosis JAPI 2003 51 951 953 14719582 \n7. Shah K Amonkar GP Kamat RN Deshpande JR Cardiac findings in leptospirosis J Clin Pathol 2010 63 2 119 23 10.1136/jcp.2009.069575 20154032 \n8. Rajiv C Manjuran RJ Sudhayakumar N Haneef M Cardiovascular involvement in Leptospirosis Indian Heart J 1996 48 691 694 9062020 \n9. Ranawaka N Jeevagan V Karunanayake P Jayasinghe S Pancreatitis and myocarditis followed by pulmonary hemorrhage, a rare presentation of leptospirosis- A case report and literature survey BMC Infect Dis 2013 13 38 10.1186/1471-2334-13-38 23347428 \n10. Panagopoulos P Terzi I Karanikas M Galanopoulos N Maltezos E Myocarditis, pancreatitis, polyarthritis, mononeuritis multiplex and vasculitis with symmetrical peripheral gangrene of the lower extremities as a rare presentation of leptospirosis: a case report and review of the literature J Med Case Reports 2014 8 150 10.1186/1752-1947-8-150 \n11. Kularatne SA Budagoda BD de Alwis VK Wickramasinghe WM Bandara JM Pathirage LP High efficacy of bolus methylprednisolone in severe leptospirosis: a descriptive study in Sri Lanka Postgrad Med J 2011 87 1023 13 17 10.1136/pgmj.2009.092734 21106802\n\n",
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"issue": "8()",
"journal": "BMC research notes",
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"medline_ta": "BMC Res Notes",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D001281:Atrial Fibrillation; D004452:Echocardiography; D017809:Fatal Outcome; D005334:Fever; D006333:Heart Failure; D006801:Humans; D007362:Intensive Care Units; D007922:Leptospirosis; D008297:Male; D009205:Myocarditis; D012770:Shock, Cardiogenic; D017211:Treatment Failure",
"nlm_unique_id": "101462768",
"other_id": null,
"pages": "80",
"pmc": null,
"pmid": "25884600",
"pubdate": "2015-03-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11292640;14719582;9062020;20154032;24885926;21414083;22818758;23347428;24454971;21106802",
"title": "Myocarditis causing severe heart failure--an unusual early manifestation of leptospirosis: a case report.",
"title_normalized": "myocarditis causing severe heart failure an unusual early manifestation of leptospirosis a case report"
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"companynumb": "LK-PFIZER INC-2015461939",
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"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
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{
"abstract": "BACKGROUND\nAcquired haemophilia is an uncommon condition caused by the development of clotting factor inhibitors. To eliminate them, immunosuppressive therapy with corticosteroids and cytotoxic drugs is required.\n\n\nMETHODS\nWe describe a case of rituximab use in acquired haemophilia refractory to conventional therapy in a 63 year old male patient with chronic hepatitis C virus infection who was receiving treatment with pegylated-interferon-a-2a plus ribavirin.\n\n\nRESULTS\nAfter 21 weeks of antiviral therapy, the patient was admitted to hospital with a large haematoma in the abdominal muscles. Factor VIII level was zero and inhibitor titer was 345 Bethesda units. Oral immunosuppressive therapy with methylprednisolone and cyclophosphamide was administered for 1 month, with limited improvement. Therefore, cyclophosphamide was replaced by a four once-weekly dose of intravenous rituximab. Two months later, factor VIII level was normal and inhibitor titer was undetectable.\n\n\nCONCLUSIONS\nRituximab may be useful for the treatment of acquired haemophilia resistant to standard therapy.",
"affiliations": "Servicio de Farmacia. Hospital Clínico Universitario Virgen de la Arrixaca. Murcia. España.",
"authors": "Fernández de Palencia Espinosa|M Á|MÁ|;Arocas Casañ|V|V|;Garrido Corro|B|B|;de la Rubia Nieto|A|A|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D012254:Ribavirin; D000069283:Rituximab; D003520:Cyclophosphamide; D005169:Factor VIII; D011239:Prednisolone",
"country": "Spain",
"delete": false,
"doi": "10.7399/FH.2013.37.6.686",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1130-6343",
"issue": "37(6)",
"journal": "Farmacia hospitalaria : organo oficial de expresion cientifica de la Sociedad Espanola de Farmacia Hospitalaria",
"keywords": null,
"medline_ta": "Farm Hosp",
"mesh_terms": "D058846:Antibodies, Monoclonal, Murine-Derived; D000998:Antiviral Agents; D003520:Cyclophosphamide; D005169:Factor VIII; D006406:Hematoma; D006467:Hemophilia A; D019698:Hepatitis C, Chronic; D006801:Humans; D007166:Immunosuppressive Agents; D016898:Interferon-alpha; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D011239:Prednisolone; D012254:Ribavirin; D000069283:Rituximab",
"nlm_unique_id": "9440679",
"other_id": null,
"pages": "494-8",
"pmc": null,
"pmid": "24256012",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acquired haemophilia A in a patient with chronic hepatitis C virus infection receiving treatment with pegylated interferon plus ribarivin: role of rituximab.",
"title_normalized": "acquired haemophilia a in a patient with chronic hepatitis c virus infection receiving treatment with pegylated interferon plus ribarivin role of rituximab"
} | [
{
"companynumb": "ES-WATSON-2014-24771",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"... |
{
"abstract": "Teaching Point: Central nervous system adverse effects of cytarabine treatment include aseptic meningitis, myelopathy, and more rarely, encephalopathy, seizures, and cerebellar dysfunction. This case illustrates a cytarabine-induced encephalitis with predominant cerebellar involvement.",
"affiliations": "Cliniques universitaires Saint-Luc, BE.;Cliniques universitaires Saint-Luc, BE.;Cliniques universitaires Saint-Luc, BE.",
"authors": "Lenfant|Christine|C|https://orcid.org/0000-0002-8847-8169;Greiner|Nathalie|N|https://orcid.org/0000-0001-9351-4630;Duprez|Thierry|T|https://orcid.org/0000-0002-1579-0100",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.5334/jbsr.2492",
"fulltext": "\n==== Front\nJ Belg Soc Radiol\nJ Belg Soc Radiol\n2514-8281\nJournal of the Belgian Society of Radiology\n2514-8281\nUbiquity Press\n\n10.5334/jbsr.2492\nImages in Clinical Radiology\nCytarabine-Induced Encephalitis\nhttps://orcid.org/0000-0002-8847-8169\nLenfant Christine christine.lenfant@student.uclouvain.be\n1\nhttps://orcid.org/0000-0001-9351-4630\nGreiner Nathalie 1\nhttps://orcid.org/0000-0002-1579-0100\nDuprez Thierry 1\n1 Cliniques universitaires Saint-Luc, BE\nCORRESPONDING AUTHOR: Christine Lenfant Cliniques universitaires Saint-Luc, BE christine.lenfant@student.uclouvain.be\n16 9 2021\n2021\n105 1 4602 4 2021\n25 8 2021\nCopyright: © 2021 The Author(s)\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/.\n\nTeaching Point: Central nervous system adverse effects of cytarabine treatment include aseptic meningitis, myelopathy, and more rarely, encephalopathy, seizures, and cerebellar dysfunction. This case illustrates a cytarabine-induced encephalitis with predominant cerebellar involvement.\n\ncytarabine\ncytosar\ncerebellar toxicity\nneurotoxicity\ncerebellar encephalitis\n==== Body\npmcCase Study\n\nA 57-year-old woman with acute myeloid leukemia (AML) underwent induction followed by consolidation treatment protocol combining intravenous daunorubicine (60 mg/m2/day for 3 days of induction and 45 mg/m2/day for three days of consolidation) and high-dose cytarabine (200 mg/m2 /day for seven days of induction and 600 mg/m2/day for six days of consolidation). Dose was adapted to the decrease in renal function during the consolidation period. One week after the consolidation injections, she suffered from sudden onset of gait ataxia, dysphagia, and dysarthria. Cerebral computed tomography (CT) and CT angiography (not shown) excluded acute ischemic stroke. Magnetic resonance (MR) was performed under general anesthesia because of irrepressible claustrophobia (Figure 1). Symmetrically increased signal intensity was observed on fluid-attenuated inversion recovery (FLAIR) images within the cortex of the cerebellum (A, asterisks), the mesial temporal areas (B, arrows) and at a lesser degree, in the insular cortex (C, dotted arrows) and the posteromedial thalamic nuclei (C, arrow heads). Diffusion-weighted images demonstrated both increased signal intensity (D, asterisks) and reduced apparent diffusion coefficient values (not shown) within damaged areas. No blood-brain-barrier disruption was observed on post-contrast T1-weighted (not shown). After review of the literature, a toxic cerebellar encephalitis due to the administration of high-doses of cytarabine in a patient with progressively worsening renal function was hypothesized, and then confirmed after the nearly complete resolution of the cerebellar syndrome after withdrawal of cytarabine (only remained a slight dysarthria). Follow-up MRI was not performed as general anesthesia should have been inappropriately applied to a patient with ongoing neurological recovery.\n\nFigure 1\n\nComment\n\nCerebellar syndrome due to high-dose cytarabine treatment is a well-known clinical entity with few radiological documentation. The perfect match between clinical and MR features at acute phase together with the major clinical recovery after withdrawal of the presumptively causative drug strongly suggested that cytarabine had been responsible for the clinical/radiological features. Worsening renal function throughout the treatment course had obviously increased the risk for toxic side effects of the drug. However, subsidence of the radiological signs paralleling the clinical recovery could not be demonstrated as follow-up MRI was not feasible in ethical conditions. Nevertheless, sufficient evidence seemed to emerge from this observation to definitely include the cytarabine in the group of antimitotic drugs responsible for reversible acute cerebellar toxicity (REACT) syndrome, which has already done for other drugs such as the 5-fluorouracile [1]. Additional mesiotemporal, insular, and thalamic involvement in the condition has remained until now an undescribed feature of cytarabine-related brain toxicity since radiological reports in the condition are missing.\n\nCompeting Interests\n\nThe authors have no competing interests to declare.\n==== Refs\n1 KokselY, McKinneyAM. Potentially reversible and recognizable acute encephalopathic syndromes: Disease categorization and MRI appearances. AJNR Am J Neuroradiol. 2020 8; 41 (8 ): 1328–1338. DOI: 10.3174/ajnr.A6634 32616580\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2514-8281",
"issue": "105(1)",
"journal": "Journal of the Belgian Society of Radiology",
"keywords": "cerebellar encephalitis; cerebellar toxicity; cytarabine; cytosar; neurotoxicity",
"medline_ta": "J Belg Soc Radiol",
"mesh_terms": null,
"nlm_unique_id": "101698198",
"other_id": null,
"pages": "46",
"pmc": null,
"pmid": "34611580",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "32616580",
"title": "Cytarabine-Induced Encephalitis.",
"title_normalized": "cytarabine induced encephalitis"
} | [
{
"companynumb": "BE-PFIZER INC-202101381574",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nBecause omalizumab was only recently approved for refractory chronic urticaria (CU), there are few studies that have evaluated patients using omalizumab for longer than 1 year.\n\n\nOBJECTIVE\nTo evaluate omalizumab's effectiveness, its feasibility in weaning, and its safety profile in patients with refractory CU who were on omalizumab for longer than 1 year.\n\n\nMETHODS\nA retrospective chart review was conducted of adults with well-defined refractory CU in the authors' clinic from October 2005 to January 2015 who responded to omalizumab and who had taken it for longer than 1 year. In addition to baseline characteristics, the duration, course, and adverse effects of omalizumab therapy were analyzed.\n\n\nRESULTS\nEight of 10 patients had complete resolution of symptoms after reaching their optimal regimen and had taken omalizumab for a median duration of 37 months (17-112 months). None of them required uptitration of dosage, an increase in frequency of dosage, or add-on therapy. Five of 8 patients, while being tapered, had recurrence of symptoms requiring the reuse of omalizumab. One successfully discontinued omalizumab, 1 was in the process of being weaned but did not experience a flare, and 1 had not attempted weaning.\n\n\nCONCLUSIONS\nThis study from the United States suggests that omalizumab is effective and safe in patients with refractory CU who use omalizumab for longer than 1 year. Periodic attempts at weaning patients with CU from omalizumab should be attempted because there could be a chance of spontaneous remission. This might be difficult because symptoms are likely to recur, but restarting omalizumab in these patients seems effective and safe.",
"affiliations": "University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address: Daniel.Har@Phhs.org.;University of Texas Southwestern Medical Center, Dallas, Texas.;University of Texas Southwestern Medical Center, Dallas, Texas.",
"authors": "Har|Daniel|D|;Patel|Saurin|S|;Khan|David A|DA|",
"chemical_list": "D018926:Anti-Allergic Agents; D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; D000069444:Omalizumab; D007073:Immunoglobulin E",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1081-1206",
"issue": "115(2)",
"journal": "Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology",
"keywords": null,
"medline_ta": "Ann Allergy Asthma Immunol",
"mesh_terms": "D000328:Adult; D018926:Anti-Allergic Agents; D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; D002908:Chronic Disease; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007073:Immunoglobulin E; D008297:Male; D008875:Middle Aged; D000069444:Omalizumab; D012008:Recurrence; D012189:Retrospective Studies; D016896:Treatment Outcome; D014581:Urticaria",
"nlm_unique_id": "9503580",
"other_id": null,
"pages": "126-9",
"pmc": null,
"pmid": "26093778",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Outcomes of using omalizumab for more than 1 year in refractory chronic urticaria.",
"title_normalized": "outcomes of using omalizumab for more than 1 year in refractory chronic urticaria"
} | [
{
"companynumb": "US-UCBSA-2015028778",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
"drugadditional": null,
... |
{
"abstract": "A 63-year-old woman was admitted to our hospital to receive a fourth course of modified rituximab-ESHAP chemotherapy for relapsed primary breast diffuse large B-cell lymphoma. She developed hemophagocytic lymphohistiocytosis (HLH) 20 days after admission. Polymerase chain reaction (PCR) detected cytomegalovirus (CMV) DNA in her peripheral blood; therefore, she was diagnosed with CMV-associated HLH and consequently treated with foscarnet (FCN). Her general condition and pancytopenia soon improved, and the antiviral drug was stopped for 1 week. However, she suddenly became disoriented 10 days later, and this condition rapidly worsened. Cerebrospinal fluid (CSF) examination revealed an elevated white blood cell count with lymphocytic predominance and a high CMV DNA load, prompting a final diagnosis of CMV meningoencephalitis. We began intravenous combination therapy with FCN and ganciclovir (GCV), and her conscious state gradually improved. CMV DNA sequencing did not reveal drug resistance associated with mutations, and intravenous GCV was stopped for 1 week. FCN treatment was then continued until CMV DNA was no longer detected in her CSF samples via PCR. CMV meningoencephalitis is a rare neurological infection complicated with hematological malignancy in non-transplant patients and can be serious and life-threatening with a high mortality rate. This infection requires a differential diagnosis of consciousness impairment that develops in a patient with lymphoid malignancy during chemotherapy.",
"affiliations": "Department of Hematology/Oncology, Wakayama Medical University.;Department of Hematology/Oncology, Wakayama Medical University.;Department of Hematology/Oncology, Wakayama Medical University.;Department of Hematology/Oncology, Wakayama Medical University.;Department of Hematology/Oncology, Wakayama Medical University.;Department of Hematology/Oncology, Wakayama Medical University.;Department of Hematology/Oncology, Wakayama Medical University.;Department of Hematology/Oncology, Wakayama Medical University.;Department of Hematology/Oncology, Wakayama Medical University.;Department of Infectious Diseases, Toranomon Hospital.;Department of Hematology/Oncology, Wakayama Medical University.;Department of Hematology/Oncology, Wakayama Medical University.",
"authors": "Yoshida|Kikuaki|K|;Kosako|Hideki|H|;Yamashita|Yusuke|Y|;Kobata|Hiroshi|H|;Oiwa|Takehiro|T|;Hosoi|Hiroki|H|;Murata|Shogo|S|;Mushino|Toshiki|T|;Nishikawa|Akinori|A|;Araoka|Hideki|H|;Sonoki|Takashi|T|;Tamura|Shinobu|S|",
"chemical_list": "D000998:Antiviral Agents; D004279:DNA, Viral; D017245:Foscarnet; D015774:Ganciclovir",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.60.124",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "60(2)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Cytomegalovirus meningoencephalitis; Diffuse large B-cell lymphoma; Foscarnet; Hemophagocytic lymphohistiocytosis",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D002648:Child; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004279:DNA, Viral; D005260:Female; D017245:Foscarnet; D015774:Ganciclovir; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008590:Meningoencephalitis; D008875:Middle Aged; D016879:Salvage Therapy",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "124-129",
"pmc": null,
"pmid": "30842379",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cytomegalovirus meningoencephalitis in a diffuse large B-cell lymphoma patient undergoing salvage chemotherapy.",
"title_normalized": "cytomegalovirus meningoencephalitis in a diffuse large b cell lymphoma patient undergoing salvage chemotherapy"
} | [
{
"companynumb": "PHHY2019JP219264",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "1",
... |
{
"abstract": "Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits (PGNMID) is a recently described, uncommon renal disorder which is considered a monoclonal gammopathy of renal significance. Although some patients will have a detectable monoclonal spike, overt hematologic malignancy is found in only a minority. Most patients with PGNMID are over the age of 50 years, and to our knowledge no cases have been reported in children or adolescents. Renal biopsy shows variable histologic patterns by light microscopy, with membranoproliferative and membranous patterns being most common. Immunofluorescence microscopy demonstrates restriction to a single immunoglobulin G heavy chain isotype and a single light chain subtype. Electron microscopy reveals granular, unorganized deposits. We report a rare pediatric case which occurred in a 17-year-old female. The rarity of this entity in the adult population has not permitted a standard treatment regimen to be established. Our adolescent patient was treated with multiple treatment regimens including prednisone, mycophenolate mofetil, rituximab, bortezomib, and daratumumab. Our case demonstrates that awareness of this disorder by pediatric nephrologists and pathologists is vital to guide accurate disease classification, prognosis, and treatment.",
"affiliations": "Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.;Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.",
"authors": "Torrealba|Jose|J|;Gattineni|Jyothsna|J|;Hendricks|Allen R|AR|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000488641",
"fulltext": "\n==== Front\nCase Rep Nephrol DialCase Rep Nephrol DialCNDCase Reports in Nephrology and Dialysis2296-9705S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000488641cnd-0008-0070Case ReportProliferative Glomerulonephritis with Monoclonal Immunoglobulin G Lambda Deposits: Report of the First Pediatric Case Torrealba Jose aGattineni Jyothsna bHendricks Allen R. a*aDepartment of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USAbDepartment of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA*Allen R. Hendricks, DO, Department of Pathology, University of Texas Southwestern Medical Center, 6201 Harry Hines Blvd., Dallas, TX 75390-9234 (USA), E-Mail allen.hendricks@utsouthwestern.eduJan-Apr 2018 24 4 2018 24 4 2018 8 1 70 75 15 12 2017 19 3 2018 Copyright © 2018 by S. Karger AG, Basel2018This 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.Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits (PGNMID) is a recently described, uncommon renal disorder which is considered a monoclonal gammopathy of renal significance. Although some patients will have a detectable monoclonal spike, overt hematologic malignancy is found in only a minority. Most patients with PGNMID are over the age of 50 years, and to our knowledge no cases have been reported in children or adolescents. Renal biopsy shows variable histologic patterns by light microscopy, with membranoproliferative and membranous patterns being most common. Immunofluorescence microscopy demonstrates restriction to a single immunoglobulin G heavy chain isotype and a single light chain subtype. Electron microscopy reveals granular, unorganized deposits. We report a rare pediatric case which occurred in a 17-year-old female. The rarity of this entity in the adult population has not permitted a standard treatment regimen to be established. Our adolescent patient was treated with multiple treatment regimens including prednisone, mycophenolate mofetil, rituximab, bortezomib, and daratumumab. Our case demonstrates that awareness of this disorder by pediatric nephrologists and pathologists is vital to guide accurate disease classification, prognosis, and treatment.\n\nKeywords\nGlomerulonephritisMonoclonal immunoglobulinsImmunoglobulin G\n==== Body\nIntroduction\nProliferative glomerulonephritis with monoclonal immunoglobulin G deposits (PGNMID) is a recently described, uncommon entity which mimics immune-complex-type glomerulonephritis (GN). Deposition of monoclonal immunoglobulins is found in a variety of other diseases affecting the kidneys, including monoclonal immunoglobulin deposition disease (MIDD), immunotactoid GN, type 1 cryoglobulinemia, and amyloidosis. Renal biopsy can aid in the distinction of PGNMID from these other entities [1, 2, 3]. By light microscopy, the most commonly reported patterns include membranoproliferative GN followed by membranous nephropathy and endocapillary proliferative GN. Immunofluorescence (IF) microscopy demonstrates restriction to a single immunoglobulin G (IgG) heavy chain subtype (usually IgG3) and a single light chain isotype (kappa more common than lambda). Electron microscopy (EM) shows granular, unorganized deposits in subepithelial, subendothelial, and mesangial locations which varies according to the histologic pattern [3, 4].\n\nClinically, the majority of patients present with renal insufficiency and nephrotic-range proteinuria, and approximately half of patients have nephrotic syndrome. Only about 30% of patients have a detectable monoclonal spike (M-spike) by serum protein electrophoresis and urine protein electrophoresis with immunofixation. The majority do not have hematologic malignancy. Most patients are Caucasian, and the majority are female. Nearly all patients with PGNMID are over the age of 40 years [3, 4].\n\nTo our knowledge, this is the first reported pediatric case of this entity. Our case broadens the epidemiologic understanding of the disease and presents it as a diagnostic consideration for pediatric nephrologists and renal pathologists in the appropriate clinical setting. The description of our experience in managing this exceedingly rare case also adds to the body of knowledge regarding clinical response to various treatments.\n\nCase Presentation\nA 17-year-old female with an unremarkable past medical history developed sudden-onset right-sided abdominal pain, gross hematuria, lower extremity edema, and nephrotic-range proteinuria following a mild upper respiratory infection. She presented to the emergency department with a fever of 39° C and complained of sharp flank pain, headaches, and fatigue. Laboratory results were notable for hypoalbuminemia (serum albumin 1.2 g/dL), low complement C3 of 63 mg/dL (range 82–163 mg/dL), low complement C4 of 10.6 mg/dL (range 14–41 mg/dL), elevated C-reactive protein (2.71 mg/dL), normal blood urea nitrogen, and normal serum creatinine (0.7 mg/dL). Antistreptolysin O titer was normal. Initial timed 24-h urine collection revealed nephrotic-range proteinuria of 3,679 mg/day with a protein creatinine ratio of 3.7.\n\nThe protein to creatinine ratio increased to 9.5 three weeks after presentation and a renal biopsy was performed. Under light microscopy, glomeruli had a membranoproliferative pattern with hyperlobulated glomeruli, diffuse endocapillary hypercellularity, diffuse glomerular basement membrane duplication, and mild mesangial matrix expansion with hypercellularity (Fig. 1a). No segmental sclerosis, crescents, or fibrinoid necrosis were seen. There was mild interstitial edema associated with a multifocal mild mononuclear leukocytic infiltrate, but no significant interstitial fibrosis or tubular atrophy. Small numbers of intratubular red blood cell casts were present.\n\nDirect IF demonstrated diffuse, global, chunky granular glomerular capillary wall and mesangial positive staining by IgG (4+ on a scale of 0–4), C1q (4+), C3 (4+), and lambda (4+) (Fig. 1b). IgA, IgM, and kappa were negative. Restriction to IgG and monoclonal lambda raised the suspicion of PGNMID, necessitating IgG subclass staining. The glomeruli showed diffuse global staining by IgG3 (4+) (Fig. 1c). IgG1, IgG2, and IgG4 were all negative.\n\nEM showed extensive (> 80%) podocyte foot process effacement and segmental duplication of glomerular basement membranes. There were numerous subendothelial and mesangial electron-dense deposits with a few scattered subepithelial deposits. These deposits were granular with focally variegated texture (Fig. 1d). No organized substructures or fibrillar deposits were present. There were no tubuloreticular inclusions and no deposits within the tubular basement membranes.\n\nThe renal biopsy findings prompted additional laboratory studies. Serological testing for cryoglobulins was negative, as was rheumatoid factor. Serum and urine protein electrophoresis did not reveal a monoclonal immunoglobulin. IgG levels were low with normal IgA and IgM levels. Immunofixation electrophoresis showed a normal pattern with no monoclonal proteins. An alternative complement pathway functional assay was low at 3% (normal 50–130%), and alternative complement pathway soluble membrane attack complex was elevated at 0.48 mg/L (normal < 0.3 mg/L).\n\nThe patient was initially treated with prednisone (40 mg b.i.d.) and lisinopril with no resolution of proteinuria or intermittent gross hematuria. Mycophenolate mofetil (1,000 mg b.i.d.) was initiated 3 weeks after presentation, and steroids were tapered to 30 mg every other day. After 3 months of this treatment there was improvement of serum albumin to 3 g/dL and protein creatinine ratio to 1.4. Complement C3 and C4 levels returned to normal. There was persistent intermittent gross hematuria and proteinuria. Rituximab therapy (four doses at 375 mg/m2/dose) was begun 4 months after diagnosis. After rituximab therapy, her albumin consistently stayed around 3–3.4 mg/dL, with her urine protein creatinine ratio at 1.1–1.2. Both alternative complement pathway functional assay and soluble membrane attack complex had normalized approximately 2 months after completion of the rituximab course. Two months after rituximab, due to a decrease in serum albumin to 2.8, she received intermittent high-dose steroids for 4 months which improved her serum albumin to 3.2–3.8. Mycophenolate mofetil was stopped due to myelosuppression 7 months after starting treatment. Ten months after initial presentation, the patient relapsed with nephrotic-range proteinuria (5 g/24 h), low serum albumin (2.7 mg/dL), and increase in serum creatinine from baseline (0.7 mg/dL) to 0.9 mg/dL. A bone marrow biopsy was performed to detect possible hematologic abnormalities, but it was not adequate for evaluation. At another institution, lambda light chains were detected in the patient's serum using a research test called monoclonal immunoglobulin rapid accurate mass measurement. The decision was made to treat with bortezomib (Velcade®) plus dexamethasone as per the multiple myeloma protocol at that institution. She received the regimen of Velcade/dexamethasone for 4 months, but due to persistent proteinuria, the anti-CD38 monoclonal antibody daratumumab was added to her regimen. She received the combined Velcade/dexamethasone/daratumumab regimen for approximately 4 months at another institution. With this regimen, her serum albumin improved to 3.3–3.6 and her urine protein creatinine ratio remained at 1–1.4. Five months after completion of her Velcade/dexamethasone/daratumumab regimen, she had another relapse, with her serum albumin decreasing to 2.9 and her urine protein creatinine ratio increasing to 2.4. The same regimen was restarted, and at the time of writing the patient is receiving this therapy with improvement in her serum albumin to 3.3 and her urine protein creatinine ratio at 1.4.\n\nDiscussion\nPGNMID is an uncommon type of monoclonal gammopathy of renal significance (MGRS), which mimics immune complex-mediated GN. MGRS refers to renal diseases which are caused by the secretion of monoclonal immunoglobulin secreted by B-cell clones which do not meet criteria for hematologic malignancies such as multiple myeloma or lymphoma. Multiple other renal lesions can fall within the category of MGRS. A combination of morphologic findings seen by light microscopy, staining patterns by IF, and ultrastructural features seen by EM is required to arrive at a precise pathologic diagnosis. MGRS can result in tubular lesions such as cast nephropathy and light chain proximal tubulopathy. In addition to PGNMID, glomerular disorders include immunotactoid glomerulopathy, type 1 cryoglobulinemic GN, and fibrillary GN. Immunoglobulin-related amyloidosis (predominantly light chain) and MIDD can result in glomerular, tubular, and vascular lesions. Some lesions can be readily recognized by their morphologic appearance. For example, cast nephropathy has fractured casts which are very pale by periodic acid-Schiff stain, and amyloid is Congo-red positive. EM is informative in many cases. Fibrillar deposits are present in amyloidosis and fibrillary GN, which can be distinguished by their size. Microtubules are seen with immunotactoid GN and cryoglobulinemic GN, and crystals can be seen in light-chain proximal tubulopathy. MIDD has punctate, powdery, granular deposits. IF is essential in all cases to demonstrate monoclonality [1]. In PGNMID, renal biopsy demonstrates monoclonality for a single light-chain isotype (kappa more commonly) and a single gamma heavy-chain subclass (most commonly IgG3, as in our case) [3, 4]. Our case showed a membranoproliferative pattern by light microscopy along with predominantly subendothelial and mesangial deposits by EM.\n\nDespite the monoclonality seen by renal biopsy, only 11/37 patients in an expanded case series reported by Nasr et al. [3] had a detectable M-spike and only 1 patient had myeloma. When a patient did have an M-spike, the monoclonal proteins had the same heavy- and light-chain isotypes as those deposited in the kidney. The authors concluded that PGNMID does not seem to precede multiple myeloma in most patients. As with our patient, 49% had full nephrotic syndrome. Approximately 11% of their patients had low complement C3 and C4, as our patient did initially. The majority of the patients in that study were female, and the mean age was 54.5 years (range 20–81 years). No standard treatment regimens were used. Patients received a variety of immunomodulatory therapies including steroids, alkylating agents, mycophenolate mofetil, rituximab, and bortezomib. Out of 32 patients with available follow-up data, 38% had partial to complete recovery, 38% had persistent renal dysfunction, and 22% progressed to end-stage renal disease.\n\nIn a series of 26 patients with PGNMID described by Guiard et al. [4], 31% had a detectable M-spike. Again, no pediatric cases were reported, with a mean age of 52 years (range 29–77 years). However, in contrast to the study by Nasr et al. [3], a hematologic malignancy (myeloma, lymphoma) was identified in 9 out the 22 patients who underwent bone marrow biopsy. The most common pattern seen by renal biopsy was membranous nephropathy (14 patients), followed by membranoproliferative GN (12 patients). IgG subclass staining was performed in 21 of the cases. The authors pointed out that there was a correspondence between the histologic pattern of disease and the subclass of the monoclonal IgG seen in deposits. Membranous nephropathy was associated with IgG1 deposits in 64% of patients, whereas membranoproliferative GN was associated with IgG3 in 80% (as in our patient). Seven of the patients received rituximab as either first- or second-line therapy, 5 of whom did not have malignancy. Good response was achieved with 5 patients having complete remission of nephrotic syndrome and 2 having partial remission.\n\nPGNMID has been described in association with hematologic malignancies in isolated case reports as well. Noto et al. [5] described a patient with nephrotic syndrome and a renal biopsy showing endocapillary proliferative GN with monoclonal IgG1 kappa deposits. Serum protein electrophoresis and urine protein electrophoresis showed M-spikes of IgG kappa, and bone marrow biopsy confirmed multiple myeloma. The patient was successfully treated with bortezomib and dexamethasone. Barbour et al. [6] described 2 patients with preexisting chronic lymphocytic leukemia who developed hypertension, increased serum creatinine, microhematuria, and nephrotic-range proteinuria. Renal biopsies from both patients showed endocapillary proliferative GN with monoclonal IgG1 deposits. Both were treated with rituximab plus cyclophosphamide in one case and fludarabine in the other, and both showed significant improvement.\n\nPGNMID has been reported to recur in kidney allografts. Nasr et al. [7] described 4 cases which recurred in the allografts at a mean of 3.8 months after transplantation. The monoclonal IgG deposits in the transplants and in the native kidneys had identical heavy- and light-chain isotypes. Albawardi et al. [8] reported that out of 21 renal biopsy specimens with PGNMID in their files, 2 were recurrent cases in allografts, and 2 more were described as de novo cases in allografts. One case recurred approximately 13 months after transplantation, and 1 recurred at about 22 months.\n\nIn conclusion, we describe PGNMID in a 17-year-old patient, who to our knowledge is the first pediatric case reported. This expands the age range for PGNMID and proves that it is not confined to the adult population. At the present time, there is no standardized treatment for this rare disease. Although a small number of patients have experienced complete response using immunomodulatory drugs, including rituximab and bortezomib, our patient achieved partial response and is still undergoing treatment. Awareness that PGNMID is part of the differential diagnosis for renal diseases caused by deposition of monoclonal IgG in pediatric patients is necessary to guide correct disease classification, prognosis, and potential therapeutic options.\n\nStatement of Ethics\nThe authors have no ethical conflicts to declare.\n\nDisclosure Statement\nThe authors declare no conflict of interest.\n\nFig. 1. Kidney biopsy findings. a Light microscopy shows a glomerulus with basement membrane double contours (arrows) and endocapillary hypercellularity. Periodic acid-Schiff stain; original magnification ×400. b Immunofluorescence microscopy shows strong (4+), granular glomerular capillary wall and mesangial staining by lambda. Original magnification ×400. c Immunofluorescence microscopy shows strong (4+), granular glomerular capillary wall and mesangial staining by IgG3. Original magnification ×400. d Electron microscopy shows subepithelial (white arrow), subendothelial (blue arrow), and mesangial (red arrow) granular electron-dense deposits, some with a variegated appearance. Original magnification ×1,500.\n==== Refs\nReferences\n1 Bridoux F Leung N Hutchison CA Touchard G Sethi S Fermand JP International Kidney and Monoclonal Gammopathy Research Group. Diagnosis of monoclonal gammopathy of renal significance. Kidney Int. 2015 4 87 (4) 698 711 25607108 \n2 Nasr SH Markowitz GS Stokes MB Seshan SV Valderrama E Appel GB Proliferative glomerulonephritis with monoclonal IgG deposits: a distinct entity mimicking immune-complex glomerulonephritis. Kidney Int. 2004 1 65 (1) 85 96 14675039 \n3 Nasr SH Satoskar A Markowitz GS Valeri AM Appel GB Stokes MB Proliferative glomerulonephritis with monoclonal IgG deposits. J Am Soc Nephrol. 2009 9 20 (9) 2055 2064 19470674 \n4 Guiard E Karras A Plaisier E Duong Van Huyen JP Fakhouri F Rougier JP Patterns of noncryoglobulinemic glomerulonephritis with monoclonal Ig deposits: correlation with IgG subclass and response to rituximab. Clin J Am Soc Nephrol. 2011 7 6 (7) 1609 1616 21700823 \n5 Noto R Kamiura N Ono Y Tabata S Hara S Yokoi H Successful treatment with bortezomib and dexamethasone for proliferative glomerulonephritis with monoclonal IgG deposits in multiple myeloma: a case report. BMC Nephrol. 2017 4 18 (1) 127 132 28385149 \n6 Barbour SJ Beaulieu MC Zalunardo NY Magil AB Proliferative glomerulonephritis with monoclonal IgG deposits secondary to chronic lymphocytic leukemia. Report of two cases. Nephrol Dial Transplant. 2011 8 26 (8) 2712 2714 21633102 \n7 Nasr SH Sethi S Cornell LD Fidler ME Boelkins M Fervenza FC Proliferative glomerulonephritis with monoclonal IgG deposits recurs in the allograft. Clin J Am Soc Nephrol. 2011 1 6 (1) 122 132 20876681 \n8 Albawardi A Satoskar A Von Visger J Brodsky S Nadasdy G Nadasdy T Proliferative glomerulonephritis with monoclonal IgG deposits recurs or may develop de novo in kidney allografts. Am J Kidney Dis. 2011 8 58 (2) 276 281 21705124\n\n",
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"title": "Proliferative Glomerulonephritis with Monoclonal Immunoglobulin G Lambda Deposits: Report of the First Pediatric Case.",
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"abstract": "We herein report a case of laryngeal Kaposi's sarcoma (KS) complicated by immune reconstitution inflammatory syndrome in a human immunodeficiency virus (HIV)-infected patient. The patient initially presented with KS involving the larynx, which was successfully treated with pegylated liposomal doxorubicin (PLD) and antiretroviral therapy (ART). PLD was discontinued after 2 courses because of a marked clinical improvement; however, the patient experienced progressive odynophagia and dyspnea 2 months after the initiation of ART. Laryngoscopy revealed a severely swollen, inflamed epiglottis. The readministration of PLD was successful, and the patient was thereafter discharged without any subsequent complications.",
"affiliations": "Department of Infectious Diseases, Tokyo Metropolitan Komagome Hospital, Japan.",
"authors": "Kato|Hirofumi|H|;Yanagisawa|Naoki|N|;Morioka|Hiroshi|H|;Sasaki|Shugo|S|;Sekiya|Noritaka|N|;Suganuma|Akihiko|A|;Imamura|Akifumi|A|;Ajisawa|Atsushi|A|",
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"mesh_terms": "D000328:Adult; D044966:Anti-Retroviral Agents; D000970:Antineoplastic Agents; D004317:Doxorubicin; D015658:HIV Infections; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D007822:Laryngeal Neoplasms; D008297:Male; D011092:Polyethylene Glycols; D012514:Sarcoma, Kaposi",
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"title": "Laryngeal Kaposi's Sarcoma Complicated by the Immune Reconstitution Inflammatory Syndrome in an HIV-infected Patient.",
"title_normalized": "laryngeal kaposi s sarcoma complicated by the immune reconstitution inflammatory syndrome in an hiv infected patient"
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"abstract": "BACKGROUND\nTotal skin electron beam therapy (TSEBT) is an effective treatment in mycosis fungoides. Total skin helical tomotherapy (TSHT) may be an alternative to TSEBT and may offer several dosimetric and treatment advantages. There are currently very few published treatment results using TSHT in place of TSEBT for treatment of mycosis fungoides.\n\n\nMETHODS\nTwo patients with mycosis fungoides were treated at our institution using TSHT. The first patient was a 69-year-old Caucasian female with stage IVA2 (T2 N3 M0 B2) disease who was treated to a dose of 12 Gy in 8 fractions, with a bone marrow mean dose of 1.66 Gy and V10 = 0.41%. Two weeks after ending treatment the patient developed myelosuppression including grade 4 thrombocytopenia and required blood and platelet transfusions. The second patient was a 29-year-old Caucasian female with stage I (T2 N0 M0 B0) disease. This patient previously had been treated for mycosis fungoides using helical tomotherapy (HT) at a dose of 20 Gy to a localized region and experienced mild thrombocytopenia at that time. The patient then underwent retreatment 17 months later with TSHT to a dose of 12 Gy in 6 fractions with a mean bone marrow dose of 2.3 Gy and V10 = 4.28%. This patient once again experienced myelosuppression that included grade 4 thrombocytopenia. She also required blood and platelet transfusions.\n\n\nCONCLUSIONS\nBoth patients treated with TSHT experienced severe bone marrow suppression including grade 4 thrombocytopenia. This was more severe than expected considering the relatively low overall prescription dose and despite a planning constraint placed on the bone marrow of a mean dose of < 2 Gy. These outcomes suggest that patients treated using TSHT should be closely monitored for myelosuppression and caution used even when treating to a dose of 12 Gy.",
"affiliations": "Michigan State University College of Human Medicine, 418 W. Magnetic Street, Marquette, MI, 49855, USA.;Department of Human Oncology, University of Wisconsin, Madison, WI, USA.;Department of Human Oncology, University of Wisconsin, Madison, WI, USA.;Department of Human Oncology, University of Wisconsin, Madison, WI, USA.;Department of Human Oncology, University of Wisconsin, Madison, WI, USA. kabradley@humonc.wisc.edu.",
"authors": "Schaff|Eric M|EM|http://orcid.org/0000-0002-1653-3800;Rosenberg|Stephen A|SA|;Olson|Stephanie J|SJ|;Howard|Steven P|SP|;Bradley|Kristin A|KA|",
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"fulltext": "\n==== Front\nRadiat OncolRadiat OncolRadiation Oncology (London, England)1748-717XBioMed Central London 101310.1186/s13014-018-1013-2Case ReportBone marrow suppression as a complication of total skin helical tomotherapy in the treatment of mycosis fungoides http://orcid.org/0000-0002-1653-3800Schaff Eric M. schaff48@msu.edu 1Rosenberg Stephen A. SRosenberg@uwhealth.org 2Olson Stephanie J. SOlson@uwhealth.org 2Howard Steven P. howard@humonc.wisc.edu 2Bradley Kristin A. kabradley@humonc.wisc.edu 21 Michigan State University College of Human Medicine, 418 W. Magnetic Street, Marquette, MI 49855 USA 2 0000 0001 0701 8607grid.28803.31Department of Human Oncology, University of Wisconsin, Madison, WI USA 13 4 2018 13 4 2018 2018 13 6720 11 2017 2 4 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\nTotal skin electron beam therapy (TSEBT) is an effective treatment in mycosis fungoides. Total skin helical tomotherapy (TSHT) may be an alternative to TSEBT and may offer several dosimetric and treatment advantages. There are currently very few published treatment results using TSHT in place of TSEBT for treatment of mycosis fungoides.\n\nCase presentation\nTwo patients with mycosis fungoides were treated at our institution using TSHT. The first patient was a 69-year-old Caucasian female with stage IVA2 (T2 N3 M0 B2) disease who was treated to a dose of 12 Gy in 8 fractions, with a bone marrow mean dose of 1.66 Gy and V10 = 0.41%. Two weeks after ending treatment the patient developed myelosuppression including grade 4 thrombocytopenia and required blood and platelet transfusions. The second patient was a 29-year-old Caucasian female with stage I (T2 N0 M0 B0) disease. This patient previously had been treated for mycosis fungoides using helical tomotherapy (HT) at a dose of 20 Gy to a localized region and experienced mild thrombocytopenia at that time. The patient then underwent retreatment 17 months later with TSHT to a dose of 12 Gy in 6 fractions with a mean bone marrow dose of 2.3 Gy and V10 = 4.28%. This patient once again experienced myelosuppression that included grade 4 thrombocytopenia. She also required blood and platelet transfusions.\n\nConclusions\nBoth patients treated with TSHT experienced severe bone marrow suppression including grade 4 thrombocytopenia. This was more severe than expected considering the relatively low overall prescription dose and despite a planning constraint placed on the bone marrow of a mean dose of < 2 Gy. These outcomes suggest that patients treated using TSHT should be closely monitored for myelosuppression and caution used even when treating to a dose of 12 Gy.\n\nKeywords\nMycosis fungoidesHelical tomotherapyTotal skin electron beam therapyCutaneous lymphomaT-cell lymphomaissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nTSEBT has been proven to be an effective treatment in T2 and T3 mycosis fungoides that is refractory to other treatment modalities. Although it has been proven effective, TSEBT has disadvantages that may complicate treatment [1]. The most common protocol used for treatment is the Stanford Protocol that requires the patient to stand for the entirety of treatment that can last 30 min [2]. Total skin electron therapy may be limited secondary to heterogeneity with areas receiving up to 40% deviation from the prescription dose [3]. There have been alternative protocols proposed which allow for the patient to lie down but these protocols sacrifice dose homogeneity to an even greater extent [4].\n\nDue to its dose delivery characteristics, helical tomotherapy (HT) with photons can be used to treat superficially and thus may be an alternative to TSEBT. Treating patients with total skin helical tomotherapy (TSHT) may provide several advantages: 1) improved dose homogeneity; 2) non-overlapping fields; and 3) patients in a comfortable supine position for treatment.\n\nAlthough there are potential benefits to the use of TSHT, there remains concern that photon therapy may lead to higher bone marrow doses and potential toxicity compared to TSEBT. Recent data regarding TSEBT suggest that lower doses of radiation may provide equally effective control of the disease, less toxicity, and leave the possibility for retreatment if relapse occurs [5]. A pooled analysis of 3 phase II trials showed an overall response of 88% and complete response of 27% treating with 12 Gy utilizing TSEBT [6]. Only 3% of patients experienced grade 1 leukopenia in these trials. If lower doses are equally effective using TSHT as well, it is possible that the treatment toxicity can be spared while still maintaining treatment efficacy with a photon-based approach. Herein we describe the outcomes of 2 patients treated with TSHT and the toxicity associated with treatment.\n\nCase presentation\nThe first patient was a 69-year-old Caucasian female with stage IVA2 (T2 N3 M0 B2) mycosis fungoides who presented to the radiation oncology clinic for treatment after failing interferon alfa-2b, photopheresis, vorinostat, brentuximab vedotin, and gemcitabine. She was treated by our department using TSHT to a dose of 12 Gy in 8 fractions 4 days per week. The patient underwent simulation and treatment with a head and shoulder mask, body fix, with arms down. The dose distribution and dose-volume histogram are shown in Figs. 1 and 2. Bone marrow mean dose was 1.66 Gy with V10 = 0.41%. The bone marrow contour sum included the entire spine, pelvis and femurs. Dose values to other bony sites have been included for additional reference in Table 1.Fig. 1 Dose distributions for patient 1 treated with TSHT for mycosis fungoides\n\nFig. 2 Dose-volume histogram for patient 1 treated with TSHT for mycosis fungoides\n\nTable 1 Patient 1 dose values\n\n\tMean\tV10\tV5\tV3\t\nBone marrow total (arms not included)\t1.66 Gy\t0.41%\t3.72%\t9.81%\t\nBone marrow total (arms included)\t2.62 Gy\t7.97%\t13.45%\t19.03%\t\nLumbar\t1.51 Gy\t0.97%\t3.15%\t7.65%\t\nDorsal\t1.95 Gy\t0.49%\t3.76%\t11.19%\t\nPelvic\t1.49 Gy\t0.32%\t3.16%\t7.55%\t\nFemurs\t1.86 Gy\t0.12%\t4.86%\t14.09%\t\nArms\t11.18 Gy\t74.54%\t98.84%\t100%\t\n\n\nOn the last day of treatment, she developed grade 1 anemia and thrombocytopenia. Two weeks following the last treatment the bone marrow toxicity progressed to grade 2 anemia, grade 2 leukopenia, and grade 4 thrombocytopenia. The patient was given multiple transfusions of packed red blood cells (PRBCs) and platelets over the course of treatment. One month after treatment she experienced an episode of epistaxis that self-resolved after 40 min. Within 1 week of treatment completion, the patient noted significant improvement of her diffuse erythroderma. Despite radiotherapy she had progressive disease on her right thigh several weeks later and began treatment with chlorambucil and low dose prednisone. She continued chlorambucil until she was hospitalized and ultimately passed away secondary to stroke several months after treatment.\n\nThe second patient was a 29-year-old Caucasian female with stage I (T2 N0 M0 B0) mycosis fungoides. She had previous treatment with topical steroids, methotrexate, interferon, mycophenolate, and cyclosporine. She was on photochemotherapy with interferon alfa-2b at the time of presentation. At that time, she was treated with photons to active sites of disease with a dose of 20 Gy in 10 fractions to the scalp, buttocks, neck, and axillae, and a dose of 10 Gy to the back in 5 fractions. The patient experienced improvement in disease burden. However, the patient also experienced myelosuppression beginning 2 weeks after this treatment with grade 3 leukopenia, grade 1 anemia, and grade 4 thrombocytopenia.\n\nShe then presented again to the radiation oncology clinic after progression of disease approximately 17 months from her previous radiotherapy treatment. She was being treated with interferon alfa-2 and methotrexate. She was then treated to a dose of 12 Gy in 6 fractions with daily treatments using TSHT with sparing of the hands and feet. The patient underwent simulation and treatment with a facemask and body fix with arms down The upper half and lower half of the body were treated separately with each hemibody receiving 6 fractions of 2 Gy. The dose distribution and dose-volume histogram are shown in Figs. 3 and 4. Bone marrow mean dose was 2.3 Gy with V10 = 4.28%. As with the first patient, the bone marrow contour sum includes the entire spine, pelvis and femurs. Dose values to other bony sites have been included for additional reference in Table 2.Fig. 3 Dose distributions for patient 2 treated with TSHT for mycosis fungoides. Note that the hands and feet of this patient were spared treatment\n\nFig. 4 Dose-volume histogram for patient 2 treated with TSHT for mycosis fungoides\n\nTable 2 Patient 2 dose values\n\n\tMean\tV10\tV5\tV3\t\nBone marrow total (arms not included)\t2.3 Gy\t4.28%\t10.11%\t12.93%\t\nBone marrow total (arms included)\t3.56 Gy\t13.76%\t24.12%\t27.49%\t\nLumbar\t1.18 Gy\t0\t0\t0.76%\t\nDorsal\t1.87 Gy\t0\t0.12%\t2.61%\t\nPelvic\t1.13 Gy\t0\t0.03%\t0.71%\t\nFemurs\t4.53 Gy\t14.31%\t37.38%\t44.77%\t\nArms\t10.41 Gy\t62.97%\t93.77%\t100%\t\n\n\nInitially the patient had a good response to therapy with many of the cutaneous lesions resolving, however her disease rapidly progressed 2 months following treatment. Bone marrow suppression occurred 3 weeks after treatment with grade 1 anemia, grade 3 leukopenia, and grade 4 thrombocytopenia. The patient did not report any bleeding events, however red blood cell and platelet transfusions were necessary before the patient’s myelosuppression eventually resolved 6 months after the end of treatment.\n\nDiscussion and conclusions\nBoth patients treated with TSHT at our institution experienced significant bone marrow toxicity. Even at a prescription dose of 12 Gy, these patients experienced grade 4 myelosuppression. Their platelet nadir occurred 2 and 3 weeks after treatment ended. This was similar to the 2-week platelet nadir Carabell et al. experienced in patients treated with total body irradiation (TBI) to a dose 1.5 Gy for advanced non-Hodgkin lymphoma [7]. Similar bone marrow toxicities have been reported when using TBI to a dose of 1.5 Gy with concurrent lonidamine to treat patients with favorable B-cell neoplasms as well [8]. Our results show similar rates of myelosuppression as patients treated using TSHT at a higher prescription dose of 30 Gy in the series by Hsieh et al. [9]. However, in the prior report, the mean bone marrow dose varied between 4 to 9 Gy. In our two patients, the mean bone marrow doses were significantly lower at 2.3 Gy and 1.66 Gy.\n\nIn a Japanese case series, 3 patients were treated for mycosis fungoides using TSHT to a dose of 10 Gy and myelosuppression occurred in 2 patients [10]. One of the patients experienced grade 4 myelosuppression which later required blood transfusion. This study is comparable to our own, as prescription doses (12 Gy vs 10 Gy) were similar. In addition, their mean bone marrow dose of 2.27 Gy was comparable to our patients. Fractionation similar to our first patient (12 Gy in 8 fractions) has been shown to result in rare grade 2 and grade 3 toxicities without myelosuppression when using TSEBT instead of TSHT [11, 12].\n\nThe question remains as to why our patients and the patient from the previously mentioned case study experienced severe myelosuppression with such low mean bone marrow dose. One explanation is that our treatment planning software may have not have accurately simulated the actual bone marrow dosage. Another possibility is that the planning parameter of a mean bone marrow dose < 2 Gy is not a strict or predictive enough treatment planning constraint for total skin treatments. Thrombocytopenia experienced in these two patients may be secondary to significant volume of low dose irradiation to the bone marrow. A total body exposure of 2.5–5 Gy results in hematopoietic syndrome. This occurs secondary to destruction of mitotically active precursor cells approximated 3–4 weeks after exposure. In these patients, mean doses to the bone marrow did approach 2 Gy and likely led to similar biological effects and the resultant thrombocytopenia.\n\nOne method that may decrease internal dose would be using a bolus to bring the dose closer to the skin surface. This was done in an anthropomorphic phantom substitute study by Lin et al. in which TSHT was used to produce a dose of at least 26 Gy to a depth of 4 mm of the truncal skin in conjunction with a 3 mm neoprene diving suit utilized as bolus [13]. This plan resulted in a simulated mean dose to OARs of 9.7 cGy per fraction during the 36 Gy treatment course of 36 fractions as compared to approximately 1–4 cGy/fx with a rival TSEBT plan. However, they defined the OARs to be heart, lung, liver, kidney, spleen, intestine, and rectum, while bone marrow was not included. Hsieh et al. also used a 3 mm neoprene diving suit to act as bolus in their actual patient treatment setup, however their patient still experienced grade 4 myelosuppression.\n\nAnother concern with patients receiving significant bone marrow radiation dose would be secondary malignancies such as leukemia and myelodysplastic syndrome. This has been reported in patients receiving a mean bone marrow dose of 5.2 Gy when treated with total body irradiation and chemotherapy for non-Hodgkin lymphoma [14].\n\nDisease response was moderate in our two treated cases with each experiencing a partial response immediately following treatment but soon after relapsing. Prior success had been shown with TSEBT to a dose of 12 Gy with a complete response in 88%, but often repeat total skin treatment may be needed at these low doses [7].\n\nAlthough TSHT allows for improvements in dose homogeneity when compared to TSEBT, these cases illustrate the need for further research on the safety of TSHT, specifically in the case of bone marrow toxicity. We attempted to avoid bone marrow toxicity by limiting the mean dose to 2 Gy. Yet, significant myelosuppression was still encountered. Caution should be utilized when using TSHT as a therapy for mycosis fungoides. Further, patients will likely benefit from enrollment on various approaches to total skin especially in the context of TSHT. Patients who have been previously treated or are currently being treated with chemotherapy that have a low hematopoietic reserve may be especially at risk. Currently, clinical trials are underway to examine patients who will receive TSHT for treatment resistant cutaneous lymphoma [15]. These results will be a welcome addition to the literature and may help clarify safety and tolerability of this treatment approach.\n\nAbbreviations\nHTHelical tomotherapy\n\nOAROrgans at risk\n\nPRBCPacked red blood cell\n\nTBITotal body irradiation\n\nTSEBTTotal skin electron beam therapy\n\nTSHTTotal skin helical tomotherapy\n\nAuthors’ contributions\nAll authors contributed to drafting the manuscript and approved the final manuscript.\n\nEthics approval and consent to participate\nPatients signed consent prior to treatment being initiated and data being collected.\n\nConsent for publication\nPatients signed consent prior to treatment being initiated and data being collected.\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. De Moraes FY HDA C Hanna SA JLF DS Marta GN Literature review of clinical results of total skin electron irradiation (TSEBT) of mycosis fungoides in adults Rep Pract Oncol Radiother 2014 19 2 92 98 10.1016/j.rpor.2013.08.003 24936326 \n2. Guerts M Bayliss A Thapa B Nelson G Total skin tomotherapy for treatment of mycosis fungoides 2014 \n3. Weaver RD Gerbi BJ Dusenbery KE Evaluation of dose variation during total skin electron irradiation using thermoluminescent dosimeters Int J Radiat Oncol Biol Phys 1995 33 2 475 478 10.1016/0360-3016(95)00161-Q 7673036 \n4. Wu JM Leung SW Wang CJ Chui CS Lying-on position of total skin electron therapy Int J Radiat Oncol Biol Phys 1997 39 2 521 528 10.1016/S0360-3016(97)00141-7 9308958 \n5. Elsayad K Susek KH Eich HT Total skin electron beam therapy as part of multimodal treatment strategies for primary cutaneous T-cell lymphoma Oncol Res Treat 2017 40 244 252 10.1159/000475634 28448985 \n6. Hoppe RT Harrison C Tavallaee M Bashey S Sundram U Li S Low-dose total skin electron beam therapy as an effective modality to reduce disease burden in patients with mycosis fungoides: results of a pooled analysis from 3 phase-II clinical trials J Am Acad Dermatol 2014 72 2 286 292 10.1016/j.jaad.2014.10.014 25476993 \n7. Carabell SC Chaffey JT Rosenthal DS Moloney WC Hellman S Results of total body irradiation in the treatment of advanced non-hodgkin’s lymphomas Cancer 1979 43 3 994 1000 10.1002/1097-0142(197903)43:3<994::AID-CNCR2820430331>3.0.CO;2-0 106956 \n8. Robins HI Combined modality clinical trials for favorable B-cell neoplasms: Ionidamine plus whole body hyperthermia and/or total body irradiation Semin Oncol 1991 18 2 23 27 2031194 \n9. Hsieh CH, Shueng PW, Lin SC, Tien HJ, Shiau AC, Chou YH, et al. Helical irradiation of the total skin with dose painting to replace total skin electron beam therapy for therapy-refractory cutaneous CD4+ T-cell lymphoma. Biomed Res Int. 2013; 10.1155/2013/717589.\n10. Okuma K Haga A Imae T Takenaka R Sugaya M Nakagawa K Total skin irradiation using helical tomotherapy: a novel experience and report of three cases Radiother Oncol 2016 119 1 676 \n11. Kroeger K Elsayad K Moustakis C Low-dose total skin electron beam therapy for cutaneous lymphoma Strahlenther Onkol 2017 193 1024 1030 10.1007/s00066-017-1188-8 28785772 \n12. Morris S, Scarisbrick J, Frew J, et al. The results of low-dose total skin electron beam radiation therapy (TSEB) in patients with mycosis fungoides from the UK cutaneous lymphoma group. Int J Radiat Oncol Biol Phys. 2017;\n13. Lin CT, Shiau AC, Tien HJ, Yeh HP, Shueng PW, Hsieh CH. An attempted substitute study of total skin electron therapy technique by using helical photon tomotherapy with helical irradiation of the total skin treatment: a phantom result. Biomed Res Int. 2013; 10.1155/2013/108794.\n14. Travis LB Weeks J Curtis RE Chaffey JT Stovall M Banks PM Leukemia following low-dose total body irradiation and chemotherapy for non-Hodgkin’s lymphoma J Clin Oncol 1996 14 2 565 571 10.1200/JCO.1996.14.2.565 8636772 \n15. Helical irradiation of total skin (HITS) for cutaneous lymphoma. 2017. Retrieved from https://clinicaltrials.gov/ct2/show/NCT02039895 (Identification No. NCT02039895).\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1748-717X",
"issue": "13(1)",
"journal": "Radiation oncology (London, England)",
"keywords": "Cutaneous lymphoma; Helical tomotherapy; Mycosis fungoides; T-cell lymphoma; Total skin electron beam therapy",
"medline_ta": "Radiat Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D001853:Bone Marrow; D005260:Female; D006801:Humans; D009182:Mycosis Fungoides; D011832:Radiation Injuries; D050397:Radiotherapy, Intensity-Modulated; D012878:Skin Neoplasms",
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"title": "Bone marrow suppression as a complication of total skin helical tomotherapy in the treatment of mycosis fungoides.",
"title_normalized": "bone marrow suppression as a complication of total skin helical tomotherapy in the treatment of mycosis fungoides"
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"abstract": "To present to and inform the practitioner of an unusual presentation of Varicella zoster virus and Ramsay-Hunt Syndrome.\nA 69-year-old bedbound male with vascular dementia presented to the emergency room with a red right eye with associated tearing and mucus production. The patient could not express if he was in pain. The initial diagnosis from the emergency room was bacterial keratitis, confirmed with a positive pseudomonas culture. However, upon examination by the ophthalmologist it was noted that there was not only a large, infected epithelial defect, but also an intraocular pressure of 35 and a candy-cane hypopyon. The diagnosis of herpes neurotrophic keratitis and iridocyclitis was made and the patient was started on intravenous acyclovir along with the appropriate topical medications. A day later, it was noted that the patient developed a right sided facial palsy and vesicular lesions inside the right ear canal, as confirmed by otolaryngology.\nRamsay-Hunt Syndrome is usually known to the ophthalmologist due to the exposure keratopathy caused by facial palsy. This case demonstrates varicella-zoster virus (VZV) neurotrophic keratitis preceding the development of facial palsy, which can further exacerbate an already neurotrophic cornea. The practitioner should be aware of these signs and symptoms and adjust their treatment with systemic acyclovir-prednisone.",
"affiliations": "Novus Total Eye Care, 518 West Ave, Tallmadge, OH, USA.;Novus Total Eye Care, 518 West Ave, Tallmadge, OH, USA.",
"authors": "Gorgani|Farzan M|FM|;Beyer|Todd L|TL|",
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"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936\nElsevier\n\nS2451-9936(21)00229-2\n10.1016/j.ajoc.2021.101220\n101220\nCase Report\nNeurotrophic corneal ulcer and iridocyclitis directly preceding Ramsay-Hunt Syndrome\nGorgani Farzan M. MS, DO. fgorgani@dellorusso.com\nabc∗\nBeyer Todd L. DO, FAAO, FASOPRS. ab\na Novus Total Eye Care, 518 West Ave, Tallmadge, OH, USA\nb Cleveland Clinic Akron General, 1 Akron General Ave, Akron, OH, USA\nc New Jersey Eye Center- Dello Russo Laser Vision, 1 N Washington Ave, Bergenfield, NJ, USA\n∗ Corresponding author. DO. 518 West Ave Tallmadge, OH, 44278, USA. fgorgani@dellorusso.com\n04 11 2021\n12 2021\n04 11 2021\n24 1012207 8 2020\n24 7 2021\n4 10 2021\n© 2021 Published by Elsevier Inc.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nPurpose\n\nTo present to and inform the practitioner of an unusual presentation of Varicella zoster virus and Ramsay-Hunt Syndrome.\n\nObservations\n\nA 69-year-old bedbound male with vascular dementia presented to the emergency room with a red right eye with associated tearing and mucus production. The patient could not express if he was in pain. The initial diagnosis from the emergency room was bacterial keratitis, confirmed with a positive pseudomonas culture. However, upon examination by the ophthalmologist it was noted that there was not only a large, infected epithelial defect, but also an intraocular pressure of 35 and a candy-cane hypopyon. The diagnosis of herpes neurotrophic keratitis and iridocyclitis was made and the patient was started on intravenous acyclovir along with the appropriate topical medications. A day later, it was noted that the patient developed a right sided facial palsy and vesicular lesions inside the right ear canal, as confirmed by otolaryngology.\n\nConclusion and Importance\n\nRamsay-Hunt Syndrome is usually known to the ophthalmologist due to the exposure keratopathy caused by facial palsy. This case demonstrates varicella-zoster virus (VZV) neurotrophic keratitis preceding the development of facial palsy, which can further exacerbate an already neurotrophic cornea. The practitioner should be aware of these signs and symptoms and adjust their treatment with systemic acyclovir-prednisone.\n\nKeywords\n\nRamsay-Hunt\nNeurotrophic\nZoster\nFacial palsy\nKeratitis\nIridocyclitis\n==== Body\npmc1 Introduction\n\nVaricella-zoster virus (VZV) reactivation in the geniculate ganglion, and involvement of the sensory nerves innervating the ear, defines herpes zoster oticus.1 When associated with facial paralysis, it is known as Ramsay-Hunt Syndrome (RHS), which includes ear pain and vesicular lesions in the ear.1 Due to the proximity of the facial nerve fascicles to the VIIIth nerve in the bony facial canal, these 2 cranial nerves are commonly co-involved characterized by not only facial paralysis and painful vesicular lesions in the ear canal, but also hearing loss.1 However, poly-cranial-neuropathy has been reported in many cases of RHS due to VZV causing ascending inflammation along the brainstem between several cranial nerve nuclei and dorsal root ganglia. It is also hypothesized that VZV can travel along brainstem reflexes which would allow it to travel to multiple cranial nerves during reactivation.2, 3, 4 RHS is usually known to the ophthalmologist due to the paralytic ectropion and exposure keratopathy caused by facial nerve palsy; it is the second most common cause of facial nerve paralysis behind Bell's palsy.4\n\nCranial nerve V is one of the more commonly co-affected cranial nerves in RHS.2, 3, 4 Herpes zoster ophthalmicus (HZO) with necrotizing retinitis, neurotrophic keratitis, and exposure keratitis have all been reported following the RHS presentation, usually along with vesicular lesions in the V1–V3 dermatomes.5,6 Our case is the first known case of neurotrophic keratitis and iridocyclitis, which are common sequela of herpes zoster reactivation in the eye, with facial palsy and vesicular lesions in the ear canal occurring subsequently. This would suggest that VZV reactivation in the trigeminal ganglion can also descend to the geniculate ganglion and cause RHS.\n\n2 Case report\n\nA 69-year-old bedbound male with type 2 diabetes mellitus (HbA1c 7.3%), end-stage renal disease on dialysis, vascular dementia, and chronic pressure ulcers presented to the emergency room for a red right eye along with tearing and mucous production. The patient was unable to provide a history or express if he was in pain due to his mental status. The initial diagnosis in the emergency room was bacterial keratitis and a culture was taken by the emergency room physician, followed by admission for around-the-clock topical antibiotics. The patient was started on moxifloxacin and tobramycin drops alternating every 2 hours. The patient was seen by ophthalmology the next day and the right eye was found to have an intraocular pressure of 35, a large central neurotrophic epithelial defect with a stromal infiltrate, and a 1mm hypopyon and hyphema, also known as a candy-cane hypopyon Fig. 1. There was good eyelid blink and closure. Pseudomonas aeruginosa was grown in culture susceptible to the current antibiotics. The diagnosis of herpes keratitis and iridocyclitis was made and the patient was promptly started on intravenous acyclovir along with topical IOP lowering drops and cycloplegics. Given the patient's physical condition, it was decided not to bring him to the operating room for an anterior chamber paracentesis for viral cultures and PCR. Moreover, the clinical signs highly suggested a viral pathology and that the bacterial infiltrate was a super-infection. The next day, the stromal infiltrate was noted to be coalesced and more superficial, so topical prednisolone was added, antibiotic drop frequency was reduced and tobramycin drops was switched to tobramycin ointment. At this time, it was noted that the patient developed a right-sided lower facial palsy and vesicular lesions inside the right ear canal, as confirmed by otolaryngology examination Fig. 2, Fig. 3. The diagnosis of VZV Ramsay-Hunt Syndrome was made and 60mg intravenous prednisone was added, dosed as a weekly taper of 10mg. The patient developed a right lateral lower lid paralytic ectropion, but still had good lid closure and ointment coverage, so a tarsorrhaphy was not performed. The facial palsy improved within 2 days of initiation of intravenous prednisone, along with improvement of the right intraocular pressure, corneal infiltrate, epithelial defect and hypopyon. The prompt response to the anti-viral and steroid medication further suggested that the patient's condition was viral in origin. The patient was discharged on tapering oral prednisone, topical prednisolone and tobramycin ointment.Fig. 1 External photograph of the right eye. A large central epithelial defect is seen along with a small hypopyon mixed with hyphema, known as a candy-cane hypopyon. This is classically associated with herpes iritis.\n\nFig. 1\n\nFig. 2 External photograph of the right ear. New vesicular eruptions in the right ear canal as confirmed by otolaryngology.\n\nFig. 2\n\nFig. 3 External photograph of the patients face. A new onset right facial palsy causing a paralytic lower lid ectropion.\n\nFig. 3\n\n3 Discussion\n\nRHS is known to involve multiple cranial nerves at one time. Cranial nerves VII and VIII are most commonly co-involved due to close proximity of the geniculate ganglion to the VIIIth nerve within the bony facial canal.1 There are several hypotheses describing the ability of VZV to affect multiple cranial nerves simultaneously: several cranial and dorsal root ganglia comprise a chain in which inflammation of a single ganglion could extend to nearby ganglia in the brainstem (ganglionitis), namely cranial nerves V, IX, X, XI, XII. It is also hypothesized that all cranial nerves involved in RHS are connected by pathways of important brainstem reflexes, which would allow VZV to spread along these pathways causing multiple cranial nerves to be involved.2, 3, 4 This case is the first of our knowledge to have a polyneuropathy involving cranial nerve V first, presenting as neurotrophic ulcer and iridocyclitis, followed by the more classic cranial nerve VII involvement. Acyclovir-prednisone administration is generally accepted as the standard of care in improving facial nerve palsy and reducing cranial nerve inflammation, however some studies with acyclovir alone are equivocal.1,7,8\n\nThe facial palsy invariably can cause lower lid paralytic ectropion and exposure keratopathy. Previous case reports have been presented with CN V and VII co-involvement presenting as neurotrophic keratitis and necrotizing retinitis, with RHS as the primary presentation. The patient with neurotrophic keratitis initially presented to the otolaryngologist and was diagnosed with RHS. The patient subsequently developed vesicular lesions along V1 and V2, followed by a painful, red eye and was diagnosed with neurotrophic keratitis. The authors hypothesized that VZV laid dormant in both the trigeminal and geniculate ganglia and reactivated simultaneously.5 Another patient was described to have acquired immunodeficiency syndrome and developed left-sided hearing loss, vesicular lesions in the left V3 distribution and necrotizing herpetic retinopathy of the left eye. Several days later, the patient developed contralateral signs of VZV; right-sided hearing loss and necrotizing retinitis of the right eye. MRI confirmed neuritis in bilateral CN VIII. The authors concluded that the ophthalmologist should monitor the fundus for retinitis in patients with RHS.6 Lastly, a patient was reported to have sequential RHS, HZO and disseminated-cutaneous herpes zoster, which more commonly happens in immunocompromised patients, but can rarely occur in immunocompetent. The authors suggested a similar mechanism as with our patient, that the affected sensory nerves can affect adjacent cranial nerves through anastomoses in the brainstem and even the spinal ganglia.9\n\nOur case differs from the others from our literature search as RHS is typically the presenting manifestation of VZV. Our patient is the first known case where CN V was involved initially and the patient developed neurotrophic keratitis and iridocyclitis, which is a typical presentation of CN V VZV, with a subsequent development of RHS. Our hypothesis of this presentation coincides with what was described previously: reactivation of VZV in one ganglion can either cause ganglionitis among neighboring ganglia or that the virus traveled to the geniculate ganglion via brainstem pathways. The practitioner should be aware that facial palsy can develop with VZV reactivation and can exacerbate an already neurotrophic cornea.\n\nPatient consent\n\nPermission for photographs was obtained by the patient's next-of-kin.\n\nFunding\n\nNo funding was received for this work.\n\nIntellectual property\n\nWe confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.\n\nResearch ethics\n\nWe further confirm that any aspect of the work covered in this manuscript that has involved human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript.\n\nWritten consent to publish potentially identifying information, such as details or the case and photographs, was obtained from the patient(s) or their legal guardian(s).\n\nAuthorship\n\nAll listed authors meet the ICMJE criteria. \nWe attest that all authors contributed significantly to the creation of this manuscript, each having fulfilled criteria as established by the ICMJE.\n\nWe confirm that the manuscript has been read and approved by all named authors.\n\nWe confirm that the order of authors listed in the manuscript has been approved by all named authors.\n\nContact with the editorial office\n\nThis author submitted this manuscript using his/her account in EVISE.\n\nWe understand that this Corresponding Author is the sole contact for the Editorial process (including EVISE and direct communications with the office). He/she is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs.\n\nWe confirm that the email address shown below is accessible by the Corresponding Author, is the address to which Corresponding Author's EVISE account is linked, and has been configured to accept email from the editorial office of American Journal of Ophthalmology Case Reports:\n\nAuthors’ contributions\n\nFarzan Gorgani, MS, DO.: Conceptualization, Methodology, Investigation, Writing - Original Draft, Visualization.\n\nTodd L. Beyer, DO, FAAO, FASOPRS, FAACS.: Writing - Review & Editing, Supervision, Project administration.\n\nDeclaration of competing interest\n\nNo conflict of interest exists.\n\nAcknowledgments and Disclosures\n\nNo conflicts of interest to disclose.\n\nNo funding or grant support.\n\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n==== Refs\nReferences\n\n1 Sweeney C.J. Gilden D.H. Ramsay hunt syndrome J Neurol Neurosurg Psychiatry 71 2 2001 149 154 11459884\n2 Kim Y.H. Chang M.Y. Jung H.H. Prognosis of Ramsay Hunt syndrome presenting as cranial polyneuropathy Laryngoscope 120 11 2010 2270 2276 20824789\n3 Alicandri-Ciufelli M. Aggazzotti-Cavazza E. Genovese E. Herpes zoster oticus: a clinical model for a transynaptic, reflex pathways, viral transmission hypotheses Neurosci Res 74 1 2012 7 9 22709534\n4 Shim H.J. Jung H. Park D.C. Ramsay Hunt syndrome with multicranial nerve involvement Acta Otolaryngol 131 2 2011 210 215 21070092\n5 Verm A.M. Scott I.U. Davis J.L. Necrotizing herpetic retinopathy associated with Ramsay Hunt syndrome Arch Ophthalmol 120 7 2002 989 990 12096978\n6 Maggon R. Ramsay-Hunt Syndrome - an unusual presentation: case report Med J Armed Forces India 55 1 1999 65 66 28775573\n7 Kinishi M. Amatsu M. Mohri M. Acyclovir improves recovery rate of facial nerve palsy in Ramsay Hunt syndrome Auris Nasus Larynx 28 3 2001 223 226 11489365\n8 Murakami S. Hato N. Horiuchi J. Treatment of ramsay hunt syndrome with acyclovir‐prednisone: significance of early diagnosis and treatment Ann Neurol 41 3 2004 353 357\n9 Pitton Rissardo J. Fornari Caprara A.L. Herpes zoster oticus, ophthalmicus, and cutaneous disseminated: case report and literature review Neuro Ophthalmol 43 6 2018 407 410\n\n",
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"issn_linking": "2451-9936",
"issue": "24()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Facial palsy; Iridocyclitis; Keratitis; Neurotrophic; Ramsay-Hunt; Zoster",
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"title": "Neurotrophic corneal ulcer and iridocyclitis directly preceding Ramsay-Hunt Syndrome.",
"title_normalized": "neurotrophic corneal ulcer and iridocyclitis directly preceding ramsay hunt syndrome"
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"abstract": "Patients with cancer undergoing chemotherapy are at risk of thrombocytopenia. The co-incidence of cancer-associated venous thromboembolism (VTE) and thrombocytopenia is a frequent complication in patients with cancer. Especially in certain tumour entities at high VTE risk, chemotherapeutic agents with myelosuppressive effects are part of the standard of care. The management of cancer-associated VTE in the setting of chemotherapy-induced thrombocytopenia is challenging, in the absence of evidence from high-quality studies. Thrombocytopenia is associated with both increased risk of recurrent VTE and risk of bleeding during anticoagulation. In this case-based concise review, we aimed at summarizing available literature and expert consensus guidance on the treatment of cancer-associated VTE in patients with chemotherapy-induced thrombocytopenia.",
"affiliations": "Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.;I. M. Sechenov First Moscow State Medical University, Moscow, Russia.;Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria; I. M. Sechenov First Moscow State Medical University, Moscow, Russia. Electronic address: cihan.ay@meduniwien.ac.at.",
"authors": "Moik|Florian|F|;Makatsariya|Alexander|A|;Ay|Cihan|C|",
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"keywords": "Anticoagulation; Cancer; Chemotherapy; Thrombocytopenia; Venous thromboembolism",
"medline_ta": "Thromb Res",
"mesh_terms": "D000925:Anticoagulants; D000970:Antineoplastic Agents; D006801:Humans; D009369:Neoplasms; D013921:Thrombocytopenia; D054556:Venous Thromboembolism",
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"title": "Challenging anticoagulation cases: Cancer-associated venous thromboembolism and chemotherapy-induced thrombocytopenia - A case-based review of clinical management.",
"title_normalized": "challenging anticoagulation cases cancer associated venous thromboembolism and chemotherapy induced thrombocytopenia a case based review of clinical management"
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"abstract": "We report a case of a patient who developed dialysis-requiring acute kidney injury (AKI) after the use of canagliflozin. A 66-year-old man with type 2 diabetes who was recovering from left knee septic arthritis at a rehabilitation facility was admitted with oliguric AKI 5 days after starting treatment with canagliflozin, an inhibitor of sodium/glucose cotransporter 2 (SGLT2). The patient presented with hematuria, non-nephrotic-range proteinuria, and serum creatinine level of 6.8 (baseline, 1.1-1.3) mg/dL. There was no recent use of radiocontrast agents or exposure to other nephrotoxins. The patient subsequently required hemodialysis. Due to recent antibiotic use (ampicillin-sulbactam), acute interstitial nephritis was considered in the differential diagnosis. Kidney biopsy was performed, which showed the presence of osmotic nephropathy. The patient's kidney function returned to baseline after 2 weeks of hemodialysis. This case provides evidence of an association of osmotic nephropathy with the use of canagliflozin and discusses potential mechanisms. We recommend kidney biopsy for cases of severe AKI associated with SGLT2 inhibitors to better understand the relationship of this complication with the use of this class of medications.",
"affiliations": "Sanford Health, University of North Dakota School of Medicine, Fargo, ND.;Sanford Health, University of North Dakota School of Medicine, Fargo, ND.;Department of Biology, Boston University, Boston, MA.;B. Braun Medical Care AG Nephrology and Dialysis Center Hochfelden, Zurich, Switzerland.;University of Colorado Anschutz Medical Campus, Aurora, CO.;University of Colorado Anschutz Medical Campus, Aurora, CO.;University of Colorado Anschutz Medical Campus, Aurora, CO.;University of Colorado Anschutz Medical Campus, Aurora, CO.;University of Colorado Anschutz Medical Campus, Aurora, CO.;Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.;Nephrology and Hypertension, Mayo Clinic, Rochester, MN.;University of Colorado Anschutz Medical Campus, Aurora, CO. Electronic address: richard.johnson@cuanschutz.edu.",
"authors": "Phadke|Gautam|G|;Kaushal|Amit|A|;Tolan|Dean R|DR|;Hahn|Kai|K|;Jensen|Thomas|T|;Bjornstad|Petter|P|;Roncal-Jimenez|Carlos|C|;Hernando|Ana Andres|AA|;Lanaspa|Miguel A|MA|;Alexander|Mariam Priya|MP|;Kukla|Aleksandra|A|;Johnson|Richard J|RJ|",
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"issue": "76(1)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Acute renal failure (ARF); SGLT2 inhibitors; acute kidney injury (AKI); canagliflozin; case report; hemodialysis; kidney biopsy; osmotic nephropathy; sodium/glucose cotransporter 2 (SGLT2)",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000068896:Canagliflozin; D004234:Diuretics, Osmotic; D006801:Humans; D008297:Male; D009401:Nephrosis; D000077203:Sodium-Glucose Transporter 2 Inhibitors",
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"title": "Osmotic Nephrosis and Acute Kidney Injury Associated With SGLT2 Inhibitor Use: A Case Report.",
"title_normalized": "osmotic nephrosis and acute kidney injury associated with sglt2 inhibitor use a case report"
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"abstract": "Drug resistant epilepsy (DRE) has been associated with a high incidence of psychotic disorders. Patients can develop psychosis after starting a new antiseizure medication, after undergoing resective surgery, or after implantation of a vagus nerve stimulation (VNS) system. The aim of this study was to investigate the modulation effect of VNS on psychotic episodes in DRE patients with a pre-existing history of periictal psychotic episodes (PPE). We retrospectively report the outcome of four patients from a single tertiary center with PPE prior to implantation. None of the implanted patients developed de novo PPE after VNS therapy. Regarding seizure outcome, all patients demonstrated a response to VNS with two who experienced who status epilepticus and three patients wtih a change in semiology with after VNS implantation. PPE disappeared in all the study patients, two of them at 6 months post-implantation and in the others after 2 and 3 years, respectively. 18F-FDG-PET results showed hypermetabolism in both anterior insular and medial frontal lobes which disappeared in the 18F -FDG-PET 4 years post-implantation. Based on the results of this series of cases we suggest that VNS therapy may be useful to modulatet PPE in patients with DRE, though effectiveness may be time-dependent.",
"affiliations": "Neuro-Oncology Unit, Neurology Department, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.;Epilepsy Unit, Psychiatry Department, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.;Epilepsy Unit, Psychiatry Department, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.;Epilepsy Unit, Neurology Department, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.;Institute of Image Diagnosis (IDI), PET Division, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.;Epilepsy Unit, Neurosurgery Department, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.;Institute of Image Diagnosis (IDI), SPECT division, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.;Epilepsy Unit, Neurology Department, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.;e4Sci, Sabadell, Spain.;Epilepsy Unit, Neurology Department, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.",
"authors": "Alemany|Montse|M|;Real|Eva|E|;Custal|Núria|N|;Sala-Padró|Jacint|J|;Rodríguez-Bel|Laura|L|;Plans|Gerard|G|;Mora|Jaume|J|;Santurino|Mila|M|;Vancamp|Tim|T|;Falip|Mercè|M|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1016/j.ebr.2021.100434",
"fulltext": "\n==== Front\nEpilepsy Behav Rep\nEpilepsy Behav Rep\nEpilepsy & Behavior Reports\n2589-9864 Elsevier \n\nS2589-9864(21)00008-3\n10.1016/j.ebr.2021.100434\n100434\nCase Report\nVagus nerve stimulation as a potential modulator of periictal psychotic episodes: A report of four cases\nAlemany Montse malemany@bellvitgehospital.cata Real Eva ereal@bellvitgehospital.catb Custal Núria ncustal@bellvitgehospital.catb Sala-Padró Jacint jacint.sala@gmail.comc Rodríguez-Bel Laura laurodriguez@bellvitgehospital.catd Plans Gerard gplans@bellvitgehospital.cate Mora Jaume jmora@bellvitgehospital.catf Santurino Mila msaturnino@bellvitgehospital.catc Vancamp Tim tim@e4sci.comg Falip Mercè mfalip@bellvitgehospital.catc⁎ a Neuro-Oncology Unit, Neurology Department, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain\nb Epilepsy Unit, Psychiatry Department, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain\nc Epilepsy Unit, Neurology Department, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain\nd Institute of Image Diagnosis (IDI), PET Division, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain\ne Epilepsy Unit, Neurosurgery Department, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain\nf Institute of Image Diagnosis (IDI), SPECT division, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain\ng e4Sci, Sabadell, Spain\n⁎ Corresponding author at: Epilepsy Unit, Neurology Department, Hospital Universitari de Bellvitge, Feixa Llarga S/N, 08907 Hospitalet de Llobregat, Barcelona, Spain. mfalip@bellvitgehospital.cat\n11 2 2021 \n2021 \n11 2 2021 \n15 10043431 10 2020 12 1 2021 21 1 2021 © 2021 The Author(s)2021This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• PPE are treatable and we report a case series of patients successfully treated with VNS.\n\n• Both antiseizure and antipsychotic VNS effects are not immediate.\n\n• Antipsychotic effect of VNS may be observed even in patients who do not become seizure free.\n\n\n\nDrug resistant epilepsy (DRE) has been associated with a high incidence of psychotic disorders. Patients can develop psychosis after starting a new antiseizure medication, after undergoing resective surgery, or after implantation of a vagus nerve stimulation (VNS) system. The aim of this study was to investigate the modulation effect of VNS on psychotic episodes in DRE patients with a pre-existing history of periictal psychotic episodes (PPE).\n\nWe retrospectively report the outcome of four patients from a single tertiary center with PPE prior to implantation. None of the implanted patients developed de novo PPE after VNS therapy. Regarding seizure outcome, all patients demonstrated a response to VNS with two who experienced who status epilepticus and three patients wtih a change in semiology with after VNS implantation. PPE disappeared in all the study patients, two of them at 6 months post-implantation and in the others after 2 and 3 years, respectively. 18F-FDG-PET results showed hypermetabolism in both anterior insular and medial frontal lobes which disappeared in the 18F -FDG-PET 4 years post-implantation.\n\nBased on the results of this series of cases we suggest that VNS therapy may be useful to modulatet PPE in patients with DRE, though effectiveness may be time-dependent.\n\nKeywords\nVagus nerve stimulationPeriictal psychotic episodesDrug-resistant epilepsyPsychosisPositron emission tomography\n==== Body\n1 Introduction\nPsychiatric disorders affect patients with epilepsy more frequently than they do the general population. The reported prevalence of psychotic disturbances varies between 2% and 7%, with a pooled prevalence of 5.6% [1]. The variation becomes higher when compared to the general population (1%), especially in those with temporal lobe epilepsy (TLE), affecting nearly 20% of patients [2]. Psychosis may be seen based upon its temporal relationship with seizures and include preictal, ictal, and postictal psychosis. We separated them into periictal psychotic episodes (PPE) and interictal psychosis (IIP) when a relationship between psychosis and seizures did not exist.\n\nFor PPE we used the same definitions as those identified by Logsdail and Toone. PIP was a defined as appearing within one week after a seizure or cluster of seizures, lasting from at least 15 hours up to 2 months, and preceded by a lucid period (24–72 h). Ictal psychosis was defined as psychosis appearing simultaneously with a prolonged seizure or status epilepticus as the clinical expression confirmed by an EEG without prominent motor symptoms [3].\n\nMost of the old and new antiseizure drugs (ASD) as well as surgical treatment have been implicated in the emergence of PPE [4], [5]. Psychotic symptoms in epileptic patients with PPE are thought to be influenced by a disruption in a chronic inhibitory mechanism. Immediately after a cluster of seizures, PIP patients may experience an unusually profound depression of limbic function producing a disconnection of the temporal-limbic structures and the prefrontal structures and a loss of control over the prefrontal structures [6]. This concept was first introduced in 1953 by Landolt with the concept of ‘forced normalization theory’ to describe the appearance of psychotic episodes associated with total or partial normalization of the electroencephalogram (EEG) in patients with epilepsy [7]. In regard to this, vagus nerve stimulation (VNS) therapy has also played a role [8], [9], [10], [11]. Paradoxically, a positive effect in the modulation of psychiatric symptoms has been observed in VNS treated patients, and it has been approved as a non-pharmacological adunctive treatment for depression [12]. Moreover, a recent study conducted in an animal model for schizophrenia found VNS provided a positive effect in controlling psychotic symptoms [13].\n\nWe aimed to study the neuro-modulatory effect of VNS on psychotic episodes in drug-resistant epilepsy (DRE) patients with a pre-existing history of PPE in a single-center retrospective analysis. A total of 48 patients diagnosed with DRE and treated with VNS therapy from 2006 to 2016 were identified. None of the implanted patients developed psychosis. In the present study we included 4 patients from the series with a prior history of PPE.\n\nPatient evaluation included a formal intermittent psychiatric examination, prolonged video-EEG (vEEG), structural magnetic resonance imaging (MRI) study with a standard epilepsy protocol, and 18F-labelled fluoro-2-deoxyglucose-positron emission tomography (18F-FDG-PET) co-registered with MRI.\n\n1.1 Case 1\nA 40-year-old male patient was diagnosed at the age of 23 with non-lesional bitemporal DRE. The patient experienced 8 episodes per month of focal impaired awareness seizure (FIAS), and occasionally focal to bilateral tonic-clonic seizure (FBTCS). Several ASDs were tested without achieving seizure control, with oxcarbazepine (OXC), clobazam (CBM) and brivaracetam (BRV) the last combination tried. Anterior temporal lobe resection of the most affected temporal lobe was done at the age of 34 without changes in seizure frequency. After nine months, the patient started suffering PIP episodes at a frequency of 3 episodes per year. PIP episodes began in the 12–24 hours after the seizure and lasted for 3–5 days. These episodes were characterised by a state of confusion and auditory hallucinations, requiring hospitalization in one case. No prior history of psychotic disorder was reported. During PIP episodes normal EEG background with fronto–temporal interictal epileptiform discharges was recorded (see Fig. 1). VNS device was implanted one year later to achieve better seizure control. After a 5-year follow-up seizures were reduced by 62.5% in additio to a change in semiology (focal aware seizure with distorted body perception) and reduced seizure severity. In terms of PIP, 3 episodes in the 2nd year was noted and no new episodes appeared after the third year of stimulation.Fig. 1 EEG recording during a postictal psychosis Patient with visual hallucinations and feelings of being harmed by others. EEG records show a left temporal breach rhythm due to previous craniotomy. There were occasional interictal epileptiform discharges in the recording (box).\n\n\n\n1.2 Case 2\nA 54-year-old male patient was diagnosed at the age of 14 with DRE secondary to a malformation of cortical development. Bitemporal seizures at a frequency of 6–8 episodes per month were reported. FIAS not preceded by aura and occasionally Focal to bilateral tonic-clonic seizures (FBTCS) were the typical seizure types. Several ASDs (OXC, phenytoin (PHT) and lacosamide (LCM)) were tested without achieving seizure control. At the age of 43 the patient started suffering recurrent episodes of postictal psychosis which started between 8 and 12 hours after a seizure, characterised by a state of confusion with hallucinations and paranoia. No prior history of psychotic disorder was reported. Antipsychotic treatment was initiated with quetiapine (QTP) and haloperidol (HLP); however, episodes were still present occurring with a frequency of 2–3 times per year, requiring hospitalization on two occasions. VNS therapy was implanted at the age of 48. After a 6-year follow-up seizures were reduced by 42.8% with a change in semiology (appearing only nocturnally). No further episodes of postictal psychosis were documented one year after VNS implantation.\n\n1.3 Case 3\nA 47-year-old female patient was diagnosed at the age of 12 with DRE secondary to a parietal tumour. Initial surgery was done in another center when the patient was 16 and the histopathology was reported as oligodendroglioma, with complete resection. The patient was seizure free for 3 years but then the seizures reappeared and became more and more frequent. No evidence of tumor relapse was observed. She was reoperated twice, at the ages of 25 and 31 including a left parietal topectomy and a right amygdalohippocampectomy. At the age of 36 she started suffering ictal psychosis during episodes characterised by delusions, anxiety, agitation, and heteroaggressivity. These psychotic episodes appeared simultaneously with an exacerbation of seizure clustering. No prior history of psychotic disorder was reported. She was monitored in our center from 2012, and at that time she suffered 1–2 seizures per day and 1 episode of psychosis per month. EEG findings during these episodes showed seizures arising in one parietal or temporal lobe evolving to contralateral areas without recovery between them (see Fig. 2). Antipsychotic treatment was initiated with QTP and clozapine (CPZ), but unfortunately the episodes remained, with a frequency of 6–8 per year. In relation to post-surgical changes, MRI showed areas of encephalomalacia-gliosis on the right temporal-insular cortex and left parietal splenium of the corpus callosum. At the age of 43, a VNS was implanted achieving a reduction of seizures by 82.5% and elimination of the episodes of SE over a 4 year follow-up period. Post-VNS the semiology of seizures also changed to focal aware seizures and falls. Only 1 episode of ictal psychosis was documented in the 1st year and was completely eliminated by the 2nd year after VNS implantation.Fig. 2 EEG recording during an ictal psychosis Patient with visual hallucinations and heteroaggressive behaviour. EEG record during the episode shows (A) interictal epileptiform activity over T7, P7, P3 (box) and (B) subclinical seizures (42 subclinical seizures in 6 hours) starting with alpha rhythm in T8 and spreading to the right frontotemporal area (box).\n\n\n\n1.4 Case 4\nA 61-year-old female patient was diagnosed at the age of 18 with non-lesional DRE, temporal and biparietal lobes. The patient experienced FIAS not preceded by aura with a frequency of 10–15 episodes per month, and 1–2 SE per month (starting with clusters of 5–7 seizures for 3–4 hours and continuing with an altered mental state of confusion and disorientation for 3 days). Several ASDs were trialed without achieving seizure control. The last trial included combination therapy with levetiracetam and lamotrigine. At the age of 50 during periods when the frequency of seizures was higher, the patient started suffering ictal psychosis characterised by episodes of agitation, auditory hallucinations, and perspicuous feelings. No prior history of psychotic disorders was reported. Antipsychotic treatment was initiated with risperidone without achieving control of psychotic episodes which continued with a frequency of 2–4 per year requiring hospitalization on 7 occasions, 3 of them due to suicide attempts.\n\nAt the age of 58 VNS was implanted achieving a reduction of seizure frequency by 60% and elimination of SE over a 4 year follow-up period. Seizure severity also changed due to changes in semiology to focal aware seizures with somatosensory aura in the right foot not followed by impaired awareness most of the time when she acutely activated magnet-induced VNS stimulation. No further psychotic episodes were documented after the first year of VNS implantation.\n\nAdditionally, 18F-FDG-PET before VNS implantation was performed showing hypometabolism in both superior parietal lobes, more evident in the right, and relative hypermetabolism in the mesial frontal areas and anterior insulas. 18F-FDG-PET after 4 years following VNS implantation showed less intense hypometabolism in both superior parietal lobes with a normalisation of the hypermetabolism in the frontal lobes, insular lobes, and left caudate nucleus (shown in Fig. 3).Fig. 3 18F-FDG-PET pre- and post-VNS implantation a)18F-FDG-PET pre-VNS shows hypometabolism in both superior parietal lobes (^), more intense in the right (epileptogenic area) and relative hypermetabolism in the mesial frontal areas (*) and the anterior insulas ( ). b)18F-FDG-PET post-VNS shows less intense hypometabolism in both superior parietal lobes (^) with a normalization of the hypermetabolism in the frontal lobes (*) and insular lobes ( ). c) Z map of the18F-FDG-PET subtraction co-recorded with the MRI, showing the cortical areas that underwent a change of more than 2SD in metabolism; frontal areas with a decrease of metabolism (blue blob) and right parietal areas with increase of metabolism (orange blob). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)\n\n\n\nA summary of demographics and clinical characteristics of the reported cases and VNS therapy effects are shown in Table 1 and Table 2, respectively.Table 1 Demographics and clinical characteristics of patients with prior history of periictal psychosis (PPE) and VNS. therapy.\n\n\tP 1\tP 2\tP 3\tP 4\t\nGender\tMale\tMale\tFemale\tFemale\t\nAge (Yrs)\t40\t54\t47\t61\t\nAge at epilepsy onset (Yrs)\t23\t14\t12\t18\t\nAetiology\tUnknown\tMalformation of cortical development\tLeft oligodendroglioma\tUnknown\t\nSeizures localization\tBitemporal\tBitemporal\tLeft parietal, bitemporal\tLeft temporal, biparietal\t\nAge at psychosis onset (Yrs)\t34\t43\t36\t50\t\nPsychiatric symptoms\tConfusion, auditory hallucinations\tConfusion, Hallucinations, paranoia\tAnxiety, agitation, heteroaggressivity\tAgitation, auditory hallucinations, perspicuous feelings\t\nPsychiatric disorder in relation to seizures*\tPostictal\tPostictal\tIctal\tIctal\t\nAge at VNS implantation (Yrs)\t35\t48\t43\t58\t\nVNS** follow-up time (Yrs)\t5\t6\t4\t3\t\nIntensity/frequency VNS*\t1 mA/ on 30″ off 5′\t2 mA/ on 30″ off 5′\t2.25 mA/ on 30″ off 1.8′\t2 mA/ on 30″ off 3′\t\n* Psychotic disorder due to epilepsy, according to DSM-IV criteria (code 293.0: Diagnostic and Statistical Manual of Mental Disorders); **VNS: Vagal nerve stimulation.\n\nTable 2 VNS therapy effects.\n\nPre-VNS\tPost-VNS\t\n\tSeizure type\tSeizure frequency (per month)\tSeizure treatment (dose mg/day)\tPsychotic episode frequency (per year)\tPsychiatric treatment (dose mg/day)\tSeizure type\tReduction Seizure frequency (%)\tSeizure treatment (dose mg/day)\tMagnet-controlled seizures\tPsychotic episode Frequency (per year)\tPsychiatric treatment (dose mg/day)\tPsychotic episode-free* (Yrs)\tPsychotic episode-free period (Yrs)\t\nPT1\tFIAS, occasionally FBTCS\t8\tSurgery OXC (1500)\nCBM (10) BRV (100)\t3\t–\tFocal awareness\t62.5%\tOXC (1200)\nCBM (10)\nLCM (20)\tYes\t3 episodes in the 1-2nd year\t–\t3rd\t2\t\nPT2\tFIAS, occasionally FBTCS\t8–6\tOXC (1200)\nPHT (350)\nLCM (200)\t2–3\tQTP (200) HLP (6)\tNocturnal seizures\t42.8%\tPHT (350)\nLCM (200)\nESL (1600)\tNo\tNo episodes\tQTP (100)\nHLP (4)\t1st\t6\t\nPT3\tFIAS\t30–50\nSE 1\tSurgery (3)\nZNS (300) CBZ (1200)\nCBM (20)\t6–8\tQTP (100) CZP (100)\tFocal awareness and falls\t82.5%\nSE 100%\tCBZ (1200)\nZNS (300)\nCBM (20)\tNo\t1 episode in the 1st year\tQTP (100)\t2nd\t3\t\nPT4\tFIAS\t10–15\nSE 1–2\tLVT (2000) LMT (400)\t2–4\tRPD (10)\tFocal awareness\t60%\nSE 100%\tLVT (1000)\nLMT (400)\tYes\tNo episodes\tQTP (100)\t1st\t3\t\nAbbreviations: FIAS: Focal impaired awareness seizure; FBTCS: focal to bilateral tonic-clonic seizure, SE: status epilepticus; BRV: brivaracetam, CBZ: carbamazepine, CBM: clobazam, LCM: lacosamide, LMT: lamotrigine, LVT: levetiracetam, OXC: oxcarbazepine, PHT: phenytoin, ZNS: zonisamide; CPZ: clozapine, HLP: haloperidol, QTP: quetiapine, RPD: risperidone. * Determined to be the first psychotic episode-free year after VNS implantation.\n\n\n\n2 Discussion/Conclusion\nNew onset psychotic episodes after VNS implantation have been reported in the literature [10]. These are may be seen in patients with DRE when they suddenly become seizure-free, presumably due to forced normalization. In contrast, one study has shown an antipsychotic effect after VNS implantation [12]. Recently, Lee et al. [14] reported the first case of forced normalization after turning off VNS in a patient suffering from Lennox-Gastaut syndrome.\n\nRegarding the VNS mechanisms of action, it is thought that afferent vagal fibers modulate the release of different neurotransmitters in the brainstem involving the locus coeruleus, the nucleus of the solitary tract, thalamus, and limbic system structures. The dysregulation of neurotransmitters has also been identified relative to altered seizure threshold and in psychiatric disorders [15].\n\nIn our study, the results showed that patients suffering from PPE had their ictal or postictal psychotic episodes controlled after VNS implantation. However, the positive psychotropic effect was not immediate. Combined time-frame analysis showed a latency effect of VNS to control psychosis of 8.3 months (range: 6–36 months). This occurred despite the absemce of seizure control, however, in three of the cases semiology changed after VNS implantation.\n\n18F-FDG-PET images showed a normalization of metabolism in both medial prefrontal cortical areas and anterior insulas in one of our patients, after VNS implantation. Interestingly, perfusion changes in the same areas have been described apart from the epileptogenic foci in psychotic and epileptic patients [16], [17], [18]. Normalization of medial frontal metabolism, one of the cortical areas of the cortico-striatal-thalamic-cortical loop circuits has been suggested as important in schizophrenia patients and has also been observed in DRE patients suffering psychosis [19].\n\nAlthough it is speculative, this positive psychotropic effect in DRE patients suffering ictal and postictal psychosis could be related to a long-term neuromodulator effect of the VNS, independent of its antiseizure effect [20], [21], [22]. Despite these encouraging preliminary results, future research is needed to confirm our findings and to determine whether VNS-induced brain changes are associated with a favorable outcome in patients with VNS and ictal or postictal psychosis. Larger prospective studies are recommendable to validate our initial observation.\n\n3 Statements\n3.1 Ethics statement\nThe study was approved by the Ethics Committee of the University Hospital of Bellvitge (Hospitalet de Llobregat, Barcelona, Spain) and conducted in accordance with the Declaration of Helsinki, PR 349/18. The patients’ confidential information was protected according to the current European and Spanish regulations. All patients signed an informed consent.\n\nAcknowledgments\nWe gratefully thank all the patients who selflessly participated in the study.\n\nDeclaration of Competing Interest\nT. Vancamp is also an employee of LivaNova. All other authors report no conflicts of interest.\n\nStudy funding\nNo financial or any other support has been provided to the authors to perform this study, nor to compose this manuscript.\n\nAuthors’ contributions:\nI. Conception and design: M. Falip, T. Vancamp, and M. Alemany.\n\nII. Administrative support: M. Santurino.\n\nIII. Provision of study materials for patients: G. Plans, E. Real, N.Custal, and J. Mora.\n\nIV. Collection and assembly of data: M. Falip, L. Rodríguez-Bel, and M. Alemany.\n\nV. Data analysis and interpretation: M. Falip, J. Sala-Padró, and M. Alemany.\n\nVI. Manuscript writing: All authors.\n\nVII. Final approval of manuscript: All authors\n==== Refs\nReferences\n1 Clancy M.J. Clarke M.C. Connor D.J. Cannon M. Cotter D.R. The prevalence of psychosis in epilepsy; a systematic review and meta-analysis BMC Psychiatry 14 2014 75 24625201 \n2 Kanner A.M. Soto A. Gross-Kanner H. Prevalence and clinical characteristics of postictal psychiatric symptoms in partial epilepsy Neurology 62 5 2004 708 713 15007118 \n3 Logsdail S.J. Toone B.K. Post-ictal psychoses. A clinical and phenomenological description Br J Psychiatry 152 1988 246 252 3167343 \n4 Ramos-Perdigués S. Baillés E. Mané A. Carreño M. Donaire A. Rumià J. Psychiatric symptoms in refractory epilepsy during the first year after surgery Neurotherapeutics 15 4 2018 1082 1092 30066084 \n5 Jalihal V. Shankar R. Henley W. Parrett M. Tittensor P. McLean B.N. Eslicarbazepine acetate as a replacement for levetiracetam in people with epilepsy developing behavioral adverse events Epilepsy Behav 80 2018 365 369 29415871 \n6 Wolf P. Acute behavioral symptomatology at disappearance of epileptiform EEG abnormality. Paradoxical or forced normalization Adv Neurol 55 1991 127 1427 2003402 \n7 Krishnamoorthy E.S. Trimble M.R. Sander J.W.A.S. Kanner A.M. Forced normalization at the interface between epilepsy and psychiatry Epilepsy Behav 3 4 2002 303 308 12609326 \n8 Trimble M.R. Behaviour changes following temporal lobectomy, with special reference to psychosis J Neurol Neurosurg Psychiatry 55 2 1992 89 91 1538232 \n9 Buranee K. Teeradej S. Chusak L. Michael M. Epilepsy-related psychoses and psychotic symptoms are significantly reduced by resective epilepsy surgery and are not associated with surgery outcome or epilepsy characteristics: a cohort study Psychiatry Res 245 2016 333 339 27573056 \n10 Blumer D. Davies K. Alexander A. Morgan S. Major psychiatric disorders subsequent to treating epilepsy by vagus nerve stimulation Epilepsy Behav 2 5 2001 466 472 12609285 \n11 De Herdt V. Boon P. Vonck K. Goossens L. Nieuwenhuis L. Paemeleire K. Are psychotic symptoms related to vagus nerve stimulation in epilepsy patients? Acta Neurol Belg 103 3 2003 170 175 14626698 \n12 Koutroumanidis M, Binnie CD, Hennessy MJ, Alarcon, G, Elwes RD, Toone BK, et al. VNS in patients with previous unsuccessful resective epilepsy surgery: antiepileptic and psychotropic effects. Acta Neurol Scand. 2003;107(2):117-121.\n13 Perez S.M. Carreno F.R. Frazer A. Lodge D.J. Vagal nerve stimulation reverses aberrant dopamine system function in the methylazoxymethanol acetate rodent model of schizophrenia J Neurosci 34 28 2014 9261 9267 25009259 \n14 Lee S. Denton A. Ladino L.D. Waterhouse K. Vitali A. Tellez-Zenteno J.F. Forced normalization after turning off vagus nerve stimulation in Lennox-Gastaut syndrome Epilepsy Behav Case Rep 11 2019 81 83 30788214 \n15 Vonck K. Boon P. The mechanism of action of vagus nerve stimulation therapy Eur Neurol Rev 3 2 2008 97 100 \n16 Allebone J. Kanaan R. Wilson S.J. Systematic review of structural and functional brain alterations in psychosis of epilepsy J Neurol Neurosurg Psychiatry 89 2018 611 617 29275328 \n17 Fong G.C.Y. Fong K.Y. Mak W. Tsang K.L. Chan K.H. Cheung R.T. Postictal psychosis related regional cerebral hyperperfusion Cit J Neurol Neurosurg Psychiatry 68 2000 100 101 \n18 Hasan A. Wolff-Menzler C. Pfeiffer S. Falkai P. Weidinger E. Jobst A. Transcutaneous noninvasive vagus nerve stimulation (tVNS) in the treatment of schizophrenia: a bicentric randomized controlled pilot study Eur Arch Psychiatry Clin Neurosci 265 7 2015 589 600 26210303 \n19 Peters S.K. Dunlop K. Downar J. Cortico-striatal-thalamic loop circuits of the salience network: a central pathway in psychiatric disease and treatment Front Syst Neurosci 10 2016 104 28082874 \n20 Graat I. Figee M. Denys D. The application of deep brain stimulation in the treatment of psychiatric disorders Int Rev Psychiatry 29 2 2017 178 190 28523977 \n21 Hadar R. Bikovski L. Soto-Montenegro M.L. Schimke J. Maier P. Ewing S. Early neuromodulation prevents the development of brain and behavioral abnormalities in a rodent model of schizophrenia Mol Psychiatry 23 4 2018 943 951 28373685 \n22 Corripio I. Roldán A. Sarró S. McKenna P.J. Alonso-Solís A. Rabella M. Deep brain stimulation in treatment resistant schizophrenia: a pilot randomized cross-over clinical trial EBioMedicine 51 2020 102568 31927311\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2589-9864",
"issue": "15()",
"journal": "Epilepsy & behavior reports",
"keywords": "Drug-resistant epilepsy; Periictal psychotic episodes; Positron emission tomography; Psychosis; Vagus nerve stimulation",
"medline_ta": "Epilepsy Behav Rep",
"mesh_terms": null,
"nlm_unique_id": "101750909",
"other_id": null,
"pages": "100434",
"pmc": null,
"pmid": "33665601",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "30066084;2003402;29415871;31927311;27573056;3167343;28373685;12580861;28082874;28523977;12609326;29275328;12609285;25009259;14626698;24625201;30788214;1538232;10671113;15007118;26210303",
"title": "Vagus nerve stimulation as a potential modulator of periictal psychotic episodes: A report of four cases.",
"title_normalized": "vagus nerve stimulation as a potential modulator of periictal psychotic episodes a report of four cases"
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"companynumb": "ES-UCBSA-2021013716",
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"activesubstancename": "OXCARBAZEPINE"
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{
"abstract": "Drug screening of breast milk in a clinical toxicology laboratory is reported. Findings from three cases include cocaine, ethylbenzoylecgonine (cocaethylene), ethanol, oxycodone, codeine, and nicotine. We believe this to be the first report of ethylbenzoylecgonine in human breast milk. One other specimen submitted for analysis was screened with negative results. Screening and confirmation procedures adapted for use with breast milk are described. Finally, the potential for cocaine intoxication from mother to baby is discussed. Estimates of infant blood cocaine concentration are given which may increase awareness of the need to monitor milk and blood cocaine concentrations in the infant when the situation warrants.",
"affiliations": "Creighton University School of Medicine, Department of Pathology, Omaha, NE.",
"authors": "Dickson|P H|PH|;Lind|A|A|;Studts|P|P|;Nipper|H C|HC|;Makoid|M|M|;Therkildsen|D|D|",
"chemical_list": "D013287:Illicit Drugs; D014179:Neurotransmitter Uptake Inhibitors; D000431:Ethanol; D009538:Nicotine; D010098:Oxycodone; C066444:cocaethylene; D003042:Cocaine; D003061:Codeine",
"country": "United States",
"delete": false,
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"issn_linking": "0022-1198",
"issue": "39(1)",
"journal": "Journal of forensic sciences",
"keywords": null,
"medline_ta": "J Forensic Sci",
"mesh_terms": "D000328:Adult; D003042:Cocaine; D003061:Codeine; D000431:Ethanol; D005260:Female; D006801:Humans; D013287:Illicit Drugs; D007231:Infant, Newborn; D008895:Milk, Human; D014179:Neurotransmitter Uptake Inhibitors; D009538:Nicotine; D010098:Oxycodone; D011247:Pregnancy; D011248:Pregnancy Complications; D011297:Prenatal Exposure Delayed Effects; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders",
"nlm_unique_id": "0375370",
"other_id": null,
"pages": "207-14",
"pmc": null,
"pmid": "8113701",
"pubdate": "1994-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The routine analysis of breast milk for drugs of abuse in a clinical toxicology laboratory.",
"title_normalized": "the routine analysis of breast milk for drugs of abuse in a clinical toxicology laboratory"
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"abstract": "BACKGROUND\nThe severity of clinical presentation of COVID-19 myocarditis ranges from incidental identification of depressed left ventricular ejection fraction, cardiogenic shock requiring percutaneous mechanical circulatory support, to fatal fulminant myocarditis. In previously reported cases, surviving patients experienced improvement in left ventricular ejection fraction with the use of glucocorticoids and antivirals (+/- intravenous immunoglobulin/ convalescent plasma). We report the first case of COVID-myocarditis in a surviving patient where a persistently depressed left ventricular ejection fraction (less than 35 percent) despite optimal therapy prompted implantable cardioverter-defibrillator (ICD) implantation for primary prevention of sudden cardiac death.\n\n\nMETHODS\nA previously healthy 67-year-old man, diagnosed with mild COVID-19 pneumonia five days prior, presented to the emergency department with suspected STEMI (hypoxia, substernal chest pain and known left bundle branch block). Left heart catheterization showed patent coronary arteries. Transthoracic echocardiogram showed severely depressed ejection fraction (15-20 percent). CT showed bilateral infiltrates: treatment was started with dexamethasone, remdesivir and convalescent plasma for acute hypoxic respiratory failure due to COVID-19 pneumonia. After a four-day hospitalization, guideline-directed medical therapy at maximum tolerated doses over three months did not improve left ventricular ejection fraction.\n\n\nCONCLUSIONS\nThis is the index case of COVID-19 myocarditis-mediated heart failure with reduced ejection fraction requiring ICD for primary prevention of sudden cardiac death.",
"affiliations": "University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota.;Sanford Cardiovascular Institute, Sioux Falls, South Dakota.;Sanford Cardiovascular Institute, Sioux Falls, South Dakota.;Sanford Cardiovascular Institute, Sioux Falls, South Dakota.;Department of Cardiology, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota.",
"authors": "Saad Shaukat|Muhammad Hamza|MH|;Petrasko|Phillip|P|;Petrasko|Mark|M|;Rynders|Beatrice|B|;Pham|Scott|S|",
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"issue": "74(8)",
"journal": "South Dakota medicine : the journal of the South Dakota State Medical Association",
"keywords": null,
"medline_ta": "S D Med",
"mesh_terms": "D000368:Aged; D000086382:COVID-19; D016757:Death, Sudden, Cardiac; D017147:Defibrillators, Implantable; D006801:Humans; D007116:Immunization, Passive; D008297:Male; D009205:Myocarditis; D011322:Primary Prevention; D000086402:SARS-CoV-2; D013318:Stroke Volume; D016277:Ventricular Function, Left",
"nlm_unique_id": "101265265",
"other_id": null,
"pages": "380-383",
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"pubdate": "2021-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Index Case of COVID-19 Myocarditis Requiring BiV-ICD for Primary Prevention of Sudden Cardiac Death.",
"title_normalized": "index case of covid 19 myocarditis requiring biv icd for primary prevention of sudden cardiac death"
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"abstract": "The pharmacokinetics of tacrolimus are influenced by many factors, including genetic variability, acute infections, liver dysfunction, and interacting medications, which can result in elevated concentrations. The most appropriate management of acute tacrolimus toxicity has not been defined though case reports exist describing the therapeutic use of enzyme inducers to increase tacrolimus metabolism and decrease concentrations. We are reporting on the utilization of phenytoin to assist in decreasing tacrolimus concentrations in a case series of four solid organ transplant recipients with acute, symptomatic tacrolimus toxicity presenting with elevated serum creatinine, potassium, and tacrolimus trough concentrations greater than 30 ng/mL. All four patients had the potential causative agents stopped or temporarily held and were given 300 to 400 mg/day of phenytoin for two to three days. Within three days of beginning phenytoin, all four patients had a decrease in tacrolimus concentration to less than 15 ng/mL, a return to or near baseline creatinine concentration, and lack of phenytoin-related side effects. Therefore, phenytoin appears to be a safe and potentially beneficial treatment option in patients with symptomatic tacrolimus toxicity.",
"affiliations": "Department of Pharmacy, The Methodist Hospital, 6565 Fannin Street, DB1-09 Houston, TX 77030, USA.",
"authors": "Jantz|Arin S|AS|;Patel|Samir J|SJ|;Suki|Wadi N|WN|;Knight|Richard J|RJ|;Bhimaraj|Arvind|A|;Gaber|A Osama|AO|",
"chemical_list": null,
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"doi": "10.1155/2013/375263",
"fulltext": "\n==== Front\nCase Rep TransplantCase Rep TransplantCRIM.TRANSPLANTATIONCase Reports in Transplantation2090-69432090-6951Hindawi Publishing Corporation 10.1155/2013/375263Case ReportTreatment of Acute Tacrolimus Toxicity with Phenytoin in Solid Organ Transplant Recipients Jantz Arin S. \n1\n*Patel Samir J. \n1\nSuki Wadi N. \n2\nKnight Richard J. \n2\nBhimaraj Arvind \n2\nGaber A. Osama \n2\n1Department of Pharmacy, The Methodist Hospital, 6565 Fannin Street, DB1-09 Houston, TX 77030, USA2J.C. Walter Jr. Transplant Center, The Methodist Hospital, 6550 Fannin Street, Smith Tower, Suite 1201, Houston, TX 77030, USA*Arin S. Jantz: arinjantz@gmail.comAcademic Editors: S. Bhandari, F. Keller, and Y. Sugawara\n\n2013 13 6 2013 2013 37526316 4 2013 15 5 2013 Copyright © 2013 Arin S. Jantz et al.2013This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The pharmacokinetics of tacrolimus are influenced by many factors, including genetic variability, acute infections, liver dysfunction, and interacting medications, which can result in elevated concentrations. The most appropriate management of acute tacrolimus toxicity has not been defined though case reports exist describing the therapeutic use of enzyme inducers to increase tacrolimus metabolism and decrease concentrations. We are reporting on the utilization of phenytoin to assist in decreasing tacrolimus concentrations in a case series of four solid organ transplant recipients with acute, symptomatic tacrolimus toxicity presenting with elevated serum creatinine, potassium, and tacrolimus trough concentrations greater than 30 ng/mL. All four patients had the potential causative agents stopped or temporarily held and were given 300 to 400 mg/day of phenytoin for two to three days. Within three days of beginning phenytoin, all four patients had a decrease in tacrolimus concentration to less than 15 ng/mL, a return to or near baseline creatinine concentration, and lack of phenytoin-related side effects. Therefore, phenytoin appears to be a safe and potentially beneficial treatment option in patients with symptomatic tacrolimus toxicity.\n==== Body\n1. Introduction\nIn solid organ transplantation, tacrolimus (FK506) has emerged as the backbone of most immunosuppressive regimens [1]. Tacrolimus exerts its immunosuppressant effects by binding to the immunophilin FK506 binding protein (FKBP12), forming a complex which inhibits calcineurin-induced dephosphorylation of the transcription factor, nuclear factor of activated T cells (NFAT) [2]. This results in suppression of interleukin-2 (IL-2) transcription and inhibition of T-cell-mediated actions. Monitoring of tacrolimus concentrations is required due to its narrow therapeutic index, in order to maintain a balance between under-immunosuppression and subsequent rejection risk with over-immunosuppression and risk of toxicities.\n\nConsiderable variation exists in the pharmacokinetic profile of tacrolimus, resulting at times in challenges in maintaining therapeutic concentrations. Several factors affect the pharmacokinetics of tacrolimus, including the age or gender of the patient, liver impairment, and genetic variances in cytochrome P450 (CYP) enzymes and/or P-glycoprotein expression [3, 4]. Tacrolimus is extensively metabolized by the CYP3A4 isoenzyme, the most abundant of the CYP enzymes, constituting approximately one-third of the CYP enzymes found in intestinal lining and the liver [4]. It is also a substrate of P-glycoprotein (PGP) transport system. As a substrate of these systems, tacrolimus is subject to numerous drug-drug interactions. CYP3A4/PGP inhibitors may increase tacrolimus concentrations, resulting in potentially toxic concentrations and serious adverse effects such as neuro- or nephrotoxicity, whereas inducers may decrease tacrolimus concentrations resulting in suboptimal immunosuppression and an elevated risk for rejection.\n\nLittle data exists on the management of acute tacrolimus toxicities, although the use of enzyme inducers to enhance metabolism and lower concentrations has been described [5–9]. Phenytoin is a commonly used antiepileptic and a potent enzyme inducer. Herein, we report on the use of phenytoin to manage four cases of acute tacrolimus toxicity, themselves incited by drug interactions, requiring urgent reduction of tacrolimus concentrations.\n\n2. Patient 1\nA 53-year-old white male was admitted for acute kidney injury and hyperkalemia 21 months after liver transplantation for hepatitis C. He had a past medical history of human immunodeficiency virus (HIV), recurrent hepatitis C after transplant (grade 2, stage 2), and stage 3 chronic kidney disease (CKD). Approximately 2 weeks prior to admission, he was converted as an outpatient to a protease-inhibitor (atazanavir) based highly active antiretroviral therapy (HAART) regimen. He presented to clinic with nausea, vomiting, a serum creatinine (SCr) of 6.3 mg/dL (baseline 1.7 mg/dL), potassium of 6.7 mEq/L, and an FK trough level > 30 ng/mL. He was subsequently admitted for hydration, treatment of hyperkalemia, and telemetry monitoring. Despite sodium polystyrene administration, hydration, and withholding of tacrolimus, and HAART, on hospital day 2, SCr remained at 6.2 mg/dL, potassium was 6 mEq/L, and FK was >30 ng/mL. Due to the magnitude of renal impairment, lack of knowledge of the precise quantitative FK level, and unpredictability of tacrolimus clearance in the presence of atazanavir use, the decision was made to initiate phenytoin as a means to induce drug metabolism. Phenytoin was administered orally at a dose of 200 mg twice daily. FK concentration decreased to 22.3 ng/mL the day after phenytoin initiation and then to 11.7 ng/mL the next day. Phenytoin was continued for 3 days, and the patient was discharged 3 days after admission with a SCr of 3.9 mg/dL and potassium level within normal range. HAART therapy was reintroduced at discharge and at an outpatient visit 2 days later tacrolimus was reinitated. SCr eventually returned to near-baseline at 1 week after discharge, and has remained stable ever since.\n\n3. Patient 2\nA 57-year-old African American female had undergone heart transplantation secondary to nonischemic cardiomyopathy, with a retransplantation secondary to hyperacute rejection within 48 hours. Her postoperative course was further complicated by development of recurrent candida sternal wound infection requiring long-term antibiotic and antifungal therapy and intermittent wound VAC application. She was admitted 9 months after transplant with fevers, chest pain, and nausea two weeks after being discharged on fluconazole 400 mg by mouth daily. It was determined that the patient was taking an incorrect amount of tacrolimus as an outpatient, as she was admitted with a SCr of 7.3 mg/dL (baseline 1 mg/dL), potassium of 6.2 mEq/L, and FK trough level of >30 ng/mL. Despite reducing the fluconazole and holding tacrolimus on arrival, the SCr and FK levels remained at 7.4 mg/dL and >30 ng/mL, respectively, on the next day. Phenytoin was therefore initiated at a dose of 200 mg twice daily on the day after admission and continued for 2 days. In the subsequent days, FK level dropped from >30 to 22.3, 10.6, and 4.1, while SCr decreased to 2.6. Tacrolimus was reinitiated 6 days after admission, and SCr further declined to baseline by 10 days. Renal function remained stable for approximately 7 months after admission until the patient expired during an admission due to cardiac arrest.\n\n4. Patient 3\nA 70-year-old man underwent combined heart-kidney transplantation in November 2010 for end-stage renal disease and heart failure due to ischemic cardiomyopathy. He had a recent diagnosis of disseminated nocardia and was on stable treatment with sulfamethoxazole-trimethoprim and moxifloxacin. He presented one year after transplant with nausea, diarrhea, vomiting, a SCr of 4.2 mg/dL (baseline 0.8 mg/dL), potassium of 6.1 mEq/L, and FK trough level of >30 ng/mL. Unbeknownst to the transplant service the patient had also recently started taking vitamin/herbal supplements including a sustained release, high-potency multiple vitamin (Vit-Min 100, NOW Foods, Bloomingdale, IL, USA) as well as an omega-3 product (Super Omega-3, EPA/DHA with sesame lignans and olive fruit extract, Life Extension, Ft. Lauderdale, FL, USA). The FK level remained at >30 ng/mL and SCr at 4.5 mg/dL on the day after admission, at which point phenytoin was instituted orally at a dose of 100 mg three times daily. After 3 days of phenytoin, SCr and FK levels dropped to 1.5 mg/dL and 8.6 ng/mL, respectively. Tacrolimus was initiated 5 days after admission, and the patient's SCr returned to baseline 10 days after admission. \n\n5. Patient 4\nA 58-year-old white male underwent deceased donor renal transplantation in January 2012 for end-stage renal disease secondary to hypertension and diabetes. He also had a history of diastolic heart failure, obesity, atrial fibrillation, and an early acute rejection episode treated with antithymocyte globulin. He was admitted to the intensive care unit nearly 6 months after transplant with fevers and progressive shortness of breath. The patient was subsequently found to have a pseudomonal pneumonia, as well as pulmonary nocardiosis. On admission, his SCr was 3.5 mg/dL (baseline of 2.1 mg/dL). In addition, potassium was 6.4 mEq/L, and FK trough level was 23.7. Empiric voriconazole was initiated on arrival prior to knowledge of the organisms or the FK level, and, despite holding tacrolimus, the concentration increased to >30 ng/mL with persistence of renal dysfunction on the day after arrival. In addition, the patient was experiencing new onset liver impairment with AST/ALT above 3 times the upper limit of normal and total bilirubin of 1.8 mg/dL. Given the circumstances, phenytoin was started at a dose of 200 mg by mouth twice daily and given for 3 days. After the last day of phenytoin administration, SCr and FK concentrations had declined to 1.8 mg/dL and 6.3 ng/mL, respectively. Tacrolimus was initated 6 days after admission, and SCr had improved to 1.5–1.7 mg/dL for the remainder of the admission and to the present day. \n\n6. Discussion\nThe pharmacokinetic profile of tacrolimus is well characterized [3]. Tacrolimus is metabolized almost entirely by the CYP3A enzymes found in the liver and intestinal wall. Expression of these enzymes can vary substantially between patients resulting in significant differences in metabolism. Additionally, a number of other factors can result in further changes in metabolism and drug concentrations including age, sex, comorbidities such as diabetes, hepatic impairment, hepatitis C and other acute infections, diet, and use of concomitant interacting medications [4]. Certain agents, including protease inhibitors, antifungal agents, and likely herbal supplements used by our patients, act as inhibitors of CYP3A resulting in a decrease in metabolism and an increase in bioavailability of tacrolimus. For example, the concomitant use of fluconazole with tacrolimus has been associated with a decrease in tacrolimus dose requirements by 40 to 60%, and empiric dosage decreases have been suggested by the manufacturer when used with other azole antifungals [2]. Additionally, tacrolimus dose requirements are decreased by 75 to 99% when administered with various protease inhibitors [10]. Various herbal supplements have been found to interact with tacrolimus and in general it is recommended that transplant recipients avoid them [11]. These interactions are experienced almost immediately upon starting the interacting agent as inhibition can occur as soon as the agent reaches the enzyme. When an enzyme inducing agent is used, the onset and length of induction can vary from days to weeks as these factors depend on the half-life of both the medication and CYP enzyme being induced [12, 13]. A report of 2 heart transplant patients demonstrated the variability of tacrolimus concentrations for up to 10 days after discontinuation of phenytoin [14]. Other studies have shown that catabolic activity of the CYP enzymes can be decreased during infection resulting in elevated drug levels [15, 16]. This suggests that elevated tacrolimus concentrations in our patients may have been in part due to acute infection as well.\n\nSymptoms of acute tacrolimus toxicity vary widely, from lack of clinical symptoms to severe renal failure or neurotoxicity. Most often symptoms are mild and include nausea, headache, mild hand tremors, liver enzyme elevation, electrolyte disturbances, and mild increases in SCr [5, 6, 8, 17, 18]. No treatment recommendations exist for tacrolimus toxicity, as hemodialysis and plasma exchange are ineffective and other modalities such as gastric lavage and activated charcoal are only minimally effective and must be given early after administration [5, 19, 20]. In some reports, CYP3A4 inducers phenytoin and phenobarbital have been used in acute overdose settings to increase the clearance and facilitate lowering of the tacrolimus concentration [5–9]. These agents also have the additional benefit of seizure prevention as neurologic toxicities, including seizure and coma, are well documented with tacrolimus. Though rifampin is another strong CYP3A4 inducer known to decrease tacrolimus concentrations, we chose to use phenytoin for its antiepileptic properties [12, 21].\n\nIn our patients, symptoms were severe with SCr elevations from 67 to 630% of baseline and potassium levels of greater than 6 mEq/L (see Table 1). Due to the uncertainties in the metabolism and rate of clearance of tacrolimus under these circumstances and the severe degree of renal injury seen, we chose to administer phenytoin in our four patients. Phenytoin was chosen as it is hepatically metabolized and well tolerated at typical doses of 300 to 400 mg/day with the main side effects being gastrointestinal related. There are other common side effects that we did not expect to encounter as they are typically either dose related, such as the sedating effects on the central nervous system, or occur with long-term therapy, such as gingival hyperplasia. This interaction was utilized therapeutically in our patients with a successful decrease in tacrolimus levels to less than 15 ng/mL with 3 days of phenytoin, return of renal function to or near baseline in all four patients, and an absence of side effects (see Table 2 and Figure 1).\n\nOur case series has some limitations. First, as our laboratory does not report specific tacrolimus concentrations greater than 30 ng/mL, the actual peak tacrolimus concentration was not accessible which makes it difficult to evaluate serial levels and describe the rate of elimination. Additionally, our case series did not include a comparator group that can be used to evaluate the difference in tacrolimus elimination and the actual effect of phenytoin on tacrolimus clearance. It is important to point out that oral phenytoin was utilized, rather than IV phenytoin, as our aim was also to induce the CYP3A enzymes in the GI tract as well as the liver resulting in further increases in tacrolimus elimination. IV phenytoin has also been associated with more side effects than the oral formulation, specifically hypotension during administration and injection site reactions.\n\nIn conclusion, short-term administration of the enzyme-inducer phenytoin facilitated reversal of elevated tacrolimus concentrations and severe renal impairment in four organ transplant recipients. Based on these results, phenytoin appears to be a potential treatment in severe cases of tacrolimus toxicity.\n\nConflict of Interests\nNone of the authors have any conflict of interests or financial relationships to disclose.\n\nFigure 1 Mean creatinine and FK levels. Day 0 represents first day of phenytoin administration.\n\nTable 1 Summary of patients. \n\nPatient number\tTransplant type\tAge race sex\tTime since transplant (months)\tCausative factor(s)\tClinical presentation\tBaseline SCr (mg/dL)\tAdmit SCr (mg/dL)/% increase from baseline\tAdmit potassium (mEq/L)\tFK level on admit (ng/mL)\t\n1\tLiver\t53 W M\t20.8\tAtazanavir therapy, hepatitis C infection\tAcute kidney injury, nausea, vomiting\t1.7\t6.3/270%\t6.7\t>30\t\n2\tHeart\t57 AA F\t9.2\tFluconazole therapy\tAcute kidney injury, fever, chest pain\t1\t7.3/630%\t6.2\t>30\t\n3\tHeart/kidney\t70 As M\t12.4\tHerbal supplements; disseminated Nocardia infection\tAcute kidney injury, nausea, diarrhea\t0.8\t4.2/425%\t6.1\t>30\t\n4\tKidney\t58 W M\t5.5\tVoriconazole therapy, pseudomonas, and nocardia pneumonia\tAcute kidney injury, fevers, shortness of breath\t2.1\t3.5/67%\t6.4\t23.7\t\nTable 2 Management of FK toxicity and outcomes.\n\nPatient number\tHospital day of phenytoin initiation\tPhenytoin dose (mg/day)/duration (days)\tOther management\tDays to FK <15 ng/mL\tDays to resuming tacrolimus\tDays to baseline SCr\tOutcome/followup (months)\t\n1\t1\t400/3\tHAART temporarily withheld\t2\t5\t∗\tAlive, stable renal function/60\t\n2\t1\t400/2\tFluconazole temporarily withheld\t3\t5\t10\tDied, cardiac arrest/7\t\n3\t1\t300/3\tHerbal products stopped\t3\t4\t10\tAlive, stable renal function/13\t\n4\t2\t400/3\tVoriconazole stopped\t3\t4\t3\tAlive, stable renal function/8\t\n*Patient baseline creatinine 1.7 mg/dL did not return back to baseline but settled with creatinine of 2.2 mg/dL.\n==== Refs\n1 Kaufman DB Shapiro R Lucey MR Cherikh WS Bustami RT Dyke DB Immunosuppression: practice and trends The American Journal of Transplantation 2004 4 9 38 53 2-s2.0-3042743794 15113354 \n2 Prograf [Package Insert] 2012 Northbrook, Ill, USA Astellas Pharma US \n3 Staatz CE Tett SE Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation Clinical Pharmacokinetics 2004 43 10 623 653 2-s2.0-3242772986 15244495 \n4 Christians U Jacobsen W Benet LZ Lampen A Mechanisms of clinically relevant drug interactions associated with tacrolimus Clinical Pharmacokinetics 2002 41 11 813 851 2-s2.0-0036380025 12190331 \n5 Quirós-Tejeira RE Chang IF Bristow LJ Karpen SJ Goss JA Treatment of acute tacrolimus whole-blood elevation with phenobarbital in the pediatric liver transplant recipient Pediatric Transplantation 2005 9 6 792 796 2-s2.0-27944489248 16269053 \n6 O’Connor AD Rusyniak DE Mowry J Acute tacrolimus toxicity in a non-transplant patient Clinical Toxicology 2008 46 9 838 840 2-s2.0-55949130015 18608277 \n7 McLaughlin GE Rossique-Gonzalez M Gelman B Kato T Use of phenobarbital in the management of acute tacrolimus toxicity: a case report Transplantation Proceedings 2000 32 3 665 668 2-s2.0-0034061281 10812158 \n8 Curran CF Blahunka PC Lawrence ID Acute overdoses of tacrolimus Transplantation 1996 62 9 1376 1377 2-s2.0-0030447432 8932293 \n9 Karasu Z Gurakar A Carlson J Acute tacrolimus overdose and treatment with phenytoin in liver transplant recipients Journal of Oklahoma State Medical Association 2001 94 4 121 123 2-s2.0-0035316896 \n10 Jain AKB Venkataramanan R Shapiro R The interaction between antiretroviral agents and tacrolimus in liver and kidney transplant patients Liver Transplantation 2002 8 9 841 845 2-s2.0-0036712014 12200788 \n11 Barone GW Gurley BJ Ketel BL Abul-Ezz SR Herbal supplements: a potential for drug interactions in transplant recipients Transplantation 2001 71 2 239 241 2-s2.0-0035956720 11213066 \n12 Venkatakrishnan K Von Moltke LL Greenblatt DJ Human drug metabolism and the cytochromes P450: application and relevance of in vitro models Journal of Clinical Pharmacology 2001 41 11 1149 1179 2-s2.0-0034770465 11697750 \n13 Michalets EL Update: clinically significant cytochrome P-450 drug interactions Pharmacotherapy 1998 18 1 84 112 2-s2.0-0031975185 9469685 \n14 Wada K Takada M Ueda T Drug interactions between tacrolimus and phenytoin in Japanese heart transplant recipients: 2 case reports International Journal of Clinical Pharmacology and Therapeutics 2007 45 9 524 528 2-s2.0-34548621154 17907595 \n15 Renton KW Alteration of drug biotransformation and elimination during infection and inflammation Pharmacology and Therapeutics 2001 92 2-3 147 163 2-s2.0-0035726732 11916535 \n16 Morgan ET Li-Masters T Cheng PY Mechanisms of cytochrome P450 regulation by inflammatory mediators Toxicology 2002 181-182 207 210 2-s2.0-0037184799 12505312 \n17 Odoul F Talbotec C Boussa N Massive ingestion of tacrolimus in a young liver transplant patient Transplantation Proceedings 1998 30 8 4327 4329 2-s2.0-0032425128 9865375 \n18 Hardwick LL Batiuk TD Severe prolonged tacrolimus overdose with minimal consequences Pharmacotherapy 2002 22 8 1063 1066 2-s2.0-0036021231 12173792 \n19 Przepiorka D Suzuki J Ippoliti C Hester JP Fritsche HA Blood tacrolimus concentration unchanged by plasmapheresis The American Journal of Hospital Pharmacy 1994 51 13 2-s2.0-0028246594 \n20 Chyka PA Seger D Position paper: single-dose activated charcoal Clinical Toxicology 2005 43 2 61 87 2-s2.0-15944384578 15822758 \n21 Rifampin [Package Insert] 2012 Philadelphia, Pa, USA Lannett Company\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6951",
"issue": "2013()",
"journal": "Case reports in transplantation",
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"medline_ta": "Case Rep Transplant",
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"nlm_unique_id": "101591863",
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"pmid": "23844312",
"pubdate": "2013",
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"references": "12190331;12505312;17907595;10812158;8932293;11697750;12173792;11392178;18608277;7524318;12200788;16269053;11916535;15822758;15244495;9865375;9469685;11213066;15113354",
"title": "Treatment of acute tacrolimus toxicity with phenytoin in solid organ transplant recipients.",
"title_normalized": "treatment of acute tacrolimus toxicity with phenytoin in solid organ transplant recipients"
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"abstract": "Lymphocytic interstitial pneumonia (LIP) is a rare condition, commonly associated with Sjogren's syndrome (SS). We report a 53-year-old woman with an incidental finding of an abnormal chest radiograph. LIP was diagnosed based on high-resolution computed tomography and lung biopsy, but treatment was not initiated. Six years later, she developed cough and dyspnoea, associated with dry eyes, dry mouth, and arthralgia. While being investigated for the respiratory symptoms, she developed cutaneous vasculitis and was treated with 1 mg/kg prednisolone, which resulted in the improvement of her respiratory symptoms. Physical examination revealed fine bibasal crepitations, active vasculitic skin lesions, and a positive Schirmer's test. Investigations revealed a restrictive pattern in the pulmonary function test, stable LIP pattern in HRCT, and positive anti-Ro antibodies. She was treated with prednisolone and azathioprine for 18 months, and within this time, she was hospitalised for flare of LIP, as well as respiratory tract infection on three occasions. During the third flare, when she also developed cutaneous vasculitis, she agreed for prednisolone but refused other second-line agents. To date, she remained well with the maintenance of prednisolone 2.5 mg monotherapy for more than one year. The lessons from this case are (i) patients with LIP can be asymptomatic, (ii) LIP can precede symptoms of SS, and (iii) treatment decision for asymptomatic patients with abnormal imaging or patients with mild severity should be weighed between the risk of immunosuppression and risk of active disease.",
"affiliations": "Faculty of Medicine, Universiti Teknologi MARA, Malaysia.;Faculty of Medicine, Universiti Teknologi MARA, Malaysia.;Institut Perubatan Respiratori, Malaysia.;Faculty of Medicine, Universiti Teknologi MARA, Malaysia.;Hospital Selayang, Malaysia.",
"authors": "Baharuddin|Hazlyna|H|https://orcid.org/0000-0003-1383-8219;Hanafiah|Mohammad|M|;Aflah|Syazatul Syakirin Sirol|SSS|;Zim|Mohd Arif Mohd|MAM|;Ch'Ng|Shereen Suyin|SS|",
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"doi": "10.1155/2021/6693031",
"fulltext": "\n==== Front\nCase Rep Pulmonol\nCase Rep Pulmonol\nCRIPU\nCase Reports in Pulmonology\n2090-6846 2090-6854 Hindawi \n\n10.1155/2021/6693031\nCase Report\nAsymptomatic Lymphocytic Interstitial Pneumonia with Extensive HRCT Changes Preceding Sjogren's Syndrome\nhttps://orcid.org/0000-0003-1383-8219Baharuddin Hazlyna hazlynabaharuddin@yahoo.com\n1\n\n2\n Hanafiah Mohammad \n1\n\n3\n Aflah Syazatul Syakirin Sirol \n4\n Zim Mohd Arif Mohd \n1\n\n2\n Ch'Ng Shereen Suyin \n2\n \n1Faculty of Medicine, Universiti Teknologi MARA, Malaysia\n\n2Hospital Selayang, Malaysia\n\n3Assunta Hospital, Malaysia\n\n4Institut Perubatan Respiratori, Malaysia\nAcademic Editor: Tun-Chieh Chen\n\n\n2021 \n7 1 2021 \n2021 669303126 10 2020 18 12 2020 19 12 2020 Copyright © 2021 Hazlyna Baharuddin et al.2021This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Lymphocytic interstitial pneumonia (LIP) is a rare condition, commonly associated with Sjogren's syndrome (SS). We report a 53-year-old woman with an incidental finding of an abnormal chest radiograph. LIP was diagnosed based on high-resolution computed tomography and lung biopsy, but treatment was not initiated. Six years later, she developed cough and dyspnoea, associated with dry eyes, dry mouth, and arthralgia. While being investigated for the respiratory symptoms, she developed cutaneous vasculitis and was treated with 1 mg/kg prednisolone, which resulted in the improvement of her respiratory symptoms. Physical examination revealed fine bibasal crepitations, active vasculitic skin lesions, and a positive Schirmer's test. Investigations revealed a restrictive pattern in the pulmonary function test, stable LIP pattern in HRCT, and positive anti-Ro antibodies. She was treated with prednisolone and azathioprine for 18 months, and within this time, she was hospitalised for flare of LIP, as well as respiratory tract infection on three occasions. During the third flare, when she also developed cutaneous vasculitis, she agreed for prednisolone but refused other second-line agents. To date, she remained well with the maintenance of prednisolone 2.5 mg monotherapy for more than one year. The lessons from this case are (i) patients with LIP can be asymptomatic, (ii) LIP can precede symptoms of SS, and (iii) treatment decision for asymptomatic patients with abnormal imaging or patients with mild severity should be weighed between the risk of immunosuppression and risk of active disease.\n==== Body\n1. Introduction\nLymphocytic interstitial pneumonia (LIP) is a rare condition. Cha et al. reported that among 1,167 lung biopsies of patients with interstitial lung disease (ILD) collected over 14 years, only 15 were found to have LIP [1]. LIP is regarded as both a disease (rare idiopathic interstitial pneumonia) and as a nonneoplastic, inflammatory pulmonary reaction to various external stimuli or systemic disease [1]. It is commonly found in connective tissue disease (CTD) especially Sjogren's syndrome (SS). A systematic review of pulmonary involvement in SS reported that of 146 histopathological diagnoses, the most common was nonspecific interstitial pneumonia (45%), followed by bronchiolitis (25%), usual interstitial pneumonia (16%), and lymphocytic interstitial pneumonia (15%) [2]. We report a case of asymptomatic LIP with extensive HRCT changes before she became symptomatic and developed features of SS, six years later.\n\n2. Case Presentation\nA 53-year-old woman was incidentally found to have an abnormal chest radiograph during preoperative assessment for elective hysterectomy, ten years ago. She sought treatment in a hospital in a neighbouring country and was diagnosed with LIP, based on high-resolution computed tomography (HRCT) finding (Figure 1(a)) and lung biopsy report of marked fibrosis of interlobular septa, diffuse interstitial and peribronchiolar lymphoplasmacytic infiltration with scattered eosinophils. She did not receive any treatment and subsequently defaulted follow-up after two years.\n\nSix years after the incidental abnormal chest radiograph, she consulted a respiratory physician with an eight-month history of cough and dyspnoea. Six-minute walk distance was 440 m with oxygen saturation of 89%, and pulmonary function test (PFT) showed a restrictive pattern with FEV1 53%, FVC 67%, and DLCO 70%. A repeat HRCT showed stable appearances of diffuse peribronchovascular thickening and ground glass changes with tiny cysts along the bronchovascular bundles in both lungs (Figure 1(b)). She was referred for a rheumatology consult a few months later when immunology investigations revealed positive antinuclear and anti-Ro antibodies. An additional history of dry eyes, dry mouth, and inflammatory arthralgia, which started three months after the onset of respiratory symptoms, was revealed. She also reported an improvement in her respiratory symptoms a month earlier, after she was prescribed prednisolone 1 mg/kg by a dermatologist for cutaneous vasculitis. At the time of the rheumatology clinic appointment, she was on prednisolone 20 mg and she reported recurrence of cutaneous vasculitis. Physical examination revealed a 52 kg lady with oxygen saturation of 93% on room air at rest, fine crepitations at the lung bases, and multiple vasculitic lesions on the lower limbs. Schirmer's test was positive. Abnormal blood investigations included anaemia (haemoglobin 10.8 g/dL), thrombocytosis (platelet 494 × 109/L), raised erythrocyte sedimentation rate (86 mm/hour), and hypergammaglobulinaemia (globulin 63 g/L). She also had pulmonary hypertension (pH), confirmed by right heart catheterisation showing mean pulmonary arterial pressure of 26 mmHg and precapillary wedge pressure of 9 mmHg.\n\nLIP secondary to primary SS was diagnosed. Prednisolone dose was increased to 0.75 mg/kg and azathioprine 2 mg/kg was started as a steroid-sparing agent. Within the next 18 months, she had three hospitalisations due to worsening respiratory symptoms. She was treated for ILD exacerbation (with high-dose prednisolone) and respiratory tract infection (with intravenous antibiotics). During her last flare, she also developed a recurrence of cutaneous vasculitis. At this time, she agreed for prednisolone but refused steroid-sparing agent. Surprisingly, she remained stable and for the last 10 months; she was well on prednisolone 2.5 mg. She was content with the status quo of NYHA Class II and regular four-monthly clinic follow-up, without any hospitalisations.\n\n3. Discussion\nThe disease course in our patient highlights some important lessons. First, LIP is a rare disease, and secondary causes should be sought. In some patients, pulmonary involvement precedes other systemic symptoms of CTD, making the distinction between idiopathic ILD and CTD-ILD impossible at the time of diagnosis [3]. Nonetheless, the involvement of multidisciplinary teams is advocated to ensure optimal management of ILD. The diagnosis of SS was delayed in our patient because her rheumatologic symptoms (inflammatory arthralgia, dry eyes, and dry mouth) were not explored when she first presented with cough and dyspnoea. In fact, they were only discovered months later by the rheumatologist, who was referred for positive ANA and anti-Ro antibodies. Without the presence of rheumatologic symptoms and signs, she would be classified as Interstitial Pneumonia with Autoimmune Features (IPAF) [4], as she fulfilled a serologic and morphologic domain only. Some may argue that the classification of IPAF or CTD-ILD is not important as the treatment for both conditions is the same. However, patient monitoring in CTD is different because of multisystem involvement.\n\nSecondly, our patient remained asymptomatic for six years despite extensive HRCT changes. Although CT is the most sensitive method of detecting lung abnormalities, radiological abnormalities do not correlate with pulmonary function tests and respiratory symptoms [5, 6]. The respiratory manifestation of SS is polymorphic and varies in severity [5]. The severity of pulmonary involvement is graded according to PFT results and functional class of patients with HRCT-proven ILD [7]. It is classified as low activity in patients with chronic respiratory symptoms associated with mucosal dryness of the upper respiratory tract with normal imaging and in asymptomatic patients with altered pulmonary imaging [7]. Our patient's disease activity was low in the first six years because she was asymptomatic, but later became moderate because of abnormal PFT and NYHA Class II.\n\nThe final lesson is to appreciate that not all pulmonary manifestations in SS need treatment especially those who are well with stable disease [5]. Although there is no conclusive standard therapy for SS with pulmonary involvement, immune therapy such as corticosteroid and/or immunosuppressive drugs is indicated when there is a presence of progressive chest symptoms, impaired respiratory function, or prominent abnormal chest or HRCT [5]. In cases such as our patient, treatment decision with cytotoxic drugs should be weighed carefully between the risk of rendering patients immunocompromised and the risk of patients developing active disease. Patients with LIP generally respond well to initial corticosteroid therapy, but up to one-third may die within several years of diagnosis from the progression of the disease or infectious complications related to immunosuppressive therapy [8]. Based on our experience, we can conclude that LIP in our patient is steroid-responsive, and steroid-sparing agent did not alter her disease course, as she had been stable on a low dose of prednisolone for more than a year.\n\nConflicts of Interest\nThe authors declare that there is no conflict of interest regarding the publication of this article.\n\nFigure 1 Selected axial CT images of the initial scan (a) and 6 years later (b) of LIP. There are diffuse peribronchovascular thickening and ground glass changes with tiny cysts along the bronchovascular bundles in both lungs.\n==== Refs\n1 Cha S.-I. Lymphoid interstitial pneumonia: clinical features, associations and prognosis The European Respiratory Journal 2006 28 2 364 369 10.1183/09031936.06.00076705 2-s2.0-33845492413 16571614 \n2 Ramos-Casals M. Brito-Zerón P. Seror R. Characterization of systemic disease in primary Sjögren’s syndrome: EULAR-SS Task Force recommendations for articular, cutaneous, pulmonary and renal involvements Rheumatology 2015 54 12 2230 2238 10.1093/rheumatology/kev200 2-s2.0-84983156742 26231345 \n3 Antoniou K. M. Margaritopoulos G. Economidou F. Siafakas N. M. Pivotal clinical dilemmas in collagen vascular diseases associated with interstitial lung involvement The European Respiratory Journal 2009 33 4 882 896 10.1183/09031936.00152607 2-s2.0-63849343420 19336591 \n4 Fischer A. Antoniou K. M. Brown K. K. An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features The European Respiratory Journal 2015 46 4 976 987 10.1183/13993003.00150-2015 2-s2.0-84942925433 26160873 \n5 Flament T. Bigot A. Chaigne B. Henique H. Diot E. Marchand-Adam S. Pulmonary manifestations of Sjögren’s syndrome European Respiratory Review 2016 25 140 110 123 10.1183/16000617.0011-2016 2-s2.0-84971572615 27246587 \n6 Papathanasiou M. P. Constantopoulos S. H. Tsampoulas C. Drosos A. A. Moutsopoulos H. M. Reappraisal of respiratory abnormalities in primary and secondary Sjogren's syndrome: a controlled study Chest 1986 90 3 370 374 10.1378/chest.90.3.370 2-s2.0-0022517506 3743149 \n7 Seror R. Theander E. Brun J. G. Validation of EULAR primary Sjögren’s syndrome disease activity (ESSDAI) and patient indexes (ESSPRI) Annals of the Rheumatic Diseases 2015 74 5 859 866 10.1136/annrheumdis-2013-204615 2-s2.0-84926609858 24442883 \n8 Stojan G. Baer A. N. Danoff S. K. Pulmonary manifestations of Sjögren’s syndrome Current Allergy and Asthma Reports 2013 13 4 354 360 10.1007/s11882-013-0357-9 2-s2.0-84881131956 23797265\n\n",
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"title": "Asymptomatic Lymphocytic Interstitial Pneumonia with Extensive HRCT Changes Preceding Sjogren's Syndrome.",
"title_normalized": "asymptomatic lymphocytic interstitial pneumonia with extensive hrct changes preceding sjogren s syndrome"
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"abstract": "BACKGROUND\nPosterior reversible leukoencephalopathy syndrome (PRES) is linked to various etiologies, including most importantly systemic hypertension. Its association with intracranial hypotension (IH), a potential sequela of various neurosurgical procedures, is underrecognized. We report a case of lumboperitoneal shunt-induced IH resulting in PRES with the goal to increase awareness and elaborate on the potential biologic mechanism, based on the Monro-Kellie hypothesis.\n\n\nMETHODS\nA 26-year-old woman with acquired immunodeficiency syndrome and epilepsy was admitted for recurrent cryptococcal meningitis and breakthrough seizures. There was radiologic evidence of ventricular enlargement, and opening pressure on serial lumbar punctures was constantly elevated. Owing to persistently elevated, symptomatic intracranial pressure and transient relief with serial lumbar punctures, a lumboperitoneal shunt was placed. The patient subsequently had a breakthrough seizure and became encephalopathic. Repeat head imaging showed reduced ventricular size, engorged venous sinuses, and tonsillar herniation in keeping with IH, coupled with extensive white matter abnormalities in bilateral parieto-occipital lobes indicative of PRES. The patient had an emergent programmable valve placed in the lumboperitoneal shunt to prevent excessive cerebrospinal fluid drainage, leading to clinical and radiologic improvement. Subsequent cerebrospinal fluid leak resulted in recurrent presentation.\n\n\nCONCLUSIONS\nIH appears to be a distinct cause of PRES not previously reported in the neurosurgical literature. It occurs in susceptible patients, on average 1-5 days after the IH trigger, and seems clinically and radiologically similar to more common hypertensive cases in terms of initial presentation and prognosis. Increased vigilance is required for prompt recognition and management.",
"affiliations": "Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA. Electronic address: ioannis.karakis@emory.edu.;Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.;Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia, USA.;Department of Radiology, Emory University School of Medicine, Atlanta, Georgia, USA.",
"authors": "Karakis|Ioannis|I|;Nuccio|Audrey H|AH|;Amadio|Jordan P|JP|;Fountain|Arthur J|AJ|",
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"keywords": "Intracranial hypotension; Monro-Kellie hypothesis; PRES; Posterior reversible encephalopathy syndrome",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000328:Adult; D065634:Cerebrospinal Fluid Leak; D002557:Cerebrospinal Fluid Shunts; D005260:Female; D006801:Humans; D019585:Intracranial Hypotension; D008279:Magnetic Resonance Imaging; D054038:Posterior Leukoencephalopathy Syndrome; D015898:Tomography Scanners, X-Ray Computed",
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"title": "The Monro-Kellie Doctrine in Action: Posterior Reversible Leukoencephalopathy Syndrome Caused by Intracranial Hypotension from Lumboperitoneal Shunt Placement.",
"title_normalized": "the monro kellie doctrine in action posterior reversible leukoencephalopathy syndrome caused by intracranial hypotension from lumboperitoneal shunt placement"
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"abstract": "Toxic epidermal necrolysis (TEN) is a severe drug induced type IV hypersensitivity syndrome that can be caused by anticonvulsant drugs, especially the aromatic anticonvulsants such as phenytoin. Most patients with brain metastasis receive whole brain radiotherapy along with anti-edema measures and anticonvulsants either as prophylactic or for symptom control; phenytoin being the most commonly used drug. In a subset of patients, cranial irradiation may act as a precipitating factor along with anticonvulsants for the development of TEN. We report a 54-year-old patient with metastatic non-small cell lung cancer treated with palliative whole brain and mediastinal radiotherapy with concurrent phenytoin-developing TEN, which started within the radiation portals with subsequent generalization. Though a rare, but serious complication, avoidance of the use of phenytoin concurrent with radiotherapy, replacing phenytoin with newer anticonvulsants, early recognition, aggressive management and awareness of this possible complication has been implied upon in this report.",
"affiliations": "Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi 110029, India. Tel. +91 (112) 9575241. E-mail. imtidr@gmail.com.",
"authors": "Ahmed|Imtiaz|I|;Biswas|Ahitagni|A|;Krishnamurthy|Sapna|S|;Julka|Pramod K|PK|",
"chemical_list": "D000927:Anticonvulsants; D010672:Phenytoin",
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"fulltext": "\n==== Front\nSaudi Med JSaudi Med JSaudiMedJSaudi Medical Journal0379-52841658-3175Saudi Medical Journal Saudi Arabia 25399219SaudiMedJ-35-1393Case ReportToxic epidermal necrolysis in a patient receiving concurrent phenytoin and whole brain and thoracic radiotherapy Ahmed Imtiaz MBBS, MDBiswas Ahitagni MD, DNBKrishnamurthy Sapna MBBS, MDJulka Pramod K. MBBS, MDFrom the Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India.Address correspondence and reprint request to: Dr. Imtiaz Ahmed, Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi 110029, India. Tel. +91 (112) 9575241. E-mail: imtidr@gmail.com2014 35 11 1393 1395 22 6 2014 15 9 2014 Copyright: © Saudi Medical Journal2014Saudi Medical Journal is an Open Access journal and articles published are distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC). Readers may copy, distribute, and display the work for non-commercial purposes with the proper citation of the original work.Toxic epidermal necrolysis (TEN) is a severe drug induced type IV hypersensitivity syndrome that can be caused by anticonvulsant drugs, especially the aromatic anticonvulsants such as phenytoin. Most patients with brain metastasis receive whole brain radiotherapy along with anti-edema measures and anticonvulsants either as prophylactic or for symptom control; phenytoin being the most commonly used drug. In a subset of patients, cranial irradiation may act as a precipitating factor along with anticonvulsants for the development of TEN. We report a 54-year-old patient with metastatic non-small cell lung cancer treated with palliative whole brain and mediastinal radiotherapy with concurrent phenytoin-developing TEN, which started within the radiation portals with subsequent generalization. Though a rare, but serious complication, avoidance of the use of phenytoin concurrent with radiotherapy, replacing phenytoin with newer anticonvulsants, early recognition, aggressive management and awareness of this possible complication has been implied upon in this report.\n==== Body\nSteven Johnson Syndrome (SJS), Steven Johnson Syndrome-toxic epidermal necrolysis (SJS-TEN), and toxic epidermal necrolysis (TEN) are a spectrum of type IV hypersensitivity drug-induced disorders, which are characterized by blisters and epidermal detachment resulting from epidermal necrosis in the absence of substantial dermal inflammation often associated with anticonvulsant medications.1,2 Patients with brain metastasis, irrespective of the primary tumor location are often symptomatic. They require active treatment in the form of palliative radiotherapy to the whole brain and symptomatic management, which includes anti-edema measures with systemic steroids and use of anticonvulsants either for seizure control or prophylactic use. Phenytoin is the most common drug used for seizure control. A subgroup of patients receiving this combination of whole brain radiotherapy and phenytoin develop severe cutaneous hypersensitive drug reaction that may manifest as SJS-TEN spectrum of systemic syndrome.3,4 In this report, we describe one case of TEN developing in a patient with metastatic lung cancer receiving palliative whole brain and thoracic radiotherapy (RT) with concurrent phenytoin, emphasizing the need for anticipation, early recognition, and aggressive management of this potentially fatal medical emergency.\n\nCase Report\nA 54-year-old male patient presented with a history of shortness of breath and multiple episodes of seizure of one week duration. On evaluation, he was diagnosed with right lung non-small cell lung cancer (squamous cell carcinoma) with metastasis to brain and superior vena caval syndrome (stage IV). He was started on tab phenytoin 300 mg at bedtime and anti-edema measures with steroids (tab dexamethasone 8 mg 3 times daily during RT and tapered over 2 weeks post RT). He received palliative RT to the mediastinum and whole brain with a total dose of 20 Gray in 5 fractions over one week with Co-60 gamma rays. Two weeks post radiotherapy, his general condition improved and he received one cycle of palliative chemotherapy with paclitaxel-carboplatin combination. Nearly 3 weeks after completing the RT, he presented with painful, erythematous lesions in the scalp, which subsequently generalized. During examination, he was afebrile with pulse rate 98/min, respiratory rate 28/min, blood pressure 109/83 mm Hg, and features of mild dehydration. Examination of the skin revealed erythematous, tender macules over the scalp, face, trunk, and limbs with areas of confluent epidermal detachment and blistering involving almost 30% of his body surface area (Figure 1). Conjunctivitis, hemorrhagic crusting on lips, erosions over buccal and nasal mucosa and over the glans penis were noted, strongly suggesting TEN caused by phenytoin. Hemogram and biochemical parameters were normal except for hyponatremia. Phenytoin was immediately discontinued, and he was managed with intravenous fluid replacement, electrolyte correction, systemic antibiotics, steroids (dexamethasone 16 mg/day tapered at 2 mg/day over one week), and local skin care with antibiotic and antifungal dressings. After primary supportive care, his condition worsened and he died due to septicemia on the seventh day of hospital admission.\n\nFigure 1 An image showing areas of: A) dusky eruptions over the entire scalp; B) extensive epidermal detachment over the scalp, nape of the neck, and upper back.\n\nDiscussion\nPatients with TEN, initially present with acute onset, painful skin lesions, fever >39°C (102.2°F), sore throat, oral and ocular mucosal complications, with rapidly spreading confluent and extensive epidermal detachment, dehydration, dyselectrolytemia, which rapidly evolves into systemic disease with 25-35% mortality.2 The risk of death of patients with TEN can be accurately predicted by TEN specific severity-of-illness score, which considers 7 independent risk factors such as age >40 years, malignancy, heart rate >120/ min, initial percentage of epidermal detatchment over 10%, serum urea >10 mmol/litre, serum glucose >14 mmol/litre, and bicarbonate <20 mmol/litre.\n\nAromatic anticonvulsants such as phenytoin, phenobarbitone, carbamazapine are not only among the common drugs inducing this reaction, but also considered as a high risk agents especially in new users.2 Phenytoin is the most common anticonvulsant used for seizure control and for prophylactic use in the brain metastasis setting. Its risk of inducing TEN is approximately 8.3 per 10,000 new users and usually occurs within 8 weeks of drug use.3\n\nRadiation alone has to date not resulted in SJS-TEN syndrome. However, concurrent use of whole brain RT and phenytoin has been shown to induce cutaneous type IV hypersensitivity drug reactions as erythema multiforme (EM), SJS or TEN.4-6 The first case was reported by Delattre et al4 in an individual who received radiation therapy while using phenytoin for seizure prophylaxis and developed EM. A special nomenclature of erythema multiforme associated with phenytoin and cranial radiation therapy (EMPACT) syndrome has been given to EM developing due to concurrent use of phenytoin and cranial RT, which begin as dusky macules in the RT portal, later spreading to other regions evolving as an eruptive disorder with systemic involvement.5,6\n\nThough the pathogenesis is largely unknown, it is postulated that it is an immunologically mediated type IV hypersensitivity to phenytoin and its metabolites, which is augmented by the concurrent use of RT.7 Though most of the EM-SJS-TEN syndromes were described in patients receiving aromatic anticonvulsants concurrent with late whole brain RT, there have been reports describing the occurrence of similar lesions in the non-cranial RT sites when anticonvulsants are given concurrently.8 The illustrative case also shows similar clinical behavior. But, it has to be noted that in all these reports there was a component of concurrent whole brain RT, which must also act as a trigger for the development of lesions in other RT sites.\n\nThis hypersensitivity reaction has also been reported in patients with non-small cell lung cancer undergoing combination chemotherapy with carboplatin-pemetrexed regimen. Thus, in the illustrative case, carboplatin based chemotherapy might also be a potential trigger behind development of TEN.9\n\nManagement should be aggressive under the intensive care unit and immediate cessation of the offending drug. Fluid, and electrolyte replacement, systemic steroids, antibiotics, and local wound care, should be included. A high dose of corticosteroids instituted early within TEN (24-48 hours) halts the hypersensitivity reaction and prevents further tissue damage. However, a rapid tapering followed by withdrawal within 2 weeks is recommended to prevent increased mortality from sepsis, gastrointestinal bleed, and delayed wound healing.10\n\nIn conclusion, although SJS-TEN syndrome associated with concurrent use of phenytoin and cranial RT is a rare clinical scenario, this is a potential complication with significant mortality. Hence, the use of phenytoin should be avoided during RT, and if indicated, phenytoin can be replaced with other anticonvulsants such as sodium valproate, benzodiazepines or the newer antiepileptic drugs such as gabapentin and topiramate. In patients receiving phenytoin and concurrent whole brain radiation, complications should be anticipated and managed aggressively.\n\n\nDisclosure\nAuthors have no conflict of interests, and the work was not supported or funded by any drug company. This study was funded by the Sultan Qaboos University Hospital, Muscat, Oman (Grant No: IG/MED/PHYS/10/03\n\n\n\n\n\nRelated Articles\nDiniz G, Unlu I, Gokce T, Kilciksiz S, Gayaf M, Komurcuoglu B, et al. Evaluation of curative and palliative radiotherapy efficacy in extensive stage small cell lung cancer. Saudi Med J 2006; 27: 992-996.\n\nUnlu I, Diniz G, Komurcuoglu B, Gayaf M, Gokce T, Karadogan I, et al. Comparison of curative and palliative radiotherapy efficacy in unresectable advanced non-small cell lung cancer patients with or without metastasis.Saudi Med J 27: 849-853.\n==== Refs\n1 Shinkai K Stern RS Wintroub BU Longo DL Cutaneous drug reactions Harrison's Principles of Internal Medicine 2012 18th ed New York (NY) McGraw-Hill Co 436 \n2 Harr T French LE Toxic epidermal necrolysis and Stevens-Johnson syndrome Orphanet J Rare Dis 2010 5 39 21162721 \n3 Mockenhaupt M Messenheimer J Tennis P Schlingmann J Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics Neurology 2005 64 1134 1138 15824335 \n4 Delattre JY Safai B Posner JB Erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and phenytoin Neurology 1988 38 194 198 3340279 \n5 Ahmed I Reichenberg J Lucas A Shehan JM Erythema multiforme associated with phenytoin and cranial radiation therapy: a report of three patients and review of the literature Int J Dermatol 2004 43 67 73 14693027 \n6 Aydoğan K Vatansever S Adim SB Saricaoglu H Empact syndrome: a case report and review of the literature Int J Dermatol 2010 49 945 949 21128922 \n7 Pichler W Yawalkar N Schmid S Helbling A Pathogenesis of drug-induced exanthems Allergy 2002 57 884 893 12269933 \n8 Kandil AO Dvorak T Mignano J Wu JK Zhu JJ Multifocal Stevens-Johnson syndrome after concurrent phenytoin and cranial and thoracic radiation treatment, a case report Radiat Oncol 2010 5 49 20525360 \n9 Bosch-Barrera J Gaztañaga M Ceballos J Pérez-Gracia JL López-Picazo JM García-Foncillas J Toxic epidermal necrolysis related to pemetrexed and carboplatin with vitamin B12 and folic acid supplementation for advanced non-small cell lung cancer Onkologie 2009 32 580 584 19816075 \n10 Pasricha JS Management of toxic epidermal necrolysis Ind J Dermatol Venereol Leprol 1990 56 458 459\n\n",
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"issue": "35(11)",
"journal": "Saudi medical journal",
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"medline_ta": "Saudi Med J",
"mesh_terms": "D000927:Anticonvulsants; D001932:Brain Neoplasms; D002294:Carcinoma, Squamous Cell; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D010672:Phenytoin; D011878:Radiotherapy; D012640:Seizures; D013262:Stevens-Johnson Syndrome; D013479:Superior Vena Cava Syndrome",
"nlm_unique_id": "7909441",
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"pages": "1393-5",
"pmc": null,
"pmid": "25399219",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12269933;14693027;3340279;21162721;19816075;20525360;21128922;15824335",
"title": "Toxic epidermal necrolysis in a patient receiving concurrent phenytoin and whole brain and thoracic radiotherapy.",
"title_normalized": "toxic epidermal necrolysis in a patient receiving concurrent phenytoin and whole brain and thoracic radiotherapy"
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"abstract": "BACKGROUND\nLittle is known about the treatment of multidrug-resistant tuberculosis (MDR-TB) in HIV-co-infected adolescents. This study aimed to present the intermediate outcomes of HIV-infected adolescents aged 10-19 years receiving second-line anti-TB treatment in a Médecins Sans Frontières (MSF) project in Mumbai, India.\n\n\nMETHODS\nA retrospective review of medical records of 11 adolescents enrolled between July 2007 and January 2013 was undertaken. Patients were initiated on either empirical or individualized second-line ambulatory anti-TB treatment under direct observation.\n\n\nRESULTS\nThe median age was 16 (IQR 14-18) years and 54% were female. Five (46%) adolescents had pulmonary TB (PTB), two (18%) extrapulmonary disease (EPTB) and four (36%) had both. Median CD4 count at the time of MDR-TB diagnosis was 162.7 cells/µl (IQR: 84.8-250.5). By January 2013, eight patients had final and 3 had interim outcomes. Favourable results were seen in four (36.5%) patients: one was cured and three were still on treatment with negative culture results. Seven patients (64%) had poor outcomes: four (36.5%) died and three (27%) defaulted. Three of the patients who died never started on antiretroviral and/or TB treatment and one died 16 days after treatment initiation. Two of the defaulted died soon after default. All patients (100%) on-treatment experienced adverse events (AEs): two required permanent discontinuation of the culprit drug and two were hospitalized due to AEs. No patient required permanent discontinuation of the entire second-line TB or antiretroviral regimens.\n\n\nCONCLUSIONS\nEarly mortality and mortality after default were the most common reasons for poor outcomes in this study. Early mortality suggests the need for rapid diagnosis and prompt treatment initiation, and adolescents might benefit from active contact-tracing and immediate referral. Default occurred at different times, suggesting the need for continuous, intensified and individualized psychosocial support for co-infected adolescents. Operational research among co-infected adolescents will be especially important in designing effective interventions for this vulnerable group.",
"affiliations": "Médecins Sans Frontières, Mumbai, India. msfocb-asia-epidemio@brussels.msf.org",
"authors": "Isaakidis|Petros|P|;Paryani|Roma|R|;Khan|Samsuddin|S|;Mansoor|Homa|H|;Manglani|Mamta|M|;Valiyakath|Asmaa|A|;Saranchuk|Peter|P|;Furin|Jennifer|J|",
"chemical_list": "D000995:Antitubercular Agents",
"country": "United States",
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"doi": "10.1371/journal.pone.0068869",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, USA 23894358PONE-D-13-1325910.1371/journal.pone.0068869Research ArticleMedicineClinical Research DesignCohort StudiesRetrospective StudiesDrugs and DevicesAdverse ReactionsInfectious diseasesBacterial DiseasesTuberculosisMulti-Drug-Resistant TuberculosisTropical Diseases (Non-Neglected)TuberculosisViral diseasesHIVHIV clinical manifestationsPediatricsAdolescent MedicinePoor Outcomes in a Cohort of HIV-Infected Adolescents Undergoing Treatment for Multidrug-Resistant Tuberculosis in Mumbai, India Outcomes in HIV/MDR-TB Co-Infected AdolescentsIsaakidis Petros \n1\n\n*\nParyani Roma \n1\nKhan Samsuddin \n1\nMansoor Homa \n1\nManglani Mamta \n2\nValiyakath Asmaa \n1\nSaranchuk Peter \n3\nFurin Jennifer \n4\n\n1 \nMédecins Sans Frontières, Mumbai, India\n\n2 \nPediatric Centre of Excellence for HIV Care, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai, India\n\n3 \nSouthern Africa Medical Unit, Médecins Sans Frontières, Cape Town, South Africa\n\n4 \nTuberculosis Research Unit, Case Western Reserve University, Cleveland, Ohio, United States of America\nWilkinson Robert J. Editor\nInstitute of Infectious Diseases and Molecular Medicine, South Africa\n* E-mail: msfocb-asia-epidemio@brussels.msf.orgCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: PI. Performed the experiments: SK HM AV RP. Analyzed the data: PI SK RP. Contributed reagents/materials/analysis tools: MM PS JF. Wrote the paper: PI JF SK.\n\n2013 19 7 2013 8 7 e6886921 3 2013 1 6 2013 © 2013 Isaakidis et al2013Isaakidis et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Background\nLittle is known about the treatment of multidrug-resistant tuberculosis (MDR-TB) in HIV-co-infected adolescents. This study aimed to present the intermediate outcomes of HIV-infected adolescents aged 10–19 years receiving second-line anti-TB treatment in a Médecins Sans Frontières (MSF) project in Mumbai, India.\n\nMethods\nA retrospective review of medical records of 11 adolescents enrolled between July 2007 and January 2013 was undertaken. Patients were initiated on either empirical or individualized second-line ambulatory anti-TB treatment under direct observation.\n\nResults\nThe median age was 16 (IQR 14–18) years and 54% were female. Five (46%) adolescents had pulmonary TB (PTB), two (18%) extrapulmonary disease (EPTB) and four (36%) had both. Median CD4 count at the time of MDR-TB diagnosis was 162.7 cells/µl (IQR: 84.8–250.5). By January 2013, eight patients had final and 3 had interim outcomes. Favourable results were seen in four (36.5%) patients: one was cured and three were still on treatment with negative culture results. Seven patients (64%) had poor outcomes: four (36.5%) died and three (27%) defaulted. Three of the patients who died never started on antiretroviral and/or TB treatment and one died 16 days after treatment initiation. Two of the defaulted died soon after default. All patients (100%) on-treatment experienced adverse events (AEs): two required permanent discontinuation of the culprit drug and two were hospitalized due to AEs. No patient required permanent discontinuation of the entire second-line TB or antiretroviral regimens.\n\nConclusions\nEarly mortality and mortality after default were the most common reasons for poor outcomes in this study. Early mortality suggests the need for rapid diagnosis and prompt treatment initiation, and adolescents might benefit from active contact-tracing and immediate referral. Default occurred at different times, suggesting the need for continuous, intensified and individualized psychosocial support for co-infected adolescents. Operational research among co-infected adolescents will be especially important in designing effective interventions for this vulnerable group.\n\nNo current external funding sources for this study.\n==== Body\nIntroduction\nMultidrug-resistant tuberculosis (MDR-TB)–defined as strains of TB with in vitro resistance to at least isoniazid and rifampin–is a major public health problem [1]. In 2010, it was estimated that there were 650,000 prevalent MDR-TB cases, few of which were actually diagnosed and treated. In fact, fewer than 40,000 patients have been put on World Health Organization (WHO)-recommended therapy in the last decade [2]. Inadequate diagnosis and treatment of MDR-TB is even worse in children, who represent an estimated 10–20% of all cases, up to 80,000 each year [3]–[4]. The published literature reports only a small number of pediatric patients receiving treatment, and a recent meta-analysis of pediatric MDR-TB treatment outcomes included only 315 children [5].\n\nWhat little pediatric data does exist tends to group all outcomes together, despite the fact that the data represents children as young as a few months old and others up to 18 years of age [6]. It is widely acknowledged that younger children face more challenges in terms of diagnosis and medication dosing [7] while older children, especially those in what is known as the “adolescent” age group (defined by the World Health Organization as those aged 10–19 years [8]), may face more challenges with adherence given their developmental state [9]. The literature on chronic disease management in adolescents has shown that this population has special physical and psychological needs [10]–[12]. Adolescents often experience spurts of growth that may lead to under-dosing with their medication [13]. Certain diseases, including TB, may also present more aggressively in this population [14]–[15]. Perhaps more significantly, adolescence is defined as a period of emotional and psychological upheaval that can affect relationships with health care providers and caregivers and ultimately adherence to medical regimens [16]–[17]. In addition, adolescence is a time period during which children must transition into adult roles; there may be increased time constraints due to school, work or family responsibilities [18]–[20]. All of these issues can affect the health outcomes of adolescent populations with chronic diseases, such as MDR-TB.\n\nTo date, there are no published reports characterizing MDR-TB treatment outcomes in the adolescent population. This paper fills that gap by presenting data from a cohort of 11 adolescent patients diagnosed with MDR-TB in Mumbai, India, all of whom were co-infected with HIV. The cohort is relatively small, but is being reported here because it demonstrates some concerning findings in the adolescent population undergoing treatment for MDR-TB. Targeted interventions to improve MDR-TB treatment outcomes in adolescents are also discussed.\n\nMethods\nStudy Design, Setting and Study Population\nThis is a retrospective review of the medical records of HIV-infected adolescents aged 10–19 years with culture-confirmed or suspected MDR-TB, undertaken as part of a larger study on MDR-TB treatment outcomes in Mumbai, India [21]. All patients were enrolled to receive treatment with second-line anti-TB medications in a Médecins Sans Frontières (MSF) clinic. Patients were referred to the clinic by public antiretroviral treatment centers (ART Centers), including the Regional Pediatric ART Centre, L.T.M. Medical College, Sion, Mumbai, which serves as one of the Centres Of Excellence in Pediatric HIV Care in India. Patients were also referred to the clinic by a network of community non-governmental organizations. Eleven (11) adolescents enrolled in care between July 2007 and January 2013 are included in this analysis.\n\nTreatment Protocol and Follow-up\nThe ambulatory, community-based MDR-TB treatment program has been described in detail in a previous publication [21]. Individualized treatment regimens are designed for each patient, based on drug susceptibility testing (DST) and prior treatment history. Standardized empiric treatment is given to patients who require immediate initiation due to disease severity or for those in whom a DST result is not available but in whom MDR-TB is diagnosed based on clinical findings, past TB treatment history and/or history of contact with a known or suspected MDR-TB patient. The standardized regimen follows international recommendations [22] and includes six drugs: pyrazinamide, capreomycin, moxifloxacin, ethionamide, cycloserine and p-aminosalicylic acid (PAS) and is modified as necessary if DST results become available. Blood test monitoring was done every month and sputum smear and culture every month during the intensive phase and every three months during the continuation phase. Treatment is continued for a minimum total duration of 18–20 months, including a minimum of 6–8 months intensive phase that includes an injectable agent. Antiretroviral therapy (ART) against HIV includes two nucleoside/tide reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) in a first-line ART regimen, while patients in need of second-line ART receive a protease inhibitor-based regimen along with NRTIs that are likely to be effective, based on HIV resistance testing results.\n\nThe adolescent patients were evaluated and followed by a multidisciplinary team of doctors, nurses, a psychologist and a social worker. They were clinically evaluated every two weeks during the first month of treatment and once a month thereafter. Home visits were conducted by the clinic team as necessary in order to provide social and emotional support to the adolescents and their families. At the community level, a network of public and private health structures and non-governmental organizations (NGOs) acted as providers of directly observed therapy (DOT) for the MDR-TB medication. DOT providers were given training on adverse events, adherence monitoring and pill counts, and referral pathways for patients with poor adherence.\n\nData Collection and Analysis\nDemographic and clinical information were systematically recorded in clinical files and entered into an electronic database. Information on HIV and antiretroviral therapy was collected in the same patient file but entered in a separate database. Each patient had a unique identification code that was used in both databases. Possible outcomes, defined according to WHO guidelines, included: cure, treatment completed, death, default, transfer out, treatment failure, and ‘alive and on treatment’.\n\nEthics\nThis study has met the criteria for analysis of routinely collected program data of the MSF Ethics Review Board, Geneva, Switzerland. As this was a study of routinely collected monitoring data, informed consent from the patients was not obtained. The named ethics committee waived the need for consent.\n\nResults\nEleven adolescents, aged 10 to 19 years, diagnosed with MDR-TB and co-infected with HIV are reported here. All had perinatally acquired HIV. The median age was 16 [Interquartile Range (IQR): 14–18] and 54 percent were female. All except one had a past history of TB treatment and four of them were contacts of known drug-resistant TB patients. Five (46%) adolescents had pulmonary TB, two (18%) had extrapulmonary disease and four (36%) had both pulmonary and extrapulmonary TB (Table 1).\n\n10.1371/journal.pone.0068869.t001Table 1 Demographic and Clinical Characteristics of the Mumbai HIV/MDR-TB co-infected adolescent cohort, 2007–2013 (N = 11).\nCharacteristic\tn (%)\t\nAge, median (IQR) years\t16 (14–18)\t\nFemale gender\t6 (54)\t\nSite of disease\t\t\nPulmonary\t5 (46)\t\nExtrapulmonary\t2 (18)\t\nPulmonary+Extrapulmonary\t4 (36)\t\nPrevious TB treatment\t10/11 (91)\t\nMDR-TB Contact\t4/11 (37)\t\nResistance (when DST available)\t\t\nH\t9/9 (100)\t\nR\t9/9 (100)\t\nE\t7/9 (78)\t\nFQ\t6/8 (75)\t\nInjectable\t1/8 (13)\t\nCD4 count at time of MDR-TB diagnosis, cells/µl, median (IQR)\t162.7 (84.8–250.5)\t\n IQR: interquartile range; H: isoniazid; R: rifampicin; E: ethambutol; FQ: fluoroquinolones.\n\nThe median CD4 count at the time of MDR-TB diagnosis was 162.7 cells/µl (IQR: 84.8–250.5). Five patients were on ART at the time of the MDR-TB diagnosis: two of them were on ART for more than 2 years and three of them for six months or less. Another three patients were started on ART following initiation of DR-TB treatment: two patients after seven months and one patient after one month of TB treatment (Table 2). The median time from diagnosis of MDR-TB to initiation of second-line treatment was 10 days (IQR: 7–12). Three patients did not start antiretroviral and second-line TB treatments as they died soon after enrolment (Figure 1). Routine HIV viral load monitoring was not available during the early years of the program.\n\n10.1371/journal.pone.0068869.g001Figure 1 Flowchart of the Mumbai HIV/MDR-TB co-infected adolescent cohort, 2007–2013.\n10.1371/journal.pone.0068869.t002Table 2 Clinical Characteristics of the Mumbai HIV/MDR-TB co-infected adolescent cohort, 2007–2013.\n\tAge/Sex\tCD4*\n\tART Regimen\tART Started\tTB Site\tSmear\tCulture\tResistance\tDR Type\t2nd-Line TB Regimen\t\n1\t14/M\t243\tD4T+3TC+EFV\t5 months prior\tP+EP (Abd LN)\tNEG\tPOS\tS,H,R,E,Km,PAS,Ofx,Eto\tXDR\tCm,Lfx,Eto,Cs,Amcl\t\n2\t10/M\t273\tD4T+3TC+NVP\t7 months after\tP\tNEG\tPOS\tS,H,R,E,Ofx,Eto\tPre-XDR\tKm,Mfx,Eto,Cs,PAS,Z,Amcl\t\n3\t18/F\t125\tTDF+3TC+EFV\t5 months prior\tP\tPOS\tPOS\tS,H,R,E,Ofx\tPre-XDR\tKm,Mfx,Eto,Cs,PAS\t\n4\t13/F\t147\tNo ART\tNever\tEP (LN)\tPOS\tPOS\tS,H,R,E,Ofx\tPre-XDR\t\t\n5\t18/F\t\tNo ART\tNever\tP\tPOS\tPOS\tS,H,R,E\tMDR\t\t\n6\t16/F\t92\tD4T+3TC+EFV\t6 months prior\tP+EP (Cereb)\tPOS\tPOS\tS,H,R,E,PAS,Z\tMDR\tCm,Mfx,Eto,PAS,Z,H,Amcl\t\n7\t15/F\t199\tAZT+3TC+NVP\t7 months after\tP\tPOS\tPOS\tS,H,R,E,PAS,Z\tMDR\tKm,Mfx,Eto,Cs,Amcl,H,E\t\n8\t19/F\t290\tTDF+3TC+ATV/r\t28 months prior\tP\tNEG\tPOS\tS,H,R,E,Ofx,PAS\tPre-XDR\tCm,Mfx,Eto,Cs,H,Cfz,Z\t\n9\t14/M\t159\tABC+3TC+LPV/r\t71 months prior\tEP Abd\tNEG\tNEG\t_\tEmpirical\tCm,Mfx,Eto,Cs,PAS,Z\t\n10\t16/M\t36\tNo ART\tNever\tP+EP (Abd LN)\tNEG\tNEG\t_\tEmpirical\t\t\n11\t18/M\t63\tTDF+3TC+EFV\t1 month after\tP+EP (Abd)\tNEG\tPOS\tS,H,R,E,Ofx,PAS,Mfx,Z\tPre-XDR\tCm,Lfx,Eto,Cs,Amcl,Hh,Cfz\t\n M: male; F: female; D4T: stavudine; 3TC: lamivudine; EFV: efavirenz; TDF: tenofovir; AZT: zidovudine; ABC: abacavir; NVP: nevirapine; ATV/r: atazanavir/ritonavir; LPV: lopinavir; PTB: pulmonary tuberculosis; EPTB: extra-pulmonary tuberculosis; Abd; abdominal; Cereb; cerebral, LN: lymph node; NEG: negative; POS: positive; S: streptomycin; Cm: capreomycin; Km: kanamycin; Lfx: levofloxacin; Eto: ethionamide; CS: cycloserine; Amcl: amoxicillin/clavulanic acid; Mfx: moxifloxacin; Ofx; ofloxacin; PAS; para-aminosalicylic acid; Z: pyrazinamide; H: isoniazid; Hh: high dose isoniazid; E: ethambutol; Cfz: clofazimine; XDR: extensively drug-resistant; MDR: multidrug-resistant.\n\n* at time of MDR-TB diagnosis.\n\nBy January 2013, eight patients had final outcomes and three had interim outcomes (Table 3). Favourable outcomes were seen in 4 (36%) of the patients, one of whom was cured and three of whom were still on treatment with negative smears and/or cultures and improving clinical signs. Two of these latter patients were about to complete their course of second-line anti-TB treatment at the time of this analysis and they were doing very well.\n\n10.1371/journal.pone.0068869.t003Table 3 Outcomes of the Mumbai HIV/MDR-TB co-infected adolescent cohort, 2007–2013.\nNo\tAge/Sex\tMDR Tx Start Date\tOutcome\tTime on Treatment\tReason for default/Cause of death/Comments\t\n1\t14/M\t27.07.2007\t\nDefaulted\n\t17 Months\tPatient defaulted after 17 months of treatment and then died 1 month after default. Convulsions, Brain Tuberculoma.\t\n2\t10/M\t31.08.2007\t\nCured\n\t18 Months\t\t\n3\t18/F\t19.06.2008\t\nDefaulted\n\t3 Months\tPatient died 1.5 months after default. Reason for default: adverse events & social issues. Cause of death not ascertained.\t\n4\t13/F\tNever\t\nDied\n\t0 Months\tDied before treatment, 1 month after enrolment\t\n5\t18/F\tNever\t\nDied\n\t0 Months\tPatient declined treatment and died 2 months later\t\n6\t16/F\t15.02.2011\t\nDied\n\t16 Days\tBrain Tuberculoma\t\n7\t15/F\t22.02.2011\t\nDefaulted\n\t21 Months\tPatient defaulted a few weeks before treatment completion due to social issues (family deaths, sexual abuse) & personal issues (sexual debut, not willing to disclose status to partner)\t\n8\t19/F\t12.05.2011\t\nAlive on Treatment\n\t21 Months\tPatient has culture converted, about to complete treatment\t\n9\t14/M\t24.11.2011\t\nAlive on Treatment\n\t15 Months\tPatient in excellent clinical condition\t\n10\t16/M\tNever\t\nDied\n\t0 Months\tDied before treatment, 1 month after enrolment. Acute renal failure.\t\n11\t18/M\t23.10.2012\t\nAlive on Treatment\n\t4 Months\tAdherence problems (behavioral issues, adverse events)\t\nThe remaining 7 patients (64%) had poor treatment outcomes: four of these patients (36.5%) died and three of them (27%) defaulted treatment. Of the four who died, three never started on MDR-TB and ART treatments and one died 16 days after treatment initiation. Treatment interruptions were recorded in all three patients who defaulted treatment. Two of the adolescents who defaulted died soon after they abandoned treatment at 3 and 17 months, reportedly due to adverse events and social problems respectively. One patient, a 15 year-old female, defaulted three weeks before treatment completion (at 21 months). The girl declined both antiretroviral and anti-TB treatments despite an excellent clinical response and lack of adverse events. We traced the patient and identified a non-supportive, problematic family environment (parental death, history of sexual abuse). Her elder sister, also HIV/MDR-TB co-infected and part of this same cohort, had died. The girl had a partner to whom she was initially unwilling to disclose her status, but eventually did give her consent for couple counseling.\n\nRefusal to start treatment and treatment interruptions were frequently (4/8) observed in this cohort of adolescents. An example illustrating the complexity of treatment acceptance and adherence is an orphan male patient who had started anti-TB treatment but refused to start on antiretroviral treatment. He later abandoned his anti-TB treatment only to restart 5 months later as his condition had deteriorated. He is presently on both treatment regimens. However the family is worried about TB transmission and is trying to send him to a hospice. As a result, the patient is experiencing behavioral issues due to a perceived fear of abandonment. Constant supportive counseling has thus far ensured that he stays on treatment, while additional family counseling is being offered.\n\nAll eight patients (100%) who started on treatment experienced adverse events (AE); 2 required permanent discontinuation of the culprit drug and 2 patients had to be hospitalized due to AEs (both for hypokalaemia). The most common adverse events were gastrointestinal intolerance (5/8 patients) followed by peripheral neuropathy (3/8) and psychiatric events (3/8). Adverse events and the time of occurrence are shown in Table 4. None of the eight patients has required permanent discontinuation of the entire second-line anti-TB or antiretroviral regimen.\n\n10.1371/journal.pone.0068869.t004Table 4 Treatment-related adverse events in the Mumbai HIV/MDR-TB co-infected adolescent cohort, 2007–2013.\n\tAge/Sex\t2ND line TB Regimen\tART Regimen\tAdverse events (AEs)\tGrade\tPossible culprit drug\tTime (weeks)\t\n1\t14/M\tCm,Lfx,Eto,Cs,Amcl\tD4T+3TC+EFV\tConvulsions\tsevere\tCs\t5\t\n\t\t\t\tGI Intolerance\tmild\tEto\t9\t\n\t\t\t\tPeripheral Neuropathy\tmild\tD4T, Cs\t56\t\n2\t10/M\tKm,Mfx,Eto,Cs,PAS,Z,Amcl\tD4T+3TC+NVP\tHearing Loss\tmild\tKm\t4\t\n3\t18/F\tKm,Mfx,Eto,Cs,PAS\tTDF+3TC+EFV (previouslyon d4T)\tPeripheral Neuropathy\tmoderate\tD4T\t4\t\n4\t13/F\tNo TB Treatment\tNo ART\t\t\t\t\t\n5\t18/F\tNo TB Treatment\tNo ART\t\t\t\t\t\n6\t16/F\tCs,Mfx,Eto,PAS,Z,H,Amcl\tD4T+3TC+EFV\tGI Intolerance\tmild\tEto, PAS\t1\t\n\t\t\t\tPsychiatric (Psychosis)\tsevere\tCs, EFV\t2\t\n7\t15/F\tKm,Mfx,Eto,Cs,Amcl,H,E\tAZT+3TC+NVP\tGI Intolerance\tmoderate\tEto, Amcl\t2\t\n\t\t\t\tAnxiety Disorder\tmild\tCs\t2\t\n8\t19/F\tCm,Mfx,Eto,Cs,H,Cfz,Z\tTDF+3TC+ATV/r\tNephrotoxicity\tmild\tCm, TDF\t4\t\n\t\t\t\tPsychiatric (Psychosis)\tsevere\tCs\t20\t\n9\t14/M\tCm,Mfx,Eto,Cs,PAS,Z\tABC+3TC+LPV/r\tGI Intolerance\tmoderate\tEto, PAS\t4\t\n\t\t\t\tHypothyroidism\tmild\tEto, PAS\t12\t\n\t\t\t\tHypokalemia\tmild\tCm\t40\t\n10\t16/M\tNo TB Treatment\tNo ART\t\t\t\t\t\n11\t18/M\tCm,Lfx,Eto,Cs,Amcl,Hh,Cfz\tTDF+3TC+EFV\tGI Intolerance\tmild\tEto, Amcl\t1\t\n\t\t\t\tHypokalemia\tmoderate\tCm\t4\t\n\t\t\t\tPeripheral Neuropathy\tmild\tCs, Eto\t9\t\n\t\t\t\tHypothyroidism\tmild\tEto\t11\t\n M: male; F: female; S: streptomycin; Cm: capreomycin; Km: kanamycin; Lfx: levofloxacin; Eto: ethionamide; CS: cycloserine; Amcl: amoxicillin/clavulanic acid; Mfx: moxifloxacin; PAS: para-aminosalicylic acid; Z: pyrazinamide; H: isoniazid; Hh: high dose isoniazid; E; ethambutol, Cfz: clofazimine; GI: gastrointestinal; CrCl: creatinine clearanc.\n\nDiscussion\nThis study shows poor treatment outcomes in a cohort of HIV-infected adolescents being treated for MDR-TB. Compared with their adult counterparts in a previous publication [23], these adolescents have both higher rates of death and default. These results are of concern and suggest the need for urgent interventions.\n\nThe majority of the adolescents (6/11) in this cohort died, and there may be several explanations for this. First, HIV co-infection has been shown to be a risk factor for mortality among persons with MDR-TB [24]. Co-infected patients may have severe forms of Immune Reconstitution Inflammatory Syndrome (IRIS) following ART initiation that can be associated with mortality [25]. There may be drug-drug interactions between second-line anti-TB medications and ART that could result in decreased efficacy of therapy [26]. Second, extent of disease and drug resistance, particularly to the fluoroquinolones, have also been associated with worse treatment outcomes in other cohorts [27]–[28] and may have played a role here, given that 75% of available DST results showed resistance to this group of drugs.\n\nWhile these factors may have played a role in the high mortality seen in this study, it should be noted that four of the six patients who died did so either prior to or within three weeks of initiating therapy. Such “early deaths” have been described in other cohorts and are usually considered “failure to treat” as opposed to “treatment failures” [29]. These deaths can generally be ascribed to problems with timely diagnosis and referral rather than ineffective treatment practices [30]. The high early mortality in this cohort suggests that special strategies should be deployed to diagnose and refer adolescents with suspected MDR-TB early in the course of their disease [31]. Although adolescents may be able to more easily provide sputum samples for diagnosis when compared with children, they may be less likely to follow up on referrals [32]. A potential strategy for earlier diagnosis is active screening and immediate clinical referral of all household contacts of persons with MDR-TB [33], given that more than one-third of the adolescents in this study had a known MDR-TB contact; had they been identified through an active case-finding strategy, perhaps they would have been diagnosed more quickly and benefitted from earlier treatment.\n\nDiscontinuation of therapy was also frequently reported in this study, with three (37.5%) of eight adolescents starting both antiretroviral and anti-TB therapy eventually defaulting. This is compared with a general loss to follow-up rate in this HIV programme of less than 3% [34]. HIV co-infection may have been a factor in patient discontinuation of therapy due to increased pill burden on ART or the occurrence of adverse events [35]–[37] that may result from interactions between TB and HIV drugs, or additive drug-related side effects. In addition to the complications of HIV co-infection, this adolescent cohort has had other risk factors for default from therapy, including family and social problems, unwillingness to disclose their status, and discrimination.\n\nThe story of the adolescent patient who defaulted just a few weeks before treatment completion clearly illustrates the complexity of factors that influence the behavior of adolescents who are HIV-infected and at the same time have to go through a long course of an intolerable and toxic treatment regimen. We have observed that patients that begin to feel better while on treatment prefer to get back to their normal routine: these activities of daily living then take priority over their health. All adolescents in this Mumbai cohort attended school at some point; it is interesting to mention that none of them has disclosed their status at school.\n\nAll patients on treatment in this adolescent cohort experienced similar adherence issues: they all reported the high pill burden, the side effects, and the long duration of the treatment as major challenges in their daily life. As expected, patients with good support and patients who experienced low to no discrimination demonstrated better adherence. We have found that supportive counseling is important not just for the patient but also for the family. Education about treatment and adherence issues is important for the family and the caretakers so that they understand the need to support the patient through this difficult treatment. On the other hand, adolescents expressed that “the constant nagging of the caretaker” worked against their adherence. Despite the degree of support and the exposure to stigma and discrimination, all adolescents were conscious of how conspicuous they were during their daily visit to DOT centers, so much so that some preferred to avoid going to the DOT centers at the expense of their health. Adolescents want to experience “normal” lives and “pretended to be normal” rather than “taking the steps to a better health” (patients quotes recorded during routine counseling sessions).\n\nAdverse events were frequent in this cohort and psychiatric events were worryingly common. We have recently introduced a baseline mental health evaluation in order to screen for depression and other mental health issues. We have also found that aggressive management of adverse events is necessary to ensure short and long term adherence.\n\nThis study has a number of limitations, most of which are related to the small sample size. Clearly, there is a need to evaluate adolescents undergoing treatment for MDR-TB on a larger scale. Second, all of the patients were infected with HIV and thus the results are not likely generalizable to HIV-negative adolescents with MDR-TB. Finally, this was a retrospective review of medical records that is subject to all the biases inherent with such methodology. In spite of these limitations, the trends identified in this small cohort are of sufficient concern to be reported to the scientific community so that increased attention can be given to adolescent populations with MDR-TB.\n\nConclusion\nTreatment outcomes seen in HIV-infected adolescents receiving community-based MDR-TB treatment in Mumbai, India were overwhelming poor, with a majority of patients either dying or defaulting from therapy. While some of this may have been due to the complicated treatment regimens required for people with HIV and MDR-TB in general, the data suggest the need for targeted interventions focused on adolescents. Active case-finding, especially among younger contacts of DR-TB cases, and shepherded referrals into treatment could decrease mortality from the disease. Targeted adherence counseling and social support around life events that are common in adolescence could also be a strategy for reducing discontinuation of therapy. Excellent treatment outcomes should be possible for adolescents suffering from MDR-TB, given the encouraging treatment results seen in both pediatric and adult cohorts with the disease. Operational research looking at interventions to improve outcomes in adolescents is sorely needed. Strategies that account for the unique needs of this population should be developed and adapted to ensure a safe and healthy transition into adulthood.\n\nThe authors wish to acknowledge the contribution of health care workers from the MSF project, staff from the LTMG Hospital, Sion, as well as the teenagers suffering from HIV and MDR-TB and their families. We are grateful to Tony Reid for his support with the ethics clearance and his editorial support.\n==== Refs\nReferences\n1 \nWorld Health Organization (2008 ) Anti-tuberculosis drug resistance in the world Report no. 4. Geneva, Switzerland . ISBN 978 92 4 156361 \n1 : WHO/HTM/TB/2008.394 .\n2 \nWorld Health Organization (2011 ) Towards universal access to diagnosis and treatment of multidrug-resistant and extensively drug-resistant tuberculosis by 2015 Geneva, Switzerland . ISBN: 978 92 4 \n150133 : WHO/HTM/TB/2011.3 .\n3 Seddon JA, Hesseling A, Willemse M, Donald PR, Schaaf HS (2011) Culture-Confirmed Multidrug-Resistant Tuberculosis in Children: Clinical Features, Treatment, and Outcomes. Clin Infect Dis. doi: 10.1093/cid/cir772.\n4 \nSchaaf HS (2007 ) Drug-resistant tuberculosis in children . S Afr Med J \n97 : 995 –97 .18000589 \n5 \nEttehad D , Schaaf HS , Seddon JA , Cooke GS , Ford N (2012 ) Treatment outcomes for children with multidrug-resistant tuberculosis: a systematic review and meta-analysis. The Lancet Infectious Diseases . 12(6) : 449 –56 .\n6 \nDrobac PC , Mukherjee JS , Joseph JK , Mitnick C , Furin JJ , et al (2006 ) Community-based therapy for children with multidrug-resistant tuberculosis. Pediatrics . 117(6) : 2022 –9 .\n7 \nCoelho Filho JC , Caribe MA , Caldas SC , Martins Netto E (2011 ) Is tuberculosis difficult to diagnose in childhood and adolescence?. Jornal Brasileiro De Pneumologia: Publicacao Oficial Da Sociedade Brasileira De Pneumologia E Tisilogia . 37(3) : 288 –93 .\n8 World Health Organization (2013) Adolescent Health. http://www.who.int/topics/adolescent_health/en/. Accessed February 12, 2013.\n9 \nPerez-Velez CM (2012 ) Pediatric tuberculosis: new guidelines and recommendations. Curr Opin Pediatr . Jun \n24(3) : 319 –28 .\n10 \nGeldenhuys H , Sorsdahl K , Kafaar F , Hatherill M , Hanekom WA , Stein DJ , et al (2011 ) Risky behaviour and psychosocial correlates in adolescents - is there a link with tuberculosis?. African Journal of Psychiatry . 14(5) : 383 –7 .\n11 \nGreenley RN , Kunz JH , Biank V , Martinez A , Miranda A , et al (2012 ) Identifying youth nonadherence in clinical settings: data-based recommendations for children and adolescents with inflammatory bowel disease. Inflammatory Bowel Diseases . 18(7) : 1254 –9 .\n12 \nNichols SL , Montepiedra G , Farley JJ , Sirois PA , Malee K , et al (2012 ) PACTG P1042S Team. Cognitive, academic, and behavioral correlates of medication adherence in children and adolescents with perinatally acquired HIV infection. Journal of Developmental & Behavioral Pediatrics . 33(4) : 298 –308 .\n13 \nChiang CY , Bai KJ , Lee CN , Enarson DA , Suo J , et al (2010 ) Inconsistent dosing of anti-tuberculosis drugs in Taipei, Taiwan.International Journal of Tuberculosis & Lung Disease . 14(7) : 878 –83 .\n14 \nThampi N , Stephens D , Rea E , Kitai I (2012 ) Unexplained deterioration during antituberculous therapy in children and adolescents: clinical presentation and risk factors. Pediatric Infectious Disease Journal . 31(2) : 129 –33 .\n15 \nPhongsamart W , Kitai I , Gardam M , Wang J , Khan K (2009 ) A population-based study of tuberculosis in children and adolescents in Ontario. Pediatric Infectious Disease Journal . 28(5) : 416 –9 .\n16 \nM’imunya JM , Kredo T , Volmink J (2012 ) Patient education and counselling for promoting adherence to treatment for tuberculosis. Cochrane Database of Systematic Reviews . 5 : CD006591 .\n17 \nChandwani S , Koenig LJ , Sill AM , Abramowitz S , Conner LC , et al (2012 ) Predictors of antiretroviral medication adherence among a diverse cohort of adolescents with HIV. Journal of Adolescent Health . 51(3) : 242 –51 .\n18 \nArnone J , Fitzsimons V (2012 ) Adolescents with celiac disease: a literature review of the impact developmental tasks have on adherence with a gluten-free diet. Gastroenterology Nursing . 35(4) : 248 –54 .\n19 \nHodgson I , Ross J , Haamujompa C , Gitau-Mburu D (2012 ) Living as an adolescent with HIV in Zambia – lived experiences, sexual health and reproductive needs. AIDS Care . 24(10) : 1204 –10 .\n20 \nFair CD , Sullivan K , Dizney R , Stackpole A (2012 ) “It’s like losing a part of my family”: transition expectations of adolescents living with perinatally acquired HIV and their guardians. AIDS Patient Care & Stds . 26(7) : 423 –9 .\n21 \nIsaakidis P , Cox HS , Varghese B , Montaldo C , Da Silva E , et al (2011 ) Ambulatory multi-drug resistant tuberculosis treatment outcomes in a cohort of HIV-infected patients in a slum setting in Mumbai, India. PLoS ONE [Electronic Resource] . 6(12) : e28066 .\n22 Mukherjee JS, Rich ML, Socci AR, Joseph JK, Viru FA, et al.. (2004) Programmes and principles in treatment of multidrug-resistant tuberculosis. Lancet. 363(9407): 474–81, 2004.\n23 Isaakidis P, Varghese B, Mansoor H, Cox HS, Ladomirska J, et al.. (2012) Adverse events among HIV/MDR-TB co-infected patients receiving antiretroviral and second line anti-TB treatment in Mumbai, India.PLoS ONE [Electronic Resource]. 7(7): e40781, 2012.\n24 \nGandhi NR , Shah NS , Andrews JR , Vella V , Moll AP , et al (2010 ) Tugela Ferry Care and Research (TF CARES) Collaboration. HIV coinfection in multidrug- and extensively drug-resistant tuberculosis results in high early mortality. American Journal of Respiratory & Critical Care Medicine . 181(1) : 80 –6 .\n25 \nNaidoo K , Yende-Zuma N , Padayatchi N , Naidoo K , Jithoo N , et al (2012 ) The immune reconstitution inflammatory syndrome after antiretroviral therapy initiation in patients with tuberculosis: findings from the SAPiT trial. Annals of Internal Medicine . 157(5) : 313 –24 .\n26 \nFurin JJ , Johnson JL (2005 ) Recent advances in the diagnosis and management of tuberculosis. Current Opinion in Pulmonary Medicine . 11(3) : 189 –94 .\n27 \nMitnick CD , Shin SS , Seung KJ , Rich ML , Atwood SS , et al (2008 ) Comprehensive treatment of extensively drug-resistant tuberculosis. NewEnglandJournalofMedicine . 359(6) : 563 –74 .\n28 \nChan ED , Strand MJ , Iseman MD (2008 ) Treatment outcomes in extensively resistant tuberculosis. New England Journal of Medicine . 359(6) : 657 –9 .\n29 \nMitnick C , Bayona J , Palacios E , Shin S , Furin J , et al (2003 ) Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. New England Journal of Medicine . 348(2) : 119 –28 .\n30 \nFarmer P (1999 ) Managerial successes, clinical failures. International Journal of Tuberculosis & Lung Disease . 3(5) : 365 –7 .\n31 \nSachdeva KS , Kumar A , Dewan P , Kumar A , Satyanarayana S (2012 ) New vision for Revised National Tuberculosis Control Programme (RNTCP): Universal access – “reaching the un-reached” . Indian Journal of Medical Research. 135(5) : 690 –4 .\n32 \nFairlie L , Beylis NC , Reubenson G , Moore DP , Madhi SA (2011 ) High prevalence of childhood multi-drug resistant tuberculosis in Johannesburg, South Africa: a cross sectional study. BMC Infectious Diseases . 11 : 28 .\n33 \nSingla N , Singla R , Jain G , Habib L , Behera D (2011 ) Tuberculosis among household contacts of multidrug-resistant tuberculosis patients in Delhi, India. International Journal of Tuberculosis & Lung Disease . 15(10) : 1326 –30 .\n34 \nErrol L , Isaakidis P , Zachariah R , Ali M , Pilankar G , et al (2012 ) Tracing patients on antiretroviral treatment lost-to-follow-up in an urban slum in India . J Adv Nurs \n68(11) : 2399 –409 .22272919 \n35 \nNansera D , Bajunirwe F , Elyanu P , Asiimwe C , Amanyire G , Graziano FM (2012 ) Mortality and loss to follow-up among tuberculosis and HIV co-infected patients in rural southwestern Uganda. International Journal of Tuberculosis & Lung Disease . 16(10) : 1371 –6 .\n36 \nGarrido Mda S , Penna ML , Perez-Porcuna TM , de Souza AB , Marreiro Lda S , et al (2012 ) Factors associated with tuberculosis treatment default in an endemic area of the Brazilian Amazon: a case control-study.PLoS ONE [Electronic Resource] . 7(6) : e39134 .\n37 \nMaruza M , Albuquerque MF , Coimbra I , Moura LV , Montarroyos UR , et al (2011 ) Risk factors for default from tuberculosis treatment in HIV-infected individuals in the state of Pernambuco, Brazil: a prospective cohort study.BMC Infectious Diseases . 11 : 351 .\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "8(7)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000293:Adolescent; D000995:Antitubercular Agents; D018791:CD4 Lymphocyte Count; D002648:Child; D060085:Coinfection; D005260:Female; D015658:HIV Infections; D006801:Humans; D007194:India; D008297:Male; D012189:Retrospective Studies; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant; D055815:Young Adult",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e68869",
"pmc": null,
"pmid": "23894358",
"pubdate": "2013",
"publication_types": "D016428:Journal Article",
"references": "22921134;16740844;22373593;22272919;22366661;22944873;18000589;22145022;22016079;22792406;22052896;22686235;22720052;14962530;10331723;22380932;22183469;18687637;20550772;22771603;22283889;12519922;21755182;21269475;22689633;19833824;19352212;22568943;22592714;22176628;18687654;22847283;22863182",
"title": "Poor outcomes in a cohort of HIV-infected adolescents undergoing treatment for multidrug-resistant tuberculosis in Mumbai, India.",
"title_normalized": "poor outcomes in a cohort of hiv infected adolescents undergoing treatment for multidrug resistant tuberculosis in mumbai india"
} | [
{
"companynumb": "IN-RANBAXY-2015R1-93256",
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"abstract": "OBJECTIVE\nMedication-related osteonecrosis of the jaw (MRONJ) has been reported as a side effect of bisphosphonate (BP). The aim of this study was to identify the prevalence of MRONJ in women taking BP for osteoporosis and for metastatic breast cancer and correlate it with risk factors and biochemical markers of bone metabolism.\n\n\nMETHODS\nPatients taking oral or intravenous BP with osteoporosis (G1; n = 153; median 72.8 years) and with metastatic breast cancer (G2; n = 134; median 58.2 years) had their hospital charts reviewed, were submitted to dental inspection, and answered a health questionnaire. Fasting blood samples were randomly collected from both groups to measure osteocalcin, carboxy-terminal cross-linking telopeptide of type I collagen, intact parathyroid hormone and procollagen type 1 amino-terminal propeptide (P1NP), 25 hydroxyvitamin D (25OHD), creatinine, and total calcium.\n\n\nRESULTS\nG1 was older (p = 0.001) and had more cases of diabetes (p = 0.043). P1NP was higher (p = 0.022) and 25OHD lower (p = 0.004) in G2 compared with G1. MRONJ was not found in the G1, whereas 4 cases (3%) were detected in G2. Positive risk factors for MRONJ were number of BP doses and number of visits to the dentist and dental extractions. The biochemical parameters, however, could not identify those who developed MRONJ.\n\n\nCONCLUSIONS\nThe prevalence of MRONJ was 3% in women with metastatic breast cancer receiving BP. No cases were identified in women receiving oral BP chronically for osteoporosis. P1NP was higher in women with metastatic breast cancer, even during treatment with antiresorptives, but could not differentiate those with MRONJ.",
"affiliations": "Division of Endocrinology, Escola Paulista de Medicina - UNIFESP and Oral Medicine Department, Hospital Oswaldo Cruz, São Paulo, Brazil. anasoaresbr@yahoo.com.br.;Centro Paulista de Oncologia, São Paulo, Brazil.;Hospital Pérola Byington, São Paulo, Brazil.;Department of Gynecology, Escola Paulista de Medicina, UNIFESP, São Paulo, Brazil.;Division of Endocrinology, Escola Paulista de Medicina, UNIFESP, São Paulo, Brazil.",
"authors": "Soares|Ana Laura|AL|http://orcid.org/0000-0003-3927-0289;Simon|Sérgio|S|;Gebrim|Luiz Henrique|LH|;Nazário|Afonso Celso P|ACP|;Lazaretti-Castro|Marise|M|http://orcid.org/0000-0001-9186-2834",
"chemical_list": "D015415:Biomarkers; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D010281:Parathyroid Hormone; D015675:Osteocalcin; D014807:Vitamin D; C104450:25-hydroxyvitamin D",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-019-05044-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": "28(5)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": "Bisphosphonates; Cancer; Medication-related osteonecrosis; Osteoporosis",
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D001943:Breast Neoplasms; D003430:Cross-Sectional Studies; D004164:Diphosphonates; D005260:Female; D006801:Humans; D008875:Middle Aged; D015675:Osteocalcin; D010024:Osteoporosis; D010281:Parathyroid Hormone; D015995:Prevalence; D012307:Risk Factors; D014807:Vitamin D",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "2265-2271",
"pmc": null,
"pmid": "31468192",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "25757408;25234529;17649805;12966493;25414052;27876532;18554944;21986094;25956267;30595601;26362366;28053907;19257812;18022461;24343364;30962171;30084362;26293329;26501428;20425090;17307580;29215447;29102331;24958808;9494781;16750501",
"title": "Prevalence and risk factors of medication-related osteonecrosis of the jaw in osteoporotic and breast cancer patients: a cross-sectional study.",
"title_normalized": "prevalence and risk factors of medication related osteonecrosis of the jaw in osteoporotic and breast cancer patients a cross sectional study"
} | [
{
"companynumb": "BR-MYLANLABS-2020M1040460",
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"activesubstancename": "ZOLEDRONIC ACID"
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... |
{
"abstract": "Introduction. Peripheral nerve stimulation (PNS) has been used for many years to treat neuropathic pain syndromes. Technical advances in neurostimulation hardware have led to a renewed interest in the use of PNS for control of intractable pain caused by peripheral mononeuropathies. One such application includes intractable groin pain. This study identified two patients with chronic groin pain, secondary to trauma, referred for interventional pain management. For each patient, PNS trial was attempted using ultrasound guided localization of the inguinal nerve. Direct sonographic visualization of the inguinal nerve has been used in other studies to facilitate regional anesthesia, but to our knowledge, no studies have used this technique for localization of nerves for percutaneous lead placement for PNS. Methods. Each patient was chosen to undergo trial stimulation using percutaneously placed peripheral nerve stimulator leads. In these two cases, both patients presented with similar complaints of chronic groin pain consistent with ilioinguinal neuralgia. Both underwent multiple previous nerve blocks, all of which gave good but transient relief using traditional block techniques. Both patients were trialed on multiple medications, which either gave incomplete relief of pain or were limited by side-effects. Results. Both patients had relatively easy localization of ilioinguinal nerves affected using ultrasound and were provided with stimulating paresthesias which covered their normal pain. Discussion. The successful use of ultrasound as described in these two cases suggests an important role for ultrasound in localization of targeted nerves in percutaneous trial stimulation of injured peripheral nerve. The use of ultrasound may also play a role in permanent lead placement as well. Conclusion. More studies are needed to further qualify the role of ultrasound in isolating peripheral nerves, but the success of trial stimulation in these two cases holds promise for continued advancements in the field of neuromodulation.",
"affiliations": "Lahey Clinic, Spine Center, Department of Neurosurgery, Burlington, MA, USA and Dartmouth Hitchcock Medical Center, Anesthesia, Pain Clinic; and Dartmouth Hitchcock Medical Center, Anesthesia, Hanover, NH, USA.",
"authors": "Carayannopoulos|Alexios|A|;Beasley|Ralph|R|;Sites|Brian|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/j.1525-1403.2009.00233.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1094-7159",
"issue": "12(4)",
"journal": "Neuromodulation : journal of the International Neuromodulation Society",
"keywords": null,
"medline_ta": "Neuromodulation",
"mesh_terms": null,
"nlm_unique_id": "9804159",
"other_id": null,
"pages": "296-301",
"pmc": null,
"pmid": "22151420",
"pubdate": "2009-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Facilitation of percutaneous trial lead placement with ultrasound guidance for peripheral nerve stimulation trial of ilioinguinal neuralgia: a technical note.",
"title_normalized": "facilitation of percutaneous trial lead placement with ultrasound guidance for peripheral nerve stimulation trial of ilioinguinal neuralgia a technical note"
} | [
{
"companynumb": "NVSC2020US073607",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN\\OXYCODONE HYDROCHLORIDE"
},
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{
"abstract": "Autoimmune cytopenias are a recognized complication of hematopoietic stem cell transplant (HSCT), and are considered to be a feature of chronic graft-versus-host disease (cGVHD). We report on a cohort of very young infants (< or =3 months of age) receiving HSCT from unrelated donor umbilical cord blood for genetic disorders who developed posttransplant autoimmune cytopenias at an increased rate compared to older aged controls. These infants received a conditioning regimen consisting of busulfan, cyclophosphamide, and antithymocyte globulin (ATG). All infants received HLA mismatched unrelated umbilical cord blood as graft source. GVHD prophylaxis was either cyclosporine + methylprednisolone (n = 16) or cyclosporine + mycophenolate mofetil (n = 3). Engraftment, acute GVHD (aGVHD) and cGVHD, survival, treatment-related mortality (TRM), and deaths were evaluated. Ten patients developed cGVHD manifesting as autoimmune cytopenias at a median 247 days posttransplant with a cumulative incidence of 44% (95% confidence interval [CI] 21%-68%) and 56% (95% CI 32%-80%) at 1 and 2 years, respectively. In 6 of 10 patients developing autoimmune cytopenias, cGVHD presented as autoimmune cytopenia de novo. The cytopenias observed included anemia (n = 4), thrombocytopenia (n = 1), anemia with thrombocytopenia (n = 3), and pancytopenia (n = 2). No graft factors were identified as being significant to development of cGVHD. All patients responded to treatment with methylprednisolone, azithioprine +/- rituximab. One patient required splenectomy. We hypothesize that posttransplant immunosuppression interferes with normal immune ontogeny creating immune dysregulation and graft directed cell destruction. Alternative strategies to prevent GVHD should be considered for this unique patient population.",
"affiliations": "Department of Pediatrics, Division of Blood and Marrow Transplant, Duke University Medical Center, Durham, North Carolina. Electronic address: kristin.page@duke.edu.;The EMMES Corporation, Rockville, Maryland.;Department of Pediatrics, Division of Blood and Marrow Transplant, Duke University Medical Center, Durham, North Carolina.;Department of Pediatrics, Division of Blood and Marrow Transplant, Duke University Medical Center, Durham, North Carolina.;Department of Pediatrics, Division of Blood and Marrow Transplant, Duke University Medical Center, Durham, North Carolina.;Department of Pediatrics, Division of Blood and Marrow Transplant, Duke University Medical Center, Durham, North Carolina.;Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina.;Department of Pediatrics, Division of Blood and Marrow Transplant, Duke University Medical Center, Durham, North Carolina; Department of Immunology, Duke University Medical Center, Durham, North Carolina.;Department of Pediatrics, Division of Blood and Marrow Transplant, Duke University Medical Center, Durham, North Carolina.",
"authors": "Page|Kristin M|KM|;Mendizabal|Adam M|AM|;Prasad|Vinod K|VK|;Martin|Paul L|PL|;Parikh|Suhag|S|;Wood|Susan|S|;Sempowski|Gregory D|GD|;Szabolcs|Paul|P|;Kurtzberg|Joanne|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2008.07.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "14(10)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": null,
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000740:Anemia; D000744:Anemia, Hemolytic, Autoimmune; D015331:Cohort Studies; D036101:Cord Blood Stem Cell Transplantation; D006086:Graft vs Host Disease; D006453:Hemoglobinopathies; D006648:Histocompatibility; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016464:Lysosomal Storage Diseases; D010198:Pancytopenia; D013921:Thrombocytopenia; D019172:Transplantation Conditioning",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "1108-1117",
"pmc": null,
"pmid": "18804040",
"pubdate": "2008-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "13655060;10455373;7581076;12058238;15384979;16435382;18804040;9134174;11498750;16635787;15111785;16522809;12486323;9052917;16338616;10828871;17351645;15128425;10204198;18176609;16443516;8807120;10556961;11781633;16545722;15127012;7479737;15167353",
"title": "Posttransplant autoimmune hemolytic anemia and other autoimmune cytopenias are increased in very young infants undergoing unrelated donor umbilical cord blood transplantation.",
"title_normalized": "posttransplant autoimmune hemolytic anemia and other autoimmune cytopenias are increased in very young infants undergoing unrelated donor umbilical cord blood transplantation"
} | [
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"companynumb": "PHHY2017US176641",
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"activesubstancename": "BUSULFAN"
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"abstract": "BACKGROUND\nCombinations of antidepressant duloxetine (at doses of 40-60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.\n\n\nMETHODS\nThe patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient's plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.\n\n\nCONCLUSIONS\nEven if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.",
"affiliations": "Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo, 194-8543, Japan.;Kyoto Medical Center, Fushimi-ku, Kyoto, 612-8555, Japan.;Kyoto Medical Center, Fushimi-ku, Kyoto, 612-8555, Japan.;Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo, 194-8543, Japan.;Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo, 194-8543, Japan. hyamazak@ac.shoyaku.ac.jp.",
"authors": "Adachi|Koichiro|K|;Beppu|Satoru|S|;Nishiyama|Kei|K|;Shimizu|Makiko|M|;Yamazaki|Hiroshi|H|http://orcid.org/0000-0002-1068-4261",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40780-021-00189-9",
"fulltext": "\n==== Front\nJ Pharm Health Care Sci\nJ Pharm Health Care Sci\nJournal of Pharmaceutical Health Care and Sciences\n2055-0294 BioMed Central London \n\n189\n10.1186/s40780-021-00189-9\nCase Report\nPharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital\nAdachi Koichiro 12 Beppu Satoru 2 Nishiyama Kei 2 Shimizu Makiko 1 http://orcid.org/0000-0002-1068-4261Yamazaki Hiroshi hyamazak@ac.shoyaku.ac.jp 1 1 grid.412579.c0000 0001 2180 2836Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo, 194-8543 Japan \n2 grid.410835.bKyoto Medical Center, Fushimi-ku, Kyoto, 612-8555 Japan \n3 2 2021 \n3 2 2021 \n2021 \n7 625 11 2020 7 1 2021 © The Author(s) 2021Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nCombinations of antidepressant duloxetine (at doses of 40–60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt.\n\nCase presentation\nThe patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient’s plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model.\n\nConclusion\nEven if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.\n\nKeywords\nFlunitrazepamPharmacokinetic modelingOverdoseTrazodoneissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\nTherapeutic drug monitoring is an accepted clinical practice of measuring the levels of specific antipsychotics drugs in blood samples from patients at designated intervals to maintain drug concentrations in the target range [1, 2]. The antidepressant duloxetine is frequently used in combination with other antipsychotics such as quetiapine in the clinical treatment of major depressive disorder. Nevertheless, both fatal and nonfatal cases of duloxetine overdose have been documented [3–8]. The monitoring of plasma concentrations of duloxetine should now be seriously considered in emergency situations and in special populations. However, there are no known reports that provide a comprehensive analysis of blood samples in an overdose setting for duloxetine self-administered with other antipsychotics.\n\nIn general, the drug monitoring of steady-state plasma concentrations of individual patients in the clinical setting could be supported by pharmacokinetic models and simulations. Simplified physiologically based pharmacokinetic (PBPK) models can predict drug monitoring results even in emergency rooms. We previously proposed simple PBPK models for direct oral anticoagulant drugs [9, 10], and, in a case of edoxaban overdose, we recently suggested the practical use of such models by paramedical staff in emergency clinical practice [10].\n\nCase presentation\nHere we describe the case of a 37-year-old man (body weight, 64 kg) who intentionally took an overdose of 780 mg duloxetine (usual clinical dose in the range 40–60 mg/day) in combination with antipsychotic drugs flunitrazepam (18 mg: usual range 0.5–2 mg/day), quetiapine (850 mg: usual range 50–600 mg/day), and trazodone (1100 mg: usual range 75–200 mg/day). The patient had a history of gender identity disorder and depression. He had self-administered these medicines in combination as a suicide attempt and was emergently admitted to Kyoto Medical Center. On arrival, the patient’s awareness level as a Glasgow Coma Scale score was eye 2, verbal 2, and motor 4 (E2V2M4), breathing rate was 16 breaths/min, body temperature was 37.1 °C, oxygen saturation was 98% on room air, blood pressure was 124/86 mmHg, and the heart rate was 89 bpm. An electrocardiogram showed normal sinus rhythm with a QTc of 473 ms. The patient was then infused with bicarbonate Ringer’s solution but was not administrated charcoal and did not undergo artificial dialysis. The clinical laboratory results for the patient 1, 32, and 56 h after the self-administered overdose are shown in Table 1. The patient’s awareness level had improved to E4V5M6 and QTc reduced to < 430 ms 35 h after admission to hospital. No abnormalities were found in vital signs at discharge 3 days after admission. We report herein the drug monitoring data for the patient and the results of pharmacokinetic modeling. The findings indicate that predictions using this tool are appropriate for application in an emergency. The ethics committee of Kyoto Medical Center approved this study (18–018).\nTable 1 Clinical laboratory results in a patient who had taken a single combined oral overdose of duloxetine, flunitrazepam, quetiapine, and trazodone\n\n\tTime after administration (h) of oral dose\t\n1\t32\t56\t\nAspartate aminotransferase (U/L)\t15\t138\t122\t\nAlanine aminotransferase (U/L)\t18\t27\t34\t\nSerum creatinine (mg/dL)\t0.66\t0.71\t0.64\t\nCreatinine clearance (mL/min)\t139\t129\t143\t\n\n\nFrozen plasma samples collected from the patient 1 and 32 h after an overdose of a combination of drugs were pharmacokinetically analyzed. The patient gave written informed consent to take part in this study and for its publication. The concentrations of duloxetine, flunitrazepam, quetiapine, and trazodone in the plasma samples were quantified by liquid chromatography using a gradient elution program followed by tandem mass spectrometry systems according to the reported methods [11–15] with slight modifications; the following transitions were used: m/z 298 → 154, m/z 314 → 268, m/z 384 → 253, and m/z 372 → 176, for duloxetine, flunitrazepam, quetiapine, and trazodone, respectively. Under the present conditions, duloxetine, flunitrazepam, quetiapine, and trazodone levels in plasma were measurable (≥10 ng/mL) or detectable (≥0.10 ng/mL) each time point. Duloxetine, flunitrazepam, quetiapine, and trazodone were purchased from Fujifilm Wako Pure Chemicals, Osaka, Japan.\n\nThe patient’s plasma duloxetine concentration during ambulance transport was 57 ng/ml after an oral overdose of 780 mg (Fig. 1), and, 32 h later, the level was still as high as 126 ng/mL. The plasma concentrations at 1 h and 32 h after administration were 46 and 26 ng/mL for flunitrazepam and 1720 and 1060 ng/mL for trazodone, respectively. In contrast, the plasma concentration of quetiapine at 1 h after administration (1140 ng/mL) had rapidly decreased to 52 ng/mL at 32 h. Of the four medicines evaluated in this patient, duloxetine disappeared most slowly from plasma, whereas quetiapine disappeared most quickly.\nFig. 1 Measured (plots) and estimated (lines) plasma concentrations of duloxetine (a), flunitrazepam (b), quetiapine (c), and trazodone (d) in a patient who took a single oral overdose of these drugs. The patient took a single excessive oral dose of duloxetine (780 mg), flunitrazepam (18 mg), quetiapine (850 mg), and trazodone (1100 mg) in combination. The modeled plasma concentration curves after virtual administrations (solid lines) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2\n\n\n\nBased on the reported human blood concentrations in patients orally treated with the normal therapeutic doses of the four antipsychotic drugs (shown in Fig. 2) [16–19], four simple PBPK models consisting of receptor (gut), metabolizing (liver), and central compartments were separately set up as described previously [9, 10, 20, 21]. Rate constants for the transfer of drug from/to the central (first) compartment to/from the peripheral (second) compartment (k12/k21) [22] were adopted for flunitrazepam. The plasma unbound fractions (fu,p), octanol–water partition coefficients (logP), blood-to-plasma concentration ratios (Rb), and liver-to-plasma concentration ratios (Kp,h) of the relevant compounds were estimated using in silico tools [9, 23, 24]. The initial values for the fraction absorbed × intestinal availability (Fa·Fg) and hepatic clearance (CLh) were estimated from the elimination constants in empirical one-compartment models. The absorption rate constant (ka), volume of the systemic circulation (V1), and hepatic intrinsic clearance (CLh,int) values for PBPK models with standard deviations were determined by fitting using nonlinear regression analyses; these final parameters are shown in Table 2 (within 25% of coefficients of variation for ka, k12, k21, CLh,int, and V1). The general ratios of CLh to the renal clearance (CLr) were set at 9:1 for the four drugs. The 95% confidence intervals (CIs) were estimated for the fitted intrinsic hepatic clearance values using 100 virtual subjects created using random numbers, as described previously [9, 10]. The resulting system of differential equations was solved to obtain the concentrations of the substrates for the overdosed patient in this study:\n dXg(t)dt=−ka⋅Xg(t)whenatt=0,Xg(0)=dose VhdChdt=Qh·Cb−Qh·Ch·RbKp,h+ka·Xg−CLh,int·ChKp,h·fu,p V1dCbdt=−Qh·Cb+Qh·Ch·RbKp,h−k12·V1·Cb+k21·Xperipheral−CLr·Cb dXperipheraldt=k12·V1·Cb−k21·Xperipheral where Xg and Xperipheral are the substrate amounts in the gut and peripheral compartments, Vh is the liver volume (1.5 L), Ch is the hepatic substrate concentration, Qh is the blood flow rate of the systemic circulation to the hepatic compartment (96.6 L/h), and Cb is the blood substrate concentration.\nFig. 2 Estimated plasma concentrations (lines) and reported/observed plasma concentrations (plots) of duloxetine (circles), flunitrazepam (triangles), quetiapine (squares), and trazodone (diamonds). Plasma concentration curves after virtual administrations (solid line) are shown with 95% confidence intervals (broken lines) based on the hepatic intrinsic clearance values shown in Table 2. Reported/observed blood levels were taken from the literature: duloxetine (60 mg, [16]), flunitrazepam (1 mg, [17]), quetiapine (25 mg, [18]), and trazodone (50 mg, [19])\n\nTable 2 Physiological, experimental, and final calculated parameters for PBPK models established in this study\n\nParameter\tAbbreviation (unit)\tDuloxetine\tFlunitrazepam\tQuetiapine\tTrazodone\t\nModel input parameters\t\n Molecular weight\tMW\t297\t313\t384\t372\t\n Octanol–water partition coefficient\tlogP\t4.26\t1.78\t2.99\t3.85\t\n Plasma unbound fraction\tfu,p\t0.114\t0.324\t0.125\t0.0732\t\n Blood–plasma concentration ratio\tRb\t0.843\t0.921\t0.852\t0.805\t\n Liver–plasma concentration ratio\tKp,h\t3.18\t1.17\t2.69\t3.01\t\n Fraction absorbed × intestinal availability\tFa·Fg\t1\t1\t1\t1\t\n Absorption rate constant\tka (1/h)\t0.372 ± 0.007a\t2.48 ± 0.05\t2.86 ± 0.05\t1.12 ± 0.26\t\n Transfer rate constant\tk12 (1/h)\t–\t0.28 ± 0.02\t–\t–\t\n Transfer rate constant\tk21 (1/h)\t–\t0.04 ± 0.01\t–\t–\t\n Volume of systemic circulation\tV1 (L)\t755 ± 1a\t80.7 ± 0.1\t206 ± 1\t66.2 ± 9.5\t\n Hepatic intrinsic clearance\tCLh,int (L/h)\t385 ± 1a\t15.8 ± 0.1\t954 ± 1\t173 ± 16\t\n Hepatic clearance\tCLh (L/h)\t30.2\t4.84\t53.4\t11.2\t\n Renal clearance\tCLr (L/h)\t3.0\t0.48\t5.3\t1.1\t\nEstimated values\t\n Cmax in plasma\tng/mL\t44.9 (0.93)b\t9.12 (1.08)\t44.2 (0.98)\t491 (0.72)\t\n AUC in plasma\tng·h/mL\t1210 (1.19)\t52.1 (1.02)\t172 (0.95)\t3610 (0.77)\t\nReported levels\t\n Cmax in plasma\tng/mL\t48.5 ± 8.3c\t8.47d\t45.0e\t681 ± 128f\t\n AUC in plasma\tng·h/mL\t1020 ± 220\t51.2\t181\t4670 ± 790\t\naData are means ± standard deviations by fitting to measured concentrations. bValues in parentheses are ratios to the reported/observed values. Reported/observed blood levels were taken from the literature: c [16], d [17], e [18], and f [19]\n\n\n\nThe measured plasma concentrations and the PBPK-modeled concentration profiles of the four drugs self-administered in a single oral overdose are shown in Fig. 1. The observed concentrations of duloxetine and flunitrazepam in this overdose patient were generally within the 95% CIs of the predicted plasma concentration curves.\n\nDiscussion and conclusions\nAlthough the observed concentrations of quetiapine and trazodone were higher than the 95% CI of the predicted plasma concentration curves, possible drug interaction effects that might have caused these observed high plasma concentrations were ruled out in this case because of the apparent wide-ranging linearity seen in overdoses in this patient and in the outputs of PBPK models (shown in Fig. 1) based on the recommended normal doses; quetiapine was the exception, because it exhibited unexpectedly rapid elimination in this case.\n\nRelatively many cases of quetiapine in overdose have been reported [25]. It has been suggested that activated charcoal has an effect on the pharmacokinetics of quetiapine in overdose [26]. However, quetiapine appears to be relatively safe in overdose, presumably because of its short terminal elimination half-life [27]. In contrast, the absorption and disappearance of duloxetine were slower than those of the other three medicines experienced in this case. A low apparent permeability of duloxetine of 12.5 nm/s was determined by following the reported method in an in vitro Caco-2 monolayer system in comparison with caffeine (544 nm/s) as a reference compound [28]. Generally, gastric lavage and administration of charcoal are recommended within 1 h of overdose in clinical practice. In a case report [28], it was reported that gastric lavage could be effective when some medicine remained in the stomach. Activated charcoal reportedly prevents the absorption of controlled-release duloxetine tablets at 1 h after administration [29]. It has been reported that liposomes could potentially be effective for treating overdoses of the antidepressant amitriptyline, with reductions in the area under the concentration–time curve estimated using a PBPK model; however, the aims of that study were different from the purpose of the current study [29]. We recently proposed the practical use of PBPK models by paramedical staff in emergency clinical practice for a case of edoxaban overdose [10]. The PBPK model established in the current study predicted the time to the maximum concentration of duloxetine to be about 6 h. Therefore, even if more than 1 h has passed after administration of duloxetine, gastric lavage and the administration of activated charcoal may be effective in clinical practice.\n\nSimplified PBPK models are useful not only in the fields of drug discovery and chemical risk assessment but also in the management of poisoning, as recently described [10]. We did not use the Michaelis-Menten equations for the in vivo intrinsic hepatic clearances in the current simplified PBPK models. Such models can predict plasma concentration curves, and then it can quickly be determined whether treatment with gastric lavage and activated charcoal is feasible. In this way, it may be possible to deal with individual cases by reflecting the differences in pharmacokinetics. In hospitals, a simplified PBPK model simulator could replace the need to routinely measure the blood levels of drugs. It is hoped that the results of this study based on drug monitoring data and pharmacokinetic predictions could serve as a guide when setting the treatment period in cases of overdoses of antipsychotic drugs, e.g., duloxetine and quetiapine, that are cleared differently.\n\nAbbreviations\nCIsConfidence intervals\n\nPBPKPhysiologically based pharmacokinetic\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nThe authors greatly thank Yusuke Kamiya, Ayane Nakano, and Shiori Hina for their technical support, and David Smallbones for copyediting a draft of this article.\n\nAuthors’ contributions\nKA, SB, and NK monitored the patients and carried out the acquisition of patient data. KA, MS, and HY conceived the pharmacokinetic study and drafted the manuscript. SB and NK analyzed the patient medical data and helped to draft the manuscript. All authors have read and approved the final manuscript.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article and are also available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThis study was approved by the Ethics Committee of Kyoto Medical Center.\n\nConsent for publication\nInformed consent was obtained from the patient.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Ereshefsky L Pharmacokinetics and drug interactions: update for new antipsychotics J Clin Psychiatry 1996 57 Suppl 11 12 25 8941167 \n2. Zhou SF Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II Clin Pharmacokinet 2009 48 761 804 10.2165/11318070-000000000-00000 19902987 \n3. 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"fulltext_license": "CC BY",
"issn_linking": "2055-0294",
"issue": "7(1)",
"journal": "Journal of pharmaceutical health care and sciences",
"keywords": "Flunitrazepam; Overdose; Pharmacokinetic modeling; Trazodone",
"medline_ta": "J Pharm Health Care Sci",
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"pages": "6",
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"pmid": "33531089",
"pubdate": "2021-02-03",
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"references": "22306002;25867688;31993333;19902987;19539103;20213834;18621591;16390352;10945320;18622372;17410121;12640218;30648587;21177420;18609436;19242403;19656434;30876545;25805149;29403794;8941167;30798209;20549836;30796754;30216091;26662354;32944263;30511563;20600458",
"title": "Pharmacokinetics of duloxetine self-administered in overdose with quetiapine and other antipsychotic drugs in a Japanese patient admitted to hospital.",
"title_normalized": "pharmacokinetics of duloxetine self administered in overdose with quetiapine and other antipsychotic drugs in a japanese patient admitted to hospital"
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... |
{
"abstract": "BACKGROUND\nLong-term follow-up (≥4 years) demonstrated a low incidence of cardiac and vascular treatment-emergent adverse events (TEAEs) with bosutinib treatment. We evaluated cardiac, vascular, hypertension, and effusion TEAEs after ≥ 7 years of follow-up in patients with Philadelphia chromosome-positive (Ph+) leukemia.\n\n\nMETHODS\nThis retrospective analysis of a phase I/II study and its ongoing extension study included data from patients with chronic phase chronic myeloid leukemia (CML) treated with bosutinib after resistance/intolerance to imatinib (CP2L) or to imatinib plus dasatinib and/or nilotinib (CP3L), and those with accelerated/blast phase CML or acute lymphoblastic leukemia after treatment with, at a minimum, imatinib (ADV).\n\n\nRESULTS\nIn all, 570 patients were treated with bosutinib; median treatment duration was 11.1 months (range: 0.03-133.1). The incidence of cardiac, vascular, hypertension, and effusion-related TEAEs was 10.9%, 8.8%, 9.1%, and 13.3%, respectively. Few patients had maximum grade 3-4 TEAEs (cardiac, 3.9%; vascular, 4.0%; hypertension, 3.0%; effusion, 4.6%). Grade 5 TEAEs occurred in the cardiac (0.7%) and vascular (1.8%) clusters only. In years 5-7, fewer than 5% of patients each year had newly occurring cardiac, vascular, hypertension, or effusion TEAEs. The exposure-adjusted TEAE rates (patients with TEAEs/total patient-year) pooled across CP2L, CP3L, and ADV cohorts were as follows: cardiac, 0.044; vascular, 0.035; hypertension, 0.038; and effusion, 0.056, of which, correspondingly, 0.9%, 1.2%, 0%, and 2.1% required treatment discontinuation.\n\n\nCONCLUSIONS\nThe incidence of cardiac, hypertension, vascular, and effusion events was low in patients with Ph+ CML resistant or intolerant to prior therapy who were treated with bosutinib.",
"affiliations": "University of Texas MD Anderson Cancer Center, Houston, TX, USA.;University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Pfizer Inc, New York, NY, USA.;Pfizer AG, Zurich, Switzerland.;Pfizer Inc, Cambridge, MA, USA.;University of Milano-Bicocca, Monza, Italy.;Universitätsklinikum RWTH Aachen, Aachen, Germany.",
"authors": "Cortes|Jorge E|JE|https://orcid.org/0000-0002-8636-1071;Kantarjian|Hagop M|HM|;Mauro|Michael J|MJ|;An|Fiona|F|;Nick|Sonja|S|;Leip|Eric|E|;Gambacorti-Passerini|Carlo|C|;Brümmendorf|Tim H|TH|",
"chemical_list": "D000814:Aniline Compounds; D009570:Nitriles; D011804:Quinolines; C471992:bosutinib",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.13608",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "106(6)",
"journal": "European journal of haematology",
"keywords": "bosutinib; cardiovascular events; chronic myeloid leukemia; clinical trial; effusion events; tyrosine kinase inhibitor",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000814:Aniline Compounds; D001752:Blast Crisis; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006331:Heart Diseases; D006801:Humans; D006973:Hypertension; D015994:Incidence; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D011804:Quinolines; D012189:Retrospective Studies",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "808-820",
"pmc": null,
"pmid": "33638218",
"pubdate": "2021-06",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Long-term cardiac, vascular, hypertension, and effusion safety of bosutinib in patients with Philadelphia chromosome-positive leukemia resistant or intolerant to prior therapy.",
"title_normalized": "long term cardiac vascular hypertension and effusion safety of bosutinib in patients with philadelphia chromosome positive leukemia resistant or intolerant to prior therapy"
} | [
{
"companynumb": "IN-PFIZER INC-IN-WYE-H00583807",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LOPERAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Delusional disorder is an uncommon, yet not rare, psychotic disorder. Because of the distinct lack of high-evidence-level research conducted in this area, no definitive clinical guidelines are available on its treatment. The aim of this article was to summarize the current literature on the pharmacological treatment of delusional disorder in the form of a review, as well as to analyze a series of 6 cases treated at the Department of Psychiatry at \"Charité-University Medicine Berlin, Campus Benjamin Franklin\" between 2005 and 2011; in each case paying special attention to the relative efficacy and acceptability of the antipsychotics used.\n\n\nMETHODS\nA MEDLINE search was conducted to capture all articles on the treatment of delusional disorder published since 2004. After viewing titles and abstracts, these articles were then assessed for relevance.\n\n\nMETHODS\nThe files of 6 cases of delusional disorder treated at the previously mentioned clinic were analyzed and information regarding the type of medication, dose, and duration of treatment as well as adverse effects was extracted and summarized. In line with previous studies, it was found that delusional disorder has a moderate prognosis when adequately treated and that noncompliance is often the reason for poor treatment results. Various novel antipsychotics as well as a combination of medication treatment and psychotherapy produced positive results. Generally, adverse effects were easily managed by a reduction in dose or a switch to another antipsychotic, and it was often necessary to try out a number of antipsychotics before arriving at a satisfactory solution.",
"affiliations": "Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.",
"authors": "Mews|Marie Rosa|MR|;Quante|Arnim|A|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/JCP.0b013e3182905796",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0271-0749",
"issue": "33(4)",
"journal": "Journal of clinical psychopharmacology",
"keywords": null,
"medline_ta": "J Clin Psychopharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D057915:Drug Substitution; D005260:Female; D006801:Humans; D008297:Male; D010359:Patient Readmission; D012189:Retrospective Studies; D012563:Schizophrenia, Paranoid; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "8109496",
"other_id": null,
"pages": "512-9",
"pmc": null,
"pmid": "23771191",
"pubdate": "2013-08",
"publication_types": "D002363:Case Reports; D003160:Comparative Study; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Comparative efficacy and acceptability of existing pharmacotherapies for delusional disorder: a retrospective case series and review of the literature.",
"title_normalized": "comparative efficacy and acceptability of existing pharmacotherapies for delusional disorder a retrospective case series and review of the literature"
} | [
{
"companynumb": "DE-MYLANLABS-2015M1002862",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of acute left ventricular dysfunction due to myocarditis, in the setting of a scleroderma renal crisis. The case is particularly intriguing for the favorable outcome of both symptoms and heart function following immunosuppressive therapy. We also highlight the changes observed over time with image techniques as well as in electrocardiograms.",
"affiliations": "Department of Cardiology, Hospital Universitario-Fundación Jiménez Díaz - Quirónsalud, Madrid, Spain. Electronic address: juan.mmilla@fjd.es.;Department of Cardiology, Hospital Universitario-Fundación Jiménez Díaz - Quirónsalud, Madrid, Spain.;Department of Rheumathology, Hospital Universitario-Fundación Jiménez Díaz - Quirónsalud, Madrid, Spain.;Department of Cardiology, Hospital Universitario-Fundación Jiménez Díaz - Quirónsalud, Madrid, Spain.;Department of Cardiology, Hospital Universitario-Fundación Jiménez Díaz - Quirónsalud, Madrid, Spain.;Department of Cardiology, Hospital Universitario-Fundación Jiménez Díaz - Quirónsalud, Madrid, Spain.",
"authors": "Martínez-Milla|Juan|J|;Gaebelt|Hans Paul|HP|;Sánchez-Pernaute|Olga|O|;Kallmeyer|Andrea|A|;Romero|José|J|;Farré|Jerónimo|J|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D007166:Immunosuppressive Agents; C481642:eculizumab",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.reuma.2018.03.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2173-5743",
"issue": "16(5 Pt 1)",
"journal": "Reumatologia clinica",
"keywords": "Acute heart failure; Cardiac funcion; Crisis renal esclerodérmica; Eculizumab; Esclerodermia; Función cardíaca; Insuficiencia cardiaca aguda; Miocarditis; Myocarditis; Schleroderma; Schleroderma renal crisis",
"medline_ta": "Reumatol Clin (Engl Ed)",
"mesh_terms": "D058186:Acute Kidney Injury; D061067:Antibodies, Monoclonal, Humanized; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D012595:Scleroderma, Systemic; D018487:Ventricular Dysfunction, Left",
"nlm_unique_id": "101717526",
"other_id": null,
"pages": "359-361",
"pmc": null,
"pmid": "29729875",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Scleroderma Renal Crisis: A Reversible Cause of Left Ventricular Dysfunction.",
"title_normalized": "scleroderma renal crisis a reversible cause of left ventricular dysfunction"
} | [
{
"companynumb": "ES-ALEXION-A201805927",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ECULIZUMAB"
},
"drugadditional": "3",
"... |
{
"abstract": "Infective endocarditis is a life threatening condition with a high mortality rate. Intravenous Drug Abusers (IVDA) are more likely to acquire endocarditis. Most of the cases of infective endocarditis are caused by a single pathogen; cases of polymicrobial endocarditis are rare and they are associated with a reported mortality rate of more than 30%. Only 21 cases of N. sicca endocarditis have been described in the literature since 1918, and only 15 reported cases of endocarditis which involved Actinomyces species have been reported since 1939. We are reporting a case of a 49-year-old male with intravenous heroin and fentanyl abuse, who presented with infective endocarditis caused by Neisseria sicca/subflava(N. sicca), Actinomyces, Streptococcus mitis, and Haemophilus parainfluenzae, complicated by septic emboli to the lungs and skin, ARDS , splenic infarct and immunocomplex mediated proliferative glomerulonephritis.",
"affiliations": "Steward Carney Hospital , Boston, MA, USA .;Tufts University School of Medicine , Boston, MA, USA .;Professor of Medicine, Department of Internal Medicine Steward Carney Hospital , USA .",
"authors": "Mehrzad|Raman|R|;Sublette|Marcus|M|;Barza|Michael|M|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2013/7303.3817",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-709X",
"issue": "7(12)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Actinomysis; Haemophilus parainfluenzae; Neisseria sicca; Septic emboli; Streptococcus mitis",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "2981-5",
"pmc": null,
"pmid": "24551699",
"pubdate": "2013-12",
"publication_types": "D016428:Journal Article",
"references": "11235043;16191149;16291005;23297179;23476838;19483662;19830211;17366042;9431403;19376668;22711599;622951;20102302;17366043;16318912;1989813;22714640;6338050;9597274;21975499;17965360",
"title": "Polymicrobial endocarditis in intravenous heroin and fentanyl abuse.",
"title_normalized": "polymicrobial endocarditis in intravenous heroin and fentanyl abuse"
} | [
{
"companynumb": "US-APOTEX-2017AP019737",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": "3",
"d... |
{
"abstract": "Tekin A, Yağmur İ, Ergün O, Ayık MF, Atay Y, Ulman İ, Avanoğlu A. Excision of the atrial Wilms` tumor thrombus without sternotomy, atriotomy and cardiovascular By-pass. Turk J Pediatr 2019; 61: 436-439. The treatment of atrial-extention Wilms` tumor thrombus is surgical excision after chemotherapy. Atriotomy with cardiovascular by-pass is the one of the most common method for this procedure. Herein, we aimed to present a case of Wilms` tumor with a tumor thrombus extending into the right atrium totally excised with retrohepatic cavatomy. A 3.5 year-old girl was admitted with the symptom of dysuria. The examinations revealed a mass consistent with Wilms` tumor in the middle and lower poles of the left kidney. Doppler ultrasound and Echocardiographic examinations showed a tumor thrombus extending into the right atrium and some pulmonary nodules which were interpreted to be metastasis. Wilms` tumor was histopathologically diagnosed by an open biopsy. After three courses of chemotherapy imaging studies revealed that the atrial axtention of the tumor thrombus persisted. The tumor thrombus was found to be fibrotic on the magnetic resonance imaging scan of the patient. Therefore, nephroureterectomy along with the excision of the tumor thrombus from the inferior vena cava was done with intraoperative continuous trans-esophageal echocardiography (TEE). The suprarenal and retrohepatic vena cava were exposed by dissecting and ligating all short hepatic veins and completely mobilizing the right lobe of the liver. The thrombus was dissected out via Vertical cavatomy at the retrohepatic level. TEE confirmed complete removal of the thrombus from the atrium; Vena cava was then repaired. There was no need for a blood transfusion, or cardiovascular by-pass (CPB) during the operation. Total exposure of the retrohepatic and subdiaphragmatic vena cava using transplantation techniques is an effective method for the excision of a tumor thrombus without sternotomy, atriotomy and CPB, avoiding possible intra- and postoperative complications in selected cases of Wilms` tumor with intraatrial thrombus extension. The case emphasises the importance of multidisciplinary communication and collaboration.",
"affiliations": "Division of Pediatric Urology, Ege University Faculty of Medicine, İzmir, Turkey.;Division of Pediatric Urology, Ege University Faculty of Medicine, İzmir, Turkey.;Departments of Pediatric Surgery, Ege University Faculty of Medicine, İzmir, Turkey.;Pediatric Cardiovascular Surgery, Ege University Faculty of Medicine, İzmir, Turkey.;Pediatric Cardiovascular Surgery, Ege University Faculty of Medicine, İzmir, Turkey.;Division of Pediatric Urology, Ege University Faculty of Medicine, İzmir, Turkey.;Division of Pediatric Urology, Ege University Faculty of Medicine, İzmir, Turkey.",
"authors": "Tekin|Ali|A|;Yağmur|İsmail|İ|;Ergün|Orkan|O|;Ayık|Mehmet Fatih|MF|;Atay|Yüksel|Y|;Ulman|İbrahim|İ|;Avanoğlu|Ali|A|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-4301",
"issue": "61(3)",
"journal": "The Turkish journal of pediatrics",
"keywords": "Wilms` tumor thrombus; children; retrohepatic vena cava disection",
"medline_ta": "Turk J Pediatr",
"mesh_terms": "D006348:Cardiac Surgical Procedures; D002675:Child, Preschool; D004452:Echocardiography; D005260:Female; D006325:Heart Atria; D006331:Heart Diseases; D006801:Humans; D007680:Kidney Neoplasms; D019028:Magnetic Resonance Imaging, Cine; D056346:Sternotomy; D013927:Thrombosis; D009396:Wilms Tumor",
"nlm_unique_id": "0417505",
"other_id": null,
"pages": "436-439",
"pmc": null,
"pmid": "31916725",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Excision of the atrial Wilms` tumor thrombus without sternotomy, atriotomy and cardiovascular By-pass.",
"title_normalized": "excision of the atrial wilms tumor thrombus without sternotomy atriotomy and cardiovascular by pass"
} | [
{
"companynumb": "TR-PFIZER INC-2020028849",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "An 82-year-old man with a history of endovascular repair for ruptured abdominal aortic aneurysm 6 years ago presented with a type II endoleak and enlarging sac. He had successful transabdominal direct sac puncture embolization but developed fever 2 days postoperatively. Contrast-enhanced computed tomography showed a rim-enhancing collection, and sac aspiration was positive for enteric organisms, confirming endograft infection. The patient underwent graft explantation and neoaortic reconstruction using superficial femoral veins. Three months postoperatively, computed tomography showed complete resolution of fluid collection and no signs of graft infection. This report illustrates direct puncture embolization complicated by endograft infection from enteric bacteria.",
"affiliations": "Division of Vascular Surgery, Department of Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.;Division of Vascular and Interventional Radiology, Department of Medical Imaging, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.;Division of Vascular Surgery, Department of Surgery, Thunder Bay Regional Health Sciences Centre, Thunder Bay, Ontario, Canada.;Division of Vascular Surgery, Department of Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.",
"authors": "Li|Ben|B|;Tan|Kong Teng|KT|;MacDonald|Mary Elizabeth|ME|;Byrne|John|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jvscit.2018.10.009",
"fulltext": "\n==== Front\nJ Vasc Surg Cases Innov TechJ Vasc Surg Cases Innov TechJournal of Vascular Surgery Cases and Innovative Techniques2468-4287Elsevier S2468-4287(18)30137-010.1016/j.jvscit.2018.10.009Vascular infectionAortic graft infection with enteric organism after embolization of late type II endoleak Li Ben BHScaTan Kong Teng MDbMacDonald Mary Elizabeth MD, PhDcByrne John MB BCh, MDjohn.byrne@uhn.caa∗a Division of Vascular Surgery, Department of Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canadab Division of Vascular and Interventional Radiology, Department of Medical Imaging, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canadac Division of Vascular Surgery, Department of Surgery, Thunder Bay Regional Health Sciences Centre, Thunder Bay, Ontario, Canada∗ Correspondence: John Byrne, MB BCh, MD, Assistant Professor, Division of Vascular Surgery, 6EN-214, Toronto General Hospital, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4 john.byrne@uhn.ca11 3 2019 3 2019 11 3 2019 5 1 61 64 31 8 2018 28 10 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).An 82-year-old man with a history of endovascular repair for ruptured abdominal aortic aneurysm 6 years ago presented with a type II endoleak and enlarging sac. He had successful transabdominal direct sac puncture embolization but developed fever 2 days postoperatively. Contrast-enhanced computed tomography showed a rim-enhancing collection, and sac aspiration was positive for enteric organisms, confirming endograft infection. The patient underwent graft explantation and neoaortic reconstruction using superficial femoral veins. Three months postoperatively, computed tomography showed complete resolution of fluid collection and no signs of graft infection. This report illustrates direct puncture embolization complicated by endograft infection from enteric bacteria.\n\nKeywords\nAbdominal aortic aneurysmEndovascular aneurysm repairGraft infectionEndoleak embolizationAortic reconstruction\n==== Body\nGraft infection after endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm is a serious complication with an incidence of 0.6% and mortality rate of 45.7%.1 Most studies of graft infection have been performed on patients receiving open rather than endovascular repair.2, 3, 4 Furthermore, there are few reports of endograft infection after endoleak embolization.5 Given the lack of guidelines on managing this life-threatening condition, we present a case of EVAR graft infection after direct sac puncture embolization for type II endoleak that was successfully treated with neoaortic reconstruction using superficial femoral veins. The patient's consent was received for this report.\n\nCase report\nAn 82-year-old man with a history of ruptured abdominal aortic aneurysm treated with EVAR 6 years ago presented to a community hospital with 4 days of right flank pain. Initial EVAR was performed with a Cook bifurcated endograft (Cook Medical, Bloomington, Ind) and intraoperative Palmaz stent (Cordis, Bridgewater, NJ) for type I endoleak. The patient had a history of type II endoleak treated with iliolumbar embolization 5 years ago and chronic kidney disease secondary to acute kidney injury after ruptured EVAR with a baseline creatinine concentration of 150 μmol/L.\n\nContrast-enhanced computed tomography (CT) showed a type II endoleak and 9.7-cm sac (Fig 1, A), which had enlarged by 1.9 cm since his last CT scan. A diagnosis of symptomatic aneurysm sac expansion secondary to type II endoleak was made. The patient was transferred to our academic vascular center for direct sac puncture embolization. Under ultrasound and CT fluoroscopic guidance, the aneurysm sac was punctured transabdominally with a trocar needle. Intraoperative angiography confirmed a type II endoleak originating from the lumbar arteries (Fig 1, B). Embolization using lipiodol and n-cyanoacrylate glue was completed with no obvious complications. Prophylactic antibiotics including cefazolin and metronidazole were administered.Fig 1 Type II endoleak demonstrated by (A) contrast-enhanced computed tomography (CT) scan and (B) angiography (originating from lumbar arteries).\n\n\n\nHe was transferred back to his community hospital but subsequently developed fever. Findings on noncontrast-enhanced CT were suggestive of graft infection. He was started on empirical broad-spectrum antibiotics and transferred back to our center for further investigation. On arrival, the patient was febrile but hemodynamically stable. His blood cultures were positive for Escherichia coli, and contrast-enhanced CT showed a rim-enhancing collection, psoas abscess, and locules of gas within the sac (Fig 2). This was consistent with endograft infection secondary to transabdominal embolization.Fig 2 Aortic endograft infection on contrast-enhanced computed tomography (CT) scan demonstrated by rim-enhancing collection, psoas abscess, and locules of gas within the sac.\n\n\n\nUnder CT fluoroscopic guidance, a drainage catheter was placed in the psoas abscess through a translumbar approach; 5 mL of fluid was aspirated, and the culture was positive for E. coli and other enteric bacteria including Bacteroides thetaiotaomicron, Parabacteroides distasonis, and Eggerthella lenta. Vein mapping showed that his femoropopliteal veins were patent, and echocardiography was negative for inducible ischemia. He was consented for endograft explantation and neoaortic reconstruction using bilateral superficial femoral veins.\n\nFrom each of the superficial femoral veins, 15 cm was harvested. The proximal ends were spliced together to create a bifurcated vein graft. A midline laparotomy was performed, and the retroperitoneum was opened. Purulent fluid with a feculent smell and dense adhesions were observed. No enterotomy was identified on full bowel examination, consistent with needle puncture of the bowel rather than fistula.\n\nAn aortic clamp site was identified just above the left renal artery. After heparinization, the aneurysm sac was opened and purulent material was washed out. We dissected out the endograft and retrieved the Palmaz stent without difficulty. An aortobi-iliac repair was performed using the neoaorta. All infected material was débrided from the aortic sac and sent for culture.\n\nAfter adequate hemostasis, the aortic sac was sutured over the vein graft, and the retroperitoneum was closed over the aorta. The laparotomy was closed, and the patient was transferred to the cardiovascular intensive care unit. Culture of the operative specimen was positive for B. thetaiotaomicron and P. distasonis, and the patient continued on intravenous fluconazole and meropenem.\n\nA CT scan on postoperative day 7 showed a patent graft with no signs of ongoing infection. His recovery was complicated by delirium and fever secondary to pneumonia. On postoperative day 19, contrast-enhanced CT scan showed a sac size of 5.4 cm with minor wall enhancement, and no free gas was detected. The patient was discharged with graduated compression stockings when his delirium and pneumonia resolved.\n\nOne month later, he was seen for follow-up and resumed daily activities. His incisions were healed and pulses were palpable. His intravenous antibiotics were transitioned to oral amoxicillin-clavulanic acid for long-term infection suppression. Three months postoperatively, CT showed complete resolution of the fluid collection and no signs of ongoing graft infection (Fig 3). The patient is alive 18 months postoperatively with no issues related to his aortic reconstruction.Fig 3 Noncontrast-enhanced computed tomography (CT) scan demonstrating no signs of endograft infection 3 months postoperatively.\n\n\n\nDiscussion\nGraft infection is a rare complication after EVAR, and no guidelines exist for managing this serious condition. The only other published case of endograft infection after direct puncture embolization for type II endoleak was reported by Harlock et al.6 However, the authors used a translumbar approach and the responsible organism was Propionibacterium acnes, a skin rather than an enteric bacterium. Because transabdominal puncture involves accessing the aorta through the abdomen, there is risk of inadvertent bowel injury and seeding of the endograft with enteric organisms.7 Our report illustrates the importance of querying graft infection in EVAR patients who develop fever after transabdominal embolization.\n\nTransarterial and direct puncture techniques demonstrate similar efficacy in treating type II endoleak and preventing sac expansion.8, 9 In this case, we performed transabdominal direct puncture embolization because the patient presented again with type II endoleak after transarterial embolization and his endoleak was anatomically suitable for a transabdominal approach. Our institution is experienced with transabdominal embolizations, having performed 33 for type II endoleak between 2011 and 2016 with a technical success rate of 97%.10\n\nThe benefits of transabdominal embolization over a translumbar technique include better toleration of surgery with supine positioning and easier cannulation of lumbar artery origins.10 A transcaval approach may have lowered the probability of bowel injury, but it presents unique risks, including inadvertent intracaval embolization and aortocaval fistula.11 Direct repair with minilaparotomy is a more invasive approach for patients with persistent type II endoleak who have failed to respond to other embolization methods.12 This technique may be considered if the patient presents again with endoleak in the future.\n\nEndograft infection can be managed medically or surgically. Because of high mortality rates, conservative management with antibiotics is reserved for patients who cannot tolerate surgery.13 Surgical management of aortic graft infection generally consists of graft explantation, débridement of infected tissue, and aortic revascularization. Traditionally, extra-anatomic bypass has been the standard of care,14 but recent evidence demonstrates that in situ reconstruction provides improved mortality, amputation, and long-term patency rates.15\n\nProsthetic, autogenous, and cryopreserved grafts are available for in situ reconstruction.16 Autogenous aortic reconstruction using the femoral-popliteal vein, first described by Clagett et al,17 provides better long-term patency, reinfection, and mortality rates than other methods.18\n\nApplying neoaortic reconstruction using superficial femoral veins to our patient allowed complete resolution of endograft infection and recovery of quality of life within 3 months. Smeds et al7 published a case series of 206 patients demonstrating similar feasibility of this technique for managing endograft infection.\n\nConclusions\nSeeding of the aneurysm sac with enteric organisms is a rare complication after transabdominal direct sac puncture embolization of post-EVAR type II endoleak. Neoaortic reconstruction using autogenous superficial femoral veins is a feasible treatment option for this complication.\n\nJ.B. was funded from the Bill and Vicky Blair Foundation as a Blair Early Career Professor in Vascular Surgery.\n\nAuthor conflict of interest: none.\n\nThe editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest.\n==== Refs\nReferences\n1 Argyriou C. Georgiadis G.S. Lazarides M.K. Georgakarakos E. Antoniou G.A. Endograft infection after endovascular abdominal aortic aneurysm repair: a systematic review and meta-analysis J Endovasc Ther 24 2017 688 697 28756719 \n2 Ehsan O. Gibbons C.P. A 10-year experience of using femoro-popliteal vein for re-vascularisation in graft and arterial infections Eur J Vasc Endovasc Surg 38 2009 172 179 19362498 \n3 Daenens K. Fourneau I. Nevelsteen A. Ten-year experience in autogenous reconstruction with the femoral vein in the treatment of aortofemoral prosthetic infection Eur J Vasc Endovasc Surg 25 2003 240 245 12623336 \n4 van Zitteren M. van der Steenhoven T.J. Burger D.H. van Berge Henegouwen D.P. Heyligers J.M. Vriens P.W. Spiral vein reconstruction of the infected abdominal aorta using the greater saphenous vein: preliminary results of the Tilburg experience Eur J Vasc Endovasc Surg 41 2011 637 646 21377384 \n5 Etienne H. Touma J. Becquemin J.P. Unusual acute onset of abdominal aortic endograft infection by Propionibacterium acnes after coil embolization for type II endoleak Ann Vasc Surg 35 2016 204.e9 204.e11 \n6 Harlock J.A. Qadura M. Lee G. Szalay D.A. Infected aortic stent graft with Propionibacterium acnes Vasc Endovascular Surg 47 2013 394 396 23632775 \n7 Smeds M.R. Duncan A.A. Harlander-Locke M.P. Lawrence P.F. Lyden S. Fatima J. Treatment and outcomes of aortic endograft infection J Vasc Surg 63 2016 332 340 26804214 \n8 Yang R.Y. Tan K.T. Beecroft J.R. Rajan D.K. Jaskolka J.D. Direct sac puncture versus transarterial embolization of type II endoleaks: an evaluation and comparison of outcomes Vascular 25 2017 227 233 27538929 \n9 Stavropoulos S.W. Park J. Fairman R. Carpenter J. Type 2 endoleak embolization comparison: translumbar embolization versus modified transarterial embolization J Vasc Interv Radiol 20 2009 1299 1302 19695902 \n10 Zener R. Oreopoulos G. Beecroft R. Rajan D.K. Jaskolka J. Tan K.T. Transabdominal direct sac puncture embolization of type II endoleaks after endovascular abdominal aortic aneurysm repair J Vasc Interv Radiol 29 2018 1167 1173 29941385 \n11 Scali S.T. Vlada A. Chang C.K. Beck A.W. Transcaval embolization as an alternative technique for the treatment of type II endoleak after endovascular aortic aneurysm repair J Vasc Surg 57 2013 869 874 23312838 \n12 Ferrari M. Sardella S.G. Berchiolli R. Adami D. Vignali C. Napoli V. Surgical treatment of persistent type 2 endoleaks, with increase of the aneurysm sac: indications and technical notes Eur J Vasc Endovasc Surg 29 2005 43 46 15570270 \n13 Lyons O.T. Patel A.S. Saha P. Clough R.E. Price N. Taylor P.R. A 14-year experience with aortic endograft infection: management and results Eur J Vasc Endovasc Surg 46 2013 306 313 23702108 \n14 Kilic A. Arnaoutakis D.J. Reifsnyder T. Black J.H. Abularrage C.J. Perler B.A. Management of infected vascular grafts Vasc Med 21 2016 53 60 26584886 \n15 Berger P. Moll F.L. Aortic graft infections: is there still a role for axillobifemoral reconstruction? Semin Vasc Surg 24 2011 205 210 22230675 \n16 Batt M. Feugier P. Camou F. Coffy A. Senneville E. Caillon J. A meta-analysis of outcomes after in situ reconstructions for aortic graft infection Angiology 69 2018 370 379 28578619 \n17 Clagett G.P. Bowers B.L. Lopez-Viego M.A. Rossi M.B. Valentine R.J. Myers S.I. Creation of a neo-aortoiliac system from lower extremity deep and superficial veins Ann Surg 218 1993 239 248 discussion 248-249 8373267 \n18 Ali A.T. Modrall J.G. Hocking J. Valentine R.J. Spencer H. Eidt J.F. Long-term results of the treatment of aortic graft infection by in situ replacement with femoral popliteal vein grafts J Vasc Surg 50 2009 30 39 19563952\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2468-4287",
"issue": "5(1)",
"journal": "Journal of vascular surgery cases and innovative techniques",
"keywords": "Abdominal aortic aneurysm; Aortic reconstruction; Endoleak embolization; Endovascular aneurysm repair; Graft infection",
"medline_ta": "J Vasc Surg Cases Innov Tech",
"mesh_terms": null,
"nlm_unique_id": "101701125",
"other_id": null,
"pages": "61-64",
"pmc": null,
"pmid": "30911701",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports",
"references": "12623336;15570270;19362498;19563952;19695902;21377384;22230675;23312838;23632775;23702108;26584886;26804214;27238987;27538929;28578619;28756719;29941385;8373267",
"title": "Aortic graft infection with enteric organism after embolization of late type II endoleak.",
"title_normalized": "aortic graft infection with enteric organism after embolization of late type ii endoleak"
} | [
{
"companynumb": "CA-GUERBET-CA-20190004",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEFAZOLIN"
},
"drugadditional": null,
... |
{
"abstract": "Association between the use of hemostatic agents made from collagen/gelatin mixed with thrombin and thromboembolic events in patients undergoing tumor resection has been suggested. This study evaluates the relationship between flowable hemostatic matrix and deep vein thrombosis in a large cohort of patients treated for brain tumor removal. The authors conducted a retrospective, multicenter, clinical review of all craniotomies for tumor removal performed between 2013 and 2014. Patients were classified in three groups: group I (flowable gelatin hemostatic matrix with thrombin), group II (gelatin hemostatic without thrombin), and group III (classical hemostatic). A total of 932 patients were selected: tumor pathology included 441 gliomas, 296 meningiomas, and 195 metastases. Thromboembolic events were identified in 4.7% of patients in which gelatin matrix with thrombin was applied, in 8.4% of patients with gelatin matrix without thrombin, and in 3.6% of cases with classical methods of hemostasis. Patients with venous thromboembolism had an increased proportion of high-grade gliomas (7.2%). Patients receiving a greater dose than 10 ml gelatin hemostatic had a higher rate of thromboembolic events. Intracranial hematoma requiring reintervention occurred in 19 cases: 4.5% of cases of group III, while reoperation was performed in 1.3 and 1.6% of patients in which gelatin matrix with or without thrombin was applied. Gelatin matrix hemostat is an efficacious tool for neurosurgeons in cases of difficult intraoperative bleeding during cranial tumor surgery. This study may help to identify those patients at high risk for developing thromboembolism and to treat them accordingly.",
"affiliations": "Department of Neurosurgery, San Giovanni Addolorata Hospital, Via Amba Aradam 9, 00184, Rome, Italy. robertogazzeri@gmail.com.;Regional Service of Neurosurgery, \"Virgen de la Arrixaca\" University Hospital, Murcia, Spain.;Department of Neurosurgery, Ospedale Santa Maria, Terni, Italy.;Department of Neurosurgery, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.",
"authors": "Gazzeri|Roberto|R|http://orcid.org/0000-0003-1356-1846;Galarza|Marcelo|M|;Conti|Carlo|C|;De Bonis|Costanzo|C|",
"chemical_list": "D006490:Hemostatics; D005780:Gelatin; D013917:Thrombin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10143-017-0856-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5607",
"issue": "41(1)",
"journal": "Neurosurgical review",
"keywords": "Brain hemostasis; Brain tumor; Floseal; Gelatin matrix; Hemostasis; Hemostatic agents; Surgiflo; Thrombin-based hemostatic matrix; Thromboembolism",
"medline_ta": "Neurosurg Rev",
"mesh_terms": "D000328:Adult; D000368:Aged; D001932:Brain Neoplasms; D005260:Female; D005780:Gelatin; D005910:Glioma; D006490:Hemostatics; D006801:Humans; D015994:Incidence; D008297:Male; D008577:Meningeal Neoplasms; D008579:Meningioma; D008875:Middle Aged; D011183:Postoperative Complications; D012189:Retrospective Studies; D013917:Thrombin; D013923:Thromboembolism",
"nlm_unique_id": "7908181",
"other_id": null,
"pages": "303-310",
"pmc": null,
"pmid": "28439721",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "20703888;14992097;23159248;12182794;8170176;7366805;16525187;10931464;16807780;9389920;6303201;7885549;14567603;24635939;8259536;19061356;15509484;25597485;19151266;9688113;11474348;25419955;22915500;19129962;9654538",
"title": "Incidence of thromboembolic events after use of gelatin-thrombin-based hemostatic matrix during intracranial tumor surgery.",
"title_normalized": "incidence of thromboembolic events after use of gelatin thrombin based hemostatic matrix during intracranial tumor surgery"
} | [
{
"companynumb": "IT-JNJFOC-20171112957",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "THROMBIN HUMAN"
},
"drugadditional": "3",
... |
{
"abstract": "De novo HCC following transplantation in a child is a rare occurrence. Even within the adult liver transplantation population, there are a limited number of published cases. In this report, we present a case of de novo HCC found in a child, post-multivisceral transplantation. A 19-year-old boy, at the age of one, received liver and small bowel transplantation due to short gut syndrome secondary to midgut volvulus and total parenteral nutrition-associated liver disease. Eighteen years later, he was found to have a large mass involving the right hepatic dome consistent with HCC. To the best of our knowledge, this is the second reported case after gut transplantation and the third case post-liver transplantation in the pediatric population.",
"affiliations": "Department of Pediatrics, Medstar Georgetown University Hospital, Washington, DC, USA.;Department of Pediatrics, Medstar Georgetown University Hospital, Washington, DC, USA.;Department of Pediatrics, Medstar Georgetown University Hospital, Washington, DC, USA.;Department of Pediatrics, Medstar Georgetown University Hospital, Washington, DC, USA.;Department of Pediatrics, Medstar Georgetown University Hospital, Washington, DC, USA.;Department of Pediatrics, Medstar Georgetown University Hospital, Washington, DC, USA.;Department of Pediatrics, Medstar Georgetown University Hospital, Washington, DC, USA.;Department of Pediatrics, Medstar Georgetown University Hospital, Washington, DC, USA.;Department of Pediatrics, Medstar Georgetown University Hospital, Washington, DC, USA.;Department of Pediatrics, Medstar Georgetown University Hospital, Washington, DC, USA.;Department of Pediatrics, Medstar Georgetown University Hospital, Washington, DC, USA.",
"authors": "Bryan|Nathan|N|0000-0003-4777-4794;Zandieh|Arash|A|;Kallakury|Bhaskar|B|;Kaufman|Stuart|S|0000-0002-5308-4565;Yazigi|Nada|N|;Girlanda|Rafaele|R|;Hawksworth|Jason|J|;Fishbein|Thomas|T|;Matsumoto|Cal|C|;Kroemer|Alexander|A|;Khan|Khalid|K|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13820",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "25(2)",
"journal": "Pediatric transplantation",
"keywords": "hepatic mass; long-term outcome; short gut syndrome",
"medline_ta": "Pediatr Transplant",
"mesh_terms": null,
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13820",
"pmc": null,
"pmid": "32844551",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "De novo hepatocellular carcinoma 18 years after liver and small bowel transplantation in a one-year-old pediatric patient.",
"title_normalized": "de novo hepatocellular carcinoma 18 years after liver and small bowel transplantation in a one year old pediatric patient"
} | [
{
"companynumb": "NVSC2020US237980",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BASILIXIMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "BACKGROUND\nDabigatran has demonstrated promising results for the prevention of strokes in patients with non-valvular atrial fibrillation (NVAF). However, there have been episodes of major bleeding, especially in elderly patients or those with renal dysfunction. The purpose of this study was to retrospectively examine the relationship between the bleeding events and activated partial thromboplastin time (APTT) values under dabigatran usage in the everyday clinical practice. Moreover, we investigated which factors would contribute to the APTT values.\n\n\nRESULTS\nA total of 139 NVAF patients (112 men, 65 ± 11 years) were included. We evaluated the influence of the putative etiological variables and the bleeding score, HAS-BLED score, on APTT values: age greater than 70 years, renal function, gender, dose of dabigatran, and the concomitant prescription of a P-glycoprotein inhibitor. There were 50 patients with an age of ≥ 70 years (36.0%). A P-glycoprotein inhibitor was administered in 18 patients. During the observation period (median 120 days) there was 1 episode of asymptomatic cerebral infarction. There were no intrinsic major bleeding events, however, 11 patients had minor hemorrhagic events. The results of the APTT measurements exhibited a variety of values both among inter- and intra-individuals. On multivariable analysis, significant associations were found between the following risk factors and the APTT values: creatinine clearance, dose of dabigatran, and concomitant use of a P-glycoprotein inhibitor. The minor bleeding events did not correlate with the APTT values, nor HAS-BLED score.\n\n\nCONCLUSIONS\nThe APTT values became prolonged under dabigatran usage and exhibited a remarkable diversity. Although major bleeding did not occur unless APTT was prolonged excessively, minor bleeding arose irrespective of the APTT values even within the range of the APTT values not exceeding 80s.",
"affiliations": "Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan. mihoko_kawabata.cvm@tmd.ac.jp",
"authors": "Kawabata|Mihoko|M|;Yokoyama|Yasuhiro|Y|;Sasano|Tetsuo|T|;Hachiya|Hitoshi|H|;Tanaka|Yasuaki|Y|;Yagishita|Atsuhiko|A|;Sugiyama|Koji|K|;Nakamura|Tomofumi|T|;Suzuki|Masahito|M|;Isobe|Mitsuaki|M|;Hirao|Kenzo|K|",
"chemical_list": "D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000991:Antithrombins; D001562:Benzimidazoles; D015091:beta-Alanine; D003404:Creatinine; D000069604:Dabigatran",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0914-5087",
"issue": "62(2)",
"journal": "Journal of cardiology",
"keywords": "Anticoagulants; Atrial fibrillation; Thrombosis",
"medline_ta": "J Cardiol",
"mesh_terms": "D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000367:Age Factors; D000368:Aged; D000991:Antithrombins; D001281:Atrial Fibrillation; D001562:Benzimidazoles; D003404:Creatinine; D000069604:Dabigatran; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D012189:Retrospective Studies; D012307:Risk Factors; D020521:Stroke; D015091:beta-Alanine",
"nlm_unique_id": "8804703",
"other_id": null,
"pages": "121-6",
"pmc": null,
"pmid": "23680005",
"pubdate": "2013-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Bleeding events and activated partial thromboplastin time with dabigatran in clinical practice.",
"title_normalized": "bleeding events and activated partial thromboplastin time with dabigatran in clinical practice"
} | [
{
"companynumb": "JP-ROXANE LABORATORIES, INC.-2011-BP-20798NB",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
},
... |
{
"abstract": "A boy at 12 days of age developed neonatal herpes simplex virus (HSV) type 2 infection with central nervous system (CNS) disease. After a 21-day course of high-dose intravenous acyclovir, the patient recovered with negative results for HSV DNA in serum and cerebrospinal fluid. Two weeks after a 6-month course of oral valacyclovir suppressive therapy with negative virological assessment, the disease recurred. Another 21-day course of intravenous acyclovir and subsequent 1-year course of oral suppressive therapy were completed. He showed mild developmental delay in language-social skills at 18 months of age. Although recurrences of neonatal HSV infection with CNS disease after suppressive therapy are uncommon, both clinical and virological assessments at the end of the suppressive therapy may be required. Administration of extended long-term suppressive ACV therapy should be considered to reduce the rate of recurrence.",
"affiliations": "Department of Pediatrics, Toyota Memorial Hospital, Toyota, Japan.;Department of Pediatrics, Toyota Memorial Hospital, Toyota, Japan.;Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: yoshi-i@med.nagoya-u.ac.jp.",
"authors": "Kato|Koji|K|;Hara|Shinya|S|;Kawada|Jun-Ichi|J|;Ito|Yoshinori|Y|",
"chemical_list": "D000998:Antiviral Agents; D000212:Acyclovir",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "21(12)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "CNS disease; Neonatal HSV infection; Recurrence; Suppressive therapy",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000212:Acyclovir; D000998:Antiviral Agents; D002493:Central Nervous System Diseases; D006558:Herpes Genitalis; D006561:Herpes Simplex; D018258:Herpesvirus 2, Human; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011251:Pregnancy Complications, Infectious; D012008:Recurrence",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "879-81",
"pmc": null,
"pmid": "26390826",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent neonatal herpes simplex virus infection with central nervous system disease after completion of a 6-month course of suppressive therapy: Case report.",
"title_normalized": "recurrent neonatal herpes simplex virus infection with central nervous system disease after completion of a 6 month course of suppressive therapy case report"
} | [
{
"companynumb": "GB-CIPLA LTD.-2015GB09305",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALACYCLOVIR HYDROCHLORIDE"
},
"drugadditiona... |
{
"abstract": "In the Australian state of Victoria, all fatalities that were recorded from 2002 through to 2008 involving the use of certain serotonin active drugs (tramadol, venlafaxine, fluoxetine, sertraline, citalopram and paroxetine), were reviewed to assess the incidence of contraindicated or ill advised drug combinations. More than 1,000 were identified of which 326 cases formed the basis of this study. These cases involved contraindicated or inappropriate drug combinations that can lead to adverse drug reactions (ADRs) and subsequent fatal toxicity. Of these, 46% were drug-related, 35% were a result of natural disease and 13% were classified as external injury cases. The remaining cases were those where the cause of death (COD) was unascertained. Tramadol was the most common drug, usually detected alongside a serotonergic antidepressant (in 20% of cases). Twenty-five (8%) cases involved contraindicated drug combinations while the remainder (301 cases, 92%) involved drug combinations that are associated with adverse interactions ranging from minor to major severity. Of these 326 cases, the Coroner determined 166 cases (51%) to be acts of intentional self-harm or drug misuse, with the remainder unascertained or attributed to natural disease. Very few post-mortem reports and Coroners' findings made mention of possible ADRs when such combinations were actually present. The majority of cases comprising contraindicated drug combinations involved the combined use of five drugs (24%) at the time of death. A combination of three to five drugs was most common in cases involving inadvisable drug combinations. Combined drug toxicity was the most common COD, with heart disease the most common co-morbidity.",
"affiliations": "Department of Forensic Medicine, Monash University, Victorian Institute of Forensic Medicine, 57-83 Kavanagh Street, Southbank, VIC 3006, Australia. jenniferp@vifm.org",
"authors": "Pilgrim|Jennifer L|JL|;Gerostamoulos|Dimitri|D|;Drummer|Olaf H|OH|",
"chemical_list": "D018490:Serotonin Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00414-010-0536-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-9827",
"issue": "125(6)",
"journal": "International journal of legal medicine",
"keywords": null,
"medline_ta": "Int J Legal Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001344:Autopsy; D002423:Cause of Death; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D057970:Inappropriate Prescribing; D008297:Male; D008875:Middle Aged; D019338:Polypharmacy; D018490:Serotonin Agents; D019966:Substance-Related Disorders; D014739:Victoria",
"nlm_unique_id": "9101456",
"other_id": null,
"pages": "803-15",
"pmc": null,
"pmid": "21120513",
"pubdate": "2011-11",
"publication_types": "D016428:Journal Article",
"references": "15784664;17535384;14660523;11576320;15169709;17471183;15172074;16968950;16584361;15172072;8199957;16490959;10221364;11585484;17187532;11910269;15625333;2035713;17630041;12771076;9271285;14709758;11918514;11300508;20172668;17361124;10950475;26256305;14641552;16460699;19175914;12959283;12842359;18614817;14678335;17303973;11184820;24936991;11566418;19946767;18754849;15172073;16051647;20432045;16781104;15635814;18386306;19129307;7576268;11816261;14970364;8765105;16005413;1905641",
"title": "Deaths involving contraindicated and inappropriate combinations of serotonergic drugs.",
"title_normalized": "deaths involving contraindicated and inappropriate combinations of serotonergic drugs"
} | [
{
"companynumb": "AU-NAPPMUNDI-GBR-2010-0007491",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "THEOPHYLLINE ANHYDROUS"
},
"drugadditiona... |
{
"abstract": "OBJECTIVE\nAggressive fibromatoses (AF; desmoid tumors) are rare clonal neoplastic proliferations of connective tissues that can be locally aggressive despite wide surgical resection and/or radiation therapy. The Sarcoma Alliance for Research through Collaboration (SARC) initiated a prospective phase II trial to investigate the outcome of patients treated with imatinib, a multiple tyrosine kinase inhibitor, in patients with AF, or 1 of 10 sarcoma subtypes. Here, we report specifically on the outcome of patients with AF as well as evaluations undertaken to examine the mechanism of imatinib.\n\n\nMETHODS\nPatients ≥10 years old with desmoid tumors that were not curable by surgical management or in whom curative surgery would lead to undesirable functional impairment were eligible. Imatinib was prescribed at 300 mg twice daily [body surface area (BSA) ≥ 1.5 m(2)], 200 mg twice daily (BSA = 1.0-1.49 m(2)), or 100 mg twice daily (BSA < 1.0 m(2)). Response outcomes at 2 and 4 months were assessed. Tissue specimens were analyzed by immunohistochemistry for expression of cKIT, platelet-derived growth factor receptor α (PDGFRα), PDGFRβ, AKT, PTEN, FKHR, and β-catenin. Tumor DNA was analyzed for PDGFRα exon 18 and APC mutations by allelic discrimination PCR.\n\n\nRESULTS\nFifty-one patients were enrolled. The median number of prior regimens was 1. Kaplan-Meier estimates of 2- and 4-month progression-free survival rates were 94% and 88%, respectively, and 1-year progression-free survival was 66%. Objective response rate was 6% (3 of 51). Expression and polymorphisms of target proteins were identified in tissue samples, but no significant correlation with outcome was observed using the samples available.\n\n\nCONCLUSIONS\nImatinib may have a role in the management of unresectable or difficult to resect desmoid tumors.",
"affiliations": "Department of Internal Medicine, University of Michigan, Ann Arbor, 48109-5843, USA. rashmim@umich.edu",
"authors": "Chugh|Rashmi|R|;Wathen|J Kyle|JK|;Patel|Shreyaskumar R|SR|;Maki|Robert G|RG|;Meyers|Paul A|PA|;Schuetze|Scott M|SM|;Priebat|Dennis A|DA|;Thomas|Dafydd G|DG|;Jacobson|Jon A|JA|;Samuels|Brian L|BL|;Benjamin|Robert S|RS|;Baker|Laurence H|LH|;|||",
"chemical_list": "D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate",
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-10-1177",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0432",
"issue": "16(19)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D001549:Benzamides; D002648:Child; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D018222:Fibromatosis, Aggressive; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010879:Piperazines; D011743:Pyrimidines; D016896:Treatment Outcome; D055815:Young Adult",
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"references": null,
"title": "Efficacy of imatinib in aggressive fibromatosis: Results of a phase II multicenter Sarcoma Alliance for Research through Collaboration (SARC) trial.",
"title_normalized": "efficacy of imatinib in aggressive fibromatosis results of a phase ii multicenter sarcoma alliance for research through collaboration sarc trial"
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"abstract": "Vlad, not his real name, a 15 year old boy with an autism spectrum disorder and intellectual disability, was referred for psychiatric consultation due to aggression and other behavioural problems. He presented for initial psychiatric consultation on five psychotropic medications with associated severe obesity. A systematic deprescribing and cross-tapering plan was implemented, removing all five psychotropic medications (which included olanzapine and quetiapine) and introducing ziprasidone. These changes were associated with a 44.8kg weight loss with no behavioral deterioration and overall lower rates of aggression. Vlad's case may typify important deficiencies in the service system which create a context that allows for aggressive psychotropic polypharmacy without apparent concomitant increase in sophistication of behavioral management design and support, while also tolerating substantial treatment adverse effects (e.g., medication induced severe obesity) within a member of a vulnerable population (e.g., a youth with developmental disability in care). Suggestions to address some of these contextual factors are outlined.",
"affiliations": "Children's Hospital of Eastern Ontario-Research Institute, Ottawa, Ontario.",
"authors": "McLennan|John D|JD|",
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"journal": "Journal of the Canadian Academy of Child and Adolescent Psychiatry = Journal de l'Academie canadienne de psychiatrie de l'enfant et de l'adolescent",
"keywords": "autism; health services; intellectual disability; obesity; psychotropic medication; ziprasidone",
"medline_ta": "J Can Acad Child Adolesc Psychiatry",
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"nlm_unique_id": "101280868",
"other_id": null,
"pages": "141-146",
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"pmid": "31798652",
"pubdate": "2019-11",
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"references": "26860953;26016407;10690996;10596256;18182600;8594834;26091194;28325061;29673269;25798731;16435327;22452529;27171466;14624190;20147714;24763306;30810348",
"title": "Deprescribing in a Youth with an Intellectual Disability, Autism, Behavioural Problems, and Medication-Related Obesity: A Case Study.",
"title_normalized": "deprescribing in a youth with an intellectual disability autism behavioural problems and medication related obesity a case study"
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"abstract": "Tuberculosis is an important opportunist infection that can complicate the posttransplant course of solid-organ transplant recipients. Lung transplant recipients are at higher risk of tuberculosis after transplant than are other solid-organ transplant recipients. Significant drug-drug interactions between antituberculous medications, especially rifampin, and immunosuppressant medications render treatment in this patient population especially challenging. Data on the management of tuberculosis in lung transplant recipients with rifamycin-sparing regimens are so far limited. Therefore, we evaluated the incidence, clinical features, treatment, and outcomes of active tuberculosis in lung transplant patients from a single center in Riyadh, Saudi Arabia.\n\n\n\nCases of active tuberculosis in lung transplant recipients diagnosed between January 2005 and December 2017 at our center were included. Data on patient demographics, clinical presentations, diagnosis, treatment regimens, and outcomes were collected.\n\n\n\nSeven of 133 lung transplant recipients (5.3%) were diagnosed with active tuberculosis during the study period, corresponding to an incidence rate of 2147/100 000 person-years. Patients were diagnosed at median time of 94 days posttransplant. Fever and weight loss were the most common presenting symptoms. All patients were initially treated with a regimen consisting of isoniazid, ethambutol, pyrazinamide, and moxifloxacin. Isoniazid was later substituted with rifabutin in 2 patients with isoniazid-resistant tuberculosis. All patients were treated for a total of 9 to 12 months, without any adverse event-related interruptions. All patients were alive at 12 months after the diagnosis of tuberculosis. There was no evidence of relapse in any of the patients after a median of 32 (range, 9-51) months of follow-up after treatment.\n\n\n\nRifamycin-sparing regimens appear to be safe and highly efficacious in the treatment of active tuberculosis in lung transplant recipients.",
"affiliations": "From the Section of Infectious Diseases, Department of Medicine, King Faisal Specialist Hospital and Research Centre, Doha, Qatar.",
"authors": "Almaghrabi|Reem S|RS|;Nizami|Imran|I|;Alameer|Reem|R|;Alshehri|Nada|N|;Almohaizeie|Abdullah|A|;Alrajhi|Abdulrahman A|AA|;Omrani|Ali S|AS|",
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"doi": "10.6002/ect.2020.0277",
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"issue": "19(4)",
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"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
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"title": "Successful Use of Rifamycin-Sparing Regimens for the Treatment of Active Tuberculosis in Lung Transplant Recipients.",
"title_normalized": "successful use of rifamycin sparing regimens for the treatment of active tuberculosis in lung transplant recipients"
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"abstract": "Herein, we describe a 14-year-old female patient with B-cell precursor acute lymphoblastic leukemia who relapsed in early consolidation. Minimal residual disease-negative complete remission was obtained after 1 cycle of inotuzumab ozogamicin therapy. She underwent HLA-haploidentical peripheral blood stem cell transplantation after a myeloablative conditioning regimen. Posttransplant cyclophosphamide, tacrolimus, and mycophenolate mofetil were administered for the prophylaxis of graft-versus-host disease. At 23 months, she was in complete remission. Although the administration of inotuzumab ozogamicin followed by haploidentical peripheral blood stem cell transplantation with posttransplant cyclophosphamide has been limited in children, this strategy may be an effective treatment for pediatric refractory acute lymphoblastic leukemia.",
"affiliations": "Department of Pediatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Kagoshima Prefecture, Japan.",
"authors": "Abematsu|Takanari|T|;Nishikawa|Takuro|T|;Nakagawa|Shunsuke|S|;Kodama|Yuichi|Y|;Okamoto|Yasuhiro|Y|;Kawano|Yoshifumi|Y|",
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"journal": "Journal of pediatric hematology/oncology",
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"pmid": "33512872",
"pubdate": "2021-01-27",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Successful Salvage of Very Early Relapse in Pediatric Acute Lymphoblastic Leukemia With Inotuzumab Ozogamicin and HLA-haploidentical Peripheral Blood Stem Cell Transplantation With Posttransplant Cyclophosphamide.",
"title_normalized": "successful salvage of very early relapse in pediatric acute lymphoblastic leukemia with inotuzumab ozogamicin and hla haploidentical peripheral blood stem cell transplantation with posttransplant cyclophosphamide"
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"abstract": "BACKGROUND\nFibrillary glomerulonephritis (FGN) is a rare primary glomerular disease that seldom coexists with other diseases. Membranoproliferative glomerulonephritis is a pathologic finding of renal lesions associated with IgM-secreting monoclonal proliferations. We present a case study of a patient with unusual simultaneous FGN and IgM-related renal disorder in nonmalignant monoclonal IgM gammopathy.\n\n\nMETHODS\nA 63-year-old male presented with nephrotic syndrome and elevated serum creatinine levels. Laboratory examination revealed elevated levels of serum IgM and low C3 levels. Serum and urine immunofixation electrophoresis showed a monoclonal IgM with a kappa light chain. A bone marrow biopsy revealed less than 5 % bone marrow infiltration by lymphoplasmacytic lymphoma, and a renal biopsy revealed mesangiocapillary glomerulonephritis on light microscopy. Immunofluorescent and immunohistochemical staining indicated granular deposits of immunoglobulin G in the mesangium and granular deposits of immunoglobulin M and κ light chains along the capillary wall. Electron microscopy revealed randomly arranged nonbranching fibrils of approximately 15 nm in diameter in the glomerular mesangium and subendothelial electron-dense deposits. According to these results, we confirmed FGN and membranoproliferative glomerulonephritis, which were attributed to monoclonal IgM deposits.\n\n\nCONCLUSIONS\nTo the best of our knowledge, this is the first report of simultaneous FGN and membranoproliferative glomerulonephritis in nonmalignant IgM monoclonal gammopathy.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, 95,Wen Chang Rd., Shih Lin District, Taipei, 11101, Taiwan.;Division of Nephrology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, 95,Wen Chang Rd., Shih Lin District, Taipei, 11101, Taiwan.;Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.;Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.;Division of Nephrology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, 95,Wen Chang Rd., Shih Lin District, Taipei, 11101, Taiwan.;Division of Nephrology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, 95,Wen Chang Rd., Shih Lin District, Taipei, 11101, Taiwan. shoushan.chiang@gmail.com.",
"authors": "Wu|Chung-Kuan|CK|;Leu|Jyh-Gang|JG|;Yang|An-Hang|AH|;Tarng|Der-Cherng|DC|;Tung|Hsiang-Yuen|HY|;Chiang|Shou-Shan|SS|",
"chemical_list": "D007074:Immunoglobulin G; D007075:Immunoglobulin M",
"country": "England",
"delete": false,
"doi": "10.1186/s12882-015-0198-y",
"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central London 19810.1186/s12882-015-0198-yCase ReportSimultaneous occurrence of fibrillary glomerulonephritis and renal lesions in nonmalignant monoclonal IgM gammopathy Wu Chung-Kuan chungkuan.wu@gmail.com Leu Jyh-Gang 056111@mail.fju.edu.tw Yang An-Hang ahyang@vghtpe.gov.tw Tarng Der-Cherng dctarng@vghtpe.gov.tw Tung Hsiang-Yuen maple541031@yahoo.com.tw Chiang Shou-Shan (886)-2-2833-2221-422386shoushan.chiang@gmail.com Division of Nephrology, Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, 95,Wen Chang Rd., Shih Lin District Taipei, 11101 Taiwan Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 18 2 2016 18 2 2016 2016 17 1726 2 2015 28 11 2015 © Wu et al. 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\nFibrillary glomerulonephritis (FGN) is a rare primary glomerular disease that seldom coexists with other diseases. Membranoproliferative glomerulonephritis is a pathologic finding of renal lesions associated with IgM-secreting monoclonal proliferations. We present a case study of a patient with unusual simultaneous FGN and IgM-related renal disorder in nonmalignant monoclonal IgM gammopathy.\n\nCase presentation\nA 63-year-old male presented with nephrotic syndrome and elevated serum creatinine levels. Laboratory examination revealed elevated levels of serum IgM and low C3 levels. Serum and urine immunofixation electrophoresis showed a monoclonal IgM with a kappa light chain. A bone marrow biopsy revealed less than 5 % bone marrow infiltration by lymphoplasmacytic lymphoma, and a renal biopsy revealed mesangiocapillary glomerulonephritis on light microscopy. Immunofluorescent and immunohistochemical staining indicated granular deposits of immunoglobulin G in the mesangium and granular deposits of immunoglobulin M and κ light chains along the capillary wall. Electron microscopy revealed randomly arranged nonbranching fibrils of approximately 15 nm in diameter in the glomerular mesangium and subendothelial electron-dense deposits. According to these results, we confirmed FGN and membranoproliferative glomerulonephritis, which were attributed to monoclonal IgM deposits.\n\nConclusion\nTo the best of our knowledge, this is the first report of simultaneous FGN and membranoproliferative glomerulonephritis in nonmalignant IgM monoclonal gammopathy.\n\nKeywords\nFibrillary glomerulonephritis (FGN)IgM monoclonal gammopathyMembranoproliferative glomerulonephritisissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nThe term “fibrillary glomerulonephritis” (FGN) was introduced by Alpers et al in 1987 to characterize the glomerular accumulation of nonbranching, randomly arranged fibril, which differ from amyloid deposits in their large size and lack of reactivity to Congo red [1]. FGN is a rare disorder, diagnosed in less than 1 % of renal biopsies and usually presents with renal insufficiency, nephrotic range proteinuria, and hematuria [2].\n\nIgM monoclonal gammopathies can be categorized into symptomatic, asymptomatic Waldenström’s disease, IgM–related disorders, and IgM monoclonal gammopathy of unknown significance (MGUS) [3]. Renal involvement in IgM monoclonal gammopathy is typically found in patients with the malignant disease, Waldenström’s macroglobulinemia, which is associated with B-cell lymphoproliferative disorder [4]. Renal lesions include the deposition of monoclonal IgM and light chains on the mesangium and glomerular capillary wall [5, 6]. In patients with nonmaligant IgM monoclonal gammopathy, renal involvement has seldom been reported [7].\n\nWe present a case report of a patient with nonmalignant IgM/κ gammopathy who developed nephrotic syndrome associated with FGN and the renal deposition of IgM and κ light chains.\n\nCase presentation\nA 63-year-old man presented at our nephrologic outpatient clinic with progressive bilateral leg edema and foamy urine, which he had experienced for 1 month. He was hospitalized for alcoholic pancreatitis in 1999 but not regularly followed up by our hospital after discharge.\n\nPhysical examination of the patient revealed a blood pressure of 150/85 mmHg, blood temperature of 36.5 °C, and pulse rate of 78 beats/minute; the grading scale for pitting edema was 3+. The laboratory results were as follows: blood urea nitrogen, 26 mg/dL; serum creatinine, 1.8 mg/dL; albumin, 3.1 g/dL; hemoglobin, 12.4 g/dL and platelets, 212 × 103 / uL. Urinalysis revealed 2+ occult blood, 3+ protein, and 5-7 red blood cells/high power field; the 24-h protein excretion was 5.7 g/day. Serum immunoglobulin (Ig) and serum complement tests yielded high IgM (498 mg/dL), low C3 and IgG (73 and 688 mg/dL, respectively), and normal IgA and C4 levels. Serum and urine immunofixation electrophoresis showed a monoclonal IgM-bearing kappa light chain. The urinary Bence Jones protein was negative. The rheumatoid factor, antinuclear antibody, cryoglobulin, and other autoantibodies were negative. Serum antibodies against HIV, hepatitis B and C were all negative. A bone marrow biopsy revealed hypocellularity with normal maturation of myeloid series, and less than 5 % of the cells had positive immunohistochemical staining of CD138/syndecan-1 plasma cells.\n\nRenal sonography showed that both kidneys were enlarged. Chest and abdominal computerized tomography ruled out organomegaly and lymphadenopathy. A whole body bone X-ray revealed no lytic bone lesions.\n\nLight microscopy of the renal biopsy revealed nodular segmental glomerulosclerosis with mesangial cell proliferation and mesangial matrix expansion (Fig. 1a) in 9 of the 11 glomeruli; the other 2 glomeruli are global scleroses. In addition, focal segmental double-contoured capillary walls were observed, and mild tubular atrophy, interstitial fibrosis, and mononuclear cell infiltration were found (Fig. 1b). Congo red staining was negative.Fig. 1 Light microscopic features of membranoproliferative glomerulonephritis. (a) The mesangium is expanded and the glomerular capillary walls appear thickened (periodic acid-Schiff). (b) Glomerular capillary walls exhibit thickened and segmental double contours (methenamine silver)\n\n\n\nWe performed immunofluorescence studies, observing a strong positive staining for IgM with a diffuse, global, granular, and capillary pattern (Fig. 2a) ; positive staining for IgG with a diffuse, granular, and mesangial pattern (Fig. 2b); and positive staining for C3 with a diffuse, segmental, and granular pattern in the mesangium and along the capillary wall (Fig. 2c). Immunohistochemistry of the light chains revealed κ positive along the capillary wall. Electron microscopy showed podocyte foot process effacement and microvillus transformation. Electron-dense materials were deposited in the subendothelial area and limited intracapillary monoclonal deposits were observed (Fig. 3a). Irregular accumulations of randomly arranged nonbranching fibrils, approximately 15 nm in diameter, were found in the glomerular mesangium (Fig. 3b, c). These findings confirmed the diagnosis of FGN with membranoproliferative glomerulonephritis in nonmalignant IgM monoclonal gammopathy.Fig. 2 Immunofluorescent staining on fibrillary glomerulonephritis and renal involvement of IgM gammopathy. (a) Diffuse granular deposits of IgM along the glomerular capillary walls. (b) Smudged diffuse granular mesangial deposits of IgG. (c) Diffuse segmental granular deposits of C3 on the mesangium and along the glomerular capillary walls\n\nFig. 3 Electron microscopic features of subendothelial deposits and fibrillary glomerulonephritis. (a) Electron micrograph image revealing granular subendothelial deposits and small intracapillary deposits. (b) Electron micrograph image showing infiltration of fibrillar materials in the mesangium. (c) Irregular accumulations of randomly arranged nonbranching fibrils in the mesangium\n\n\n\nThe patient was treated initially with diuretics, angiotensin receptor blockers, 0.5 mg/kg of prednisolone per day, and 1.5 mg/kg of cyclophosphamide per day. Because steroid-induced diabetes occurred, we halved the steroid dose within the first 3 months. After 6 months, serum creatinine levels were maintained at 1.8 mg/dL and the 24-h protein excretion decreased to 1.8 g/day. 1 year later, the patient experienced herpes zoster; therefore, we discontinued cyclophosphamide treatment. However, the patient progressed to stage 4 chronic kidney disease the second year after diagnosis and advanced to end-stage renal disease (ESRD) without dialysis the third year after diagnosis.\n\nConclusions\nFGN, first described by Rosenmann and Eliakim in 1977 [8], is a rare primary glomerulonephritis diagnosed by the ultrastructural features of nonbranching random fibrils measuring 10-30 nm in diameter. The fibrils are deposited in the mesangium, the glomerular basement membranes, or both. The light microscopic findings are highly variable, and most exhibit mesangial expansion and hypercellularity with or without the duplication of glomerular basement membranes. Immunofluorescence staining is almost consistently positive for IgG, C3, and both κ and λ chains, indicating polyclonal deposits. Weak staining for IgM, IgA, and C1q has been reported in a few cases [2, 9, 10].\n\nOur patient with FGN exhibited various atypical characteristics, including a strong positive immunofluorescent intensity of IgM along the glomerular capillary wall; the presence of IgM κ, as detected by immunofixation electrophoresis, and hypocomplementemia. In a large single-center series of 66 FGN cases, 47 % of the cases were weakly positive for IgM according to the immunofluorescence stain, and the mean intensity of the positive cases was 1.0+. Of the 11 patients exhibiting a positive M-spike, all were IgG with or without light chains according to immunofixation electrophoresis. Only one patient in this study had hypocomplementemia [11]. Only one case of FGN with unusual IgM deposits and hypocomplementemia has been reported in the English literature. A 12-year-old girl who presented with nephrotic-nephritic syndrome had IgM deposits in the mesangium and randomly arranged fibrillary electron-dense deposits in the mesangium, and the subendothelial and subepithelial area of capillary loops. However, the patient did not have elevated levels of serum IgM or positive IgM detected by urine protein electrophoresis [12].\n\nAt an international workshop on Waldenström’s macroglobulinemia, 4 categories of IgM monoclonal gammopathies were proposed. Patients with bone marrow infiltration by lymphoplasmacytic lymphoma who (1) might or might not (2) have symptoms caused by IgM are categorized as having symptomatic or asymptomatic Waldenström’s disease, respectively. (3) Patients with symptoms attributable to IgM but with no bone marrow infiltration are classified as having IgM-related disorder. (4) Patients with IgM monoclonal gammopathy but no bone marrow infiltration or IgM-related symptoms are classified as having MGUS [3].\n\nThe incidence of renal complications of malignant IgM-secreting proliferation is rare, and renal involvement in IgM monoclonal disorders is generally described in patients with Waldenström’s macroglobulinemia [6]. The typical pathologic findings of Waldenström’s macroglobulinemia-related nephropathies include intracapillary deposits of IgM with or without cryoglobulinemia, light chain amyloidosis, and infiltration of the interstitium by neoplastic lymphoplasmacytic cells [5]. Glomerular involvement was noted in some patients with typical mesangioproliferative or mesangiocapillary glomerulonephritis with IgM deposits in the mesangium and/or along the glomerular basement membrane [13]. Upon immunofluorescence stain, the deposits of IgM and the single light chain isotype were consistent with circulating M components. Electron microscopy revealed that the subendothelial deposits contain nonamyloid fibrillar materials [14].\n\nOur patient had renal lesions associated with IgM-secreting monoclonal proliferations but did not fulfill the criteria for having Waldenström’s macroglobulinemia. Audard et al. revisited the spectrum of renal lesions occurring in patients with a circulating monoclonal IgM and kidney disease related to B cell proliferation. Of the 14 patients examined, 5 patients had intracapillary IgM monoclonal deposits disease, 3 patients had a neoplastic lymphoplasmacytic infiltration of the interstitium, 3 patients had membranoproliferative glomerulonephritis, 2 patients had amyloidosis, and 1 patient had acute tubular necrosis. According to immunologic data, only 3 patients had low blood complement C3, C4, and CH50 levels; all these patients were diagnosed with Waldenström’s macroglobulinemia [15]. Our patient had circulating monoclonal IgM and a low blood complement C3 level but no bone marrow infiltrations. A kidney disease related to B- cell proliferation is membranoproliferative glomerulonephritis, but unusual nonbranching randomly fibrils is found in the mesangium.\n\nRegarding treatment, although no effective therapy has been established for FGN, some clinicians have treated the disease according to pathologic findings. Cyclosporine has been used successfully to treat patients with a membranous pattern, and rituximab has been used successfully to treat patients with an MPGN pattern [9, 16]. In previous investigations, the prognosis of patients with FGN has been poor, and 40 %-50 % of such patients have developed ESRD within 6 years of presentation [2, 17]. Treatment recommendations for Waldenström’s macroglobulinemia were established in the aforementioned international workshop. Patients with Waldenström’s macroglobulinemia should be treated when their hemoglobin level is less than 100 g/L, their platelet count is less than 100 × 109/L, and they present with bulky disease, symptomatic hyperviscosity, severe neuropathy, amyloidosis, cryoglobulinemia, cold-agglutinin disease, or evidence of disease transformation [3, 6]. Several drugs are used for frontline therapy, such as alkylators (ie, chlorambucil), nucleoside analogues (ie, fludarabine) and monoclonal antibodies (ie, rituximab), and combination therapies include cyclophosphamide, doxorubicin, vincristine, and prednisolone. Other alternative treatments included autologous transplantation, thalidomide or thalidomide plus steroids, and alemtuzumab [6]. Rituximab was suggested for our patient, but his condition did not satisfy the criteria for health insurance payment. Finally, in addition to conservative treatment with angiotensin receptor blocker and diuretic drugs, he was treated with cyclophosphamide and prednisolone. Nevertheless, he progressed to ESRD after 2 years of treatment.\n\nIn summary, we report a rare simultaneous occurrence of FGN and membranoproliferative glomerulonephritis attributed to IgM/κ deposits in a patient with nonmalignant IgM monoclonal gammopathy. This patient exhibited a wide spectrum of renal lesions caused by IgM-secreting monoclonal proliferations, and renal prognosis was as poor as that for FGN.\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\nAbbreviations\nFGNfibrillary glomerulonephritis\n\nMGUSIgM monoclonal gammopathy of unknown significance\n\nESRDend-stage renal disease\n\nCompeting interests\n\nThe authors declare that they have no competing interests\n\nAuthors’ contributions\n\nCW wrote the manuscript and was a treating physician for the patient. SC was also a treating physician for the patient and assisted drafting the manuscript. AY interpreted the histopathological data and helped draft the manuscript. JL performed the literature review and collected the data. HT collected the data. DT helped to draft the manuscript. All authors read and approved the final manuscript.\n\nThis study was not funded by any third party.\n==== Refs\nReferences\n1. Alpers CE Rennke HG Hopper J Jr Biava CG Fibrillary glomerulonephritis: an entity with unusual immunofluorescence features Kidney Int 1987 31 3 781 789 10.1038/ki.1987.66 3106698 \n2. Iskandar SS Falk RJ Jennette JC Clinical and pathologic features of fibrillary glomerulonephritis Kidney Int 1992 42 6 1401 1407 10.1038/ki.1992.433 1474772 \n3. Owen RG Treon SP Al-Katib A Fonseca R Greipp PR McMaster ML Morra E Pangalis GA San Miguel JF Branagan AR Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia Seminars in oncology 2003 30 2 110 115 10.1053/sonc.2003.50082 12720118 \n4. Fonseca R Hayman S Waldenstrom macroglobulinaemia Br J Haematol 2007 138 6 700 720 10.1111/j.1365-2141.2007.06724.x 17672883 \n5. Morel-Maroger L Basch A Danon F Verroust P Richet G Pathology of the kidney in Waldenstrom's macroglobulinemia. Study of sixteen cases N Engl J Med 1970 283 3 123 129 10.1056/NEJM197007162830304 4987279 \n6. Treon SP Gertz MA Dimopoulos M Anagnostopoulos A Blade J Branagan AR Garcia-Sanz R Johnson S Kimby E Leblond V Update on treatment recommendations from the Third International Workshop on Waldenstrom's macroglobulinemia Blood 2006 107 9 3442 3446 10.1182/blood-2005-02-0833 16410453 \n7. Ramos R Poveda R Sarra J Domingo A Carreras L Grinyo JM Renal involvement in non-malignant IgM gammopathy Nephrol Dial Transplant 2007 22 2 627 630 10.1093/ndt/gfl709 17164317 \n8. Rosenmann E Eliakim M Nephrotic syndrome associated with amyloid-like glomerular deposits Nephron 1977 18 5 301 308 10.1159/000180846 865657 \n9. Rosenstock JL Markowitz GS Valeri AM Sacchi G Appel GB D'Agati VD Fibrillary and immunotactoid glomerulonephritis: Distinct entities with different clinical and pathologic features Kidney international 2003 63 4 1450 1461 10.1046/j.1523-1755.2003.00853.x 12631361 \n10. Bridoux F Hugue V Coldefy O Goujon JM Bauwens M Sechet A Preud'Homme JL Touchard G Fibrillary glomerulonephritis and immunotactoid (microtubular) glomerulopathy are associated with distinct immunologic features Kidney international 2002 62 5 1764 1775 10.1046/j.1523-1755.2002.00628.x 12371978 \n11. Nasr SH Valeri AM Cornell LD Fidler ME Sethi S Leung N Fervenza FC Fibrillary glomerulonephritis: a report of 66 cases from a single institution Clin J Am Soc Nephrol 2011 6 4 775 784 10.2215/CJN.08300910 21441134 \n12. Shim YH Lee SJ Sung SH A case of fibrillary glomerulonephritis with unusual IgM deposits and hypocomplementemia Pediatric nephrology 2008 23 7 1163 1166 10.1007/s00467-008-0765-6 18288497 \n13. Kyle RA Garton JP The spectrum of IgM monoclonal gammopathy in 430 cases Mayo Clin Proc 1987 62 8 719 731 10.1016/S0025-6196(12)65225-2 3110508 \n14. Gallo GR Feiner HD Buxbaum JN The kidney in lymphoplasmacytic disorders Pathology annual 1982 17 Pt 1 291 317 6812009 \n15. Audard V Georges B Vanhille P Toly C Deroure B Fakhouri F Cuvelier R Belenfant X Surin B Aucouturier P Renal lesions associated with IgM-secreting monoclonal proliferations: revisiting the disease spectrum Clin J Am Soc Nephrol 2008 3 5 1339 1349 10.2215/CJN.01600408 18632851 \n16. Collins M Navaneethan SD Chung M Sloand J Goldman B Appel G Rovin BH Rituximab treatment of fibrillary glomerulonephritis Am J Kidney Dis 2008 52 6 1158 1162 10.1053/j.ajkd.2008.07.011 18823685 \n17. Fogo A Qureshi N Horn RG Morphologic and clinical features of fibrillary glomerulonephritis versus immunotactoid glomerulopathy Am J Kidney Dis 1993 22 3 367 377 10.1016/S0272-6386(12)70138-5 8372831\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "17()",
"journal": "BMC nephrology",
"keywords": null,
"medline_ta": "BMC Nephrol",
"mesh_terms": "D005921:Glomerulonephritis; D015432:Glomerulonephritis, Membranoproliferative; D006801:Humans; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008297:Male; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance; D009404:Nephrotic Syndrome",
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "17",
"pmc": null,
"pmid": "26892336",
"pubdate": "2016-02-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12631361;12371978;18632851;18288497;17672883;17164317;16410453;8372831;1474772;3110508;3106698;21441134;18823685;4987279;12720118;6812009;865657",
"title": "Simultaneous occurrence of fibrillary glomerulonephritis and renal lesions in nonmalignant monoclonal IgM gammopathy.",
"title_normalized": "simultaneous occurrence of fibrillary glomerulonephritis and renal lesions in nonmalignant monoclonal igm gammopathy"
} | [
{
"companynumb": "TW-WATSON-2016-06498",
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"occurcountry": "TW",
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"activesubstancename": "PREDNISOLONE"
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"drugadditional": null,
... |
{
"abstract": "Sarcoidosis is a multisystem granulomatous disease of unknown etiology that rarely presents in childhood. Here, we report a case of pediatric sarcoidosis presenting with renal failure and hypercalcemia.\n\n\n\nA previously well 14-year-old Caucasian boy was admitted to the Hospital for Sick Children, Canada, for hypertension and renal failure following work-up by his family physician for initial concerns of growth failure. On admission, his weight was 35 kg (<3rd percentile), his height was 148 cm (≪3rd percentile), and his blood pressure was 154/116 mmHg (>99th percentile for height). Laboratory findings showed elevated creatinine (218 μmol/L), hypercalcemia (3.21 mmol/L), and normocytic anemia (hemoglobin 105 g/L). His further assessment showed a urinary concentrating defect with hypercalciuria (calcium/creatinine 1.76 mmol/mmol) and nephrocalcinosis on ultrasound. His eye examination showed uveitis with conjunctival biopsy remarkable for granulomas, which led to pursuit of a diagnosis of possible sarcoidosis. Angiotensin-converting enzyme was found to be high at 96 U/L, and he had a renal biopsy that was consistent with interstitial nephritis with granulomas. Treatment was started with prednisone leading to resolution of his hypercalcemia but persistence of his mild chronic kidney disease.\n\n\n\nThis case represents an atypical presentation of a rare pediatric disease and highlights the spectrum of renal manifestations and treatment options in sarcoidosis.",
"affiliations": "Division of Nephrology, University of Toronto, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.;Division of Nephrology, University of Toronto, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.;Division of Rheumatology, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada.;Division of Rheumatology, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada.;Division of Ophthalmology, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada.;Division of Endocrinology, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada.;Division of Endocrinology, Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada.;Department of Pathology, University Health Network, University of Toronto, Toronto, ON, Canada.;Division of Nephrology, University of Toronto, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.;Division of Nephrology, University of Toronto, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada. diane.hebert@sickkids.ca.",
"authors": "Downie|Mallory L|ML|;Mulder|Jaap|J|;Schneider|Rayfel|R|;Lim|Lillian|L|;Tehrani|Nasrin|N|;Wasserman|Jonathan D|JD|;Fuchs|Shai|S|;John|Rohan|R|;Noone|Damien G|DG|;Hebert|Diane|D|",
"chemical_list": "D005938:Glucocorticoids; D011241:Prednisone",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00467-017-3768-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-041X",
"issue": "33(6)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": "Children; Granuloma; Hypercalcemia; Pediatric; Renal failure; Sarcoidosis",
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D000293:Adolescent; D003937:Diagnosis, Differential; D005183:Failure to Thrive; D005938:Glucocorticoids; D006801:Humans; D006934:Hypercalcemia; D007668:Kidney; D008297:Male; D011241:Prednisone; D051437:Renal Insufficiency; D012507:Sarcoidosis",
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "991-993",
"pmc": null,
"pmid": "28785983",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A curious case of growth failure and hypercalcemia: Questions.",
"title_normalized": "a curious case of growth failure and hypercalcemia questions"
} | [
{
"companynumb": "CA-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-293001",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drug... |
{
"abstract": "Warfarin-related nephropathy.\n\n\n\nWarfarin.\n\n\n\nA 31-year-old female, managed with warfarin for rheumatic heart disease with atrial fibrillation.\n\n\n\nThere were no alternative causes of nephropathy that could have caused the adverse event in this patient.\n\n\n\nShifting the drug from warfarin to acenocoumarol.\n\n\n\nDifference in renal elimination between warfarin and acenocoumarol.\n\n\n\nClinicians should be aware of this rare adverse effect of warfarin, and acenocoumarol can be considered as an alternative therapy for this condition.\n\n\n\nFurther prospectively designed studies are needed to consider acenocoumarol as an alternative therapy in warfarin-related nephropathy.",
"affiliations": "Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.;Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.;Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.;Department of Cardiothoracic & Vascular Surgery, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.;Department of Nephrology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.;Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.",
"authors": "Behera|Sapan Kumar|SK|;Xavier|Alphienes Stanley|AS|0000-0001-5820-7862;Selvarajan|Sandhiya|S|0000-0002-7948-7821;Munuswamy|Hemachandren|H|;Haridasan|Satish|S|;Srinivas|Bheemanathi Hanuman|BH|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin; D000074:Acenocoumarol",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.13541",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "84(5)",
"journal": "British journal of clinical pharmacology",
"keywords": null,
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000074:Acenocoumarol; D000328:Adult; D000925:Anticoagulants; D001281:Atrial Fibrillation; D005260:Female; D006801:Humans; D007674:Kidney Diseases; D012214:Rheumatic Heart Disease; D014859:Warfarin",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "1068-1071",
"pmc": null,
"pmid": "29424022",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports",
"references": "26885473;29149325;23560034;26830352;19577348;29424022;28182051;29055034;27730796;26670286",
"title": "Acenocoumarol as an alternative anticoagulant in a patient with warfarin-related nephropathy.",
"title_normalized": "acenocoumarol as an alternative anticoagulant in a patient with warfarin related nephropathy"
} | [
{
"companynumb": "IN-MYLANLABS-2018M1033817",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIGOXIN"
},
"drugadditional": null,
... |
{
"abstract": "Objective To evaluate the safety profile of ixazomib combined with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM) in clinical practice in Japan through an all-case post-marketing surveillance. Methods This was a nationwide non-interventional observational study conducted in Japan. The study included all patients who received ixazomib from May 24 to September 24, 2017. Ixazomib was administered to RRMM patients according to the Japanese package insert. All enrolled patients were observed until the completion of the sixth treatment cycle or until ixazomib discontinuation. The patient treatment course, including adverse events (AEs), was reported. Results The safety analysis set included 741 patients; the median age was 71 (range 35-92) years old, and the median number of prior treatment lines was 3 (range 1-30). Adverse drug reactions (ADRs) occurred in 572 (77.2%) patients, most commonly being thrombocytopenia (49.9%), diarrhea (29.2%), and nausea (12.4%). Serious ADRs occurred in 193 (26.0%) patients, most commonly being thrombocytopenia (9.9%) and diarrhea (5.9%). Thrombocytopenia, severe gastrointestinal disorders, infections, skin disorders, and peripheral neuropathy were prespecified as ADRs of clinical importance; the frequency of these ADRs (grade ≥3) were 28.5%, 9.4%, 7.4%, 2.2%, and 1.3%, respectively. Treatment discontinuation was most common with thrombocytopenia and severe gastrointestinal disorders (49 and 43 patients, respectively). Eleven patients died due to ADRs (16 events). Conclusion These results suggest that ixazomib has a tolerable safety profile in clinical practice in Japan. However, close AE management for thrombocytopenia and gastrointestinal disorders should be considered.",
"affiliations": "Japan Medical Affairs, Japan Oncology Business Unit, Takeda Pharmaceutical Company Limited, Japan.;Japan Medical Office, Japan Pharma Business Unit, Takeda Pharmaceutical Company Limited, Japan.;Japan Medical Office, Japan Pharma Business Unit, Takeda Pharmaceutical Company Limited, Japan.;Pharmacovigilance, Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Japan.;Biostatistics, Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Japan.;Department of Internal Medicine, Niigata Cancer Center Hospital, Japan.",
"authors": "Kakimoto|Yoshihide|Y|;Hoshino|Miyako|M|;Hashimoto|Mikiko|M|;Hiraizumi|Masaya|M|;Shimizu|Kohei|K|;Chou|Takaaki|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.7768-21",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n34645759\n10.2169/internalmedicine.7768-21\nOriginal Article\nSafety Profile of Ixazomib in Patients with Relapsed/Refractory Multiple Myeloma in Japan: An All-case Post-marketing Surveillance\nKakimoto Yoshihide 1\nHoshino Miyako 2\nHashimoto Mikiko 2\nHiraizumi Masaya 3\nShimizu Kohei 4\nChou Takaaki 56\n1 Japan Medical Affairs, Japan Oncology Business Unit, Takeda Pharmaceutical Company Limited, Japan\n2 Japan Medical Office, Japan Pharma Business Unit, Takeda Pharmaceutical Company Limited, Japan\n3 Pharmacovigilance, Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Japan\n4 Biostatistics, Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Japan\n5 Department of Internal Medicine, Niigata Cancer Center Hospital, Japan\n6 Niigata Kenshin Plaza, General Incorporated Foundation, Health Medicine Prevention Association, Japan\nCorrespondence to Miyako Hoshino, miyako.hoshino@takeda.com\n\n12 10 2021\n1 5 2022\n61 9 13371343\n14 4 2021\n16 8 2021\nCopyright © 2022 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The 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/).\nObjective\n\nTo evaluate the safety profile of ixazomib combined with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM) in clinical practice in Japan through an all-case post-marketing surveillance.\n\nMethods\n\nThis was a nationwide non-interventional observational study conducted in Japan. The study included all patients who received ixazomib from May 24 to September 24, 2017. Ixazomib was administered to RRMM patients according to the Japanese package insert. All enrolled patients were observed until the completion of the sixth treatment cycle or until ixazomib discontinuation. The patient treatment course, including adverse events (AEs), was reported.\n\nResults\n\nThe safety analysis set included 741 patients; the median age was 71 (range 35-92) years old, and the median number of prior treatment lines was 3 (range 1-30). Adverse drug reactions (ADRs) occurred in 572 (77.2%) patients, most commonly being thrombocytopenia (49.9%), diarrhea (29.2%), and nausea (12.4%). Serious ADRs occurred in 193 (26.0%) patients, most commonly being thrombocytopenia (9.9%) and diarrhea (5.9%). Thrombocytopenia, severe gastrointestinal disorders, infections, skin disorders, and peripheral neuropathy were prespecified as ADRs of clinical importance; the frequency of these ADRs (grade ≥3) were 28.5%, 9.4%, 7.4%, 2.2%, and 1.3%, respectively. Treatment discontinuation was most common with thrombocytopenia and severe gastrointestinal disorders (49 and 43 patients, respectively). Eleven patients died due to ADRs (16 events).\n\nConclusion\n\nThese results suggest that ixazomib has a tolerable safety profile in clinical practice in Japan. However, close AE management for thrombocytopenia and gastrointestinal disorders should be considered.\n\nmultiple myeloma\nixazomib\nproteasome inhibitor\npost-marketing all-case surveillance\nadverse drug reaction\nsafety\n==== Body\npmcIntroduction\n\nEvery year, 5.9-6.2 per 100,000 people in Japan develop multiple myeloma (MM) (1). In the past decades, the prognosis of patients with MM has improved, from a median overall survival of 38.9 months in 1990-2000 to 60.6 months in 2001-2012 (2). At present, the Japanese Society of Hematology practical guidelines recommend the use of proteasome inhibitors (PIs) and immunomodulatory drugs, and these agents have contributed to the significant improvement in the survival of patients with MM (2-5).\n\nThe TOURMALINE-MM1 study (MM1 study), a double-blind, placebo-controlled, Phase III trial, demonstrated that patients with relapsed/refractory MM (RRMM) who received the oral PI ixazomib combined with lenalidomide-dexamethasone (LenDex) had a significantly longer progression-free survival than those who received placebo plus LenDex (median 20.6 months vs. 14.7 months; hazard ratio, 0.74; p=0.01) (6).\n\nBased on the MM1 study, ixazomib was approved in Japan in March 2017 for the treatment of RRMM in combination with LenDex. The MM1 study also showed that the frequency of serious adverse events (SAEs) was similar in those who received ixazomib vs. placebo (47% and 49%), whereas grade 3/4 thrombocytopenia and rash occurred more frequently among patients who received ixazomib than among those who received placebo (19% vs. 9% and 36% vs. 23%, respectively). However, the number of Japanese patients included in the MM1 study was limited.\n\nTherefore, the present all-case post-marketing surveillance aimed to evaluate the safety profile of ixazomib in combination with LenDex in patients with RRMM in clinical practice in Japan.\n\nMaterials and Methods\n\nThis was a nationwide non-interventional observational study conducted in Japan in accordance with the Declaration of Helsinki and Good Post-Marketing Study Practice (GPSP). Approvals from each institutional ethics committee and written informed consent from patients were not mandatory in this study, in accordance with GPSP. The study protocol was registered with the Japan Pharmaceutical Information Center-Clinical Trials Information (JapicCTI-173592) and ClinicalTrials.gov (NCT03169361).\n\nThe study included all patients who received ixazomib in Japan from May 24 to September 24, 2017. Ixazomib was administered to RRMM patients in accordance with the Japanese package insert, in which the recommended starting doses were 4 mg of ixazomib on Days 1, 8, and 15 plus lenalidomide (25 mg) on Days 1 through 21 and dexamethasone (40 mg) on Days 1, 8, 15, and 22 of a 28-day cycle. Patients who did not receive ixazomib, as indicated in the case report form, and those for whom the occurrence of adverse events (AEs) was unknown were excluded from the analysis.\n\nAll enrolled patients were observed from the start of ixazomib treatment until the completion of the sixth treatment cycle or until ixazomib discontinuation. During the observation period, the following variables were observed: starting doses, dose modifications (i.e., reductions, interruptions, and discontinuations), medications used as infection prophylaxis, any AE, and pregnancy status for women. All outcomes were recorded by the investigating physician on a standardized case report form. As the aim of this surveillance was to collect safety data for ixazomib in clinical practice in Japan, the collection of other data was not strictly enforced, and the duration of follow-up for AEs was not strictly defined. Reported AEs were coded using terminology from the Medical Dictionary for Regulatory Activities (MedDRA) ver. 22.0, and their severity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0. AEs that were life-threatening or those leading to death, hospitalization, or permanent impairment of a bodily function were defined as SAEs.\n\nAEs for which a causal relationship to ixazomib was at least considered possible (i.e. the relationship could not be ruled out) as deemed by the investigating physician were defined as adverse drug reactions (ADRs). Based on the safety results from the MM1 study, the following five events were pre-designated as ADRs of clinical importance: thrombocytopenia (including decreased platelet count), severe (grade ≥3) gastrointestinal disorders (diarrhea, nausea, vomiting, etc.), skin disorders, peripheral neuropathy (including sensory and motor), and infection.\n\nStatistical analyses\n\nResults were analyzed using descriptive statistics. Categorical variables were expressed as counts and frequencies, while continuous variables were expressed as medians and ranges or interquartile ranges, as appropriate. Based on the frequency of ADRs of clinical importance in the second interim analysis of the MM1 study (6), the target sample size was set at 480 patients.\n\nResults\n\nOf the 774 ixazomib-treated patients who were registered to the post-marketing surveillance, case report forms were collected for 743. The safety analysis set ultimately included 741 patients (Fig. 1).\n\nFigure 1. Patient flowchart of the analysis set (n=741). Data on the number of treatment cycles received were missing for one patient.\n\nThe baseline characteristics of all enrolled patients are described in Table 1. The median age was 71 (range 35-92) years old, with 36.8% of patients ≥65 and <75 years old, and 38.5% ≥75 years old. The median duration from the initial diagnosis of MM until patient enrollment was 3.5 (range 0.1-22.4) years. The median number of prior treatment lines was 3 (range 1-30), with 89.3% of patients having received prior PIs and 89.9% having received immunomodulatory drugs. The proportions of patients with liver and kidney dysfunction as judged by the investigating physicians were 6.2% and 39.5%, respectively.\n\nTable 1. Baseline Patient Characteristics.\n\nCategory\t\tn=741*\t\nMedian age (range), years\t\t71 (35-92)\t\nAge groups, n(%)\t\t\t\n<65 years\t\t183 (24.7)\t\n≥65 and <75 years\t\t273 (36.8)\t\n≥75 years\t\t285 (38.5)\t\nGender, n (%)\t\t\t\nFemale\t\t390 (52.6)\t\nMale\t\t351 (47.4)\t\nMedian weight (range), kg\t\t52.7 (29.9-104.0)\t\nMedian BSA (range), m2\t\t1.5 (1.0-2.3)\t\nRange of BSA, n (%)\t\t\t\n<1.4\t\t149 (20.1)\t\n≥1.4 and <1.6\t\t254 (34.3)\t\n≥1.6\t\t302 (40.8)\t\nInternational Staging System, n (%)\t\t\t\nStage 1\t\t140 (18.9)\t\nStage 2\t\t259 (35.0)\t\nStage 3\t\t290 (39.1)\t\nUnknown\t\t50 (6.7)\t\nECOG performance status, n (%)\t\t\t\n0\t\t240 (32.4)\t\n1\t\t294 (39.7)\t\n2\t\t111 (15.0)\t\n3\t\t81 (10.9)\t\n4\t\t15 (2.0)\t\nLiver dysfunction, n (%)\t\t46 (6.2)\t\nKidney dysfunction, n (%)\t\t293 (39.5)\t\nMedian time since initial diagnosis (range), years\t\t3.5 (0.1-22.4)\t\nMedian number of prior regimens (range)\t\t3 (1-30)\t\nNumber of prior regimens, n (%)\t\t\t\n1\t\t142 (19.2)\t\n2\t\t167 (22.5)\t\n3\t\t107 (14.4)\t\n≥4\t\t318 (42.9)\t\nPrior therapy, n (%)\t\t\t\nProteasome inhibitors\t\t661 (89.2)\t\nImmunomodulatory drugs\t\t665 (89.7)\t\nRefractory to prior therapy, n (%)\t\t\t\nAny\t\t582 (78.5)\t\nProteasome inhibitors\t\t440 (59.4)\t\nImmunomodulatory drugs\t\t508 (68.6)\t\nProteasome inhibitors and immunomodulatory drugs\t\t366 (49.4)\t\n*Some categories do not include all the 741 patients.\n\nBSA: body surface area, ECOG: Eastern Cooperative Oncology Group\n\nThe median initial dose of ixazomib was 4 (range 2.3-4) mg, whereas the average single dose of ixazomib over treated cycles was a median of 3.0 (range 0.8-4.0) mg. The average single doses of lenalidomide and dexamethasone over treated cycles were a median of 10.0 (range 0-25.0) mg and 17.5 (range 0-71.7) mg, respectively. More than three-quarters of patients (77.3%) received prophylaxis for infections, including herpes zoster.\n\nOf the 741 patients included in the analysis set, 461 (62.2%) discontinued treatment on or before the sixth cycle, with data missing for 1 patient. The median number of cycles received by these patients was 2 (range 1-6). The most common causes of treatment discontinuation were AEs (243/741; 32.8%) and insufficient effectiveness (191/741; 25.8%). The most common AEs leading to discontinuation were thrombocytopenia (55/461; 11.9%), diarrhea (54/461; 11.7%), vomiting (21/461; 4.6%), nausea (17/461; 3.7%), and pneumonia (15/461; 3.3%).\n\nSAEs occurred in 26.0% (193/741) of patients. The most common SAEs were thrombocytopenia (73/741; 9.9%) and diarrhea (44/741; 5.9%). Of the overall 741 patients, 48 (6.5%) died in this study; 28 (3.8%) died due to progression of the primary disease; and 11 (1.5%) died due to ADRs (16 events; Table 2).\n\nTable 2. Summary of Patients who Died Due to ADRs.\n\nNo.\tSex\tAge group (years)\tECOG PS\tNumber of prior regimens\tADR leading to death\n(MedDRA preferred term)\tTime (days) from\ntreatment initiation to the occurrence of the ADR\tTime (days) from treatment initiation to death\t\n1\tFemale\t≥75\t3\t3\tSeptic shock\t20\t21\t\n\t\t\t\t\tPlasma cell myeloma\t21\t-\t\n2\tFemale\t≥65 and <75\t1\t6\tDeath\t44\t44\t\n3\tMale\t<65\t1\t5\tPancytopenia\t42\t43\t\n\t\t\t\t\tSeptic shock\t42\t-\t\n\t\t\t\t\tRenal dysfunction\t42\t-\t\n4\tMale\t≥75\t1\t2\tPneumonia\t14\t16\t\n5\tMale\t≥75\t1\t3\tColisepticemia\t15\t20\t\n6\tFemale\t≥65 and <75\t3\t4\tPulmonary edema\t17\t17\t\n7\tMale\t≥75\t2\t6\tVomiting of blood\t5\t5\t\n8\tMale\t≥65 and <75\t0\t2\tBronchioloalveolar carcinoma\t205\t353\t\n9\tFemale\t≥75\t3\t4\tStaphylococcal pneumonia\t65\t68\t\n\t\t\t\t\tStaphylococcal sepsis\t65\t-\t\n10\tMale\t<65\t0\t4\tPneumonia\t173\t180\t\n\t\t\t\t\tC-reactive protein increase\t172\t-\t\n11\tFemale\t<65\t4\t6\tGastrointestinal necrosis\t46\t47\t\nCoding with MedDRA Ver.22.0. When a single patient experiences several events, each event is counted but is counted as 1 case.\n\nADR: adverse drug reaction, ECOG: European Cooperative Oncology Group, MedDRA: Medical Dictionary for Regulatory Activities, PS: performance status\n\nOverall, ADRs occurred in 77.2% of patients (572/741 patients). ADRs reported in ≥1% of patients are reported in Fig. 2. The most common ADRs were thrombocytopenia (370/741; 49.9%), diarrhea (216/741; 29.2%), nausea (92/741; 12.4%), vomiting (68/741; 9.2%), rash (54/741; 7.3%), and peripheral neuropathy (52/741; 7.0%). Grade 3 and 4 ADRs occurred in 38.6% (286/741) and 15.4% (114/741) of patients, respectively.\n\nFigure 2. Adverse drug reactions reported in ≥3% of all patients (n=741). When a single patient experienced several events of the same preferred term, one patient was counted for all events. Any Common Terminology Criteria for Adverse Events missing value was counted as unknown.\n\nAmong the ADRs of clinical importance, the proportions of patients with grade ≥3 ADRs were 28.5% (211/741) for thrombocytopenia, 9.4% (70/741) for gastrointestinal disorders, 7.4% (55/741) for infections, 2.2% (16/741) for skin disorders, and 1.3% (10/741) for peripheral neuropathy.\n\nTable 3 shows the frequency of ADR events of clinical importance leading to treatment modification and/or discontinuation. Among these ADRs, the number of events leading to treatment discontinuation was highest with thrombocytopenia and severe gastrointestinal disorders (49 and 43 events, respectively).\n\nTable 3. ADRs of Clinical Importance Leading to Treatment Dose Modification or Discontinuation.\n\nADR\tTotal no. of events\tEvents leading to ixazomib dose modification or discontinuation, n (%)\t\nReduction\tInterruption\tDiscontinuation\tReduction and interruption\t(Reduction and/or interruption) and discontinuation\t\nThrombocytopenia\t710\t23 (3.2)\t129 (18.2)\t39 (5.5)\t51 (7.2)\t10 (1.4)\t\nSevere GI disorders*\t117\t13 (11.1)\t13 (11.1)\t39 (33.3)\t20 (17.1)\t4 (3.4)\t\nSkin disorders**\t138\t5 (3.6)\t17 (12.3)\t13 (9.4)\t14 (10.1)\t2 (1.4)\t\nPeripheral neuropathy\t58\t6 (10.3)\t4 (6.9)\t7 (12.1)\t4 (6.9)\t4 (6.9)\t\nInfections***\t133\t0\t67 (50.4)\t24 (18.0)\t8 (6.0)\t0\t\n*Includes diarrhea, nausea, emesis, abdominal pain, constipation, GI necrosis, obstruction, melena, stomatitis, axial volvulus, mechanical ileus, bleeding.\n\n**Includes rash, pruritus, erythema, exanthem, acute febrile neutrophilic dermatosis, eczema, purpura, alopecia, acne, papules, nail disorder.\n\n***Includes herpes; ear, nose, and throat infections; respiratory infections; GI tract infections; cystitis; bacteremia.\n\nADR: adverse drug reaction, GI: gastrointestinal\n\nDiscussion\n\nIn this all-case post-marketing surveillance, we assessed the safety profile of ixazomib in patients with RRMM in the real-world clinical practice setting in Japan. We found that common ADRs experienced by patients treated with ixazomib combined with LenDex were thrombocytopenia, diarrhea, nausea, vomiting, rash, peripheral neuropathy, decreasing neutrophil count, decreasing white blood cell count, pneumonia, anemia, fatigue, loss of appetite, and herpes zoster. These ADRs were consistent with those reported previously in the MM1 study.\n\nApproximately half of the patients in this study had thrombocytopenia, compared to 31% reported in the MM1 study (6). One possible reason for this difference is that the current study included patients who had platelet counts of <75,000/mm3; whereas in the MM1 study, such patients were not eligible. A second contributory factor may have been that the proportion of patients ≥65 years old was higher in this study than in the MM1 study (75.3% vs. approximately 53%). Owing to the presence of comorbidities and a decreased physiological function, elderly patients have a higher tendency to exhibit thrombocytopenia than younger patients (7). Another contributory factor might be the higher number of prior regimens in this study (median 3, range 1-30) than in the MM1 study (median 1, range 1-3). Previous studies on other PIs have shown that a higher number of prior regimens was associated with an increased risk of grade 3/4 thrombocytopenia (odds ratio 1.259; p=0.007) (8).\n\nIn the present study, dose reduction or interruption occurred in more than 35% of thrombocytopenia events, but such events resulted in discontinuation in <7% of all patients with thrombocytopenia (Table 3). These results are consistent with the safety data from the MM1 study (9), in which patients receiving ixazomib reported grade ≥3 thrombocytopenia twice as frequently as those receiving placebo, yet the frequency of treatment discontinuation was similar between the two groups. This suggests that the use of dose-modification guidelines was able to effectively reduce treatment discontinuation in clinical practice. According to Kumar et al. (2017), platelet counts should be monitored during ixazomib treatment (weekly during the first three cycles and at least monthly thereafter), and if the count drops to <30,000/mm3, ixazomib and lenalidomide should be withheld (9).\n\nHowever, one in every three events of severe gastrointestinal disorders caused discontinuation (Table 3), accounting for the highest frequency of treatment discontinuation among ADRs of clinical importance. This might have contributed to patients' reluctance to continue treatment with ixazomib despite the potential feasibility of long-term treatment, as indicated by available safety data (9). To ameliorate nausea, the use of serotonin receptor antagonists prior to ixazomib dosing should be considered in patients who develop nausea (9). Anti-diarrheal mediation and laxative adjustments may also be used as needed; however, these are not recommended as prophylactics. Careful monitoring of gastrointestinal symptoms, interventions to relieve these symptoms, and appropriate prophylaxis are thus necessary for ensuring continuous treatment.\n\nIn an exploratory analysis of our study, the frequencies of thrombocytopenia and diarrhea were numerically higher by more than 5% in patients ≥75 years old than in younger patients (≥65 and <75 years old, and <65 years old) (data not shown). Based on a previous pharmacokinetics analysis (10), severe renal impairment, end-stage renal disease requiring dialysis, and moderate-to-severe hepatic impairment are associated with increased total systemic exposure to ixazomib, and the increased drug exposure may lead to increased incidence of known ADRs (grade ≥3, anemia and thrombocytopenia; grade ≥2, diarrhea, fatigue, nausea, peripheral neuropathy, and rash) in these patients. Therefore, close monitoring and dose modification should be considered for patients with an older age, severe renal impairment, and moderate-to-severe hepatic impairment.\n\nTwo deaths were due to septic shock, and two were due to pneumonia. The increased susceptibility to infections may also have been related to the underlying immunodeficiency due to the primary disease and the presence of other concomitant therapies (11-13).\n\nBased on these findings, the results of this all-case surveillance are consistent with the safety profile of ixazomib observed in the clinical study in combination with LenDex in patients with RRMM (6). It should be kept in mind that thrombocytopenia is an expected ADR, as indicated in the ixazomib package insert.\n\nOf note, the results of this surveillance should be evaluated alongside a thorough consideration of several study limitations, including the non-blinded, non-randomized, non-controlled study design, which lends inherent risks for bias. Furthermore, the patients were observed only until the end of the sixth treatment cycle or until treatment discontinuation (whichever came first); therefore, the study was unable to detect any long-term ADRs.\n\nConclusion\n\nThis analysis showed an acceptable safety profile of ixazomib for RRMM patients in clinical practice in Japan. The ADRs observed in this post-marketing surveillance were similar to those reported in the MM1 study despite patients in this study being older and heavily pre-treated. Thrombocytopenia was frequent, and this should be managed with appropriate dose modification or interruption if warranted. Gastrointestinal symptoms require appropriate prophylaxis and symptomatic therapy for continuous treatment.\n\nThe datasets, including the redacted study protocol, redacted statistical analysis plan, and individual participants' data supporting the results reported in this article, will be made available within three months from the initial request to researchers who provide a methodologically sound proposal. The data will be provided after de-identification, in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization.\n\nAuthor's disclosure of potential Conflicts of Interest (COI).\n\nYoshihide Kakimoto: Employment, Takeda Pharmaceutical. Miyako Hoshino: Employment, Takeda Pharmaceutical. Mikiko Hashimoto: Employment, Takeda Pharmaceutical. Masaya Hiraizumi: Employment, Takeda Pharmaceutical. Kohei Shimizu: Employment, Takeda Pharmaceutical. Takaaki Chou: Honoraria, Takeda Pharmaceutical, Janssen Pharmaceuticals, Celgene and BMS.\n\nFinancial Support\n\nThis study was funded by Takeda Pharmaceutical.\n\nMedical writing support was provided by Ivan Olegario of MIMS Pte, Ltd., which was funded by Takeda Pharmaceutical Company Limited (Tokyo, Japan), and complied with Good Publication Practice 3 ethical guidelines (Battisti et al. Ann Intern Med 163: 461-464, 2015).\n\nAcknowledgement\n\nWe thank the patients who participated in this study, their families, and all participating investigators. We also thank Ichirou Nakayama for providing valuable advice on the interpretation of the study data.\n==== Refs\n1. Cancer Information Service, National Cancer Center, Japan. Cancer Registry and Statistics. [Internet]. Ministry of Health, Labour and Welfare, National Cancer Registry. 2016-2017 [cited 2021 Jun]. Available from: https://ganjoho.jp/reg_stat/statistics/dl/ (in Japanese)\n2. Ozaki S , Handa H , Saitoh T , et al . Trends of survival in patients with multiple myeloma in Japan: a multicenter retrospective collaborative study of the Japanese Society of Myeloma. Blood Cancer J 5 : e349, 2015.26383822\n3. Kumar SK , Rajkumar SV , Dispenzieri A , et al . Improved survival in multiple myeloma and the impact of novel therapies. Blood 111 : 2516-2520, 2008.17975015\n4. Ozaki S . Treatment algorithms for multiple myeloma in Japan. Rinsho Ketsueki (Jpn J Clin Hematol) 58 : 1014-1023, 2017.\n5. Iida S , Ishida T , Murakami H , et al . JSH practical guidelines for hematological malignancies, 2018: III. Myeloma-1. Multiple myeloma (MM). Int J Hematol 109 : 509-538, 2019.30949913\n6. Moreau P , Masszi T , Grzasko N , et al . Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 374 : 1621-1634, 2016.27119237\n7. Mehta J , Cavo M , Singhal S . How I treat elderly patients with myeloma. Blood 116 : 2215-2223, 2010.20644120\n8. Lonial S , Waller EK , Richardson PG , et al . Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood 106 : 3777-3784, 2005.16099887\n9. Kumar S , Moreau P , Hari P , et al . Management of adverse events associated with ixazomib plus lenalidomide/dexamethasone in relapsed/refractory multiple myeloma. Br J Haematol 178 : 571-582, 2017.28485007\n10. Gupta N , Hanley MJ , Xia C , Labotka R , Harvey RD , Venkatakrishnan K . Clinical pharmacology of ixazomib: the first oral proteasome inhibitor. Clin Pharmacokinet 58 : 431-449, 2019.30117017\n11. Youssef J , Novosad SA , Winthrop KL . Infection risk and safety of corticosteroid use. Rheum Dis Clin North Am 42 : 157-176, ix-x, 2016.26611557\n12. Blimark C , Holmberg E , Mellqvist UH , et al . Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients. Haematologica 100 : 107-113, 2015.25344526\n13. Ying L , YinHui T , Yunliang Z , Sun H . Lenalidomide and the risk of serious infection in patients with multiple myeloma: a systematic review and meta-analysis. Oncotarget 8 : 46593-46600, 2017.28423741\n\n",
"fulltext_license": "CC BY-NC-ND",
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"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Multiple myeloma; adverse drug reaction; ixazomib; post-marketing all-case surveillance; proteasome inhibitor; safety",
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"pubdate": "2021-10-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety Profile of Ixazomib in Patients with Relapsed/Refractory Multiple Myeloma in Japan: An All-case Post-marketing Surveillance.",
"title_normalized": "safety profile of ixazomib in patients with relapsed refractory multiple myeloma in japan an all case post marketing surveillance"
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"abstract": "Medication use during pregnancy is gradually increasing; however, the safety of this practice remains largely unknown.We investigated medications with the most adverse drug reactions (ADRs) among pregnant women and the clinical features of those medications.Reports of ADRs among pregnant women were extracted from the Korea Adverse Events Reporting System (January 2012-December 2015). We analyzed the data of drugs frequently reported to cause ADRs and their clinical features among 3 age groups.A total of 5642 ADRs among 3428 patients were analyzed. The number of ADR reports increased annually. The most common drug categories causing ADRs were analgesics, followed by gynecologic, uterotocolytic, anti-infective, antidiabetic, analgesic, and antihypertensive drugs. Analgesics comprised 6 opioids (morphine, fentanyl, hydromorphone, oxycodone, tramadol, pethidine) and an anti-pyretics (nefopam and ketorolac). As an individual drug, ritodrine (24.4%) was the most frequently reported, followed by morphine, 5-HT3 serotonin antagonist, nefopam, fentanyl, magnesium sulfate, insulin lispro, cefazedone, sodium chloride, hydromorphone, oxycodone, cefotetan, nifedipine, human insulin, tramadol, ketorolac, pethidine, methylergometrine, metoclopramide, and misoprostol (in that order). ADRs most frequently occurred in women aged 25 to 34 years, and the trend of ADR with the 20 most commonly reported medications significantly differed among the age groups (P = .011). In addition, the kind of common causative drugs was different among the age groups.Knowledge of medications and clinical conditions resulting in the highest ADR rates among pregnant women is necessary for medical practitioners to administer proper care.",
"affiliations": "Department of Obstetrics and Gynecology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon.;Department of Obstetrics and Gynecology, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Gyeonggido.;Department of Obstetrics and Gynecology, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon.;Department of Obstetrics and Gynecology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul.;Division of Infectious Diseases, Department of Internal Medicine, Seoul St, Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul.;Department of Obstetrics and Gynecology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul.;Department of Obstetrics and Gynecology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon.;Department of Obstetrics and Gynecology, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Gyeonggido.;Department of Obstetrics and Gynecology, Seoul St, Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea .",
"authors": "Choi|Sae Kyung|SK|;Kim|Yeon Hee|YH|;Kim|Su Mi|SM|;Wie|Jung Ha|JH|;Lee|Dong-Gun|DG|;Kwon|Ji Young|JY|;Song|Jeong Hwa|JH|;Lee|Su Jeong|SJ|;Park|In Yang|IY|",
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"doi": "10.1097/MD.0000000000015756",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31124960MD-D-19-0016910.1097/MD.0000000000015756157565600Research ArticleObservational StudyOpioid analgesics are the leading cause of adverse drug reactions in the obstetric population in South Korea Choi Sae Kyung PhDaKim Yeon Hee PhDb∗Kim Su Mi MDcWie Jung Ha MDdLee Dong-Gun PhDeKwon Ji Young PhDdSong Jeong Hwa MDaLee Su Jeong MDbPark In Yang PhDfLi. Yan a Department of Obstetrics and Gynecology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheonb Department of Obstetrics and Gynecology, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Gyeonggidoc Department of Obstetrics and Gynecology, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeond Department of Obstetrics and Gynecology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoule Division of Infectious Diseases, Department of Internal Medicine, Seoul St, Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoulf Department of Obstetrics and Gynecology, Seoul St, Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea .∗ Correspondence: Yeon Hee Kim, Associated Professor, Department of Obstetrics and Gynecology, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 271 Cheonboro, Uijeongbu-si, Post No: 11765, Gyeonggido, South Korea (e-mail: yoni@catholic.ac.kr).5 2019 24 5 2019 98 21 e1575611 1 2019 14 4 2019 27 4 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Supplemental Digital Content is available in the text\n\nAbstract\nMedication use during pregnancy is gradually increasing; however, the safety of this practice remains largely unknown.\n\nWe investigated medications with the most adverse drug reactions (ADRs) among pregnant women and the clinical features of those medications.\n\nReports of ADRs among pregnant women were extracted from the Korea Adverse Events Reporting System (January 2012–December 2015). We analyzed the data of drugs frequently reported to cause ADRs and their clinical features among 3 age groups.\n\nA total of 5642 ADRs among 3428 patients were analyzed. The number of ADR reports increased annually. The most common drug categories causing ADRs were analgesics, followed by gynecologic, uterotocolytic, anti-infective, antidiabetic, analgesic, and antihypertensive drugs. Analgesics comprised 6 opioids (morphine, fentanyl, hydromorphone, oxycodone, tramadol, pethidine) and an anti-pyretics (nefopam and ketorolac). As an individual drug, ritodrine (24.4%) was the most frequently reported, followed by morphine, 5-HT3 serotonin antagonist, nefopam, fentanyl, magnesium sulfate, insulin lispro, cefazedone, sodium chloride, hydromorphone, oxycodone, cefotetan, nifedipine, human insulin, tramadol, ketorolac, pethidine, methylergometrine, metoclopramide, and misoprostol (in that order). ADRs most frequently occurred in women aged 25 to 34 years, and the trend of ADR with the 20 most commonly reported medications significantly differed among the age groups (P = .011). In addition, the kind of common causative drugs was different among the age groups.\n\nKnowledge of medications and clinical conditions resulting in the highest ADR rates among pregnant women is necessary for medical practitioners to administer proper care.\n\nKeywords\nadverse drug reactionopioid analgesicspharmacovigilancepregnancyritodrineOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nAccording to the World Health Organization (WHO), an adverse drug reaction (ADR) is any noxious, unintended, and undesired effect of a drug that occurs at doses used by humans for prophylaxis, diagnosis, or therapy.[1] This definition excludes therapeutic failures, intentional and accidental poisoning, and drug abuse. Common ADRs are related to the dose of the drugs such as dry mouth, respiratory depression, bleeding, and orthostatic hypotension. These ADRs are predictable and have low mortality. On the other hand, there are unpredictable ADRs that are not related to the pharmacologic action of the drugs, such as hypersensitivity reactions. Anaphylaxis to penicillin and malignant hyperthermia with general anesthetic agents correspond to these ADRs.[1] The incidence of ADRs has steadily increased, and fatal ADRs are the fourth and sixth leading causes of death in the United States.[2,3] During a longitudinal study, the trend of serious ADRs increase over time.[4]\n\nThe safety of drug exposure during pregnancy is not well-understood because clinical trials typically exclude pregnant women for ethical reasons; therefore, knowledge is limited to postmarketing data generated from observational studies. In addition, premarketing pharmaceutical studies often fail to accurately identify adverse effects of drugs on humans.[5] A study performed in Great Britain found 47 new serious ADRs reported by both consumers and professional health providers that were not previously included in the summaries of product characteristics.[6] Therefore, because of the sparse premarketing research regarding the effects of medications during pregnancy, small studies or case reports are important for detecting their undesirable effects on pregnant women and the fetus or neonate. An investigation of ADRs in the obstetric population could provide critical information regarding public health.\n\nDespite the lack of relevant information regarding the potential drug effects on pregnancy, a longitudinal investigation noted that medication use and the number of drugs used during pregnancy have continuously increased over time.[7–12] According to the estimates determined using a database of the Medicaid enrollees, approximately 80% of pregnant women were exposed to 1 or more medications during pregnancy, and the use of 4 or more drugs increased by more than 3-fold over decades. The United States Food and Drug Administration (FDA) announced a change in the labeling information of prescription drugs during pregnancy and lactation; instead of using A, B, C, D, and X to label drug categories during pregnancy,[13] a narrative describing the drug information is provided. However, during the transition period, this change might cause confusion for physicians who prescribe various medications to patients during pregnancy, thus compromising the safety of the mother, fetus, and/or neonate. Therefore, there is renewed interest in the need for information regarding drug safety and ADRs during pregnancy.\n\nIn South Korea, the Korea Institute of Drug Safety and Risk Management (KIDS) was established to expand national pharmacovigilance by monitoring ADRs observed in the Korean population and to suggest regulatory interventions.[14] In 2012, KIDS developed the Korea Adverse Event Reporting System (KAERS) based on cumulative reports to facilitate the reporting and management of adverse events. It has become the management center for all regional pharmacovigilance centers (RPVCs). In 2016, there were 27 RPVCs, including 25 local teaching hospitals and 2 nationwide RPVCs, including the National Medical Center and Korea Pharmaceutical Association, which are linked with nationwide health centers and pharmacies, respectively.\n\nThe present study aimed to determine the medications with the highest ADR rates (referred to hereafter as “most commonly reported”) among pregnant women and their clinical features using the KAERS database.\n\n2 Methods\n2.1 Data collection\nThis study used the KIDS-KAERS database (KIDS-KD) from January 2012 to December 2015. Data were collected from spontaneously reported individual case safety reports (ICSRs) from RPVCs, health care professionals, consumers, and pharmaceutical companies, from studies (re-examination, post-marketing studies, individual case studies), and from the literature. KIDS evaluated cumulative reports to generate the database and perform signal detection to provide drug safety information. This database is compatible with the international standards of the WHO-UMC (Uppsala Monitoring Centre) international drug monitoring program.[15]\n\nThe study proposal was submitted to the institutional review board at Uijeongbu St. Mary's Hospital, and ethical approval was waived as the research included analysis of the existing data that are publicly available and did not include any personal information.\n\nData were selected to include cases with disease codes related to pregnancy and its associated conditions or diseases, including childbirth and puerperium (O00-O99.8, Z32–34.99, 35, 35.9, 64, and 87) according to the Korean Classification of Diseases revision 6 (KCD-6) (supplementary data 1). We excluded cases with disease codes pertaining to neoplastic or malignant diseases that possibly involved chemotherapy; patients younger than 15 years or older than 50 years, and patients who were male or who had an unclear gender (Fig. 1). This study only included ADRs associated with a dose normally used by humans and reports associated with drugs administered for ordinary prophylactic or therapeutic purposes. To reduce duplication of data, each report was individually compared based on patients’ initials and age and the source of the report. If these factors were identical, then the reports were further examined for other information, including the reaction term; suspected duplicated reports were omitted. Patient records were anonymized before analysis.\n\nFigure 1 Selection of study cases from the KAER database. ∗Codes of malignant or neoplastic disease, KCD-6: C00 - C97, malignant neoplasm; D00-D099, in situ neoplasm; D37-D48, neoplasms of uncertain or unknown behavior. KAER = Korea Adverse Events Reports.\n\nThe reports were inspected for patient age, year of the report, drug indication, the diagnosis or description of the adverse reaction according the WHO adverse reaction terminology (WHO-ART), the reporter's profession, progress of the adverse reaction, and causality assessment.[16] Causality was assessed using the 6 categories outlined by the WHO-UMC criteria: certain, probable, possible, unlikely, conditional, and unassessable.[17] This assessment was primarily performed by the ADR monitoring team at each regional pharmacovigilance center and confirmed by KIDS healthcare professionals. Cases classified as certain, probable and possible were analyzed for this study. Medications that caused ADRs were grouped using the second degree of the anatomical therapeutic chemical (ATC) classification system.[18] Medications may have multiple classes according to various indications, drug mechanisms, routes of administration, and ingredients. Therefore, medications with multiple ATC codes were assigned a category according to the clinical indication of the drug prescription. We identified the 20 medications that were most commonly reported to cause ADRs in this study population. We reported the overall prevalence, the prevalence according to maternal age groups, and the prevalence according to the ATC classification system category. Additionally, the common indicative disease codes and symptoms of ADRs associated with the medications were examined.\n\nPatients were divided into 3 age groups (15–24, 25–34, and 35–50 years) to examine age differences. In a recent report of the birth registry in Korea, those in the younger than 25 years and 25- to 35-year age groups had the lowest and highest live birth rates, respectively.[19] We assumed that the features of ADRs were differently observed. In addition, maternal age older than 35 years was regarded as one of the risk factors that increased adverse pregnancy outcomes and obstetric complications; therefore, these women were likely exposed to therapeutic or prophylactic medications during pregnancy.[20–23]\n\nAccording to the International Conference on Harmonization (ICH) E2D Guidelines, all ADRs were categorized as either serious or not serious.[24] Adverse events that caused death, were life-threatening, caused prolonged hospitalization, induced a congenital anomaly, or caused any other outcome considered medically important were classified as serious. Outcomes were evaluated according to 6 different categories: recovered, not recovered, recovering, recovered with sequelae, recovered with fatal damage, and unknown result.\n\nClinical symptoms were categorized using the WHO-ART system. Among the 4-level hierarchical system structure, system-organ classes (SOCs) and preferred terms (PTs) were used during the analysis.[16] ICSRs describing 2 or more PTs in 1 patient who was receiving 1 drug were treated as different adverse reactions. For patients using 2 or more medications at the same time, it was assumed that each medication was responsible for any reported adverse reactions. The frequency of clinical symptoms was assessed according to the age group and compared to the clinical symptom frequency of all cases reported to KIDS in 2015.\n\n2.2 Statistical analyses\nDemographic and clinical characteristics were analyzed using means and standard deviation (for continuous variables) and frequencies and percentages (for categorical variables). Causative medications with the highest ADRs and overall symptoms of ADRs were compared among age groups using the Chi-squared test or Fisher exact test. The significance level was set at P < .05. All statistical calculations were performed using SAS statistical software package version 9.3 (SAS Institute Inc., Cary, NC).\n\n3 Results\nA total of 657,226 patients experienced ADRs during the study period; 4035 patients were selected using KCD-6 disease codes related to obstetric conditions. During the initial inspection, we excluded 607 patients with malignant diseases, ineligible sex, or ineligible age (Fig. 1). No duplicates were identified. A total of 5642 cases for 3428 patients were analyzed in the current study, which comprised 4907 cases involving suspicious drugs and 735 cases involving combined drugs (Table 1). The number of reported cases increased annually, reaching 2875 cases in 2015. Management included stopping the medication (n = 2306), maintaining the dosage (n = 1260), decreasing the dosage (n = 232), not applicable (n = 535), and unknown (n = 826). The mean patient age was 32.8 years, and most (63.5%) were in the 25- to 34-year age group. An average of 1.5 ADR cases per patient (range, 1–6; median, 1) was observed.\n\nTable 1 General patient characteristics and clinical outcomes.\n\nA total of 280 cases were classified as serious ADRs, and the most commonly reported medications were (from most frequent to least frequent): ritodrine (n = 32); insulin lispro (n = 26); insulin (human) (n = 14); fentanyl (n = 9); everolimus (n = 8); insulin detemir (n = 8); serotonin (5HT3) antagonists (n = 7); tramadol (n = 7); amlodipine (n = 6); and morphine (n = 6). Among the serious cases, the following were observed: death (n = 1) with propofol; disability (n = 3) with levonorgestrel and ritodrine; life threatening (n = 5) with fentanyl, gentamicin, methylergometrine, and midazolam; hospitalization (n = 244); and other medical concern (n = 151).\n\nFigure 2 shows the 20 medications with the highest rates of ADRs; 3935 out of a total of 4907 cases were classified. Ritodrine (24.4%) was the most commonly reported individual drug, followed by morphine, 5-HT3 serotonin antagonist, nefopam, fentanyl, magnesium sulfate, insulin lispro, cefazedone, sodium chloride, hydromorphone, oxycodone, cefotetan, nifedipine, human insulin, tramadol, ketorolac, pethidine, methylergometrine, metoclopramide, and misoprostol (in that order). Ritodrine is a potent beta-2 stimulant that produces direct relaxation of uterine smooth muscle and is clinically used to manage preterm labor. According to the category classified by the second degree of the ATC code, analgesics were the most common category, followed by gynecologic drugs (ritodrine, methylergometrine, misoprostol), antiemetic drugs (serotonin antagonist), drugs for constipation (magnesium sulfate), anti-diabetes drugs (insulin lispro, insulin human), blood substitutes and perfusion solutions (sodium chloride, magnesium sulfate), antibacterial agents for systemic use (cefotetan, cefazedone), calcium channel blockers (nifedipine), anti-inflammatory and anti-rheumatic products (ketorolac), and drugs for functional gastrointestinal disorder (metoclopramide). Notably, analgesics comprised 5 opioids (morphine, fentanyl, hydromorphone, oxycodone, tramadol, pethidine) and other kind of analgesics (antipyretics for nefopam).\n\nFigure 2 The prevalence of 20 causative medications with highest ADRs by the category classified according to the second degree of Anatomical Therapeutic Chemical (ATC) classification system. ATC-code = the second degree codes of Anatomical Therapeutic Chemical classification system; ∗, blood substitutes and perfusion solution; ∗∗, anti-inflammatory and anti-rheumatic products; †, drug for functional gastrointestinal disorders. Analgesics are morphine, nefopam, fentanyl, hydrormophone, oxycodone, tramadol, and pethidine, in order of frequency. Among the drugs of gynecologicals (ritodrine, methylergometrine, misoprostol), ritodrine is the most frequently reported drug in the population with obstetric condition. Anti-emetics and antinauseants (serotonin (5HT3) antagonist), blood substitutes and perfusion solution (magnesium sulfate, sodium chloride), anti-diabetes (insulin lispro, insulin (human)), antibacterial for systemic use (cefazedone, cefotetan), calcium channel blocker (nifedipine), anti-inflammatory and anti-rheumatic products (ketorolac), and drug for functional gastrointestinal disorder (metoclopramide).\n\nIn the comparison of age groups, Figure 3 shows that the trend of the 20 medications differed among age groups (P = .011, Fig. 3). The prevalence of the 20 medications was different among age groups (P = .004, supplementary data 2). Pain was the most common clinical indication, followed by preterm labor and delivery (supplementary data 3). The type of commonly reported medications was different among age groups; morphine and misoprostol were more prevalent for women 15 to 24 years, and anti-diabetes agents were associated with the highest rates of ADRs for women older than 35 years (Table 2).\n\nFigure 3 The 20 causative medications with highest ADR according to age group. P value, .011 for comparison of the trend of medications among age groups.\n\nTable 2 Medications commonly associated with adverse drug reactions according to age groups.\n\nRegarding clinical manifestations of ADR in the study population, the most commonly affected SOCs were the central and peripheral nervous systems, followed by the gastrointestinal system and the skin and appendage system. In all Korean adverse effect reports in 2015, trends of palpitations, tremors, chest discomfort, and tachycardia were more frequent in the study population (Table 3).\n\nTable 3 Comparison of commonly reported clinical manifestations of adverse drug reactions between the study population and the entire KAER report in 2015.\n\n4 Discussion\nAnalgesics comprised the most commonly reported ATC category causing ADRs in the population with obstetric conditions, followed by gynecologists, antiemetics, drugs for constipation, anti-diabetes drugs, blood substitutes, calcium channel blockers, anti-inflammatories, and antirheumatics for functional gastrointestinal disorder. Most analgesics were classified as prescription opioids. Ritodrine was the most common individual medication that caused ADRs. ADRs were most commonly reported in the 25- to 34-year age group, and the type of causative medication significantly differed according to age groups. The most common manifestation was nausea for the involved organ system; the central and peripheral nervous systems were most frequently involved in SOC in the study population.\n\nPregnant women can be prescribed opioids for various conditions during pregnancy and the postpartum period, to manage pain in the abdomen, low back, and pelvis, migraines prenatally, and to manage labor and delivery-related pain.[25,26] In particular, the use of opioid analgesics during pregnancy has steadily increased approximately 6% in European countries and up to 22.8% in the United States in 2014[27,28]; however, fetal safety after exposure to these medications is not well understood. Subsequently, the increasing opioid exposure experienced by the fetus in the intrauterine environment has led to an increased rate of neonate abstinence syndrome in the United States.[29,30] In this study, analgesics were the most common drug category related to ADRs and included several prescription opioids (morphine, fentanyl, hydromorphone, oxycodone, tramadol, and pethidine). There have been reports of other substance abuse, such as alcohol or smoking, during pregnancy; however, but there has been no report of the use of prescription opioids during pregnancy in Korea. Most opioid analgesic usage during pregnancy might be occurred during the process of vaginal or cesarean delivery. Results concerning the frequency of ADRs related to opioid analgesics, however, address the need to evaluate prescribing and dispensing opioids to pregnant women.\n\nRitodrine was the most commonly reported individual drug causing ADRs in the study population. It is a beta-adrenergic agonist that is used as a tocolytic agent to treat preterm labor or delivery. However, it frequently causes maternal side effects such as tachycardia, palpitations, tremors, chest discomfort and dyspnea, and hyperglycemia. There are no clear guidelines regarding the first-line therapy for preterm labor; currently, it is different among nations. The practice guidelines of the American Committee of Obstetrics and Gynecology recommend that the first-line tocolytics should be beta-mimetics, calcium channel blockers, and oxytocin receptor antagonists.[31] However, in 2015, the National Institute for Health and Care Excellence and Royal Committee of Obstetrics and Gynecology stated that nifedipine should be the first-line treatment for acute preterm labor, and that beta-agonists should not be used.[32]\n\nA longitudinal investigation performed over decades noted that the rate of using medications during pregnancy and the number of drugs used are steadily increasing.[11] Common drugs dispensed during pregnancy were similar among the studies, including anti-infectives, analgesics, respiratory and gastrointestinal drugs, and dermatological steroids, with difference found for maternal age and ethnicity.[8–12] This study evaluated ADRs of patients with obstetric conditions; therefore, it cannot be directly compared with previous studies regarding common medications used during pregnancy. However, it is assumed that both studies were affected by maternal age and the risk of pregnancy complications. ADRs were most frequently reported in the 25- to 34-year age group, followed by the older than 35-year age group and 15- to 24-year age group. This finding might reflect comorbidity, basic physical strength, and the degree of adaptation to the physiologic changes during pregnancy. Mothers of advanced age are likely to have coexisting chronic diseases such as hypertension or pregestational diabetes, in addition to being at increased risk for obstetric morbidities such as miscarriage, preterm labor, hypertension, gestational diabetes, and cesarean delivery,[20–23] which might reflect the more frequent reports of drugs classes such as analgesics (fentanyl and oxycodone) and antidiabetic drugs (Fig. 3).\n\nAfter observing disease codes for prescriptions of drugs related to ADRs, it can be presumed that the frequency of ADRs is dependent on the clinical indications for the drug used. Disease codes related to preterm labor and delivery were the most common among prescription drugs that caused ADR, regardless of the approved labels. Nifedipine, a calcium channel blocker that is the primary drug indicated for angina and hypertension, was reportedly most commonly dispensed in the United States for cardiovascular reasons during pregnancy regardless of its clinical indications.[33] In this study, the disease code O60 (preterm labor and delivery) was a leading reason for nifedipine- related ADR cases. A Cochrane review reported that as a tocolytic, nifedipine is comparable to magnesium sulfate and beta-agonists (including ritodrine) but with fewer side effects.[34] Nevertheless, it causes more ADRs when used as a tocolytic than when used as an antihypertensive. Magnesium sulfate for parenteral injection was categorized as a drug for blood substitute and perfusion solution, and mineral supplements in the ATC code index. Among the ADRs associated with magnesium sulfate, ADRs caused by magnesium sulfate were most frequently associated with the disease code for preterm labor and delivery (O60); they were second most frequently associated the disease code for eclampsia.\n\nThis study had several limitations. First, data were obtained from spontaneous reporting, which has a tendency to underestimate the true rate of ADRs and may include heterogeneous reports with a range of sources and a lack of information. Therefore, we could not perform statistical analyses that controlled for confounding factors during group comparisons. Second, we could not produce a reliable estimate of the overall incidence of adverse reactions experienced by patients who received specific drugs because of the lack of information regarding total drug usage. Third, the ADR occurrence when a specific drug was “off-label” could not be analyzed. Further research is needed to evaluate medication used during pregnancy in Korea because the management of pregnant women of advanced age is an important issue for the public health service because these patients have more opportunities to receive medications during pregnancy.\n\nIn conclusion, ADRs experienced by the obstetric population were frequently associated with opioid analgesics and treatment agents for preterm labor and delivery. Ritodrine caused the highest ADR rates across all age groups and the highest rates of serious cases. The findings regarding medications frequently resulting in ADRs contribute to the informed and safe prescribing of relevant drugs as health care providers manage obstetric conditions.\n\nAcknowledgments\nThe authors thank the Department of Medical Life Science, The Catholic University of Korea, and Mr. Jin-Hyung Jung for performing statistical analyses for this study.\n\nAuthor contributions\nConceptualization: Dong-Gun Lee, Ji Young Kwon.\n\nData curation: Jung Ha Wie, Jeong Hwa Song, Su Jeong Lee.\n\nFormal analysis: Su Mi Kim.\n\nMethodology: Su Mi Kim, Ji Young Kwon.\n\nProject administration: Dong-Gun Lee.\n\nResources: Jung Ha Wie, Dong-Gun Lee.\n\nSupervision: Yeon Hee Kim, In Yang Park.\n\nValidation: In Yang Park.\n\nVisualization: In Yang Park.\n\nWriting – original draft: Sae Kyung Choi.\n\nWriting – review & editing: Yeon Hee Kim.\n\nSupplementary Material\nSupplemental Digital Content\n Abbreviations: ADR = adverse drug reaction, ART = adverse reaction terminology, ATC = anatomical therapeutic chemical, FDA = Food and Drug Administration, ICH = International Conference on Harmonization, ICSR = individual case safety report, KAERS = Korea Adverse Event Reporting System, KCD-6 = Korean Classification of Diseases revision 6, KIDS = Korea Institute of Drug Safety and Risk Management, KIDS-KD = KIDS-KAERS database, PT = preferred term, RPVC = regional pharmacovigilance center, SOC = system-organ class, UMC = Uppsala Monitoring Centre, WHO = World Health Organization.\n\nThis research was supported by the National Research Foundation of Korea (2017R1D1A1B03031412). And Yeon Hee Kim wishes to acknowledge the financial support of the Catholic Medical Center Research Foundation made in the program year of 2019.\n\nThe authors have no conflicts of interest directly relevant to the content of this work.\n\nSupplemental Digital Content is available for this article.\n==== Refs\nReferences\n[1] Edwards IR Aronson JK \nAdverse drug reactions: definitions, diagnosis, and management . Lancet \n2000 ;356 :1255–9 .11072960 \n[2] Miller RR \nHospital admissions due to adverse drug reactions. A report from the Boston Collaborative Drug Surveillance Program . Arch Intern Med \n1974 ;134 :219–23 .4843186 \n[3] Lazarou J Pomeranz BH Corey PN \nIncidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies . JAMA \n1998 ;279 :1200–5 .9555760 \n[4] Moore TJ Cohen MR Furberg CD \nSerious adverse drug events reported to the Food and Drug Administration, 1998–2005 . Arch Intern Med \n2007 ;167 :1752–9 .17846394 \n[5] Brewer T Colditz GA \nPostmarketing surveillance and adverse drug reactions: current perspectives and future needs . JAMA \n1999 ;281 :824–9 .10071004 \n[6] Avery AJ Anderson C Bond CM \nEvaluation of patient reporting of adverse drug reactions to the UK ’Yellow Card Scheme’: literature review, descriptive and qualitative analyses, and questionnaire surveys . Health Technol Assess \n2011 ;15 :1–234 .\n[7] Cleary BJ Butt H Strawbridge JD \nMedication use in early pregnancy-prevalence and determinants of use in a prospective cohort of women . Pharmacoepidemiol Drug Saf \n2010 ;19 :408–17 .20099251 \n[8] Lacroix I Damase-Michel C Lapeyre-Mestre M \nPrescription of drugs during pregnancy in France . Lancet \n2000 ;356 :1735–6 .11095263 \n[9] Hardy JR Leaderer BP Holford TR \nSafety of medications prescribed before and during early pregnancy in a cohort of 81,975 mothers from the UK General Practice Research Database . Pharmacoepidemiol Drug Saf \n2006 ;15 :555–64 .16767799 \n[10] Andrade SE Gurwitz JH Davis RL \nPrescription drug use in pregnancy . Am J Obstet Gynecol \n2004 ;191 :398–407 .15343213 \n[11] Mitchell AA Gilboa SM Werler MM \nMedication use during pregnancy, with particular focus on prescription drugs: 1976–2008 . Am J Obstet Gynecol \n2011 ;205 :e1–8 . 51 .\n[12] Palmsten K Hernandez-Diaz S Chambers CD \nThe most commonly dispensed prescription medications among pregnant women enrolled in the U.S. Medicaid Program . Obstet Gynecol \n2015 ;126 :465–73 .26244530 \n[13] Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling. Final rule . Fed Regist \n2014 ;79 :72063–103 .25509060 \n[14] Ye-Jee K Joong-Yub L Nam-Kyung C \nPharmacovigilance system in general hospitals applied for the regional pharmacovigilance center in Korea . J Pharmacoepidemiol Risk Manag \n2009 ;2 :89–96 .\n[15] Olsson S \nThe role of the WHO Programme on International Drug Monitoring in coordinating worldwide drug safety efforts . Drug Saf \n1998 ;19 :1–0 .9673854 \n[16] World Health Organization . Adverse Reactions Terminology (WHO-ART) . Geneva, Switzerland : WHO ; 2005 .\n[17] World Health Organization . The Use of the WHO-UMC System for Standardized Case Causality Assessment. \nUppsala, Sweden : The Uppsala Monitoring Centre ; 2005 .\n[18] World Health Organization . Anatomical Therapeutic Chemicals (ATC) Classification System . 2013 \nAvailable at: https://www.whocc.no/atc_ddd_index/ \n[accessed January 8, 2018].\n[19] Lim JW \nThe changing trends in live birth statistics in Korea, 1970–2010 . Korean J Pediatr \n2011 ;54 :429–35 .22253639 \n[20] Callaway LK Lust K McIntyre HD \nPregnancy outcomes in women of very advanced maternal age . Aust N Z J Obstet Gynaecol \n2005 ;45 :12–6 .15730358 \n[21] Lamminpaa R Vehvilainen-Julkunen K Gissler M \nPreeclampsia complicated by advanced maternal age: a registry-based study on primiparous women in Finland 1997–2008 . BMC Pregnancy Childbirth \n2012 ;12 :47.22687260 \n[22] Koo Y-J Ryu H-M Yang J-H \nPregnancy outcomes according to increasing maternal age . Taiwan J Obstet Gynecol \n2012 ;51 :60–5 .22482970 \n[23] Kenny LC Lavender T McNamee R \nAdvanced maternal age and adverse pregnancy outcome: evidence from a large contemporary cohort . PLoS One \n2013 ;8 :e56583.23437176 \n[24] Nebeker JR Barach P Samore MH \nClarifying adverse drug events: a clinician's guide to terminology, documentation, and reporting . Ann Intern Med \n2004 ;140 :795–801 .15148066 \n[25] Bateman BT Cole NM Maeda A \nPatterns of opioid prescription and use after cesarean delivery . Obstet Gynecol \n2017 ;130 :29–35 .28594763 \n[26] Bateman BT Hernandez-Diaz S Rathmell JP \nPatterns of opioid utilization in pregnancy in a large cohort of commercial insurance beneficiaries in the United States . Anesthesiology \n2014 ;120 :1216–24 .24525628 \n[27] Engeland A Bramness JG Daltveit AK \nPrescription drug use among fathers and mothers before and during pregnancy. A population-based cohort study of 106,000 pregnancies in Norway 2004–2006 . Br J Clin Pharmacol \n2008 ;65 :653–60 .18294334 \n[28] Desai RJ Hernandez-Diaz S Bateman BT \nIncrease in prescription opioid use during pregnancy among Medicaid-enrolled women . Obstet Gynecol \n2014 ;123 :997–1002 .24785852 \n[29] Klaman SL Isaacs K Leopold A \nTreating women who are pregnant and parenting for opioid use disorder and the concurrent care of their infants and children: Literature review to support national guidance . J Addict Med \n2017 ;11 :178–90 .28406856 \n[30] Patrick SW Dudley J Martin PR \nPrescription opioid epidemic and infant outcomes . Pediatrics \n2015 ;135 :842–50 .25869370 \n[31] Practice Bulletin, No. 171 . Management of preterm labor . Obstet Gynecol \n2016 ;128 :e155–64 .27661654 \n[32] Sarri G Davies M Gholitabar M \nPreterm labour: summary of NICE guidance . BMJ Clin Res Ed \n2015 ;351 :h6283.\n[33] Andrade SE Raebel MA Brown J \nOutpatient use of cardiovascular drugs during pregnancy . Pharmacoepidemiol Drug Saf \n2008 ;17 :240–7 .18200619 \n[34] Flenady V Wojcieszek AM Papatsonis DN \nCalcium channel blockers for inhibiting preterm labour and birth . Cochrane Database Syst Rev \n2014 ;6 :Cd002255.24901312\n\n",
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"issue": "98(21)",
"journal": "Medicine",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000700:Analgesics; D000701:Analgesics, Opioid; D000900:Anti-Bacterial Agents; D000932:Antiemetics; D001802:Blood Substitutes; D002317:Cardiovascular Agents; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D008875:Middle Aged; D011247:Pregnancy; D056910:Republic of Korea; D012312:Ritodrine; D012720:Severity of Illness Index; D055815:Young Adult",
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"title": "Opioid analgesics are the leading cause of adverse drug reactions in the obstetric population in South Korea.",
"title_normalized": "opioid analgesics are the leading cause of adverse drug reactions in the obstetric population in south korea"
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"abstract": "Anti-glaucoma agents-induced corneal toxicity may be misdiagnosed as herpetic simplex keratitis (HSK). In our study, nineteen glaucoma patients were presumed to have HSK before referral. Corneal lesions were classified into (I) linear pseudodendritic lesions formed by elevated opacified cells, (II) linear pseudodendritic lesions formed by grouped superficial punctate keratitis (SPK), (III) satellite full-thickness epithelial defects, (IV) satellite lesions formed by elevated opacified cells, and (V) geographic lesions formed by grouped SPK. We observed thirty-one events, with 15 in the lower and 16 in the central corneas. There were 21 (67.7%) type II, five (16.1%) type V, two (6.5%) of each for types III and IV, and one (3.2%) type I events. Among linear lesions (types I and II), 17 (77.3%) had horizontal and 5 (22.7%) had curvilinear orientations. Exposure duration to the last-added anti-glaucoma agent was three days to 14.5 years. About half of the events (16/31, 51.6%) used prostaglandin analogues, and 30/31 (96.8%) applied benzalkonium chloride (BAK)-containing agents. All lesions resolved within two months after decreasing offending medications or enhancing protection of ocular surface. In conclusion, anti-glaucoma agents-induced pseudodendritic keratitis presents majorly in central-lower cornea as horizontally linear lesions, and BAK-containing agents are observed in the most events.",
"affiliations": "Department of Ophthalmology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan.;Department of Ophthalmology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan.;Shiley Eye Institute and Viterbi Family Department of Ophthalmology, Hamilton Glaucoma Center, University of California, San Diego, CA, USA.;Department of Ophthalmology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan.;Department of Ophthalmology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan.;Department of Ophthalmology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan. chenweili@ntu.edu.tw.",
"authors": "Chang|Huai-Lung|HL|;Kuo|Bo-I|BI|;Wu|Jo-Hsuan|JH|;Huang|Wei-Lun|WL|;Su|Chien-Chia|CC|;Chen|Wei-Li|WL|",
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"doi": "10.1038/s41598-021-01073-0",
"fulltext": "\n==== Front\nSci Rep\nSci Rep\nScientific Reports\n2045-2322\nNature Publishing Group UK London\n\n1073\n10.1038/s41598-021-01073-0\nArticle\nAnti-glaucoma agents-induced pseudodendritic keratitis presumed to be herpetic simplex keratitis: a clinical case series\nChang Huai-Lung 1\nKuo Bo-I 124\nWu Jo-Hsuan 3\nHuang Wei-Lun 1\nSu Chien-Chia 1\nChen Wei-Li chenweili@ntu.edu.tw\n\n156\n1 grid.412094.a 0000 0004 0572 7815 Department of Ophthalmology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan\n2 grid.19188.39 0000 0004 0546 0241 Section of Ophthalmology, National Taiwan University Cancer Center, Taipei, Taiwan\n3 grid.266100.3 0000 0001 2107 4242 Shiley Eye Institute and Viterbi Family Department of Ophthalmology, Hamilton Glaucoma Center, University of California, San Diego, CA USA\n4 grid.19188.39 0000 0004 0546 0241 Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan\n5 grid.412094.a 0000 0004 0572 7815 Advanced Ocular Surface and Corneal Nerve Regeneration Center, National Taiwan University Hospital, Taipei, Taiwan\n6 grid.19188.39 0000 0004 0546 0241 Department of Ophthalmology, National Taiwan University College of Medicine, Taipei, Taiwan\n2 11 2021\n2 11 2021\n2021\n11 2144318 7 2021\n20 10 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nAnti-glaucoma agents-induced corneal toxicity may be misdiagnosed as herpetic simplex keratitis (HSK). In our study, nineteen glaucoma patients were presumed to have HSK before referral. Corneal lesions were classified into (I) linear pseudodendritic lesions formed by elevated opacified cells, (II) linear pseudodendritic lesions formed by grouped superficial punctate keratitis (SPK), (III) satellite full-thickness epithelial defects, (IV) satellite lesions formed by elevated opacified cells, and (V) geographic lesions formed by grouped SPK. We observed thirty-one events, with 15 in the lower and 16 in the central corneas. There were 21 (67.7%) type II, five (16.1%) type V, two (6.5%) of each for types III and IV, and one (3.2%) type I events. Among linear lesions (types I and II), 17 (77.3%) had horizontal and 5 (22.7%) had curvilinear orientations. Exposure duration to the last-added anti-glaucoma agent was three days to 14.5 years. About half of the events (16/31, 51.6%) used prostaglandin analogues, and 30/31 (96.8%) applied benzalkonium chloride (BAK)-containing agents. All lesions resolved within two months after decreasing offending medications or enhancing protection of ocular surface. In conclusion, anti-glaucoma agents-induced pseudodendritic keratitis presents majorly in central-lower cornea as horizontally linear lesions, and BAK-containing agents are observed in the most events.\n\nSubject terms\n\nMedical research\nOutcomes research\nThe Department of Medical Research National Taiwan UniversityNational Taiwan University Hospital Research Grant108-A144 Chen Wei-Li issue-copyright-statement© The Author(s) 2021\n==== Body\npmcIntroduction\n\nGlaucoma is a major cause of irreversible blindness, estimated to involve almost 111 million people in 2040 worldwide1,2, and anti-glaucoma agents are currently the most common treatment strategies. Despite the effects of lowering intraocular pressure (IOP)3–5, ocular toxicity of these agents is frequently reported, including subconjunctival fibrosis, allergy, decreased tear film, and superficial corneal toxicity6–10. Daily and repetitive exposure of ocular surface to the active compounds or the preservatives in the topical anti-glaucoma medications may be deleterious to ocular surface. The most commonly applied preservative in glaucoma medications is benzalkonium chloride (BAK), and had been reported to interrupt the corneal epithelial barrier function with its detergent properties and damage the corneal nerves, as well as disrupting the production and stabilization of tear film11–14. Although the evolving fixed combination drugs15 and new surgical techniques16,17 can mitigate drug application frequency and associated ocular surface damage, many glaucoma patients are still receiving multi-eye drop treatments. The intricate medication history may confound ophthalmologists and complicate the diagnosis of ocular surface diseases in these patients.\n\nAmong the possible ocular surface complications in patients receiving anti-glaucoma agents, herpetic simplex keratitis (HSK) is one of the most severe and had been emphasized in patients receiving topical prostaglandins. After the first announcement of this complication of prostaglandins in 199918, several reports have been published19–24. Awareness of this side effect is important since HSK can be managed with antiviral medications, while significant visual impairments may occur if left untreated25,26. However, over-alert of this complication may lead to misdiagnosis in patients presenting with similar corneal lesions of other causes, especially those with pseudodendritic lesions caused by certain anti-glaucoma agents23,27. Since treatment strategies for HSK and medication-induced corneal toxicity are different, distinguishing them is essential.\n\nTo the best of our knowledge, there has not been a large-scaled case series analysing the corneal lesions caused by anti-glaucoma agents that were initially misdiagnosed as HSK. We enrolled 19 patients diagnosed with anti-glaucoma agents-induced pseudodendritic keratitis in tertiary medical center with the presumed diagnosis of HSK in primary care clinics before referral. Based on the lesion morphology and medication history, a simple reference guideline to ameliorate identification of this disease was provided.\n\nMethods\n\nIn this 6-year retrospective, non-comparative, non-interventional case series study, we enrolled patients referred to our hospital from January, 2015 to January, 2021 with the presumed diagnosis of HSK made by different primary care doctors. The study was approved by the Institutional Review Board of NTUH (202007139RIND) as per the tenets of the Declaration of Helsinki. Informed consent was obtained from all subjects for utilizing their information and de-identified images for study and publication.\n\nCriteria for subject inclusion\n\nAll patients were immunocompetent and had been under topical anti-glaucoma agents unilaterally or bilaterally before referral. They were all diagnosed with HSK by different referral doctors, with symptoms including ocular pain, foreign body sensations, blurred visions, etc. None had ocular surgery within one year prior to the presumed diagnosis of HSK. Detailed history of topical anti-glaucoma agents (drug species and duration), demographic information, past ocular history, external eye photos, and treatment course before and after referral were obtained.\n\nThe topical medications used in this study included dorzolamide 2% (Trusopt, Merk & Co., Onv., Whitehouse Station, NJ, US, with 0.0075% BAK), latanoprost 0.005% (Xalatan, Pfizer, New York, NY, US, with 0.02% BAK), brimonidine 0.15% (Alphagan P, Allergan, Irvine, CA, US with 0.005% purite), carteolol 2% (Mikelan, Otsuka, Tokyo, Japan, with 0.005% BAK), timolol 0.5% (Timoptic, Merk & Co. White house station, NJ, US, with 0.01% BAK), pilocarpine 2% (Isopto Carpine, Alcon, Fort Worth, TX, USA, with 0.01% BAK), preservative free bimatoprost 0.03% (Lumigan, Allergan, Madison, NJ, US), and dorzolamide 2%/timolol 0.5% combination (Cosopt, Merck & Co., Inc., Whitehouse Station, NJ, US, with 0.0075% BAK).\n\nConfirmation of non-HSK pseudodendritic keratitis\n\nTo confirm the HSK-unrelated nature of the lesions, all patients were examined by the following criteria: (1) improvement of corneal lesions after removing the presumed triggering medications or applying ocular surface protecting methods, including topical lubricants or therapeutic soft contact lens (TSCL) without using antiviral medications, (2) no recurrence of the corneal lesions after removing the presumed triggering medications, (3) absences of characteristics corneal lesions of HSV, such as dendritic lesions with terminal bulbs, (4) negative viral culture results of the lesions, and (5) bilateral involvement, which is less likely HSK if the patient is immunocompetent. The prevalence of bilateral HSK is estimated to be 1.3–12% in the immunocompetent adults28,29. To confirm the diagnosis of a non-HSK pseudodendritic keratitis, it is required that subjects should meet rules one to three, and may be further confirmed by the addition of either rules four or five.\n\nAnalysis of the corneal lesions\n\nSince some patients had recurrent diseases, the corneal lesions were counted based on “event,” defined as the occurrence of lesions per time in per eye. Bilateral involvement at the same time was identified as two events, and lesions presenting in the same eye during separated periods were counted as individual events. Meanwhile, the “episode” was defined as the occurrence of lesions per time in per patient, with bilateral involvement at the same time identified as one episode.\n\nThe lesions were classified into five types based on morphological presentations (Fig. 1), including (I) linear pseudodendritic lesions formed by elevated opacified cells, (II) linear pseudodendritic lesions formed by grouped superficial punctate keratitis (SPK), (III) satellite full-thickness epithelial defects, (IV) satellite lesions formed by elevated opacified cells, and (V) geographic ulcers formed by grouped SPK. Characteristics of HSK, including terminal bulbs and central fluorescein stains, were not present. The cornea was divided into upper, central, and lower thirds. Locations of the lesions were based on the majorly involved areas (> 2/3 of the lesion area). The linear lesions (types I and II) were divided into horizontal and curvilinear based on their orientations. Examples of different locations and orientations were shown in Fig. 2.Figure 1 Examples of type I–V anti-glaucoma agent-induced pseudodendritic lesions, in comparison with typical superficial punctate keratitis (SPK). (a) Type I. Linear pseudodendritic lesions with elevated opacified cells. (b) Type II. Linear pseudodendritic lesions formed by grouped superficial punctate keratitis. (c) Type III. Satellite full thickness epithelial defects. (d) Type IV. Satellite lesions formed by elevated opacified cells. (e) Type V. Geographic lesions formed by grouped superficial punctate keratitis. (f) Typical superficial punctate keratitis in patients with dye eye diseases (DED) without pseudodendritic presentation.\n\nFigure 2 Examples of the orientation and location of anti-glaucoma agent-induced pseudodendritic lesions. The orientation was only measured in linear lesions (type I and II). The white dashed lines illustrate the contour of corneal lesions. The black solid lines divided the corneas as three equal parts. (a) Horizontal orientation. (b) Curvilinear orientation. (c) Lower-located pseudodendritic lesions, with more than 2/3 of the lesion involved the lower cornea. (d) Central-located pseudodendritic lesions, with more than 2/3 of the lesions involving the central cornea.\n\nResults\n\nCharacteristics of subjects\n\nA total of 22 episodes, 31 events of 19 patients were included. Characteristics of the participants were in Table 2. Mean age of the patients was 72.5 ± 15.6 years. Sixteen (84.2%) patients were older than 65 years old. Male patients were predominant (14, 73.7%).\n\nAmong the 19 participants, three (15.8%) had type 2 diabetes mellitus, two (10.5%) had Sjogren’s syndrome (SS) with dry eye disease (DED), and nine (47.4%) had non-Sjogren’s DED characterized by decreased tear-film breakup time, decreased tear film meniscus or positive Schirmer’s test (Table 2).\n\nCharacteristics of the pseudodendritic lesions\n\nMost patients experienced single episode, while three patients had two episodes. Thirteen (59.1%) of the 22 episodes were unilateral and the other nine (40.9%) were bilateral, contributing to 13 and 18 events, respectively. Among the unilateral episodes, two had unilateral eye drop application and 11 had bilateral eye drop treatment. Among those using bilateral eye drops, case 2 administered additional topical pilocarpine to the diseased eye, while all others applied same medications in both eyes. In the nine bilateral episodes, all patients administered same anti-glaucoma agents in both eyes.\n\nTo exclude HSK, HSV viral culture was performed in the first seven patients (cases 1 to 7) and elicited negative results. The rest patients were not tested for HSV and was examined using the aforementioned criteria, which we believed was sufficient for differentiation.\n\nAll 31 events were classified by lesion locations, types of morphological presentation, and lesion orientations. About half (16, 51.6%) of the events were found located in the lower cornea and the other half (15, 48.4%) were in the central cornea. None was in the upper cornea. For the types of morphological presentation, there are 21 (67.7%) type II, five (16.1%) type V, two (6.5%) of each for types III and IV, and one (3.2%) type I events. Among the 22 linear events (types I and II), 17 (77.3%) were horizontal in orientation and five (22.7%) were curvilinear. No vertical linear lesion was noted. For the three patients that experienced two episodes, there were changes in lesion morphology during the recurrent episodes. In the first episodes, case 8 had horizontal, central type I lesion in the left eye, case 10 had horizontal, central type II lesion in both eyes, and case 16 had central type III lesion in the right eye. In the recurrent episodes, case 8 had central type III lesion in the right eye, case 10 had horizontal, central type II lesion in the left eye, and case 16 had lower type II lesions with curvilinear orientation in the right eye and horizontal orientation in the left eye.\n\nMedication history of applying anti-glaucoma agents\n\nIn our study, 19 (61.2%) of the 31 events used single anti-glaucoma medication and 12 (38.7%) used two medications. No patient received over two drugs. The most frequently used long-term medication in our study was latanoprost (10, 38.5%), followed by carteolol (5, 19.2%), brimonidine (4, 15.4%) and dorzolamide/timolol (4, 15.4%). The last-added meditations included dorzolamide (2, 33.3%), latanoprost (2, 33.3%), carteolol (1, 16.7%) and dorzolamied/timolol (1, 16.7%). Although it is difficult to conclude whether the active compounds or preservatives in the drugs contributed to corneal toxicity, BAK was found in most of the medications in this study. A total of eight kinds of anti-glaucoma agents were used in our patients, in which seven were applied before corneal lesions appeared. BAK preservative was found in six (85.7%) of the seven medications, except for brimonidine, which contained purite as preservative. Preservative-free bimatoprost was used as the alternative anti-glaucoma agent after corneal lesions appeared (cases 3, 9–13, 19). BAK-containing medications were used in 30 (96.8%) out of the 31 events (Tables 1 and 2).Table 1 Demographic and clinical characteristics of study participants.\n\nCharacteristics\tNo. (%)a, mean ± SD, or range\t\nAge (years)\t\nMean\t72.5 ± 15.6\t\nRange\t26–96\t\n< 65\t3 (15.8)\t\n≥ 65\t16 (84.2)\t\nGender\t\nMale\t14 (73.7)\t\nFemale\t5 (26.3)\t\nPast medical history\t\nDM\t3 (15.8)\t\nDED\t9 (47.4)\t\nSS\t2 (10.5)\t\nAtopic dermatitis\t1 (5.3)\t\nAnti-glaucoma agents (preservative)\t\nLong-term medications\t\n Latanoprost (BAK)\t10 (38.5)\t\n Carteolol (BAK)\t5 (19.2)\t\n Brimonidine (purite)\t4 (15.4)\t\n Dorzolamide/Timolol (BAK)\t4 (15.4)\t\n Timolol (BAK)\t2 (7.7)\t\n Pilocarpine (BAK)\t1 (3.8)\t\nLast-added mediations\t\n Dorzolamide (BAK)\t2 (33.3)\t\n Latanoprost (BAK)\t2 (33.3)\t\n Carteolol (BAK)\t1 (16.7)\t\n Dorzolamide/Timolol (BAK)\t1 (16.7)\t\nDurations of anti-glaucoma agents usage\t\nLong-term medications\t\n ≤ 3 months\t4 (18.2)\t\n > 3 months, ≤ 1 year\t8 (36.4)\t\n > 1 year, ≤ 5 years\t6 (27.3)\t\n > 5 years\t4 (18.2)\t\nLast-added medications\t\t\n ≤ 1 month\t3 (50)\t\n > 1 month\t3 (50)\t\nTypes of pseudodendritic lesions\t\n I\t1 (3.2)\t\n II\t21 (67.7)\t\n III\t2 (6.5)\t\n IV\t2 (6.5)\t\n V\t5 (16.1)\t\nLocations of pseudodendritic lesions\t\n Upper\t0\t\n Center\t16 (51.6)\t\n Lower\t15 (48.4)\t\nOrientations of linear pseudodendritic lesions (type I and II lesions)\t\n Horizontal\t17 (77.3)\t\n Curvilinear\t5 (22.7)\t\nDM diabetes mellitus, DED non-Sjogren dry eye disease, SS Sjogren syndrome.\n\naThe No. for age, gender and past medical history refers to the numbers of patients for each characteristic. The No. for anti-glaucoma agents refers to the numbers of episodes that each medication was used in. The No. for types and locations of pseudodendritic lesions, and orientations of linear pseudodendritic lesions refers to the numbers of events for each characteristic.\n\nTable 2 Brief history of the case series.\n\nCase\tAge\tGender\tPast history\tEpisode\tCorneal lesion, laterality\tLong-term medication (preservatives)/laterality\tDuration\tLast-added medication (preservatives)/laterality\tDuration\tHSV culture\tManagementa\t\n1\t26\tM\tDED\t1st\tType IV, ou\tTimolol (BAK)/ou\t1 year\tNA\t\tNegative\tA, B\t\n2\t67\tM\tDED\t1st\tType II, od\tPilocarpine (BAK)/od\t1 year\tDorzolamide (BAK)/ou\t1 month\tNegative\tC\t\n3\t60\tF\tDM\t1st\tType II, os\tLatanoprost (BAK)/ou\t14 years\tNA\t\tNegative\tA, F\t\n4\t70\tF\t–\t1st\tType II, os\tLatanoprost (BAK)/ou\t6 years\tNA\t\tNegative\tA, C, E\t\n5\t93\tM\tDED\t1st\tType V, ou\tDorzolamide/timolol (BAK)/ou\t1 year\tNA\t\tNegative\tA\t\n6\t75\tM\tDED\t1st\tType II, ou\tCarteolol (BAK)/ou\t7 years\tLatanoprost (BAK)/ou\t3 months\tNegative\tA, C, E\t\n7\t69\tM\tDED\t1st\tType II, os\tLatanoprost (BAK)/os\t1 year\tNA\t\tNegative\tB, C\t\n8\t78\tM\tDED, DM\t1st\tType I, os\tLatanoprost (BAK)/ou, dorzolamide/timolol (BAK)/ou\t3.5 years\tNA\t\tNA\tA,C, E\t\n2nd\tType III, od\tBrimonidine (purite)/ou\t8 months\tNA\t\t\tA, C, E\t\n9\t74\tF\tSS\t1st\tType II, ou\tCarteolol(BAK)/ou\t1.5 years\tLatanoprost (BAK)/ou\t2 months\tNA\tA, C, F\t\n10\t75\tF\tSS\t1st\tType II, ou\tLatanoprost (BAK)/ou\t5 years\tNA\t\tNA\tA, C, F\t\n2nd\tType II, os\tLatanoprost (BAK)/ou\t1 month\tDorzolamide/Timolol (BAK)/ou\t3 days\tNA\tA, B, D, F\t\n11\t70\tM\t–\t1st\tType V, ou\tCarteolol (BAK)/ou\t6 months\tNA\t\tNA\tA, B\t\n12\t79\tM\t–\t1st\tType II, ou\tTimolol (BAK)/ou, Latanoprost (BAK)/ou\t5 years\tNA\t\tNA\tA, C, F\t\n13\t79\tM\t–\t1st\tType II, od\tLatanoprost (BAK)/od\t1 year\tCarteolol (BAK)/od\t2 months\tNA\tA, C, E, F\t\n14\t96\tM\tDED\t1st\tType II, od\n\nType V, os\n\n\tCarteolol (BAK)/ou\t3 years\tNA\t\tNA\tA\t\n15\t78\tM\t–\t1st\tType II, os\tBrimonidine (purite)/os\t1 month\tDorzolamide (BAK)/os\t8 days\tNA\tC\t\n16\t78\tM\tDED\t1st\tType III, od\tBrimonidine (purite)/ou, Dorzolamide/timolol (BAK)/ou\t1 month\tNA\t\tNA\tB\t\n2nd\tType II, ou\tCarteolol(BAK)/ou\t1 year\tNA\t\tNA\tB\t\n17\t70\tM\tDED, DM\t1st\tType II, os\tLatanoprost (BAK)/ou\t2 months\tNA\t\tNA\tB, C\t\n18\t50\tM\tAD\t1st\tType II, os\tBrimonidine (purite)/ou dorzolamide/timolol (BAK)/ou\t5 years\tNA\t\tNA\tA, C, F\t\n19\t91\tM\t–\t1st\tType II, os\tLatanoprost (BAK)/ou\t10 years\tNA\t\tNA\tA\t\nM male, F female, DED non-Sjogren dry eye disease, BAK benzalkonium chloride, NA not-available, DM diabetic mellitus, SS Sjogren syndrome, AD atopic dermatitis.\n\naManagement type: A: preservative-free lubricant, B: TSCL, C: Stopped all glaucoma drugs, D: Stopped last-added glaucoma drugs, E: Shifted to oral anti-glaucoma medications, F: Shifted to preservative-free bimatoprost or carteolol (with BAK).\n\nExposure durations of long-term eye drops before corneal lesions emerged ranged from one month (case 15, purite-containing brimonidine) to 14 years (case 3, BAK-containing latanoprost). Among the 22 episodes, eight used long-term eye drops for over three months to one year, six used for over 1 year to 5 years, and four used for no more than three months and over 5 years, each. Exposure durations of the last added anti-glaucoma agents before onset of corneal lesions ranged from three days (case 10, second episode, BAK-containing dorzolamide/timolol) to three months (case 6, BAK-containing latanoprost) (Table 2).\n\nTreatments of anti-glaucoma agents-induced pseudodendritic keratitis\n\nDurations of ocular surface symptoms before referral to our hospital ranged from five to 14 days. Of the 19 subjects, five tried acyclovir ointment before referral but showed no amelioration (cases 1, 2, 3, 9 and 13). Following the diagnosis of anti-glaucoma agents-induced pseudodendritic keratitis at our hospital, 15 (68.2%) out of 22 episodes were treated with alternations in anti-glaucoma agents, including change, decrease, or discontinuation of topical medications, while seven (31.8%) reached complete resolution after application of TSCL or preservative-free lubricants without alternating the anti-glaucoma agents (Table 2). Representative external eye photos throughout the clinical course were shown in Figs. 3 and 4.Figure 3 A 75-year-old female (case 10, second episode) with Sjogren syndrome who used latanoprost 0.005% (Xalatan, Pfizer, New York, NY, US, with 0.02% BAK) for one month and dorzolamide 2%/timolol 0.5% combination (Cosopt; Merck & Co., Inc., Whitehouse Station, NJ, US, with 0.0075% BAK) for three days. She presented with type II pseudodendritic lesion from by grouped superficial punctate keratatitis in the left eye with the presumed diagnosis of HSK by the referral ophthalmologist (a, b). Dorzolamide 2%/timolol 0.5% combination was discontinued, followed by adding preservative free bimatoprost 0.03% (Lumigan, Allergan, Madison, NJ, US) and lubricants. The pseudodendritic lesion resolved within two weeks (c, d).\n\nFigure 4 A 69-year-old male (case 7) with dry eye disease used latanoprost 0.005% (Xalatan, Pfizer, New York, NY, US, with 0.02% BAK) for one year. He was referred to our clinic with the presumed diagnosis of HSK, and centrally located type II linear pseudodendritic lesions formed by grouped superficial punctate keratitis was found in the left eye (a, b). The viral culture was negative. The topical anti-glaucoma agents were discontinued followed by application of therapeutic soft contact lenses. The main lesion resolved within two weeks (c, d).\n\nAll pseudodendritic lesions resolved after treatments at our hospital within two months (Table 2). There was no adverse nor unanticipated event. Three patients had recurrent episodes after treatments stopped and the initial anti-glaucoma therapies were resumed. Recurrent episodes relieved after recommence of appropriate treatments.\n\nDiscussion\n\nTopical anti-glaucoma agents, especially prostaglandin analogues, have been proposed to stimulate the recurrence of HSK18,20,21. However, corneal toxicity resulted from long-term anti-glaucoma agents usage may also cause pseudodendritic lesions similar to HSK, thus a simple reference guideline to facilitate differentiation is valuable.\n\nBack in 1999, Wand et al. reported three cases of HSK after topical latanoprost therapy, in which one case had viral culture evidence18. All cases recovered after discontinuation of latanoprost and one was treated additionally with antiviral agents. Meanwhile, Sudesh et al. reported sterile pseudodendrites caused by latanoprost toxicity19. Ekatomatis later reported two cases of HSK diagnosed by immunofluorescence study of corneal epithelium, after using topical latanoprost within three months20. Antiviral treatment and discontinuation of latanoprost were applied simultaneously, and elicited lesion recovery. Deai et al. reported positive HSV-1 in tear film through PCR in cases with similar presentation21. However, the cases simultaneously applied beta-blocker, a topical agent reported to cause dendritic keratopathy27. Notably, a positive PCR result of tear cannot differentiate active HSK and normal viral shedding30. Later, several conference reports proposed the existence of non-infectious pseudodendritic keratitis caused by latanoprost, which often manifests as horizontal, opaque, elevated epithelial congregations forming rough branching dendritic figures without terminal bulbs, and broadly surrounded by punctate keratopathy23,31. To clarify the association between HSK and prostaglandin analogs, several epidemiological studies were performed, which demonstrated a similar prevalence of HSK between patients treated with anti-glaucoma agents and general public, and a comparable risk of HSK for prostaglandin analogs and other ocular hypotensive agents22,24. With the aforementioned findings, the causal relationship between reactivation of HSK and latanoprost should be reconsidered.\n\nIn our study, several anti-glaucoma agents, not limited to prostaglandin analogues and mostly BAK-containing, may cause non-infectious pseudodendritic keratitis. Various morphological presentations of the corneal lesions were observed in this study, possibly due to different severities of corneal toxicity, disease stages, and triggering medications with varying active compounds and preservatives. All lesions in our study were located in central to lower corneas. As described above, we classified the lesions into five types, with the majority presenting as linear pseudodendritic lesions formed by grouped superficial punctate keratitis. All linear events (type I and II) were horizontal or curvilinear, which reflected the gravity-dependent accumulation of the toxic topical agents. Notably, different types of lesions were found in some patients with bilateral or recurrent corneal lesions, which supports our presumption that different morphological types of pseudodendritic lesions were all products of similar pathological mechanisms.\n\nThe most frequently used medication in our study was latanoprost (0.02% BAK), while other medications included carteolol (0.0075% BAK), brimonidine (0.005% purite), dorzolamide/timolol (0.0075% BAK), dorzolamide, timolol (0.01% BAK), pilocarpine (0.01% BAK). Although it is challenging to conclude whether the corneal toxicity was caused by the active compounds or the preservatives in these anti-glaucoma agents, BAK was found in most of the candidate triggering medications. The exposure durations of long-term and last-added anti-glaucoma agents before the onset of pseudodendritic lesions were one month to 14 years, and three days to three months, respectively. Contrary to the wide range of long-term drug application durations, the patients seemed to notice the symptoms more rapidly when new topical agents were added. Hence, it is crucial for clinicians to be attentive to those receiving long-term therapy, since the prolonged medication use and lack of significant pharmacological changes may easily lead to negligence of the drug toxicity. For patients receiving long-term medications and prescribed with new anti-glaucoma agents, frequent follow-ups should be arranged initially. While it is known that the ocular toxicity of BAK is dose-dependent13,32, the exact amount of BAK exposure needed for pseudodendritic keratitis development is yet to be determined. In addition, since most of our enrolled patients were older than 65 years old and had underlying conditions prone to ocular surface diseases, including DED, DM, SS, selection of anti-glaucoma agents and application duration should be carefully determined in patients with these characteristics.\n\nThe main challenge of our study is the confirmation to exclude HSK. No patient in our study had known history of HSK or herpes zoster infection. Cases 1–7 received viral culture and demonstrated negative results, thus laboratory viral tests were not performed on the others. About half of the patients suffered from bilateral corneal lesions, which may indirectly rule out the possibility of HSK, since HSK rarely cause bilateral involvement in immunocompetent individuals. Interestingly, in the other patients with unilateral lesions, most received bilateral anti-glaucoma treatment with same medications. The reason for the observed unilateral involvement in these cases may be related to the asymmetrical dosage application by patients or the different baseline characteristics of each eye, for example, various degrees of dry eye disease severity. This observation requires further investigations.\n\nThe orientation and location of the pseudodendritic lesions implied the underlying gravity-dependent toxin accumulation. This is different from HSK, in which no preference on the location and orientation of the dendrites were documented. Disregarding the types of morphology, all lesions in this study demonstrated lack of the characteristic terminal bulbs and central fluorescein stain usually found in HSK. In addition, most lesions were surrounded by grouped SPK. The unique presentations can be considered a clue for differential diagnosis. No antiviral medication was prescribed to any patient after referral, and the corneal lesions mitigated under decreased anti-glaucoma drug burden or ocular surface protection with TSCL or lubricants. Satisfactory therapeutic responses after these measures further indicated the non-infectious entity of these lesions. Although other causes including healing epithelial defect, recurrent erosion syndrome33,34, soft contact lens wear35, neurotrophic ulcer36, acanthamoeba keratitis37, systemic tyrosinemia38,39, and Thygesons’s superficial punctate keratitis40 may also cause pseudodendritic lesions, clinical presentations and past history of our patients suggested these etiologies to be unlikely.\n\nTreatments for anti-glaucoma agents-induced pseudodendritic keratitis followed previous guidelines41. Discontinuation or alternation of anti-glaucoma agents, application of preservative-free lubricant or TSCL were the main approaches. Time to recovery varied, but complete resolution was reached within two months in all patients. Ultimately, a stepwise approach is needed to determine the most suitable substitute anti-glaucoma agents that balances between the adverse effects and the therapeutic effects, and oral anti-glaucoma agents may be considered in the meantime. Since most cases in our study applied BAK-containing anti-glaucoma agents, changing to non-BAK-containing or preservative-free anti-glaucoma agents may be eligible. Fixed-combined medication, which can decrease the overall drug burdens, can also be beneficial for reducing drug toxicity. However, some patients in our study were already using fixed-combined medication, either as monotherapy or in combination with other anti-glaucoma agents, before the occurrence of the pseudodendritic lesions. After treatments, there were three patients with recurrence. Patients 8 and 16 resolved completely after removing all presumed triggering anti-glaucoma medications, but recurred when applying new medications. Patient 10 also achieved complete resolution in the first episode, but recurred when resuming latanoprost. Hence the second episodes of these patients should be viewed as separate incidents and required independent evaluation. All three patients had past ocular history of DED or SS and two of them used anti-glaucoma agents for over three years before the first episodes, which might have compromised the ocular surface integrity and led to greater susceptibility to the second episodes.\n\nThere are some limitations in this study. First, the retrospective nature and limited case number are the main drawbacks. Second, despite that we provided a comprehensive diagnosis guideline, lack of laboratory test confirmation in the enrolled cases is still a concern. Third, corneal sensitivity test was not performed to rule out the possibility of neurotrophic keratitis. Both HSK and chronic use of topical medications containing BAK can cause impaired corneal sensation14. Since most patients have applied anti-glaucoma agents for a while and decreased corneal sensitivity might have already occurred, this test may not be optimal to differentiate HSK and anti-glucoma agents-induced lesions, as both conditions are characterized by abnormal corneal sensitivity. Hence, corneal sensation was not tested as it would be difficult to differentiate the exact cause if decreased result was observed.\n\nIn conclusion, our study described a non-infectious pseudodendritic keratitis caused by anti-glaucoma agents, which can be easily misdiagnosed as HSK. However, the patient’s medical history and the unique morphological characteristics of the corneal lesions can help distinguish them, even without microbial confirmation. These features include horizontal-linear or curvilinear, instead of vertical-linear, orientations of the lesions with predominant locations at the lower to middle parts of corneas, and the absence of terminal bulbs. Physicians should also keep in mind that, in addition to linear lesions, anti-glaucoma agents-induced pseudodendritic keratitis can occasionally present as satellite lesions and geographic ulcers. Discontinuation of the triggering medication, decreasing drug burden, and providing ocular surface protection are sufficient for complete resolution of these lesions, while antiviral therapy is not recommended. Most importantly, clarification of medication history and disease course and observation of the corneal lesions are keys to identify this disease, which were included in the reference guideline provided in our study.\n\nAuthor contributions\n\nH.L.C., B.I.K. and J.H.W. analyzed the data, prepared the figures and wrote the manuscript. W.L.H. provided intellectual input and assisted in preparing the manuscript. C.C.S. collected the data. W.L.C. designed the study, collected the data and provided critical review of the manuscript. All authors reviewed the manuscript.\n\nFunding\n\nThe work is partially supported by (1) the department of Medical Research at the NTUH, and (2) National Taiwan University Hospital Research Grant for Advanced Ocular Surface and Cornea Nerve Research Center (108-A144).\n\nData availability\n\nAll data relevant to the study are included in the article.\n\nCompeting interests\n\nThe authors declare no competing interests.\n\nPublisher's note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nThese authors contributed equally: Huai-Lung Chang and Bo-I Kuo.\n==== Refs\nReferences\n\n1. Quigley HA Broman AT The number of people with glaucoma worldwide in 2010 and 2020 Br. J. Ophthalmol. 2006 90 262 267 10.1136/bjo.2005.081224 16488940\n2. Tham YC Global prevalence of glaucoma and projections of glaucoma burden through 2040: A systematic review and meta-analysis Ophthalmology 2014 121 2081 2090 10.1016/j.ophtha.2014.05.013 24974815\n3. van der Valk R Intraocular pressure-lowering effects of all commonly used glaucoma drugs: A meta-analysis of randomized clinical trials Ophthalmology 2005 112 1177 1185 10.1016/j.ophtha.2005.01.042 15921747\n4. Stewart WC Konstas AG Nelson LA Kruft B Meta-analysis of 24-hour intraocular pressure studies evaluating the efficacy of glaucoma medicines Ophthalmology 2008 115 1117 1122 10.1016/j.ophtha.2007.10.004 18082886\n5. Konstas AG 24-h efficacy of glaucoma treatment options Adv. Ther. 2016 33 481 517 10.1007/s12325-016-0302-0 26909513\n6. Shimazaki J Changes in ocular surface caused by antiglaucomatous eyedrops: Prospective, randomised study for the comparison of 05% timolol v 012% unoprostone Br. J. Ophthalmol. 2000 84 1250 1254 10.1136/bjo.84.11.1250 11049949\n7. Jaenen N Ocular symptoms and signs with preserved and preservative-free glaucoma medications Eur. J. Ophthalmol. 2007 17 341 349 10.1177/112067210701700311 17534814\n8. Baudouin C Prevalence and risk factors for ocular surface disease among patients treated over the long term for glaucoma or ocular hypertension Eur. J. Ophthalmol. 2013 23 47 54 10.5301/ejo.5000181\n9. Portela RC Evaluation of ocular surface disease in patients with glaucoma: Clinical parameters, self-report assessment, and keratograph analysis J. Glaucoma 2018 27 794 801 10.1097/IJG.0000000000001007 29916999\n10. Fogagnolo P Tear film osmolarity, ocular surface disease and glaucoma: A review Curr. Med. Chem. 2019 26 4241 4252 10.2174/0929867326666190725160621 31345142\n11. Kahook MY Noecker RJ Comparison of corneal and conjunctival changes after dosing of travoprost preserved with sofZia, latanoprost with 0.02% benzalkonium chloride, and preservative-free artificial tears Cornea 2008 27 339 343 10.1097/ICO.0b013e31815cf651 18362664\n12. Sarkar J Corneal neurotoxicity due to topical benzalkonium chloride Invest. Ophthalmol. Vis. Sci. 2012 53 1792 1802 10.1167/iovs.11-8775 22410563\n13. Zhang R Dose-dependent benzalkonium chloride toxicity imparts ocular surface epithelial changes with features of dry eye disease Ocul. Surf. 2020 18 158 169 10.1016/j.jtos.2019.11.006 31740391\n14. Martone G An in vivo confocal microscopy analysis of effects of topical antiglaucoma therapy with preservative on corneal innervation and morphology Am. J. Ophthalmol. 2009 147 725 735.e721 10.1016/j.ajo.2008.10.019 19181302\n15. Konstas AG Dorzolamide/timolol fixed combination: Learning from the past and looking toward the future Adv. Ther. 2021 38 24 51 10.1007/s12325-020-01525-5 33108623\n16. Moisseiev E Zunz E Tzur R Kurtz S Shemesh G Standard trabeculectomy and Ex-PRESS miniature glaucoma shunt: A comparative study and literature review J. Glaucoma 2015 24 410 416 10.1097/IJG.0000000000000047 24633088\n17. Richter GM Coleman AL Minimally invasive glaucoma surgery: Current status and future prospects Clin. Ophthalmol. 2016 10 189 206 10.2147/OPTH.S80490 26869753\n18. Wand M Gilbert CM Liesegang TJ Latanoprost and herpes simplex keratitis Am. J. Ophthalmol. 1999 127 602 604 10.1016/s0002-9394(99)00050-1 10334356\n19. Sudesh S Cohen EJ Rapuano CJ Wilson RP Corneal toxicity associated with latanoprost Arch. Ophthalmol. 1999 117 539 540 10.1001/archopht.117.4.539 10206588\n20. Ekatomatis P Herpes simplex dendritic keratitis after treatment with latanoprost for primary open angle glaucoma Br. J. Ophthalmol. 2001 85 1008 1009 10.1136/bjo.85.8.1007a 11501520\n21. Deai T Herpes simplex virus genome quantification in two patients who developed herpetic epithelial keratitis during treatment with antiglaucoma medications Cornea 2004 23 125 128 10.1097/00003226-200403000-00004 15075880\n22. Bean G Reardon G Zimmerman TJ Association between ocular herpes simplex virus and topical ocular hypotensive therapy J. Glaucoma 2004 13 361 364 10.1097/01.ijg.0000133146.52310.3d 15354072\n23. Chang KK Affeldt JC Latanoprost associated noninfectious dendritiform keratitis Invest. Ophthalmol. Vis. Sci. 2005 46 2620 10.1167/iovs.04-1254 15980256\n24. Yeung SSAIMES Effect of topical anti-glaucoma drugs on the incidence of herpetic simplex keratitis Invest. Ophthalmol. Vis. Sci. 2019 60 2403\n25. Valerio GS Lin CC Ocular manifestations of herpes simplex virus Curr. Opin. Ophthalmol. 2019 30 525 531 10.1097/ICU.0000000000000618 31567695\n26. Kalezic T Mazen M Kuklinski E Asbell P Herpetic eye disease study: Lessons learned Curr. Opin. Ophthalmol. 2018 29 340 346 10.1097/ICU.0000000000000482 29846207\n27. Wilhelmus KR McCulloch RR Gross RL Dendritic keratopathy associated with beta-blocker eyedrops Cornea 1990 9 335 337 10.1097/00003226-199010000-00012 1981868\n28. Liesegang TJ Herpes simplex virus epidemiology and ocular importance Cornea 2001 20 1 13 10.1097/00003226-200101000-00001 11188989\n29. Souza PM Holland EJ Huang AJ Bilateral herpetic keratoconjunctivitis Ophthalmology 2003 110 493 496 10.1016/s0161-6420(02)01772-4 12623810\n30. Kaufman HE HSV-1 DNA in tears and saliva of normal adults Invest. Ophthalmol. Vis. Sci. 2005 46 241 247 10.1167/iovs.04-0614 15623779\n31. Chang KK Affeldt JC Labree L Agarwal M Noninfectious pseudodendritic keratitis Invest. Ophthalmol. Vis. Sci. 2004 45 2954 10.1167/iovs.03-1113\n32. Epstein SP Wei Y Asbell PA Toxicity of low-concentration benzalkonium chloride on the ocular surface (corneal and conjunctival epithelium) Invest. Ophthalmol. Vis. Sci. 2009 50 5525 5525\n33. Williams R Buckley RJ Pathogenesis and treatment of recurrent erosion Br. J. Ophthalmol. 1985 69 435 437 10.1136/bjo.69.6.435 3873960\n34. Ramamurthi S Rahman MQ Dutton GN Ramaesh K Pathogenesis, clinical features and management of recurrent corneal erosions Eye 2006 20 635 644 10.1038/sj.eye.6702005 16021185\n35. Margulies LJ Mannis MJ Dendritic corneal lesions associated with soft contact lens wear Arch. Ophthalmol. 1983 101 1551 1553 10.1001/archopht.1983.01040020553009 6626007\n36. Dua HS Neurotrophic keratopathy Prog. Retin. Eye Res. 2018 66 107 131 10.1016/j.preteyeres.2018.04.003 29698813\n37. Maycock NJ Jayaswal R Update on acanthamoeba keratitis: Diagnosis, treatment, and outcomes Cornea 2016 35 713 720 10.1097/ICO.0000000000000804 26989955\n38. Charlton KH Binder PS Wozniak L Digby DJ Pseudodendritic keratitis and systemic tyrosinemia Ophthalmology 1981 88 355 360 10.1016/s0161-6420(81)35036-2 6454871\n39. Kocabeyoglu S Mocan MC Irkec M In vivo confocal microscopic features of corneal pseudodendritic lesions in tyrosinemia type II Cornea 2014 33 1106 1108 10.1097/ICO.0000000000000226 25119963\n40. Thygeson P Clinical and laboratory observations on superficial punctate keratitis Am. J. Ophthalmol. 1966 61 1344 1349 10.1016/0002-9394(66)90265-0 5938018\n41. Ferreras A Figus M Fogagnolo P Iester M Frezzotti P Managing side effects on ocular surface caused by glaucoma eye drops Curr Med. Chem. 2019 26 4223 4224 10.2174/092986732622190920092210 31612807\n\n",
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"title": "Anti-glaucoma agents-induced pseudodendritic keratitis presumed to be herpetic simplex keratitis: a clinical case series.",
"title_normalized": "anti glaucoma agents induced pseudodendritic keratitis presumed to be herpetic simplex keratitis a clinical case series"
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"abstract": "Background Idiopathic intracranial hypertension (IIH) is a headache syndrome due to raised intracranial pressure of unknown etiology. Before making the diagnosis of IIH, secondary causes of raised intracranial pressure must be ruled out. The radiological features associated with this condition have variable sensitivity and specificity. In this case series, we aim to describe a potential new radiological marker of IIH, that is, diffusion restriction, in the optic disc head and propose that this can be a specific finding in the appropriate clinical picture. Importance IIH causes vision loss and disabling daily headaches. The diagnosis of this condition is based on history and physical examination findings. Magnetic resonance imaging (MRI) is used to exclude other causes, but specific radiological markers for the diagnosis of IIH are lacking. Observations Five patients presented with the main complaint of headache, which was associated with blurry vision. All of our patients had a formal neuro-ophthalmological evaluation that confirmed the presence of optic disc edema in both eyes. They also underwent an MRI of the brain that showed diffusion restriction in the optic nerve head in either eye or both eyes. Patients underwent lumbar puncture in the lateral decubitus position, which revealed cerebrospinal fluid opening pressures > 25 cm H 2 O. They all responded well to standard treatments, with the resolution of symptoms in their follow-up appointments. Conclusion and Relevance The MRI diffusion restriction in the optic nerve head may be a reliable noninvasive marker for the diagnosis of IIH in the appropriate clinical picture.",
"affiliations": "Department of Neurology, Columbia University, New York, New York, United States.;Department of Neurology, University of Missouri, Columbia, Missouri, United States.;Department of Neurology, University of Missouri, Columbia, Missouri, United States.;Department of Neurology, University of Missouri, Columbia, Missouri, United States.",
"authors": "Nagarajan|Elanagan|E|;Digala|Lakshmi P|LP|;Sivaraman|Manjamalai|M|;Bollu|Pradeep C|PC|",
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"fulltext": "\n==== Front\nJ Neurosci Rural Pract\nJ Neurosci Rural Pract\n10.1055/s-00043281\nJournal of Neurosciences in Rural Practice\n0976-3147 0976-3155 Thieme Medical and Scientific Publishers Private Ltd. A-12, Second Floor, Sector -2, NOIDA -201301, India \n\n10.1055/s-0039-3402621\nJNRP1900197\nBrief Report\nIs Magnetic Resonance Imaging Diffusion Restriction of the Optic Disc Head a New Marker for Idiopathic Intracranial Hypertension?\nNagarajan Elanagan 1 Digala Lakshmi P. 2 Sivaraman Manjamalai 2 Bollu Pradeep C. 2 1 Department of Neurology, Columbia University, New York, New York, United States\n2 Department of Neurology, University of Missouri, Columbia, Missouri, United States\nAddress for correspondence Elanagan Nagarajan, MD Department of Neurology, Columbia UniversityNew York, 710 West 168th Street, NY 10032United Statesen2452@cumc.columbia.edu\n1 2020 \n27 12 2019 \n11 1 170 174\nThis is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.\nBackground\nIdiopathic intracranial hypertension (IIH) is a headache syndrome due to raised intracranial pressure of unknown etiology. Before making the diagnosis of IIH, secondary causes of raised intracranial pressure must be ruled out. The radiological features associated with this condition have variable sensitivity and specificity. In this case series, we aim to describe a potential new radiological marker of IIH, that is, diffusion restriction, in the optic disc head and propose that this can be a specific finding in the appropriate clinical picture.\n\n\n\nImportance\nIIH causes vision loss and disabling daily headaches. The diagnosis of this condition is based on history and physical examination findings. Magnetic resonance imaging (MRI) is used to exclude other causes, but specific radiological markers for the diagnosis of IIH are lacking.\n\n\n\nObservations\nFive patients presented with the main complaint of headache, which was associated with blurry vision. All of our patients had a formal neuro-ophthalmological evaluation that confirmed the presence of optic disc edema in both eyes. They also underwent an MRI of the brain that showed diffusion restriction in the optic nerve head in either eye or both eyes. Patients underwent lumbar puncture in the lateral decubitus position, which revealed cerebrospinal fluid opening pressures > 25 cm H\n2\nO. They all responded well to standard treatments, with the resolution of symptoms in their follow-up appointments.\n\n\n\nConclusion and Relevance\nThe MRI diffusion restriction in the optic nerve head may be a reliable noninvasive marker for the diagnosis of IIH in the appropriate clinical picture.\n\n\nKeywords\nidiopathic intracranial hypertensionpseudotumor cerebripapilledemadiffusion restrictionFunding\nNone.\n==== Body\nIntroduction\n\nHeadaches are one of the leading causes of both outpatient and emergency room visits and are an important public health problem, particularly among women during their reproductive years. Migraine is the most common headache disorder in this age group followed by idiopathic intracranial hypertension (IIH).\n1\nIIH is a well-characterized headache syndrome caused by elevated intracranial pressure (ICP) of unknown etiology. It causes significant morbidity in untreated cases, including permanent vision loss, and therefore early diagnosis and intervention is warranted.\n2\nMagnetic resonance imaging (MRI) is the imaging modality of choice to rule out other potential causes of raised ICP. Common neuroimaging findings in patients with IIH include empty sella, flattening of the posterior globes, distention of the optic nerve sheaths (ONSs), cerebellar tonsillar herniation, meningoceles, and transverse venous sinus stenosis.\n3\nAll these reported MRI findings have high sensitivity and specificity in diagnosing patients with IIH.\n3\n4\n5\n\n\nIn this case series, we present five patients with IIH who had diffusion restriction in one or both optic discs with a corresponding apparent diffusion coefficient (ADC) correlate.\n\nMethods\nThe study was reviewed and approved by the Institutional Review Board of the University of Missouri Hospital.\n\nCase 1\n\nA 29-year-old Hispanic female presented to our emergency department with a 5-day history of headache. The headache was associated with blurry vision, nausea, and vomiting. She was on tacrolimus because of focal segmental glomerular sclerosis. She was evaluated by a neuro-ophthalmologist and noted to have grade 2 optic disc edema in the left eye and grade 5 optic disc edema in the right eye along with subtle hemorrhage. The MRI of her brain showed edema and restricted diffusion in the optic papillae bilaterally, suggestive of ischemic changes (\nFig. 1\n). There were no other abnormal findings on MRI of the brain. Magnetic resonance (MR) venogram did not show any major vessel occlusion or stenosis. Lumbar puncture showed an opening pressure of 50 cm H\n2\nO. These findings in the context of her clinical presentation and examination were consistent with IIH. She was started on acetazolamide, and tacrolimus was stopped. Her headache improved significantly by the time of discharge.\n\n\nFig. 1 \nMRI (magnetic resonance imaging) of the brain showing edema and restricted diffusion in the optic papillae bilaterally, suggestive of ischemic changes.\n\n\nCase 2\n\nA 20-year-old Caucasian female with no significant past medical history, except for recent steady weight gain, presented to our ophthalmology clinic for an evaluation of occasional headaches. These headaches were associated with pulsating tinnitus and occasional pressure in the back of her eye. The headaches were not associated with photophobia, nausea, emesis or, alteration by positional changes. Funduscopic examination showed grade 2 optic disc edema in the right eye and grade 3 optic disc edema in the left eye. Humphrey’s visual field (HVF) testing showed enlargement of blind spots in both eyes and nasal scotoma in the left eye. The MRI of the brain showed edema and restricted diffusion in the optic papillae bilaterally, more pronounced in the right eye (\nFig. 2\n). The papillae also demonstrated mild postcontrast enhancement. MR venogram showed a hypoplastic left transverse sinus, but no significant vessel stenosis or occlusion was noted. Lumbar puncture showed an elevated opening pressure of 35 cm H\n2\n0. The patient was started on acetazolamide. Her subsequent clinic visit showed improvement in papilledema (grade 1 in the right eye and grade 2 in the left eye). HVF testing also showed improvement of blind spots in both eyes and nasal scotoma in the left eye that has improved from the previous clinic visit.\n\n\nFig. 2 \nMRI (magnetic resonance imaging) of the brain showing edema and restricted diffusion in the optic papillae bilaterally, which is more pronounced in the right eye.\n\n\nCase 3\n\nA 26-year-old Caucasian female presented to our emergency department with a 5-day history of intermittent binocular diplopia and headache. She complained of retro-orbital pain that was more pronounced in the left eye with occasional floaters. She was noted to have a weight gain of 10 pounds over the past 6 months. Funduscopic examination revealed bilateral optic disc edema (grade 2 in the left eye and grade 1 in the right eye) along with mild left lateral rectus palsy. The MRI of her brain showed edema, restricted diffusion, and postcontrast enhancement in the optic papillae bilaterally that was more pronounced on the left side (\nFig. 3A\n). MR venogram did not show any major vessel occlusion or stenosis. Lumbar puncture showed an elevated opening pressure of 37 cm H\n2\n0. HVF showed peripheral scotoma on the right and dense central scotoma on the left. The diagnosis of IIH was made and the patient was started on acetazolamide. The intensity and frequency of headaches improved at her subsequent clinical visit. But the patient was not able to tolerate the acetazolamide due to nausea, and subsequently a lumboperitoneal shunt was placed. The repeat MRI after the shunt placement did not show any evidence of edema of the optic disc (\nFig. 3B\n).\n\n\nFig. 3 \n(A)\nMRI (magnetic resonance imaging) of the brain showing edema, restricted diffusion, and postcontrast enhancement in the optic papillae bilaterally that was more pronounced in the left eye.\n(B)\nThe repeat MRI (magnetic resonance imaging) after the shunt placement did not show any evidence of edema of the optic disc.\n\n\nCase 4\n\nA 26-year-old Caucasian male presented to the hospital with a 3-week history of blurry vision in both eyes. His vision was worse in the right eye and was associated with dark spots and a mild headache. He reported a weight gain of 20 pounds in the past 6 months. Funduscopic examination revealed grade 4 optic disc edema in the right eye and grade 3 in the left eye with peripapillary hemorrhage. MRI of his brain with contrast showed edema and restricted diffusion in the optic papillae bilaterally, significantly more so in the right eye than the left eye (\nFig. 4\n). Venous sinuses did not show any abnormality. Lumbar puncture revealed an opening pressure of 55 cm H\n2\n0. He was started on acetazolamide. During the follow-up, the patient had worsening of headache and blurry vision and therefore underwent optic nerve sheath (ONS) fenestration.\n\n\nFig. 4 \nMRI (magnetic resonance imaging) of the brain with contrast showing edema and restricted diffusion in the optic papillae bilaterally, significantly more so in the right eye than the left eye.\n\n\nCase 5\n\nA 23-year-old right-handed woman presented with a 4-day history of blurry vision. She describes her visual disturbance as a painful blurring in both eyes (greater in the right eye) and double vision along with seeing flashes of light and floaters. She also had vertical gaze paresis. The patient was evaluated by a neuro-ophthalmologist and was found to have a grade 4 papilledema bilaterally. HVF showed constriction of peripheral visual field in both eyes (greater in the right eye). MRI of the brain with contrast showed edema and diffusion restriction in the bilateral optic papillae, more significantly in the right eye (\nFig. 5\n). Lumbar puncture was performed that showed an elevated opening pressure of >55 cm H\n2\nO. Her headache did not improve with medical management, and the patient eventually underwent ONS fenestration.\n\n\nFig. 5 \nMRI (magnetic resonance imaging) of the brain with contrast showing edema and diffusion restriction in the bilateral optic papillae, more significantly in the right eye.\n\n\nDiscussion\n\nPapilledema refers to optic disc swelling because of raised ICP.\n3\nMRI is the commonly used noninvasive diagnostic modality to study the optic nerves and other orbital structures.\n3\nCommon radiological signs associated with IIH are given in\nTable 1\n3\nBrodsky and Vaphiades\n3\nproposed that the presence of posterior scleral flattening and prelaminar enhancement on imaging is a confirmatory finding of IIH in the presence of papilledema.\n6\nThe other radiological signs that are associated with IIH, however, are nonspecific.\n3\n4\n5\n6\nIn our study, we present high T2-weighted signal changes in the optic disc head along with restriction of diffusion as a potential new radiological marker in cases of IIH, and this finding suggests optic nerve ischemia in these patients.\n\n\nTable 1 Common radiological signs with IIH\nImaging findings\tSensitivity (%)\tSpecificity (%)\t\nEmpty sella\t80\t83\t\nMeningocele/meningoencephalocele\t11\t0\t\nForamen ovale widening\t50\t80\t\nPosterior flattening of the posterior poles\t66\t98\t\nOptic nerve head protrusion\t36\t99\t\nDistention of the optic nerve sheath\t58\t89\t\nVertical tortuosity of the optic nerve\t43\t90\t\nTransverse sinus stenosis\t97\t93\t\nEnhancement of the optic nerve head\t17\t99\t\nTonsillar herniation > 5 mm\t16\t95\t\n\nThe sensitivity of transverse sinus stenosis was reported to be approximately 90% in patients with IIH.\n7\nThree patients in our case series had a dedicated imaging for the venous system. Among them, one patient had hypoplastic left transverse sinus, and the venous system was unremarkable in all other patients. Two patients did not have venogram, but MRI of the brain with contrast did not show any suggestion of venous sinus occlusion. Sari et al reported that MRI of the brain with contrast is highly sensitive for studying the venous system when compared with MR venogram and noncontrast imaging of the brain.\n7\n\n\n\nAll the patients in our case series underwent lumbar puncture, and the opening pressure was >25 mm H\n2\nO. These findings are concordant with the opening pressure reported in patients with IIH for the diagnosis.\n8\n\n\n\nThe first case of IIH was reported in the 1890s by a German physician Heinrich Quincke, who called it “serous meningitis.”\n9\nSubsequently, Nonne and Dandy reported similar case series of increased ICP without tumor and coined the name “pseudotumor cerebri.”\n10\n11\n\n\n\nThe reported incidence of IIH in the general population is between 1 and 3 per 100,000 per year, with a higher incidence in females (up to 12 to 28 per 100,000 per year) during their reproductive years.\n12\n13\n14\nClinical features of this condition include headache, transient visual obscurations, diplopia, and pulsatile tinnitus. In untreated cases, vision loss is a major complication and sometimes can be very profound within a few days. In a recent study from the United Kingdom, the annual incidence of blindness in patients with IIH is 1 to 2%.\n15\nFriedman proposed diagnostic criteria for IIH that include both patients with and those without papilledema,\n16\nand all of the patients in this case series fulfill those diagnostic criteria. The management of these patients is based on preserving the visual function along with reducing the disability from headache. The treatment options include weight loss in conjunction with medications such as acetazolamide, topiramate, furosemide, and, sometimes, corticosteroids. If the medical therapy fails, the surgical options include serial lumbar punctures, ONS fenestration, ventriculoperitoneal shunt, lumboperitoneal shunt, and transverse sinus stenting. Studies have shown that surgical interventions are effective in improving visual symptoms, preventing vision loss and reducing the morbidity associated with headache.\n9\n15\n16\n\n\n\nThe pathophysiology of IIH and papilledema is still controversial, and the exact mechanism is not clear. The subarachnoid space underneath the ONS is in direct anatomical connection with cerebrospinal fluid (CSF) surrounding the brain. Increased ICP causes a direct transmission of this pressure, resulting in distention of the ONS, as shown in\nFig. 6A\nB\n, The increase in ICP causes an enlargement of the ONS diameter and changes in tortuosity. This process eventually leads to alteration in the metabolic processes of the nerve and subsequent edema, ischemia, and, finally, visual impairment or loss.\n3\n17\nT2-weighted images are used for the analysis of orbital structures and the optic sheath.\n18\nMost of the optic nerve findings are reported from thin-section or volumetric fat-saturated T2-weighted images of the orbit.\n19\nIn our series, in addition to all reported findings from the literature, we found increased T2-weighted signal changes in the optic disc head and diffusion restriction. We propose that continued pressure on the optic nerves would result in ischemic insult in the optic nerve head. In ischemic stroke, diffusion sequence on brain MRI shows increased signal with a low ADC signal, and these are the same MRI findings in our case series. To our knowledge, MRI findings involving optic disc heads have not been described in IIH. Given the paucity of specific radiological features in cases of IIH, we propose that the diffusion restriction in the optic disc heads in a patient with clinically suggestive IIH may be considered a fairly specific finding.\n\n\nFig. 6 \n(\nA\n) Anatomy of the optic nerve and the central retinal artery and vein present in the center at normal pressure. (\nB\n) Compression of both the central retinal artery and vein during raised intracranial pressure.\n\n\nConclusion\nIIH is a headache syndrome that can result in visual deficits including permanent vision loss if left untreated. Diagnosis of this condition relies on proper clinical history and physical examination findings along with measurement of CSF pressure. The finding of a unilateral or bilateral MR diffusion restriction of optical heads in IIH patients has the potential to become a new IIH diagnostic marker if it is confirmed in larger and controlled series. We propose that diffusion restriction in the optic disc heads in the appropriate clinical picture may be a specific radiological finding of IIH.\n\nNoteConflict of Interest This study was approved by the Institutional Board Review of the University of Missouri Health Care- Columbia.\n\nNone declared.\n==== Refs\nReferences\n1 Burch R C Loder S Loder E Smitherman T A The prevalence and burden of migraine and severe headache in the United States: updated statistics from government health surveillance studies\nHeadache 2015 55 01 21 34\n25600719 \n2 Jensen R H Radojicic A Yri H The diagnosis and management of idiopathic intracranial hypertension and the associated headache\nTher Adv Neurol Disorder 2016 9 04 317 326\n\n3 Bidot S Saindane A M Peragallo J H Bruce B B Newman N J Biousse V Brain imaging in idiopathic intracranial hypertension\nJ Neuroophthalmol 2015 35 04 400 411\n26457687 \n4 Lim M J Pushparajah K Jan W Calver D Lin J P Magnetic resonance imaging changes in idiopathic intracranial hypertension in children\nJ Child Neurol 2010 25 03 294 299\n19638638 \n5 Agid R Farb R I Willinsky R A Mikulis D J Tomlinson G Idiopathic intracranial hypertension: the validity of cross-sectional neuroimaging signs\nNeuroradiology 2006 48 08 521 527\n16703359 \n6 Brodsky M C Vaphiades M Magnetic resonance imaging in pseudotumor cerebri\nOphthalmology 1998 105 09 1686 1693\n9754178 \n7 Sari S Verim S Hamcan S MRI diagnosis of dural sinus - cortical venous thrombosis: immediate post-contrast 3D GRE T1-weighted imaging versus unenhanced MR venography and conventional MR sequences\nClin Neurol Neurosurg 2015 134 44 54\n25938564 \n8 Corbett J J Mehta M P Cerebrospinal fluid pressure in normal obese subjects and patients with pseudotumor cerebri\nNeurology 1983 33 10 1386 1388\n6684240 \n9 Mollan S P Ali F Hassan-Smith G Botfield H Friedman D I Sinclair A J Evolving evidence in adult idiopathic intracranial hypertension: pathophysiology and management\nJ Neurol Neurosurg Psychiatry 2016 87 09 982 992\n26888960 \n10 Nonne M Über Fälle vom Symptomkomplex ‘tumor cerebri’ mit Ausgang in Heilung (Pseudotumor cerebri). Über Letal Verlaufene Fälle von ‘Pseudotumor Cerebri’ mit Sektionsbefund\nDtsch Z Nervenheilkd 1904 27 169 216\n\n11 Dandy W E Intracranial pressure without brain tumor: diagnosis and treatment\nAnn Surg 1937 106 04 492 513\n17857053 \n12 Radhakrishnan K Thacker A K Bohlaga N H Maloo J C Gerryo S E Epidemiology of idiopathic intracranial hypertension: a prospective and case-control study\nJ Neurol Sci 1993 116 01 18 28\n8509801 \n13 McCluskey G Mulholland D A McCarron P McCarron M O Idiopathic intracranial hypertension in the Northwest of Northern Ireland: epidemiology and clinical management\nNeuroepidemiology 2015 45 01 34 39\n26201454 \n14 Andrews L E Liu G T Ko M W Idiopathic intracranial hypertension and obesity\nHorm Res Paediatr 2014 81 04 217 225\n24642712 \n15 Best J Silvestri G Burton B Foot B Acheson J The incidence of blindness due to idiopathic intracranial hypertension in the UK\nOpen Ophthalmol J 2013 7 26 29\n23898356 \n16 Friedman D I The pseudotumor cerebri syndrome\nNeurol Clin 2014 32 02 363 396\n24703535 \n17 Sivasankar R Pant R Indrajit I K Imaging and interventions in idiopathic intracranial hypertension: a pictorial essay\nIndian J Radiol Imaging 2015 25 04 439 444\n26752823 \n18 Kimberly H H Noble V E Using MRI of the optic nerve sheath to detect elevated intracranial pressure\nCrit Care 2008 12 05 181 18831721 \n19 Holbrook J Saindane A M Imaging of intracranial pressure disorders\nNeurosurgery 2017 80 03 341 354\n27471977\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0976-3155",
"issue": "11(1)",
"journal": "Journal of neurosciences in rural practice",
"keywords": "diffusion restriction; idiopathic intracranial hypertension; papilledema; pseudotumor cerebri",
"medline_ta": "J Neurosci Rural Pract",
"mesh_terms": null,
"nlm_unique_id": "101533710",
"other_id": null,
"pages": "170-174",
"pmc": null,
"pmid": "32140023",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article",
"references": "24703535;26752823;27471977;25600719;25938564;23898356;9754178;18831721;8509801;24642712;26201454;16703359;27366239;17857053;26888960;19638638;26457687;6684240",
"title": "Is Magnetic Resonance Imaging Diffusion Restriction of the Optic Disc Head a New Marker for Idiopathic Intracranial Hypertension?",
"title_normalized": "is magnetic resonance imaging diffusion restriction of the optic disc head a new marker for idiopathic intracranial hypertension"
} | [
{
"companynumb": "US-ASTELLAS-2020US012800",
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"occurcountry": "US",
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... |
{
"abstract": "Metoclopramide is commonly used to treat vomiting caused by seasickness and acute gastroenteritis on cruise ships and serious adverse effects have not been reported from use at sea. We report severe long-lasting adverse effects in a young female seafarer following short-term, low-dose use of metoclopramide. During rough seas a 25-year-old female musician on a cruise vessel presented with nausea and vomiting. She was given intramuscular metoclopramide 10 mg and diphenhydramine 25 mg. Vomiting stopped after the injections, but she felt tired, confused and dizzy. She then had been taking metoclopramide 5-10 mg a day, but stopped after a total per oral dose of 30 mg as she developed disturbing symptoms that she related to the medication, including dizziness, anxiety, fatigue, depression and involuntary movements (twitches, jerks, ticks, and tremors of the eyelids, tongue, neck, fingers, arms and legs). Neurological examination, blood tests, electrocardiography and magnetic resonance imaging of the brain were all normal. Although gradually reduced in strength and frequency, the adverse effects were very disturbing for about 10 months, but at 13 months she was almost fully recovered. For many years numerous vomiting sea travellers have been successfully treated with a single parenteral 10 mg dose of metoclopramide. There are no obvious reasons why our previously healthy patient experienced such serious and long-lasting side effects after low-dose, short-term metoclopramide administration. Until more is known, metoclopramide should be reserved for debilitating cases - and only be given after other remedies have been tried and found ineffective.",
"affiliations": "Department of Occupational Medicine, Haukeland University Hospital, Norwegian Centre for Maritime Medicine, Bergen, Norway. eilifdahl@hotmail.com.",
"authors": "Dahl|Eilif|E|;Diskin|Arthur L|AL|",
"chemical_list": "D000932:Antiemetics; D004155:Diphenhydramine; D008787:Metoclopramide",
"country": "Poland",
"delete": false,
"doi": "10.5603/MH.2014.0004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1641-9251",
"issue": "65(1)",
"journal": "International maritime health",
"keywords": null,
"medline_ta": "Int Marit Health",
"mesh_terms": "D000328:Adult; D000932:Antiemetics; D004155:Diphenhydramine; D020820:Dyskinesias; D005260:Female; D005759:Gastroenteritis; D006801:Humans; D007273:Injections, Intramuscular; D001523:Mental Disorders; D008787:Metoclopramide; D009041:Motion Sickness; D009326:Naval Medicine; D009422:Nervous System Diseases; D012767:Ships; D014839:Vomiting",
"nlm_unique_id": "100958373",
"other_id": null,
"pages": "16-9",
"pmc": null,
"pmid": "24677122",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Long-lasting adverse effects after short-term low-dose treatment with metoclopramide for vomiting.",
"title_normalized": "long lasting adverse effects after short term low dose treatment with metoclopramide for vomiting"
} | [
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"companynumb": "PHHY2015NO010571",
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"activesubstancename": "METOCLOPRAMIDE"
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"... |
{
"abstract": "OBJECTIVE\nThe aims of the present study were (a) to evaluate the pharmacokinetics of linezolid, and (b) to assess the toxicity and clinical efficacy of linezolid in Japanese pediatric patients.\n\n\nMETHODS\nRoutine clinical data including serum linezolid total and unbound concentrations were collected from 15 pediatric patients (0-13 years old). Pharmacokinetics of linezolid was assumed to follow one-compartment with the first-order absorption model. The relationship between risk for thrombocytopenia and linezolid concentrations, and the variations in C-reactive protein (CRP) concentrations and body temperatures were evaluated as clinical efficacy assessment.\n\n\nRESULTS\nBody weight (WT) and maturation of body function were significant covariates for pharmacokinetics of linezolid in pediatric patients. The elimination half-life of linezolid in a pediatric patient with a WT of 9.9 kg and age of 24 months (median of this study) was 3.0 h. Thrombocytopenia was detected in three patients (21.4%), and the minimum concentrations (Cmin) in these patients were significantly higher than those in patients without thrombocytopenia (P < 0.05). The CRP concentrations decreased more than 50% in all pediatric patients after the treatment with linezolid, however body temperatures at the end of treatment were higher than 37.5 °C in 6 patients (42.9%).\n\n\nCONCLUSIONS\nAlthough dose adjustment based on body size was performed for pediatric patients, thrombocytopenia was detected in 21.4% of pediatric patients, and higher Cmin was associated with the risk of thrombocytopenia. These results encourage the implementation of individual dose adjustment based on linezolid serum concentrations for safe and appropriate treatment with linezolid.",
"affiliations": "Department of Medical Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.;Center for Pharmacist Education, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba, 274-8555, Japan. Electronic address: tsuji.yasuhiro@nihon-u.ac.jp.;Department of Medical Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.;Department of Clinical Infectious Diseases, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.",
"authors": "Ogami|Chika|C|;Tsuji|Yasuhiro|Y|;To|Hideto|H|;Yamamoto|Yoshihiro|Y|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002097:C-Reactive Protein; D000069349:Linezolid",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2019.05.025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "25(12)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Children; Efficacy; Linezolid; Pharmacokinetics; Toxicity",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D061605:Administration, Intravenous; D000284:Administration, Oral; D000293:Adolescent; D000367:Age Factors; D000900:Anti-Bacterial Agents; D001424:Bacterial Infections; D001831:Body Temperature; D001835:Body Weight; D002097:C-Reactive Protein; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007564:Japan; D000069349:Linezolid; D008297:Male; D012307:Risk Factors; D013921:Thrombocytopenia; D016896:Treatment Outcome",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "979-986",
"pmc": null,
"pmid": "31208925",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Pharmacokinetics, toxicity and clinical efficacy of linezolid in Japanese pediatric patients.",
"title_normalized": "pharmacokinetics toxicity and clinical efficacy of linezolid in japanese pediatric patients"
} | [
{
"companynumb": "JP-PFIZER INC-2020009707",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": "3",
... |
{
"abstract": "Optimal management of infection with mycobacterial species requires accurate identification down to complex/species level due to variations in outcomes. Over the last few decades, there have been significant advances in laboratory diagnostics with development of newer and rapid molecular methods. Here we describe a case of Mycobacterium smegmatis that was misidentified as Mycobacterium fortuitum by DNA line probe assay.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Infectious Diseases, Department of Medicine, Mayo Clinic, Rochester, MN, USA.;Division of Clinical Microbiology, Mayo Clinic, Rochester, MN, USA.",
"authors": "Fida|Madiha|M|;Beam|Elena|E|;Wengenack|Nancy L|NL|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.jctube.2021.100268",
"fulltext": "\n==== Front\nJ Clin Tuberc Other Mycobact Dis\nJ Clin Tuberc Other Mycobact Dis\nJournal of Clinical Tuberculosis and Other Mycobacterial Diseases\n2405-5794\nElsevier\n\nS2405-5794(21)00057-7\n10.1016/j.jctube.2021.100268\n100268\nArticle\nMisidentification of Mycobacterium smegmatis as Mycobacterium fortuitum by DNA line probe assay\nFida Madiha Fida.madiha@mayo.edu\nab⁎\nBeam Elena a\nWengenack Nancy L. b\na Division of Infectious Diseases, Department of Medicine, Mayo Clinic, Rochester, MN, USA\nb Division of Clinical Microbiology, Mayo Clinic, Rochester, MN, USA\n⁎ Corresponding author at: Mayo Clinic Rochester, 200 1st Street SW, Rochester, MN, USA. Fida.madiha@mayo.edu\n26 8 2021\n12 2021\n26 8 2021\n25 100268© 2021 Published by Elsevier Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nOptimal management of infection with mycobacterial species requires accurate identification down to complex/species level due to variations in outcomes. Over the last few decades, there have been significant advances in laboratory diagnostics with development of newer and rapid molecular methods. Here we describe a case of Mycobacterium smegmatis that was misidentified as Mycobacterium fortuitum by DNA line probe assay.\n\nKeywords\n\nMycobacterium smegmatis\nMycobacterium fortuitum\nMolecular diagnostics\nLine probe assay\nNon-tuberculous mycobacterial infection\n==== Body\npmc1 Introduction\n\nAccurate and timely identification of mycobacterial species is crucial for optimal management of patients since treatment and outcomes vary depending on the mycobacterial species identified. Older biochemical tests have now been replaced by newer diagnostic methods including matrix associated laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and molecular methods including line probe hybridization assays, as well as 16S ribosomal RNA gene, rpoB, and hsp65 PCR. DNA line probe assays provide rapid means of identification and currently there are two commercially available assays including INNO-LiPA MYCOBACTERIA v2 assay (Fujirebio Europe, Ghent, Belgium) and GenoType assays (Hain Lifescience GmbH, Nehren, Germany) however neither is currently approved by the FDA and therefore use is largely restricted to the public health laboratories in United States. Studies utilizing these lines probe assays have reported satisfactory sensitivity and specificity [1], [2], [3], [4], [5]. Here we present a case of Mycobacterium smegmatis that was misidentified as Mycobacterium fortuitum by a DNA line probe assay.\n\nA 69-year-old female was admitted to our facility with right elbow arthroplasty infection. Two months prior to hospitalization she sustained a fall outdoors and had a distal humeral open fracture. She underwent debridement followed by total elbow arthroplasty two weeks later. Five weeks after arthroplasty she developed increasing right elbow redness and swelling and was seen in another institution where she underwent multiple occurrences of surgical debridement. Multiple operative cultures grew an acid-fast bacilli. These were sent to a reference laboratory and were identified as M. fortuitum complex by INNO-LiPA MYCOBACTERIA v2 line probe assay (Fujirebio Europe, Ghent, Belgium). The patient was subsequently transferred to our facility for definitive surgical management and underwent resection arthroplasty. Surgical cultures showed growth on sheep blood agar after 48 h of incubation. Gram stain showed beaded Gram-positive bacilli. MALDI-TOF MS (Bruker MALDI Biotyper 3.1 using Mayo Clinic’s Custom Library Database) was done with organism identified as Mycobacterium smegmatis (score value 2.4). We additionally obtained the isolate previously identified as M. fortuitum from the outside institution which was also identified as Mycobacterium smegmatis by MALDI-TOF MS. We then performed 16S 500 bp rRNA gene sequencing on both isolates which yielded a 466 base pair long fragment with 100% match with M. smegmatis (ATCC® 14468) using Mayo Clinic’s custom library version # MAA2018. Broth microdilution was performed using Sensititre™ RAPMYCO AST Plate as per CLSI guidelines. showed inducible macrolide resistance and intermediate susceptibility to cefoxitin with MIC of 32 mcg/mL by broth microdilution and susceptibility to amikacin, ciprofloxacin, doxycycline, imipenem, linezolid, minocycline, moxifloxacin, tobramycin, and trimethoprim sulfamethoxazole (TMP-SMX). The patient was started on intravenous imipenem, doxycycline, and trimethoprim-sulfamethoxazole with plans to do total of 3–6 months of total therapy depending on clinical response.\n\nHere we describe a case of M. smegmatis prosthetic joint infection likely resulting from traumatic inoculation during the initial fall. Among the rapidly growing NTMs, the majority of reported infections are secondary to M. fortuitum, and M. abscessus-chelonae complex. M. smegmatis is an environmental saprophyte and has rarely been identified as a cause of infection in humans [6], [7], [8], [9], [10]. Identification in the lab typically involves MALDI-TOF MS, sequencing or DNA probes. INNO-LiPA is a line probe assay which identifies 16 mycobacterial species including M. smegmatis and M. fortuitum. This assay is based on amplification of 16S-23S ribosomal RNA spacer region followed by reverse-hybridization with probes immobilized on the nitrocellulose strips. The positive result is depicted by a color change with each line corresponding to a specific mycobacterial species. Per manufacturer’s instructions with M. fortuitum, probe line 23 (MFO) is positive in addition to the control line and the Mycobacterium genus line. With M. smegmatis line 23 (MFO) and line 24 (MSM) are both positive however in this case only line 23 was positive. On literature review we found one previous report of such misidentification with INNO-LiPA assay [11]. In this case M. smegmatis was misidentified as M. fortuitum which was also due to lack of reaction with line 24. In another study of INNO-LiPA line probe assay all 5 M. smegmatis isolates were correctly identified [12]. There have been previous reports of misidentification of M. smegmatis as M. fortuitum as well as M. fortuitum as M. smegmatis by another line probe assay, GenoType assay [5], [13]. The management in our case did not change related to this misidentification as susceptibility panel tested was same for both organisms with use of same treatment regimen however this situation created some degree of confusion for the treatment team. Both M. fortuitum and M. smegmatis are typically tested for inducible macrolide resistance which was performed in this case and inducible resistance was seen. One concern with such misidentification is the errors in the post-analytic phase as isolation of non-tuberculous mycobacterium species from clinical isolate does not always suggest mycobacterial infection and results are interpreted based on the underlying clinical scenario, pathology findings and individual patient risk factors. As such, M. fortuitum may be more likely to be implicated as a pathogen if identified from a clinical specimen as it is known to cause a wide spectrum of clinical syndromes compared to M. smegmatis which is rarely identified as a cause of infection. However, in our case, multiple surgical cultures were positive for M. smegmatis without any other organism identified. Correct identification is necessary to report in the literature as well which will help with establishing hosts at risk, location of infection and pathogenesis in human infections and management strategies and how these may differ from other rapid growers.\n\nHere we have presented a 2nd case of M. smegmatis misidentified as M. fortuitum by a DNA line probe assay. More studies are required to identify the sequence variations associated with such misidentification.\n\nCRediT authorship contribution statement\n\nMadiha Fida: Data curation, Writing – original draft, Writing – review & editing. Elena Beam: Writing – review & editing. Nancy L. Wengenack: Writing – review & editing.\n\nDeclaration of Competing Interest\n\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n==== Refs\nReferences\n\n1 Mäkinen J. Sarkola A. Marjamäki M. Viljanen M.K. Soini H. Evaluation of GenoType and LiPA MYCOBACTERIA assays for identification of finnish mycobacterial isolates J Clin Microbiol 40 9 2002 3478 3481 12202597\n2 García-Agudo L. Jesús I. Rodríguez-Iglesias M. García-Martos P. Evaluation of INNO-LiPA mycobacteria v2 assay for identification of rapidly growing mycobacteria Braz J Microbiol Publ Braz Soc Microbiol 42 3 2011 1220 1226\n3 Tortoli E. Mariottini A. Mazzarelli G. Evaluation of INNO-LiPA MYCOBACTERIA v2: improved reverse hybridization multiple DNA probe assay for mycobacterial identification J Clin Microbiol 41 9 2003 4418 4420 12958281\n4 Mijs W. Vreese K.D. Devos A. Pottel H. Valgaeren A. Evans C. Evaluation of a commercial line probe assay for identification of mycobacterium species from liquid and solid culture Eur J Clin Microbiol Infect Dis 21 11 2002 794 802 12461589\n5 Padilla E. González V. Manterola J.M. Pérez Andrés Quesada M.D. Gordillo S. Comparative evaluation of the new version of the INNO-LiPA mycobacteria and GenoType mycobacterium assays for identification of mycobacterium species from MB/BacT liquid cultures artificially inoculated with mycobacterial strains J Clin Microbiol 42 7 2004 3083 3088 15243064\n6 Skiest Daniel J. Levi Marilyn E. Catheter-related bacteremia due to mycobacterium smegmatis Southern Med J 91 1 1998 36 37 9438400\n7 Pierre-Audigier C. Jouanguy E. Lamhamedi S. Fatal disseminated mycobacterium smegmatis infection in a child with inherited interferon γ receptor deficiency Clin Infect Dis 24 1997 982 984 9142806\n8 Ergan B. Coplu L. Alp A. Artvinli M. Mycobacterium smegmatis pneumonia Respirology 9 2 2004 283 285 15182284\n9 Eid A.J. Berbari E.F. Sia I.G. Wengenack N.L. Osmon D.R. Razonable R.R. Prosthetic joint infection due to rapidly growing mycobacteria: report of 8 cases and review of the literature Clin Infect Dis 45 6 2007 687 694 17712751\n10 Newton J.A. Weiss P.J. Bowler W.A. Oldfield E.C. Soft-Tissue Infection Due to Mycobacterium smegmatis: report of Two Cases Clin Infect Dis 16 4 1993 531 533 8513061\n11 van den Broek T. Janssen N.G. Hetem D.J. Bekers W. Kamst M. Fluit A.C. INNO-LiPA DNA line probe assay misidentification of M. smegmatis as Mycobacterium fortuitum complex Diagn Micr Infec Dis 95 3 2019 114858 10.1016/j.diagmicrobio.2019.06.010\n12 Tortoli E. Pecorari M. Fabio G. Messinò M. Fabio A. Commercial DNA Probes for Mycobacteria Incorrectly Identify a Number of Less Frequently Encountered Species▿† J Clin Microbiol 48 1 2010 307 310 19906898\n13 Richter E. Rüsch-Gerdes S. Hillemann D. Evaluation of the GenoType mycobacterium assay for identification of mycobacterial species from cultures J Clin Microbiol 44 5 2006 1769 1775 16672405\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2405-5794",
"issue": "25()",
"journal": "Journal of clinical tuberculosis and other mycobacterial diseases",
"keywords": "Line probe assay; Molecular diagnostics; Mycobacterium fortuitum; Mycobacterium smegmatis; Non-tuberculous mycobacterial infection",
"medline_ta": "J Clin Tuberc Other Mycobact Dis",
"mesh_terms": null,
"nlm_unique_id": "101682877",
"other_id": null,
"pages": "100268",
"pmc": null,
"pmid": "34522793",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": "15243064;9142806;19906898;12461589;17712751;12202597;24031745;12958281;31358343;8513061;15182284;9438400;16672405",
"title": "Misidentification of Mycobacterium smegmatis as Mycobacterium fortuitum by DNA line probe assay.",
"title_normalized": "misidentification of mycobacterium smegmatis as mycobacterium fortuitum by dna line probe assay"
} | [
{
"companynumb": "US-009507513-2202USA002056",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CILASTATIN SODIUM\\IMIPENEM"
},
"drugadditio... |
{
"abstract": "OBJECTIVE\nTo investigate bevacizumab as alternative treatment of aggressive pituitary adenomas after exhaustion of standard therapies.\n\n\nMETHODS\nRetrospectively, 3 patients undergoing microscopic transsphenoidal surgery of aggressive pituitary adenomas from 2008 till 2018 that were treated with bevacizumab were identified. Development of disease and treatment were evaluated.\n\n\nRESULTS\nTwo patients suffered from ACTH-secreting adenomas, one from a non-functioning adenoma. All patients underwent multiple surgical, chemo- and radiotherapeutical approaches including temozolomide, showing favorable results in one patient. Deterioration of clinical condition in all patients led to an individual, palliative attempt of bevacizumab. Patients 1 and 2 showed a decrease of ACTH after first administrations, but therapy had to be ended shortly after due to a further deterioration of their condition. Patient 3 showed a stabilization of the disease for 18 months. Patients died 8, 15 and 7 years after initial diagnosis, respectively, and 2, 4, and 24 months after initiation of bevacizumab therapy, respectively.\n\n\nCONCLUSIONS\nThe demonstrated results suggest a considerable effect of bevacizumab in aggressive pituitary adenomas. The advanced stage of disease in all three patients, the overall short period of administration and just one patient showing a clinical benefit do not allow a general statement on the effectiveness. At the current stage of clinical experience, an approach with bevacizumab can be considered as an individual palliative attempt of treatment, when standard treatments are exhausted. Our results underline the need for further studies to evaluate this drug as potential player in therapy resistant aggressive pituitary tumors.",
"affiliations": "Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Endocrinology Medicover MVZ, Oldenburg, Germany.;Department of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;ENDOC Center for Endocrine Tumors, Hamburg, Germany.;Department of Endocrinology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.",
"authors": "Osterhage|Katharina|K|;Rotermund|Roman|R|;Droste|Michael|M|;Dierlamm|Judith|J|;Saeger|Wolfgang|W|;Petersenn|Stephan|S|;Aberle|Jens|J|;Flitsch|Jörg|J|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000068258:Bevacizumab",
"country": "Germany",
"delete": false,
"doi": "10.1055/a-1260-3975",
"fulltext": null,
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"issn_linking": "0947-7349",
"issue": "129(3)",
"journal": "Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association",
"keywords": null,
"medline_ta": "Exp Clin Endocrinol Diabetes",
"mesh_terms": "D000236:Adenoma; D000074322:Antineoplastic Agents, Immunological; D000068258:Bevacizumab; D017809:Fatal Outcome; D006801:Humans; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010911:Pituitary Neoplasms",
"nlm_unique_id": "9505926",
"other_id": null,
"pages": "178-185",
"pmc": null,
"pmid": "33285600",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bevacizumab in Aggressive Pituitary Adenomas - Experience with 3 Patients.",
"title_normalized": "bevacizumab in aggressive pituitary adenomas experience with 3 patients"
} | [
{
"companynumb": "DE-MYLANLABS-2021M1020365",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
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"activesubstancename": "CABERGOLINE"
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... |
{
"abstract": "OBJECTIVE\nTo compare differences in blood pressure levels between patients with severe post-partum pre-eclampsia using ibuprofen or acetaminophen.\n\n\nMETHODS\nA randomized controlled trial was made in women with severe pre-eclampsia or superimposed pre-eclampsia after vaginal birth. The patient was randomly selected to receive either 400 mg of ibuprofen every 8 h or 1 g of acetaminophen every 6 h during the post-partum. The primary variable was systolic hypertension ≥150 mmHg and/or diastolic hypertension ≥100 mmHg after the first 24 h post-partum. Secondary variables were the arterial blood pressure readings at 24, 48, 72, and 96 h post-partum and maternal complications.\n\n\nRESULTS\nA total of 113 patients were studied: 56 in the acetaminophen group and 57 in the ibuprofen group. With regard to the primary outcome, more cases were significantly hypertensive in the ibuprofen group (36/57; 63.1%) than in the acetaminophen group (16/56; 28.6%). Severe hypertension (≥160/110 mmHg) was not significantly different between the groups, 14.5% (acetaminophen) and 24.5% (ibuprofen). The levels of arterial blood pressure show a hammock-shaped curve independent of the drug used, however, is more noticeable with ibuprofen.\n\n\nCONCLUSIONS\nThis study shows that ibuprofen significantly elevates blood pressure in women with severe pre-eclampsia during the post-partum period.",
"affiliations": "a Departamento de Ginecología y Obstetricia , Complejo hospitalario de la caja de seguro social, Unidad de CEGO , Panamá , Panama.;a Departamento de Ginecología y Obstetricia , Complejo hospitalario de la caja de seguro social, Unidad de CEGO , Panamá , Panama.;a Departamento de Ginecología y Obstetricia , Complejo hospitalario de la caja de seguro social, Unidad de CEGO , Panamá , Panama.",
"authors": "Vigil-De Gracia|Paulino|P|;Solis|Valentin|V|;Ortega|Nelson|N|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D007052:Ibuprofen",
"country": "England",
"delete": false,
"doi": "10.1080/14767058.2016.1210599",
"fulltext": null,
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"issn_linking": "1476-4954",
"issue": "30(11)",
"journal": "The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians",
"keywords": "Acetaminophen; aggregate pre-eclampsia; ibuprofen; post-partum; severe pre-eclampsia,",
"medline_ta": "J Matern Fetal Neonatal Med",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D018712:Analgesics, Non-Narcotic; D001794:Blood Pressure; D005260:Female; D006801:Humans; D007052:Ibuprofen; D049590:Postpartum Period; D011225:Pre-Eclampsia; D011247:Pregnancy; D012720:Severity of Illness Index; D055815:Young Adult",
"nlm_unique_id": "101136916",
"other_id": null,
"pages": "1279-1282",
"pmc": null,
"pmid": "27384376",
"pubdate": "2017-06",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Ibuprofen versus acetaminophen as a post-partum analgesic for women with severe pre-eclampsia: randomized clinical study.",
"title_normalized": "ibuprofen versus acetaminophen as a post partum analgesic for women with severe pre eclampsia randomized clinical study"
} | [
{
"companynumb": "PA-JNJFOC-20170502821",
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... |
{
"abstract": "This case report describes a patient with arthritis of the large joints, bilateral sacroiliitis, and positive anti-SSA and anti-dsDNA antibody, who received sulfasalazine and shortly thereafter became critically ill. He developed toxic epidermal necrolysis, hemolytic anemia, lymphopenia, markedly elevated ferritin, and muscle wasting. A diagnosis of systemic lupus erythematosus was made, and mycophenolate mofetil and systemic glucocorticoids brought this severe disease under control. Toxic epidermal necrolysis-like lesions and hemophagocytic syndrome have been reported as manifestations of systemic lupus erythematosus. This patient possibly had spondyloarthritis or an undifferentiated connective tissue disease at presentation, and we suggest, based on the timing of events, that sulfasalazine may have acted as a trigger of the severe disease manifestations.",
"affiliations": "Center for Rheumatology and Spine Diseases, Rigshospitalet, 2100 Copenhagen, Denmark.;Department of Dermatology, Gentofte Hospital, 2900 Hellerup, Denmark.;Department of Rheumatology, Nordsjællands Hospital, 3400 Hillerød, Denmark.;Center for Rheumatology and Spine Diseases, Rigshospitalet, 2100 Copenhagen, Denmark.",
"authors": "Krabbe|Simon|S|0000-0002-2877-1582;Gül|Cigdem|C|;Andersen|Bjarne|B|;Tvede|Niels|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2016/4501937",
"fulltext": "\n==== Front\nCase Rep RheumatolCase Rep RheumatolCRIRHCase Reports in Rheumatology2090-68892090-6897Hindawi Publishing Corporation 10.1155/2016/4501937Case ReportToxic Epidermal Necrolysis-Like Lesions and Systemic Lupus Erythematosus Possibly Triggered by Sulfasalazine http://orcid.org/0000-0002-2877-1582Krabbe Simon \n1\n\n*\nGül Cigdem \n2\nAndersen Bjarne \n3\nTvede Niels \n1\n1Center for Rheumatology and Spine Diseases, Rigshospitalet, 2100 Copenhagen, Denmark2Department of Dermatology, Gentofte Hospital, 2900 Hellerup, Denmark3Department of Rheumatology, Nordsjællands Hospital, 3400 Hillerød, Denmark*Simon Krabbe: simonkrabbe@gmail.comAcademic Editor: Jamal Mikdashi\n\n2016 12 7 2016 2016 45019375 2 2016 18 6 2016 23 6 2016 Copyright © 2016 Simon Krabbe et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.This case report describes a patient with arthritis of the large joints, bilateral sacroiliitis, and positive anti-SSA and anti-dsDNA antibody, who received sulfasalazine and shortly thereafter became critically ill. He developed toxic epidermal necrolysis, hemolytic anemia, lymphopenia, markedly elevated ferritin, and muscle wasting. A diagnosis of systemic lupus erythematosus was made, and mycophenolate mofetil and systemic glucocorticoids brought this severe disease under control. Toxic epidermal necrolysis-like lesions and hemophagocytic syndrome have been reported as manifestations of systemic lupus erythematosus. This patient possibly had spondyloarthritis or an undifferentiated connective tissue disease at presentation, and we suggest, based on the timing of events, that sulfasalazine may have acted as a trigger of the severe disease manifestations.\n==== Body\n1. Introduction\nA patient developed a life-threatening disease with toxic epidermal necrolysis- (TEN-) like lesions and systemic lupus erythematosus. Based on earlier case reports with some similarity to this patient's history and disease manifestations, intravenous immunoglobulins, high-dose systemic glucocorticoids, and mycophenolate mofetil were given. Here we report the good outcome of using this strategy for this patient.\n\n2. Case Presentation\nA 48-year-old man presented with symmetrical arthritis of the wrists, metacarpophalangeal and proximal interphalangeal joints, elbows, and knees. He had had intermittent inflammatory back pain since the age of 40 years. His brother suffered from psoriasis. The physical examination revealed alopecia areata, which he said he had had for a long time, but he had never had psoriasis or other skin manifestations. Radiography showed bilateral sacroiliitis but no erosions of hands or feet. His serology was notable for a high-titer positive anti-SSA antibody of ≥240 kU/L (ref. <7), a low-titer positive anti-dsDNA antibody of 14 kIU/L (<10), and a positive IgM-rheumatoid factor of 19 kIU/L (<10). Anti-CCP and HLA-B27 were negative, and proteinuria was not present. However, he had no symptoms of systemic lupus erythematosus or Sjögren syndrome. A diagnosis of spondyloarthritis was made, and his symptoms improved on NSAID and prednisolone. However, he developed diabetes mellitus, and sulfasalazine was prescribed.\n\nA week after starting sulfasalazine, he presented with erythema of the trunk and neck. A cutaneous drug reaction was suspected, sulfasalazine was immediately stopped, and methotrexate was prescribed instead. Three weeks after stopping sulfasalazine, he was admitted because of fever, cough, dyspnea, loss of appetite, night sweats, and weight loss. The erythema had spread to the extremities with a dark red, confluent maculopapular exanthema, and bullae and denudation of the epidermis in large patches of the back were now observed (Figure 1(a)). MRI of the sacroiliac joints and lumbar spine was consistent with bilateral sacroiliitis but showed no active inflammatory changes. His serology was negative for hepatitis B, hepatitis C, and HIV and not indicative of current infection with EBV, CMV, or parvovirus. Anti-dsDNA antibody had increased to 43 kIU/L, and he had proteinuria 0.7 g/day.\n\nHe was managed with intravenous antibiotics and continued on prednisolone 7,5 mg qd, and his skin gradually improved. After 3 weeks, high fever recurred, erythroderma with small pustules on the trunk and extremities was observed, and he developed TEN-like lesions of 10% of body surface area (Figure 1(b)), mostly the back and nates. He was transferred to an intensive care unit due to Staphylococcus aureus sepsis and stabilized with intravenous immunoglobulin (IvIg), intravenous antibiotics, methylprednisolone 100 mg qd, and Flamazine cream.\n\nAfter recovering from the sepsis, PET-CT revealed multiple pathologically enlarged lymphatic glands with increased FDG uptake in the neck and axillary and inguinal regions, near porta hepatis, and in the retroperitoneum. A lymph node biopsy showed large areas of histiocytosis but was not diagnostic for dermatopathic lymphadenopathy or hemophagocytosis. Skin biopsy was consistent with TEN-like lesions, showing full thickness necrosis of the epidermis and pigment incontinence (Figure 2). His mucous membranes were not involved. Bone marrow biopsy showed an increased number of myelopoietic precursor cells, sparse erythropoiesis, and slight interstitial infiltration of B and T lymphocytes but no malignancy. Renal biopsy showed focal mesangial hypercellularity and 1 of 15 glomeruli with sclerosis, a faint linear reaction for IgG, and a slight unspecific reaction in IgM and IgA but no complement deposition, and this was not found to be indicative of glomerulonephritis.\n\n3. Discussion\nA diagnosis of systemic lupus erythematosus (SLE) was made based on the following SLICC criteria: arthritis, proteinuria, hemolytic anemia with a positive direct antiglobulin test after recovering from the sepsis, lymphopenia, high-titer ANA by ELISA and Hep2-cells, and repeatedly positive anti-dsDNA. Hemophagocytic syndrome was highly considered based on the enduring fever, markedly elevated ferritin of 14,900 μg/L (reference interval: 12–300), and a low number of NK-cells, elevated IL-2 receptor of 1500 kU/L (223–710), and CD163 of 10.7 mg/L (0.69–3.86). However, as mentioned, we did not find evidence for this in the biopsies of the bone marrow or lymphatic gland.\n\nMycophenolate mofetil (MMF) was prescribed based on earlier case reports of successful management of hemophagocytosis in SLE [1–3]. The patient gradually recovered, and one year later he was back to work continuing on MMF and low-dose prednisolone as maintenance treatment. The mortality of TEN has been estimated at 30%, and high doses of intravenous immunoglobulins may be efficacious [4, 5]. IvIg may thus have contributed to the resolution of the TEN-like lesions in this case.\n\nThe Naranjo Adverse Drug Reaction probability scale indicated a possible relation between sulfasalazine and the skin and biochemical manifestations. First, life-threatening cutaneous adverse reactions to sulfasalazine have been reported in patients receiving sulfasalazine for inflammatory bowel diseases and psoriatic arthritis [6], and drug-induced SLE has been reported in patients receiving sulfasalazine with sustained autoimmunity even years after stopping the drug [7]. Second, the skin manifestations appeared shortly after sulfasalazine was administered. However, toxic epidermal necrolysis-like skin lesions and hemophagocytic syndrome are possible manifestations of systemic lupus erythematosus, which would be an alternative explanation [8–10]. The lack of mucous membrane involvement is not typical for TEN; however, there were no photodistribution and no histopathologic signs of systemic lupus erythematosus as the cause of the epidermal necrosis [11], and therefore we diagnosed this patient with TEN. In this case, it is peculiar that his skin and fever were ameliorating one month after stopping sulfasalazine, but two months afterwards, his condition suddenly worsened again, suggesting that it was not a direct toxic effect on the skin but an immunological phenomenon and that sulfasalazine may have acted as a trigger.\n\nAcknowledgments\nThanks are due to Dr. Anne Falensteen Lauritzen, Department of Pathology, Herlev Hospital, Denmark, for providing the photomicrograph.\n\nCompeting Interests\nThe authors declare that they have no competing interests.\n\nFigure 1 (a) Confluent maculopapular exanthema and bullae and skin erosions of the back. (b) Toxic epidermal necrolysis-like lesions of the anterior chest and neck with bacterial superinfection.\n\nFigure 2 Toxic epidermal necrolysis-like lesion with full thickness necrosis of the epidermis and pigment incontinence (H&E ×40).\n==== Refs\n1 Ueda Y. Yamashita H. Takahashi Y. Kaneko H. Kano T. Mimori A. Refractory hemophagocytic syndrome in systemic lupus erythematosus successfully treated with intermittent intravenous cyclophosphamide: three case reports and literature review Clinical Rheumatology 2014 33 2 281 286 10.1007/s10067-013-2451-8 2-s2.0-84893960250 24343456 \n2 Paliga A. Shahbazi N. Gonsalves C. Bormanis J. Padmore R. Trilineage myelodysplasia and hemophagocytosis associated with systemic lupus erythematosus American Journal of Hematology 2012 87 5 529 530 10.1002/ajh.22144 2-s2.0-84859887836 22038620 \n3 Uttenthal B. J. Layton D. M. Vyse T. J. Schreiber B. E. Clinical problem-solving. The wolf at the door The New England Journal of Medicine 2012 366 23 2216 2221 10.1056/nejmcps1010093 2-s2.0-84861872361 22670907 \n4 Barron S. J. Del Vecchio M. T. Aronoff S. C. Intravenous immunoglobulin in the treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis: a meta-analysis with meta-regression of observational studies International Journal of Dermatology 2015 54 1 108 115 10.1111/ijd.12423 2-s2.0-84919841976 24697283 \n5 Mahar P. D. Wasiak J. Hii B. A systematic review of the management and outcome of toxic epidermal necrolysis treated in burns centres Burns 2014 40 7 1245 1254 10.1016/j.burns.2014.02.006 2-s2.0-84908120417 24685065 \n6 Jullien D. Wolkenstein P. Roupie E. Roujeau J. C. Revuz J. Toxic epidermal necrolysis after sulfasalazine treatment of mild psoriatic arthritis: warning on the use of sulfasalazine for a new indication Arthritis and Rheumatism 1995 38 4 p. 573 10.1002/art.1780380420 2-s2.0-0028944593 \n7 Gunnarsson I. Kanerud L. Pettersson E. Lundberg I. Lindblad S. Ringertz B. Predisposing factors in sulphasalazine-induced systemic lupus erythematosus British Journal of Rheumatology 1997 36 10 1089 1094 10.1093/rheumatology/36.10.1089 2-s2.0-0030724065 9374926 \n8 Cetin G. Y. Sayar H. Ozkan F. Kurtulus S. Kesici F. Sayarlioglu M. A case of toxic epidermal necrolysis-like skin lesions with systemic lupus erythematosus and review of the literature Lupus 2013 22 8 839 846 10.1177/0961203313492242 2-s2.0-84879697011 23761100 \n9 Horne N. S. Narayan A. R. Young R.-M. Frieri M. Toxic epidermal necrolysis in systemic lupus erythematosus Autoimmunity Reviews 2006 5 2 160 164 10.1016/j.autrev.2005.10.003 2-s2.0-31344470162 16431352 \n10 Kumakura S. Murakawa Y. Clinical characteristics and treatment outcomes of autoimmune-associated hemophagocytic syndrome in adults Arthritis and Rheumatology 2014 66 8 2297 2307 10.1002/art.38672 2-s2.0-84904992221 24756912 \n11 Ziemer M. Kardaun S. H. Liss Y. Mockenhaupt M. Stevens-Johnson syndrome and toxic epidermal necrolysis in patients with lupus erythematosus: a descriptive study of 17 cases from a national registry and review of the literature British Journal of Dermatology 2012 166 3 575 600 10.1111/j.1365-2133.2011.10705.x 2-s2.0-84857606655 22014091\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6897",
"issue": "2016()",
"journal": "Case reports in rheumatology",
"keywords": null,
"medline_ta": "Case Rep Rheumatol",
"mesh_terms": null,
"nlm_unique_id": "101585353",
"other_id": null,
"pages": "4501937",
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"pmid": "27478675",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "22038620;22014091;22670907;24697283;7718014;24756912;24343456;16431352;9374926;23761100;24685065",
"title": "Toxic Epidermal Necrolysis-Like Lesions and Systemic Lupus Erythematosus Possibly Triggered by Sulfasalazine.",
"title_normalized": "toxic epidermal necrolysis like lesions and systemic lupus erythematosus possibly triggered by sulfasalazine"
} | [
{
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... |
{
"abstract": "Oral oxycodone has been available since 2003 in Japan. Oxycodone consumption is increasing along with the decrease in morphine consumption. Although this drug currently has a central role in cancer pain treatment, at this time pure oxycodone injection has not yet been available in Japan. As an alternative, we can subcutaneously administer a compound oxycodone injection (Pavinal) containing a small amount of hydrocotarnine. Since few clinical reports on efficacy and safety of the compound oxycodone injection have been published in Japan, we conducted a retrospective multicenter survey with structured sheets. Monthly survey data regarding the compound prescriptions for cancer pain control have been collected from 3 cancer hospitals. Finally, sixty adult patients were analyzed with the following results. (1) The adverse effects caused by the prior opioids improved in more than half of the patients, and worsened in none. (2) Dose escalation of the drug was achieved through subcutaneous administration(the mean was 1.6 times), and resulted in pain relief with tolerable adverse effects in more than 80% of patients. (3) Adverse effects occurred in 13% of patients, but more than 80% of the episodes were mild in severity. Conversely, we found no adverse effects becoming sequelae, failure and/or fatal in severity. (4) Subcutaneous administrations with the drug were available in long-term(mean 15.4 days, maximum 53 days), including home palliative care use (1.7%). No toxicities due to accumulation were observed. (5) The conversion ratio from oral oxycodone to compound oxycodone injection was 0.82+/-0.20, and the domestic and international reports are basically consistent with our result. So we speculate that the compound can be regarded as a pure oxycodone injection using subcutaneous administration. While further studies are needed, our study indicated that compound oxycodone injection has efficacy and safety in cancer pain treatment. Especially in switching opioids and/or their routes of administration to enhance the analgesic potency along with reducing the adverse effect, we conclude that prescribing this drug can be a convenient alternative.",
"affiliations": "Palliative Care Team, Social Insurance Chukyo Hospital.",
"authors": "Yoshimoto|Tetsusuke|T|;Hisada|Atsuo|A|;Yomiya|Kinomi|K|;Tomiyasu|Shiro|S|;Hasegawa|Toru|T|;Murakami|Satoshi|S|;Matoba|Motohiro|M|",
"chemical_list": "D010098:Oxycodone",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "37(5)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D011307:Drug Prescriptions; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D010098:Oxycodone; D010146:Pain; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "7810034",
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"pubdate": "2010-05",
"publication_types": "D004740:English Abstract; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Efficacy and safety of compound oxycodone injection for cancer pain relief-a multicenter survey of prescriptions.",
"title_normalized": "efficacy and safety of compound oxycodone injection for cancer pain relief a multicenter survey of prescriptions"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2016-04076",
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"activesubstancename": "OXYCODONE"
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{
"abstract": "In utero exposure to antiepileptic drugs has previously been associated with adverse outcome among offspring, but evidence on longer term milestone development remains limited. We investigated the association between in utero exposure to antiepileptic drugs and learning disabilities in the first year of compulsory education among offspring and assessed which antiepileptic drugs carried the highest risk.\n\n\n\nThis population-based case-cohort study used Danish nationwide register data from 2005 to 2008. Cases were offspring exposed to antiepileptic drugs in utero, and controls were unexposed offspring of mothers previously redeeming antiepileptic drug prescriptions. Offspring were followed from birth until the first year of compulsory education from 2011 to 2015. Learning disabilities were defined as mental retardation, specific developmental disorders, autism spectrum disorders, emotional/behavioural disorders or having special educational needs. Logistic regression was used to compute ORs with 95% CIs adjusted for potential confounding.\n\n\n\nOf 117 475 incident singleton births, 636 cases and 434 controls were included (median age: 6.1 years, males: 55.7%). Learning disabilities were identified among 7.1% cases compared with 3.7% for controls. During any trimester, the adjusted OR of the association between in utero exposure to antiepileptic drugs and learning disabilities was 2.20 (95% CI 1.16 to 4.17). Among cases not exposed to polytherapy (n=556), in utero exposure to lamotrigine compared with another antiepileptic drug was associated with the lowest adjusted risk (OR 0.42, 95% CI 0.19 to 0.92), and valproate carried a higher risk (OR 4.67, 95% CI 1.73 to 12.59).\n\n\n\nIn utero exposure to antiepileptic drugs was significantly associated with learning disabilities among offspring. Lamotrigine should preferentially be considered over, for example, valproate if clinically feasible.",
"affiliations": "Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark laurafbech@hotmail.com.;Unit of Epidemiology and Biostatistics, Aalborg University Hospital, Aalborg, Denmark.;Unit of Epidemiology and Biostatistics, Aalborg University Hospital, Aalborg, Denmark.;Unit of Epidemiology and Biostatistics, Aalborg University Hospital, Aalborg, Denmark.;Mental Health Centre Glostrup, Copenhagen University Hospital, Copenhagen, Denmark.;Unit of Epidemiology and Biostatistics, Aalborg University Hospital, Aalborg, Denmark.;Mental Health Centre Glostrup, Copenhagen University Hospital, Copenhagen, Denmark.;Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark.",
"authors": "Bech|Laura Fuglsang|LF|;Polcwiartek|Christoffer|C|;Kragholm|Kristian|K|;Andersen|Mikkel Porsborg|MP|;Rohde|Christopher|C|;Torp-Pedersen|Christian|C|;Nielsen|Jimmi|J|;Hagstrøm|Søren|S|",
"chemical_list": "D000927:Anticonvulsants",
"country": "England",
"delete": false,
"doi": "10.1136/jnnp-2018-318386",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3050",
"issue": "89(12)",
"journal": "Journal of neurology, neurosurgery, and psychiatry",
"keywords": "Antiepileptic drugs; Cognitive functioning; In utero exposure; Learning disabilities; Neurodevelopment",
"medline_ta": "J Neurol Neurosurg Psychiatry",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D016022:Case-Control Studies; D002648:Child; D003718:Denmark; D005260:Female; D006801:Humans; D007859:Learning Disabilities; D008297:Male; D011247:Pregnancy; D011248:Pregnancy Complications; D011297:Prenatal Exposure Delayed Effects; D012042:Registries",
"nlm_unique_id": "2985191R",
"other_id": null,
"pages": "1324-1331",
"pmc": null,
"pmid": "30076271",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "In utero exposure to antiepileptic drugs is associated with learning disabilities among offspring.",
"title_normalized": "in utero exposure to antiepileptic drugs is associated with learning disabilities among offspring"
} | [
{
"companynumb": "DK-JNJFOC-20190202448",
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"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
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{
"abstract": "Natalizumab is associated with the occasional occurrence of progressive multifocal leukoencephalopathy (PML). While natalizumab-associated PML is well described in multiple sclerosis (MS) patients, herpes and other infections have rarely been reported.\n\n\n\nTo report a case of varicella-zoster (VZV) meningovasculitis in a MS patient treated with natalizumab.\n\n\n\nCase report.\n\n\n\nA 48-year-old woman diagnosed with MS in treatment with natalizumab (Expanded Disability Status Scale (EDSS): 4.0). After 72 infusions, she complained of a holocraneal headache and a new unsteady gait with diplopia (EDSS: 5.0). A brain and spinal cord magnetic resonance (MR) scan showed a multifocal leptomeningeal enhancing nodular lesions and an angiography revealed irregularity of the proximal segments of cerebral arteries. Testing for VZV DNA by polymerase chain reaction (PCR) amplification was positive in cerebrospinal fluid. Treatment with endovenous acyclovir was started. After clinical improvement (EDSS: 4.5), treatment with natalizumab was restarted associated with oral acyclovir as prophylaxis.\n\n\n\nNeurologists should be aware of other possible neuroinfections besides PML in MS patients under natalizumab.",
"affiliations": "Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitario Vall d'Hebron, Barcelona, Spain.;Unitat de Ressonància Magnètica (IDI), Servei de Radiologia, Hospital Universitario Vall d'Hebron, Barcelona, Spain.;Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitario Vall d'Hebron, Barcelona, Spain.;Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitario Vall d'Hebron, Barcelona, Spain.;Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitario Vall d'Hebron, Barcelona, Spain.;Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitario Vall d'Hebron, Barcelona, Spain.;Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitario Vall d'Hebron, Barcelona, Spain.;Unitat de Ressonància Magnètica (IDI), Servei de Radiologia, Hospital Universitario Vall d'Hebron, Barcelona, Spain.;Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitario Vall d'Hebron, Barcelona, Spain.",
"authors": "Mulero|Patricia|P|;Auger|Cristina|C|;Parolin|Laura|L|;Fonseca|Elena|E|;Requena|Manuel|M|;Rio|Jordi|J|;Tintoré|Mar|M|;Rovira|Alex|A|;Montalban|Xavier|X|",
"chemical_list": "D007155:Immunologic Factors; D000069442:Natalizumab",
"country": "England",
"delete": false,
"doi": "10.1177/1352458517711569",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-4585",
"issue": "24(3)",
"journal": "Multiple sclerosis (Houndmills, Basingstoke, England)",
"keywords": "Natalizumab; meningovasculitis; multiple sclerosis; varicella-zoster",
"medline_ta": "Mult Scler",
"mesh_terms": "D005260:Female; D006801:Humans; D007155:Immunologic Factors; D008587:Meningitis, Viral; D008875:Middle Aged; D009103:Multiple Sclerosis; D000069442:Natalizumab; D000073618:Varicella Zoster Virus Infection; D020293:Vasculitis, Central Nervous System",
"nlm_unique_id": "9509185",
"other_id": null,
"pages": "358-360",
"pmc": null,
"pmid": "28643544",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Varicella-zoster meningovasculitis in a multiple sclerosis patient treated with natalizumab.",
"title_normalized": "varicella zoster meningovasculitis in a multiple sclerosis patient treated with natalizumab"
} | [
{
"companynumb": "ES-BIOGEN-2017BI00426606",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
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"actiondrug": "4",
"activesubstance": {
"activesubstancename": "NATALIZUMAB"
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"drugadditional": null,
... |
{
"abstract": "Autoimmune diabetes is a rare but severe endocrine toxicity induced by immune checkpoint inhibitor (ICI) treatment. It is unclear if ICI causes selective islet toxicity or non-selective pancreas toxicity. We analyzed 11 patients treated with ICI who developed ICI-related autoimmune diabetes. Eight patients had lipase and/or amylase tested on the same day of diagnosis of autoimmune diabetes. Among them, 75% (6/8) had normal lipase and 100% (6/6) had normal amylase. There was no correlation between glucose level at onset and biochemical pancreatitis. We characterized the clinical features of ICI-induced autoimmune diabetes. Fifty-five percent (6/11) of patients tested positive for GAD65 autoantibodies, and 55% (6/11) developed diabetic ketoacidosis at manifestation of hyperglycemia. In all 11 patients, C-peptide levels were low in the presence of hyperglycemia. ICI-induced thyroiditis was found in 64% (7/11), of which 36% (4/11) were newly diagnosed with thyroiditis while the remaining 27% (3/11) had pre-existing hypothyroidism followed by ICI-induced thyroiditis. Additionally, 27% (3/11), developed ICI-induced hypophysitis. Thyroiditis and autoimmune diabetes coexisted in all patients with ICI-induced hypophysitis. The median time from ICI treatment to the onset of autoimmune diabetes was 11 weeks. Our data suggest that few patients had coexistent ICI-induced autoimmune diabetes and pancreatitis, suggesting ICI mainly caused selective islet toxicity.",
"affiliations": "Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, MA, United States.;Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, MA, United States.;Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, MA, United States.;Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, MA, United States.;Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, MA, United States.",
"authors": "Zhang|Amy L|AL|;Wang|Fang|F|;Chang|Lee-Shing|LS|;McDonnell|Marie E|ME|;Min|Le|L|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fendo.2021.620522",
"fulltext": "\n==== Front\nFront Endocrinol (Lausanne)\nFront Endocrinol (Lausanne)\nFront. Endocrinol.\nFrontiers in Endocrinology\n1664-2392\nFrontiers Media S.A.\n\n10.3389/fendo.2021.620522\nEndocrinology\nOriginal Research\nCoexistence of Immune Checkpoint Inhibitor-Induced Autoimmune Diabetes and Pancreatitis\nZhang Amy L.\n\nWang Fang\nChang Lee-Shing\nMcDonnell Marie E.\nMin Le *\n\nDivision of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Boston, MA, United States\nEdited by: Lingling Wei, Capital Medical University, China\n\nReviewed by: Emily Jane Gallagher, Icahn School of Medicine at Mount Sinai, United States; Jiangfeng Mao, Peking Union Medical College Hospital (CAMS), China\n\n*Correspondence: Le Min, lmin@bwh.harvard.edu\nThis article was submitted to Clinical Diabetes, a section of the journal Frontiers in Endocrinology\n\n13 4 2021\n2021\n12 62052223 10 2020\n16 3 2021\nCopyright © 2021 Zhang, Wang, Chang, McDonnell and Min\n2021\nZhang, Wang, Chang, McDonnell and Min\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.\nAutoimmune diabetes is a rare but severe endocrine toxicity induced by immune checkpoint inhibitor (ICI) treatment. It is unclear if ICI causes selective islet toxicity or non-selective pancreas toxicity. We analyzed 11 patients treated with ICI who developed ICI-related autoimmune diabetes. Eight patients had lipase and/or amylase tested on the same day of diagnosis of autoimmune diabetes. Among them, 75% (6/8) had normal lipase and 100% (6/6) had normal amylase. There was no correlation between glucose level at onset and biochemical pancreatitis. We characterized the clinical features of ICI-induced autoimmune diabetes. Fifty-five percent (6/11) of patients tested positive for GAD65 autoantibodies, and 55% (6/11) developed diabetic ketoacidosis at manifestation of hyperglycemia. In all 11 patients, C-peptide levels were low in the presence of hyperglycemia. ICI-induced thyroiditis was found in 64% (7/11), of which 36% (4/11) were newly diagnosed with thyroiditis while the remaining 27% (3/11) had pre-existing hypothyroidism followed by ICI-induced thyroiditis. Additionally, 27% (3/11), developed ICI-induced hypophysitis. Thyroiditis and autoimmune diabetes coexisted in all patients with ICI-induced hypophysitis. The median time from ICI treatment to the onset of autoimmune diabetes was 11 weeks. Our data suggest that few patients had coexistent ICI-induced autoimmune diabetes and pancreatitis, suggesting ICI mainly caused selective islet toxicity.\n\nautoimmune diabetes\nimmunotherapy\npancreatitis\nendocrine toxicity\nimmune check inhibitor (ICI)\n==== Body\nIntroduction\n\nUnleashing the immune system by using immune checkpoint inhibitors (ICIs) can improve overall survival for patients with advanced cancers (1). Since the FDA approval of ipilimumab (human IgG1 k anti-CTLA-4 monoclonal antibody) in 2011, six more ICIs have been approved for cancer therapy (2).\n\nDespite the often durable clinical benefits of the immune checkpoint blockade therapy, ICI use is associated with a spectrum of adverse effects related to the mechanism of action, commonly referred to as immune-related adverse events (irAEs). Autoimmune diabetes induced by ICIs is a rare irAE occurring in less than 1% of patients treated with ICIs (3), but it can be life-threatening. Studies of autoimmune diabetes thus far have been limited to case reports or case series, with variable clinical presentations. Patients who develop ICI-induced autoimmune diabetes are older than those presenting with classic type 1 diabetes, often require admission for treatment, and require insulin treatment (4–10). ICI-induced autoimmune diabetes is more commonly associated with anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 therapy but has been associated with anti-CTLA-4 or anti-PD-L1 monotherapy, albeit less commonly (11). Anti-GAD65 positivity, HLA type DR4, and preexisting or concurrent ICI-related thyroiditis have all been linked to ICI-induced autoimmune diabetes (5).\n\nICI-induced pancreatitis has been reported (12) but to our knowledge, no case series to date characterized the co-existence of pancreatitis and autoimmune diabetes.\n\nMethods\n\nIn this retrospective cohort study, patients with ICI-induced autoimmune diabetes were identified from patients seen at our longitudinal endocrine clinic. We referred to the American Diabetes Association (ADA) guideline (13) for the criteria to make the diagnosis of autoimmune diabetes. We defined patients with ICI-induced autoimmune diabetes as patients without a history of type 1 diabetes who, upon receiving ICI treatment for underlying malignancy, developed insulin-dependent diabetes following initiation of ICI treatment. The study period (January 2014 to June 2020) was defined as the time from the first patient identified with ICI-induced autoimmune diabetes in our institution to June 2020, the time of last chart review. We performed chart reviews to study demographic characteristics, clinical features, biochemical laboratory characteristics, and medical treatment. This study was approved by our institutional IRB.\n\nStatistical Analyses\n\nDescriptive statistics were calculated for continuous variables. The data were expressed as median with range.\n\nResults\n\nEleven patients met criteria for ICI-related diabetes during the study period.\n\nDemographics and ICI Treatment\n\nICIs were first administered in this cohort between 2014 and 2017. The onset of autoimmune diabetes was documented between 2014 and 2018. Demographic data are summarized in Table 1 . Among 11 patients, 7 were female and 4 were male. Primary malignancies included melanoma (n=4), non-small cell lung cancer (n=3), breast cancer (n=2), renal cancer (n=1) and gastric cancer (n=1). The median age of onset of autoimmune diabetes was 61 years (range 36-78). The median body mass index (BMI) was 24 kg/m2 (range 19-33). Six patients received pembrolizumab monotherapy, one patient received nivolumab monotherapy, two patients received ipilimumab-nivolumab combination therapy and one patient received ipilimumab-nivolumab combination therapy followed by pembrolizumab. Six of the 11 subjects were deceased at the end of the study period. No subjects in this cohort were exposed to high-dose glucocorticoids at the onset of autoimmune diabetes.\n\nTable 1 Demographic data.\n\nPatient\tAge\tSex\tBMI\tType of cancer\tICI\tAlive\t\n1\t68\tF\t21.8\tBreast cancer\tPembrolizumab\tNo\t\n2\t72\tM\t21.8\tNon-small cell lung cancer\tNivolumab/Ipilimumab\tYes\t\n3\t36\tF\t31.9\tMalignant melanoma\tNivolumab/Ipilimumab\tYes\t\n4\t41\tF\t32.9\tMalignant melanoma\tPembrolizumab, Ipilimumab\tNo\t\n5\t61\tF\t21\tBreast cancer\tPembrolizumab\tNo\t\n6\t62\tF\t23.5\tNon-small cell lung cancer\tNivolumab\tNo\t\n7\t60\tM\t24.6\tRenal cell (clear cell) cancer\tPembrolizumab\tYes\t\n8\t44\tF\t19.8\tMalignant melanoma\tNivolumab/Ipilimumab, Pembrolizumab\tYes\t\n9\t55\tF\t19\tGastric cancer\tNivolumab/Ipilimumab\tNo\t\n10\t78\tM\t25.8\tMalignant melanoma\tPembrolizumab\tNo\t\n11\t68\tM\t21.8\tNon-small cell lung cancer\tPembrolizumab\tYes\t\nF, Female; M, Male; ICI, Immune checkpoint inhibitors; BMI, Body mass index.\n\nClinical Characteristics of Autoimmune Diabetes\n\nEight patients had a lipase and/or amylase level measured at the onset of hyperglycemia/autoimmune diabetes. Only 2/8 (25%) had elevated lipase and/or amylase ( Table 2 ).\n\nTable 2 Clinical and biochemical features.\n\nPatients\tBG level at onset of DM (mg/dl)\tDKA\tOther endocrine toxicity\tA1C at onset of DM\tC-peptide (ng/ml)\tTime to onset of DM after ICI (weeks)\tGAD65\tAmylase (U/L)\tLipase (U/L)\t\n1\t1970\tYes\tThyroiditis\t9.5\t0.3\t9\t0.28\t-\t375\t\n2\t210\tNo\tPre-existing hypothyroidism, thyroiditis\t9.5\t0.7\t10\t0\t53\t51\t\n3\t243\tNo\tThyroiditis and hypophysitis\t7.8\t1\t40\t43.1\t16\t22\t\n4\t269\tNo\tThyroiditis and hypophysitis\t6.9\t0\t15\t0.02\t57\t52\t\n5\t340\tNo\tnone\t7.6\t0.4\t26\t0.02\t47\t37\t\n6\t256\tYes\tnone\t7.3\t0\t11\t0.16\t–\t630\t\n7\t222\tNo\tPre-existing hypothyroidism, thyroiditis\t7.6\t1.8\t6\t2.67\t–\t–\t\n8\t386\tYes\tPre-existing hypothyroidism, thyroiditis and hypophysitis\t7.4\t0.6\t122\t0\t42\t27\t\n9\t684\tYes\tThyroiditis\t7.4\t0.3\t5\t23.8\t16\t<10\t\n10\t768\tYes\tnone\t6.2\t0.5\t11\t0\t18\t21\t\n11\t636\tYes\tnone\t6.2\t0.3\t10\t0.03\t–\t–\t\nBG, blood glucose; DM, diabetes mellitus; DKA, diabetic ketoacidosis; ICI, immune checkpoint inhibitor; GAD65, glutamic acid decarboxylase 65 antibody. Reference range: GAD65, <=0.02 nmol/L; Amylase, 3-100 U/L; Lipase, 13-60 U/L.\n\nThe median hemoglobin A1C at onset of autoimmune diabetes was 7.4% (range 6.2-9.5%). The median onset time from initial ICI dose to onset of ICI-induced autoimmune diabetes was 11 weeks (range 5-122 weeks). The median glucose level at presentation was 443 mg/dl (range 210-1970 mg/dl). All patients had measurement of C-peptide and concomitant blood glucose values. The median C-peptide value measured with concomitant plasma glucose >210 mg/dl at the time of presentation of diabetes was low at 0.4 ng/ml (range 0-1.8). Six patients (54.5%) presented with diabetic ketoacidosis (DKA). Seven patients (64%) developed ICI-induced thyroiditis, including 27% who had preexisting hypothyroidism at the time of onset of autoimmune diabetes and 36% who were newly diagnosed with thyroiditis at the time of onset of autoimmune diabetes. Three patients (27%) had coexistence of hypophysitis, thyroiditis and autoimmune diabetes.\n\nApproximately half had positive GAD65 antibody (54% or 6/11). Other tested antibodies including islet antigen 2 (IA-2), islet cell antibody (ICA) and zinc transporter 8 antibody (ZNT8) were negative. (Data not shown).\n\nDiscussion\n\nIn this retrospective cohort study, we found 8 and 6 patients had concomitant lipase and amylase tests at the presentation of autoimmune diabetes respectively. 25% (2/8) had an increased lipase level, and no patient (0/6) had an increased amylase level. Interestingly, although ICI-induced hypophysitis can lead to isolated pituitary hormone deficiencies such as isolated ACTH deficiency (14, 15), to our knowledge, no case series has been published analyzing ICI-induced selective pancreatic endocrine (islet) and exocrine toxicity. This is the first retrospective cohort demonstrating a selective islet toxicity in most of the patients who developed ICI-induced autoimmune diabetes. In addition, other patients (n = 4) in our longitudinal clinic developed pancreatitis with elevated lipase but did not develop autoimmune diabetes, suggestive of a selective exocrine pancreas toxicity. The findings suggest ICI can induce selective pancreatic endocrine or exocrine toxicity. Because simultaneous cross-sectional abdominal imaging studies were not routinely done in these cases, we could not analyze coexistence of radiographic evidence of pancreatitis. Notably, the incidence of ICI-induced pancreatitis was only 2.7% in a recent meta-analysis study (16). The incidence of 25% of pancreatitis in our cohort suggests an increased risk of pancreatitis in patients who develop ICI-induced autoimmune diabetes (17). We performed literature search to identify the correlation between pancreatic enzyme and ICI-induced autoimmune diabetes, there were only 2 case reports had lipase value and both were elevated (10, 18). This find underscores the novelty of this study to evaluate ICI-induced pancreatic toxicity.\n\nIn our analysis, all cases of ICI-induced autoimmune diabetes were associated with either anti-PD-1 monotherapy or combination anti-PD-1/anti-CTLA-4 therapy; no cases were associated with anti-CTLA-4 monotherapy ( Table 1 ). This is consistent with previous studies (5, 11, 19). The majority of the patients (8/11) in this study had normal BMI at the onset of autoimmune diabetes. The median age of onset of ICI-induced autoimmune diabetes was 61 years. The onset age of diabetes probably reflects the age of development of malignancies and age at ICI treatment, although it is worth noting that ICI-induced autoimmune diabetes has been reported in a 12-year-old patient with relapsed classical Hodgkin lymphoma (20).\n\nA strong link between thyroid autoimmunity and spontaneous type 1 diabetes has been well-documented (21, 22). Similarly, the coexistence of ICI-induced thyroiditis and autoimmune diabetes has been described (17, 23). In our study, 27% of patients (3/11) had preexisting hypothyroidism, and ICI-induced thyroiditis manifested as transient thyrotoxicosis while these patients were on a steady dose of levothyroxine replacement. It is unclear if preexisting thyroid autoimmunity predisposed patients to develop ICI-induced autoimmune diabetes. We identified 4 patients (36%) with normal thyroid function prior to initiation with ICIs who developed ICI-induced thyroiditis. While a link between these conditions is suspected in the setting of ICI exposure, whether they have a shared underlying mechanism remains to be determined.\n\nWe also identified the coexistence of hypophysitis and thyroiditis in 3 patients (27%). This occurred following different regimens: one subject received combination anti-PD1 and anti-CTLA-4 therapy, one received combination anti-PD-1 and anti-CTLA-4 followed by anti-PD-1 monotherapy ( Table 1 ), and one subject received anti-PD-1 monotherapy. These findings suggest that varied mechanisms might have mediated autoimmunity in endocrine organs.\n\nAbout half (54%) of our subjects had positive GAD65 antibodies. This is similar to but slightly higher than previous reports in which GAD65 antibodies were positive in 40% of patients (23) but different from spontaneous type 1 diabetes in which over 95% of patients have developed at least one positive autoantibody by the time of diagnosis (24). In addition to GAD65 antibody, other autoantibodies related to type 1 diabetes were reported positive in some patients with ICI-induced autoimmune diabetes, albeit at a lower rate (23). In a recent case report with systemic review by online literature search, 88 patients with ICI-induced autoimmune diabetes, there were 47 (53%) patients had positive pancreatic antibodies. Among the antibodies, there were 43 patients had positive GAD antibody, 10 patients had positive IA-2 antibody, 9 patients had positive insulin antibody, 3 patient had positive ICA antibody and 1 patient had positive ZnT8 antibody (10). In our cohort, no patients had positive titers of anti-islet cell antibody or anti-insulin antibody. GAD65 antibody therefore appears to be the most sensitive autoantibody related to ICI-induced autoimmune diabetes. Notably, as about half of patients had a negative GAD65 antibody, GAD65 antibody positivity should not be used as a required criterion to make the diagnosis of ICI-induced autoimmune diabetes.\n\nBlood glucose at initial presentation of autoimmune diabetes was markedly elevated at 443 mg/dl (range 210-1970 mg/dl) ( Table 2 ) in the setting of low C-peptide level (median 0.4 ng/ml, range 0-1.8 ng/ml), which is consistent with previous findings (23) and suggests rapid loss of beta-cell function in ICI-induced autoimmune diabetes. Although the median glucose level was above 400 mg/dl, the median A1C was 7.4%. The discordance of blood glucose and A1C at presentation of autoimmune diabetes again indicates rapid loss of beta-cell function. As A1C reflects the average blood glucose level over the past 120 days through percentage of glycated hemoglobin, acute onset of severe hyperglycemia within the prior days to weeks would not be expected to significantly impact the A1C. Early identification of ICI-induced autoimmune diabetes is critical because timely initiation with insulin treatment can potentially avoid severe complications from autoimmune diabetes, such as DKA. It is therefore important to educate all patients treated with ICI regarding symptoms related to hyperglycemia of which to be aware.\n\nManagement of ICI-induced autoimmune diabetes is changeling. Many patients required insulin pump and continuous glucose monitoring (CGM). Given the nature of type 1 diabetes, the insulin doses overall were low and stable. The patient had no signs of insulin resistance.\n\nLimitations of this study include its retrospective design and small sample size. Future prospective trials and larger sample sizes are needed to better characterize ICI-induced autoimmune diabetes.\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\nThe studies involving human participants were reviewed and approved by Brigham and Women’s Hospital Institutional Review Board. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.\n\nAuthor Contributions\n\nConception and study design: LM. Development of methodology: LM and AZ. Acquisition of data from chart review and analysis: AZ and FW. Wrote and edited the manuscript: LM and AZ. Review and revision of manuscript: LM, AZ, FW, L-SC, and MM. 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 Conforti F Pala L Bagnardi V De Pas T Martinetti M Viale G . Cancer immunotherapy efficacy and patients’ sex: a systematic review and meta-analysis. Lancet Oncol (2018) 19 (6 ):737–46. 10.1016/S1470-2045(18)30261-4\n2 Vaddepally RK Kharel P Pandey R Garje R Chandra AB . Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence. Cancers (Basel) (2020) 12 (3 ):738–56. 10.3390/cancers12030738\n3 Barroso-Sousa R Barry WT Garrido-Castro AC Hodi FS Min L Krop IE . Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis. 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Clinical characteristics and outcomes of immune checkpoint inhibitor-induced pancreatic injury. J Immunother Cancer (2019) 7 (1 ):31. 10.1186/s40425-019-0502-7 30728076\n13 American Diabetes A. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2019. Diabetes Care (2019) 42 (Suppl 1 ):S13–28. 10.2337/dc19-S002\n14 Min L Hodi FS Giobbie-Hurder A Ott PA Luke JJ Donahue H . Systemic high-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: a retrospective cohort study. Clin Cancer Res (2015) 21 (4 ):749–55. 10.1158/1078-0432.CCR-14-2353\n15 Min L Vaidya A Becker C . Association of ipilimumab therapy for advanced melanoma with secondary adrenal insufficiency: a case series. Endocr Pract (2012) 18 (3 ):351–5. 10.4158/EP11273.OR\n16 George J Bajaj D Sankaramangalam K Yoo JW Joshi NS Gettinger S . Incidence of pancreatitis with the use of immune checkpoint inhibitors (ICI) in advanced cancers: A systematic review and meta-analysis. Pancreatology (2019) 19 (4 ):587–94. 10.1016/j.pan.2019.04.015\n17 Chae YK Chiec L Mohindra N Gentzler R Patel J Giles F . A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes. Cancer Immunol Immunother (2017) 66 (1 ):25–32. 10.1007/s00262-016-1913-7 27761609\n18 Lopes AR Russo A Li AY McCusker MG Kroopnick JM Scilla K . Development of autoimmune diabetes with severe diabetic ketoacidosis and immune-related thyroiditis secondary to durvalumab: a case report. Transl Lung Cancer Res (2020) 9 (5 ):2149–56. 10.21037/tlcr-20-408\n19 Akturk HK Kahramangil D Sarwal A Hoffecker L Murad MH Michels AW . Immune checkpoint inhibitor-induced Type 1 diabetes: a systematic review and meta-analysis. Diabetes Med (2019) 36 (9 ):1075–81. 10.1111/dme.14050\n20 Samoa RA Lee HS Kil SH Roep BO . Anti-PD-1 Therapy Associated Type 1 Diabetes in a Pediatric Patient With Relapsed Classical Hodgkin Lymphoma. Diabetes Care (2020) 43 (9 ):2293–5. 10.2337/dc20-0740\n21 Umpierrez GE Latif KA Murphy MB Lambeth HC Stentz F Bush A . Thyroid dysfunction in patients with type 1 diabetes: a longitudinal study. Diabetes Care (2003) 26 (4 ):1181–5. 10.2337/diacare.26.4.1181\n22 Kordonouri O Klinghammer A Lang EB Gruters-Kieslich A Grabert M Holl RW . Thyroid autoimmunity in children and adolescents with type 1 diabetes: a multicenter survey. Diabetes Care (2002) 25 (8 ):1346–50. 10.2337/diacare.25.8.1346\n23 Stamatouli AM Quandt Z Perdigoto AL Clark PL Kluger H Weiss SA . Collateral Damage: Insulin-Dependent Diabetes Induced With Checkpoint Inhibitors. Diabetes (2018) 67 (8 ):1471–80. 10.2337/dbi18-0002\n24 Bingley PJ . Clinical applications of diabetes antibody testing. J Clin Endocrinol Metab (2010) 95 (1 ):25–33. 10.1210/jc.2009-1365 19875480\n\n",
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"issn_linking": "1664-2392",
"issue": "12()",
"journal": "Frontiers in endocrinology",
"keywords": "autoimmune diabetes; endocrine toxicity; immune check inhibitor (ICI); immunotherapy; pancreatitis",
"medline_ta": "Front Endocrinol (Lausanne)",
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"nlm_unique_id": "101555782",
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"title": "Coexistence of Immune Checkpoint Inhibitor-Induced Autoimmune Diabetes and Pancreatitis.",
"title_normalized": "coexistence of immune checkpoint inhibitor induced autoimmune diabetes and pancreatitis"
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"abstract": "Dermatophytosis in children caused by Trichophyton rubrum is preferably treated with topical or systemic terbinafine. We report the first case of terbinafine resistance in a child with recurrent T. rubrum dermatophytosis and congenital ichthyosiform erythroderma.",
"affiliations": "Department of Dermato-Venereology, Aarhus University Hospital, Aarhus C, Denmark.;Department of Dermato-Venereology, Aarhus University Hospital, Aarhus C, Denmark.;Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark.;Department of Dermato-Venereology, Aarhus University Hospital, Aarhus C, Denmark.",
"authors": "Schøsler|Louise|L|;Andersen|Louise Kronborg|LK|http://orcid.org/0000-0001-9744-3876;Arendrup|Maiken Cavling|MC|;Sommerlund|Mette|M|",
"chemical_list": "D000935:Antifungal Agents; D009281:Naphthalenes; D017964:Itraconazole; D000077291:Terbinafine",
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"issue": "35(2)",
"journal": "Pediatric dermatology",
"keywords": "antifungal treatment; dermatophytosis; ichthyosis; resistance",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000935:Antifungal Agents; D002648:Child; D025141:Drug Resistance, Fungal; D006801:Humans; D016113:Ichthyosiform Erythroderma, Congenital; D017964:Itraconazole; D008297:Male; D009281:Naphthalenes; D012008:Recurrence; D000077291:Terbinafine; D014005:Tinea; D014249:Trichophyton",
"nlm_unique_id": "8406799",
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"pages": "259-260",
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"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent terbinafine resistant Trichophyton rubrum infection in a child with congenital ichthyosis.",
"title_normalized": "recurrent terbinafine resistant trichophyton rubrum infection in a child with congenital ichthyosis"
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"companynumb": "DK-MYLANLABS-2018M1053894",
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"abstract": "This case report presents the clinical evolution and management of a patient with a hereditary paraganglioma syndrome. This disease is characterized by rare tumors of neural crest origin that are symmetrically distributed along the paravertebral axis from the base of the skull and neck to the pelvis. In addition, these patients may develop renal cancer, gastrointestinal stromal tumors, pituitary adenomas, and bone metastasis in some cases. To date no successful therapeutic treatment has been reported. Total resection with postoperative radiotherapy and chemotherapy have been advocated, especially for the multiple metastasis. Here we show how the combination of high doses of the beta blocker propranolol (3 mg/Kg/day) and the DNA intercalating agent, temozolomide, has been successful in the treatment of a SDHA metastatic paraganglioma.",
"affiliations": "PHEiPAS, Castellón de la Plana, 12006, Spain.;Alianza VHL, Centro Cívico Rogelio Soto, Sabadell, 08204, Spain.;Servicio de Oncología, Hospital Universitario Carlos Haya, Málaga, 29010, Spain.;Servicio de Oncología, Hospital Universitario Virgen de las Nieves, Granada, 18014, Spain.;Centro de Investigaciones Biológicas, U-707 CIBERER, Madrid, Spain.;Centro de Investigaciones Biológicas, U-707 CIBERER, Madrid, Spain.",
"authors": "Díaz-Castellanos|Miguel-Angel|MA|;Gómez de Las Heras|Karina Villar|KV|;Díaz-Redondo|Tamara|T|;González-Flores|Encarnación|E|;Albiñana|Virginia|V|;Botella|Luisa-María|LM|https://orcid.org/0000-0002-6310-2245",
"chemical_list": null,
"country": "England",
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"doi": "10.12688/f1000research.13185.1",
"fulltext": "\n==== Front\nF1000ResF1000ResF1000ResearchF1000Research2046-1402F1000 Research Limited London, UK 10.12688/f1000research.13185.1Case ReportArticlesNeuro-OncologyCase Report: Propranolol increases the therapeutic response to temozolomide in a patient with metastatic paraganglioma [version 1; referees: 2 approved]\n\nDíaz-Castellanos Miguel-Angel ConceptualizationData CurationSupervisionValidationVisualizationWriting – Review & Editing1Gómez de las Heras Karina Villar ConceptualizationData CurationSupervisionWriting – Review & Editing23Díaz-Redondo Tamara ConceptualizationInvestigationMethodology4González-Flores Encarnación ConceptualizationFormal AnalysisInvestigationMethodology5Albiñana Virginia ConceptualizationInvestigationValidation6Botella Luisa-María ConceptualizationValidationWriting – Original Draft PreparationWriting – Review & Editinghttps://orcid.org/0000-0002-6310-2245a6\n1 PHEiPAS, Castellón de la Plana, 12006, Spain\n2 Alianza VHL, Centro Cívico Rogelio Soto, Sabadell, 08204, Spain\n3 Sanidad Castilla-La Mancha, Toledo, Spain\n4 Servicio de Oncología, Hospital Universitario Carlos Haya, Málaga, 29010, Spain\n5 Servicio de Oncología, Hospital Universitario Virgen de las Nieves, Granada, 18014, Spain\n6 Centro de Investigaciones Biológicas, U-707 CIBERER, Madrid, Spaina cibluisa@cib.csic.esMD-C, KVGH, VA and L-MB wrote the paper. MD-C, TD-R and EG-F are the physicians responsible for the patient.\n\nNo competing interests were disclosed.\n\n4 12 2017 2017 6 208724 11 2017 Copyright: © 2017 Díaz-Castellanos MA et al.2017This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.This case report presents the clinical evolution and management of a patient with a hereditary paraganglioma syndrome. This disease is characterized by rare tumors of neural crest origin that are symmetrically distributed along the paravertebral axis from the base of the skull and neck to the pelvis. In addition, these patients may develop renal cancer, gastrointestinal stromal tumors, pituitary adenomas, and bone metastasis in some cases. To date no successful therapeutic treatment has been reported. Total resection with postoperative radiotherapy and chemotherapy have been advocated, especially for the multiple metastasis. Here we show how the combination of high doses of the beta blocker propranolol (3 mg/Kg/day) and the DNA intercalating agent, temozolomide, has been successful in the treatment of a SDHA metastatic paraganglioma.\n\nParagangliomarare oncologic diseasesrepurposing drugspseudohypoxic cancer syndromesThe author(s) declared that no grants were involved in supporting this work.\n==== Body\nIntroduction\nHereditary paraganglioma and pheochromocytoma syndromes (HPP) are characterized by rare tumors called pheochromocytomas (PHEOs) and paragangliomas (PGLs). These are highly vascularized catecholamine-secreting tumors of neural crest origin (chromaffin cells derived from the adrenal medulla – pheochromocytoma – or extra-adrenal paraganglia - paragangliomas), distributed symmetrically along the paravertebral axis. Although tumors are usually histologically benign, most of them hyper-secrete catecholamines, causing high cardiovascular morbidity and mortality\n1, and symptoms related to mass effect. If left untreated, a subset of these tumors will metastasize in bones, lungs, liver or lymph nodes\n2. These patients can develop other rare tumors too, such as renal cancer and gastrointestinal stromal tumors. However, tumorigenesis is rare in the first decade of life.\n\nHPP syndromes are due to pathogenic variants of genes, SDHx genes, a group of multiple nuclear genes encoding subunits of the succinate dehydrogenase (SDH) enzyme complex. Similarly to other autosomal-dominant hereditary cancer disease - von Hippel-Lindau (VHL) -paraganglioma–pheochromocytoma (PGL/PCC) syndrome is related to the hypoxia pathway\n3. Hypoxia-inducible factor 1 (HIF1) regulates the cellular response according to oxygen levels. HIF is a heterodimer of a HIF1-α subunit, regulated by oxygenation and a β subunit. Under normal oxygen conditions, HIF1-α degradation is promoted by the E3 ubiquitin ligase pVHL (von Hippel Lindau factor). In lower oxygen cell environments, VHL recognition of HIF-1α is decreased, allowing HIF1 to promote cellular survival and growth\n4. In cancer, the hypoxia pathway is switched by the tumoral cells leading to the tumor growth\n5. Pseudo-hypoxic states are those leading to the hypoxia-pathway gene expression, under normoxic conditions.\n\nGermline mutations in the onco-suppressor gene, called\nVhl leads to the autosomal-dominant hereditary cancer disease VHL. VHL disease is clinically characterized by retinal and CNS hemangioblastomas, RCC (renal clear cell carcinoma), PCC, neuroendocrine pancreatic tumors and pancreatic cystadenomas, endolymphatic sac tumors and broad ligament cystadenomas. Closely related to this disease are the mutations involving the succinate dehydrogenase genes (SDHx genes)\n6. The lack of function of SDHx genes leads to an inhibition of prolyl hydroxylases by alpha-ketoglutarate. These hydroxylases “target” HIF1/2-α by specific hydroxylation to be recognized and bound by VHL. In this way, hydroxylases cannot help in the degradation of HIF, and a state of pseudo-hypoxia\n7 is created. Thus, pseudo-hypoxic states display similar hypoxia-pathway triggered gene expression, but under normoxic conditions.\n\nSurveillance recommendations for both diseases (VHL disease and PHEO/PGL)\n2 are very similar. It is important to suspect, localize and resect these tumors.\n\nThe present case presents the clinical evolution and management of a patient with a hereditary paraganglioma syndrome. The combination of high doses of the beta blocker propranolol (3 mg/Kg/day) and the DNA intercalating agent, temozolomide, was been successful in the treatment of the SDHA metastatic paraganglioma.\n\nCase description\nA 53 year old man, with personal and family history of hypertension, was diagnosed with a 4 cm tumoral mass at costovertebral D6–D7 with a 21 max SUV, during a routine check-up in March 2010. The only manifestation of disease was elevated blood pressure. He was being treated at this time with irbesartan/hydrochlorothiazide (1250mg/12.5mg, respectively). After surgery, the pathology diagnosis was of PGL with a Ki67 around 5-8%, and synaptophysin and chromogranin positive. Genetic analysis found a mutation in the\nSDHA gene, leading to a heterozygous missense\np.Ser445Leu change, defined as pathogenic\n8. The patient remained without treatment and symptom-free until August 2014, when a back pain appeared around the D10 region, with progressive worsening. In October, as the pain persisted, he underwent MRI and 18F-DG-PET scan and was diagnosed with several metastasis at: D6–D7, right acetabulum (3cm); vertebral hemi-body D10 (3cm); vertebral body of D12 (2cm); and left iliac crest (1cm). A scintigraphy with Indium-111 pentetreotide suggested metastatic disease of probably neuroendocrine origin. D10 lesion biopsy confirmed the diagnosis of PGL metastasis with a Ki67 around 15–20% (\nFigure 1A). The patient was treated with doxazosin (8 mg/day) and bisoprolol (10 mg/day).\n\nFigure 1. MRI and 18F-DG-PET scan.\n(\nA) In October 2014, several metastasis at D6–D7, right acetabulum (3cm); vertebral hemi-body D10 (3cm); vertebral body of D12 (2cm); and left iliac crest (1cm) were observed. (\nB) 4 months later, a PET-TAC showed a metabolic stabilization of the disease, but with a slight growth of lesions according to MRI. (\nC) During the following 11 months, the patient remained stable without disease progression. (\nD) In May 2016, a 18 FDG-PET-TAC revealed an important metastatic dissemination all over the skeleton, showing more than 40 small new lesions (<2 cm), and with scarce or null Octreoscan and\n123I-MIBG uptake. (\nE) In December 2016, most of lesions had disappeared according to PET-TAC. (\nF) In July 2017, a new PET supported the previous results, showing the remaining two lesions but with maximum SUV lower. (\nG) In October 2017, 4 months since the last dose of temozolomide, and propranolol as the only treatment (240mg/day), the disease remains controlled according to this last PET-TAC.\n\nIn November 2014, the patient started on systemic treatment with denosumab (120 mg every 28 days) and lanreotide (120 mg every 14 days). After 4 months, a PET-TAC showed a metabolic stabilization of the disease, but with a slight growth of lesions according to MRI (\nFigure 1B). D6 and D10 lesions were then treated by radiotherapy (Cyberknife). To this purpose, in March/April 2015 the patient underwent SBRT with CiberKnife (24 Gy in D10, 15 Gy in D12 and 35 Gy in D6–7), and the pain disappeared. After 6 months, the D7 and D12 lesions were also irradiated and completed SBRT with CiberKnife (24 Gy in left iliac bone and 24 Gy to right acetabulum).\n\nResponse to radiotherapy was good, showing stability of lesions and decrease of max SUV. No new lesions appeared. In June 2015, a thermoablation and right acetabulum metastasis cementation was performed with good results.\n\nAt this moment, the anti-hypertensive bisoprolol was changed to propranolol(120mg/day), due to preliminary reports of propranolol’s good results in VHL tumors\n9. During the following 11 months, the patient remained stable without disease progression (\nFigure 1C). Lanreotide dose was decreased to 120 mg every 3 weeks, due to side effects. Side effects included nausea, vomits, diarrhea and hyperglycaemia.\n\nIn May 2016, metanephrines and chromogranin were raised above normal levels, as follows: Chromogranin A, 106 ng/mL (normal level, <93); urine fractionated Norepinephrine, 196 mcg/24h (normal levels, 15–80); urine fractionated normetanephrine, 1316 mcg/24 h (normal levels, 128-484); urine total metanephephrine, 1394 mcg/24h (normal levels, 220-680). A 18FDG-PET-TAC revealed an important metastatic dissemination all over the skeleton, showing more than 40 small new lesions less than 2 cm, and with scarce or null Octreoscan and\n123I-MIBG uptake (\nFigure 1D).\n\nFrom this moment on, a combined treatment of temozolomide (75 mg/m² for 21 days every 28 days) and an increase of propranolol up to 3 mg/kg/day (240 mg/day) was prescribed. After the first cycle of temozolomide, results were evaluated in August 2016 at National Institutes of Health, where the previously detected metastatic dissemination was confirmed, although catecholamines and chromogranin levels were decreasing compared with the previous measures. Treatment was kept the same for 6 cycles of temozolomide. In December 2016, most of lesions had disappeared according to PET-TAC (\nFigure 1E). The two remaining lesions had maximum SUV significantly decreased. In January 2017, lanreotide was retired due to adverse side effects (as before).\n\nIn July 2017, a new PET supported the previous results, showing the remaining two lesions but with maximum SUV lower (\nFigure 1F). Temozolomide was withdrawn because of side effects (lymphopenia and thrombopenia). In October 2017, 4 months since the last dose of temozolomide, and propranolol as the only treatment (240mg/day), the disease remains controlled according to the last PET-TAC (F18-FDG) (\nFigure 1G). This imaging study suggests the presence of two neoplastic bone lesions in the dorsal spine and right acetabulum; regarding the previous examination (July 2017), the lesions described in D6 and acetabulum persist without major changes, whereas that of vertebra D10 has disappeared.\n\nDiscussion\nThe present case report describes an impressive clinical and metabolic improvement of a patient suffering from a metastatic paraganglioma after using a combination of temozolomide and propranolol at high doses. The improvement has been kept even after 7 months of lanreotide removal (usually used as standard treatment).\n\nWe can only hypothesize about the reason for this spectacular result. However, there are some literature reports on the synergy between chemotherapeutic agents inducing DNA damage, and therefore blocking DNA replication (as it is here the case of temozolomide) and β-blockers, which have shown antiangiogenic and pro-apoptotic effects in tumoral cells\n9,\n10.\n\nRecent examples of these combinations found in the literature include the action of β-blockers increasing response to different chemotherapeutic agents. Pasquier\net al. used a mouse model of neuroblastoma, where β-blockers were shown to increase treatment efficacy\n11. Propranolol in combination with vinblastine (chemotherapeutic agent belonging to the group of vegetable alkaloids), proved to be a successful treatment for advanced angiosarcoma\n12, with optimal results in seven patients following a clinical trial\n13.Chow\net al. showed the regression of a rapidly enlarging stage T2 angiosarcoma of the scalp and face, following combination therapy with propranolol hydrochloride, paclitaxel (other vegetable alkaloid), and radiotherapy\n14. More recently, a prospective study using propranolol for off-label treatment of patients with melanoma, confirmed a significantly inversely association with recurrence of melanoma when propranolol was used at the time of diagnosis\n15. We could infer that propranolol seems to potentiate the anti-angiogenic effects and antitumor efficacy of chemotherapy.\n\nFocusing our attention to propranolol- an unspecific β-blocker - as an antitumoral agent, Albiñana and coworkers\n16 recently published the clinical and biomarker follow-up of a clinical trial conducted in seven VHL patients with retinal hemangioblastomas. These patients had no surgical option, and the tumors remained stable in size (with reabsorption of exudates) following 120 mg propranolol treatment for 12 months. This clinical trial led recently to the European Medicines Agency’s designation of propranolol as Orphan drug for VHL disease.\n\nThe hypothesis supporting the antiangiogenic properties of propranolol relies on its proven effect on decreasing HIF-inducible transcription targets\n9. Propranolol would decrease HIF protein levels, and therefore, the activation of the hypoxia program developed by the hypoxia target genes, among them, angiogenic factors, such as VEGF, FGF, PDGF, EPO, and metalloproteases, activated in tumors that favor migration and dissemination of cancer cells.\n\nThe advantages of the use of propranolol and temozolomide derive mainly from the long experience as therapeutic agents. Both are old drugs, and therefore, the safety profile and side effects are well known. In this context, we can state that if they are proven effective in tumoral cases difficult to manage, the therapeutic solution may be immediate from the bench to the patient. In our case, after 4 months taking propranolol as the only medication, the improvement is maintained, which would support the use of propranolol as a drug that significantly increases the progression-free survival in absence of temozolomide. If these results are confirmed in more studies, its use would represent an advantage, allowing - once the disease is in remission - periods of time for the marrow to recover from the adverse effects of chemotherapy with the alkylating agent.\n\n The strengths of the treatment are the results and the absence of serious side effects for the propranolol in this particular case. The limitations of using propranolol derive from the anti-hypertensive effects. Hypotensive patients should take care with the treatment, and be always under cardiologist supervision.\n\nFor these rare diseases where therapeutic options are scarce and with not very successful results, outcomes like the one reported here have to be seriously considered if we want to improve the quality and life expectancy for these - in most cases - young patients.\n\nConsent\nWritten informed consent for the publication of the patient’s clinical details and images was obtained from the patient.\n\n10.5256/f1000research.14305.r30292Referee response for version 1 Jara Carlos 1Refereehttps://orcid.org/0000-0003-1158-9415\n1 Alcorcón Foundation University Hospital, King Juan Carlos University (URJC), Madrid, Spain\nCompeting interests: No competing interests were disclosed.\n\n21 2 2018 Version 1recommendationapproveI suggest to consider this work for indexing.\n\n I think the subject is interesting, the presentation is appropriate and the arguments in favor of the advantage provided by propranolol are consistent. The mechanism by which this drug adds therapeutic advantage in this type of tumor remains an enigma, but I think that as a clinical case the arguments presented are sufficient.\n\n The description of the case is correct and detailed. The clinical evolution is surprising and the role that propranolol can exercise together with temozolamide is promising and frankly novel. The clinical improvement and its maintenance over time are striking, particularly after the failure to previous standard therapies.\n\n An especially positive feature of this study is to focus on a relatively rare pathology and in which the therapeutic possibilities are limited.\n\n For a definitive evaluation of the role that propranolol may have in the treatment of these neoplasms, together with chemotherapy, it will be necessary to develop a multicenter phase III study, which, judging by the data provided by the authors, seems to be appropriate. It is of course necessary to investigate the mechanism by which propranolol potentiate the anti-angiogenic effects and antitumor efficacy of chemotherapy.\n\n Suggestions for the authors:\nAt the beginning the phrase \"Hereditary paraganglioma and pheochromocytoma syndromes (HPP) are characterized by rare tumors called pheochromocytomas (PHEOs) and paragangliomas (PGLs).\" Should be reversed by \"Hereditary paraganglioma and pheochromocytoma syndromes (HPP) are characterized by rare tumors called paragangliomas (PGLs) and pheochromocytomas (PHEOs).\n\nIn the description of the case it should be mentioned that the study carried out presumably was an 8F-DG-PET (no data is provided other than the SUV value).\n\nI would suggest modifying \"National Institutes of Health\" by its name in Spanish, mentioning the specific hospital center.\n\nI would suggest modifying the expression 'spectacular' by a more restrained one as 'striking'.\n\n\n\n\nI have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n\n10.5256/f1000research.14305.r30293Referee response for version 1 Juarranz Angeles 1Referee\n1 Department of Biology, Autonomous University of Madrid, Madrid, Spain\nCompeting interests: No competing interests were disclosed.\n\n12 2 2018 Version 1recommendationapproveThe present case report describes an impressive clinical improvement of a patient suffering from a metastatic paraganglioma. The case is well written and documented with images. The good news is that the treatment is a combination of temozolomide and propranolol at high doses, old drugs from which the safety profile and side effects are well known.\n\n It is noteworthy that the improvement was kept even after 7 months of lanreotide removal. Lanreotide remains one of the choice drugs as standard treatment for metastatic paragangliome, although with high side effects, and only limited success.\n\n While temozolomide is commonly used for brain tumors, the novelty is the concomitant treatment with a beta blocker, propranolol. The authors explain the results based on the antiangiogenic properties of propranolol, decreasing HIF-inducible transcription targets according to previous papers published elsewhere. Propranolol would decrease HIF protein levels, and thus the activation of hypoxia target genes, among them, angiogenic factors, such as VEGF, FGF, PDGF, EPO, and metalloproteases.\n\n The advantages of the use of propranolol and temozolomide derive mainly from the long experience as therapeutic agents. Both are old drugs, and therefore, the safety profile and side effects are well known. In this context, we can state that if they are proven effective in tumoral cases difficult to manage.\n\n For rare diseases where therapeutic options are scarce and with not very successful results, outcomes like the one reported here have to be seriously considered and spread in literature, since patients may get an enormous benefit. On top of this, the proposed treatment is cheap, and with minimal side effects.\n\n However, this is a case report, and to be sure that the treatment really is effective, we need more knowledge derived from other cases.\n\nI have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.\n==== Refs\n1 \nLenders JW Duh QY Eisenhofer G :\nPheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline. \nJ Clin Endocrinol Metab. \n2014 ;99 (6 ):1915 –1942 .\n10.1210/jc.2014-1498 \n24893135 \n2 \nRednam SP Erez A Druker H :\nVon Hippel-Lindau and hereditary pheochromocytoma/paraganglioma syndromes: Clinical features, genetics, and surveillance recommendations in childhood. \nClin Cancer Res. \n2017 ;23 (12 ):e68 –e75 .\n10.1158/1078-0432.CCR-17-0547 \n28620007 \n3 \nHenegan JC JrGomez CR :\nHeritable Cancer Syndromes Related to the Hypoxia Pathway. \nFront Oncol. \n2016 ;6 :68 .\n10.3389/fonc.2016.00068 \n\n27047799 \n4 \nSemenza GL :\nOxygen homeostasis. \nWiley Interdiscip Rev Syst Biol Med. \n2010 ;2 (3 ):336 –61 .\n10.1002/wsbm.69 \n20836033 \n5 \nDhani N Fyles A Hedley D :\nThe clinical significance of hypoxia in human cancers. \nSemin Nucl Med. \n2015 ;45 (2 ):110 –21 .\n10.1053/j.semnuclmed.2014.11.002 \n25704384 \n6 \nTaïeb D Pacak K :\nNew Insights into the Nuclear Imaging Phenotypes of Cluster 1 Pheochromocytoma and Paraganglioma. \nTrends Endocrinol Metab. \n2017 ;28 (11 ):807 –817 .\n10.1016/j.tem.2017.08.001 \n\n28867159 \n7 \nSelak MA Durán RV Gottlieb E :\nRedox stress is not essential for the pseudo-hypoxic phenotype of succinate dehydrogenase deficient cells. \nBiochim Biophys Acta - Bioenerg. \n2006 ;1757 (5–6 ):567 –72 .\n10.1016/j.bbabio.2006.05.015 \n16797480 \n8 \nMiettinen M Killian JK Wang ZF :\nImmunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. \nAm J Surg Pathol. \n2013 ;37 (2 ):234 –40 .\n10.1097/PAS.0b013e3182671178 \n\n23282968 \n9 \nAlbiñana V Villar Gómez de Las Heras K Serrano-Heras G :\nPropranolol reduces viability and induces apoptosis in hemangioblastoma cells from von Hippel-Lindau patients. \nOrphanet J Rare Dis. \n2015 ;10 (1 ):118 .\n10.1186/s13023-015-0343-5 \n\n26394686 \n10 \nAlbiñana V Recio-Poveda L Zarrabeitia R :\nPropranolol as antiangiogenic candidate for the therapy of hereditary haemorrhagic telangiectasia. \nThromb Haemost. \n2012 ;108 (1 ):41 –53 .\n10.1160/TH11-11-0809 \n22552254 \n11 \nPasquier E Street J Pouchy C :\nΒ-Blockers Increase Response To Chemotherapy Via Direct Antitumour and Anti-Angiogenic Mechanisms in Neuroblastoma. \nBr J Cancer. \n2013 ;108 (12 ):2485 –94 .\n10.1038/bjc.2013.205 \n\n23695022 \n12 \nPasquier E André N Street J :\nEffective Management of Advanced Angiosarcoma by the Synergistic Combination of Propranolol and Vinblastine-based Metronomic Chemotherapy: A Bench to Bedside Study. \nEBioMedicine. \n2016 ;6 :87 –95 .\n10.1016/j.ebiom.2016.02.026 \n\n27211551 \n13 \nJenkins K :\nPropranolol in Angiosarcoma: First Major Advance in Decades. \nMedscape. \n2017 \nReference Source\n\n14 \nChow W Amaya CN Rains S :\nGrowth Attenuation of Cutaneous Angiosarcoma With Propranolol-Mediated β-Blockade. \nJAMA dermatology. \n2015 ;151 (11 ):1226 –1229 .\n10.1001/jamadermatol.2015.2554 \n26375166 \n15 \nDe Giorgi V Grazzini M Benemei S :\nPropranolol for Off-label Treatment of Patients With Melanoma Results From a Cohort Study .\nJAMA Oncol. \n2017 .\n10.1001/jamaoncol.2017.2908 \n28973254 \n16 \nAlbiñana V Escribano RMJ Soler I :\nRepurposing propranolol as a drug for the treatment of retinal haemangioblastomas in von Hippel-Lindau disease. \nOrphanet J Rare Dis. \n2017 ;12 (1 );122 .\n10.1186/s13023-017-0664-7 \n\n28662711\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2046-1402",
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"keywords": "Paraganglioma; pseudohypoxic cancer syndromes; rare oncologic diseases; repurposing drugs",
"medline_ta": "F1000Res",
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"nlm_unique_id": "101594320",
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"title": "Case Report: Propranolol increases the therapeutic response to temozolomide in a patient with metastatic paraganglioma.",
"title_normalized": "case report propranolol increases the therapeutic response to temozolomide in a patient with metastatic paraganglioma"
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"abstract": "Rituximab is a mouse/human chimeric anti-CD20 IgG1 monoclonal antibody used to treat cancer and autoimmune conditions. Side effects of rituximab include fever, rash, cytopenia and hypotension, back pain, arthralgia, and myalgia. Here, we report on 3 patients who developed moderate to severe tendonitis after the second infusion of rituximab.\nWe report 3 patients who developed tendonitis after the second infusion of rituximab. These patients were undergoing treatment for connective tissue diseases. All 3 patients received 2 rituximab infusions, 2 weeks apart. The 3 cases developed clinical tendonitis that was confirmed by magnetic resonance imaging in 2 cases.\n\n\nCONCLUSIONS\nThis is the first case series reporting new onset tendonitis in patients with connective tissue diseases after rituximab therapy. All 3 cases developed tendonitis 1 week after receiving the second dose of rituximab. Clinical features of tendonitis resolved 3-4 months in all cases. The underlying pathogenic mechanism by which rituximab causes tendonitis is not clear, but tendonitis and tendon rupture have been reported after using other medications such as quinolones. The tendon damage was progressive leading to tendon rupture in 1 patient, highlighting the importance of early recognition. It is plausible that there is a cause-effect relation between tendonitis and administration of rituximab in our 3 cases, since none of these cases had previous history of tendonitis; however, more data are needed to confirm this observation.",
"affiliations": "1Department of Internal Medicine, University of Toledo Medical Center, Toledo, OH; and 2Division of Rheumatology and Immunology, Department of Internal Medicine, University of Toledo Medical Center, Toledo, OH.",
"authors": "Alqahtani|Ali|A|;Sabha|Marwa|M|;Abdelfattah|Thaer|T|;Srour|Khaled|K|;Dhayihi|Turki|T|;Kahaleh|Bashar|B|;Altorok|Nezam|N|",
"chemical_list": "D007155:Immunologic Factors; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000000591",
"fulltext": null,
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"issn_linking": "1075-2765",
"issue": "24(5)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000125:Achilles Tendon; D000328:Adult; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009220:Myositis; D010146:Pain; D011928:Raynaud Disease; D000069283:Rituximab; D012421:Rupture; D052256:Tendinopathy; D013708:Tendon Injuries",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e592-e595",
"pmc": null,
"pmid": "28418945",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tendonitis and Tendon Rupture After Treatment With Rituximab: A Case Series.",
"title_normalized": "tendonitis and tendon rupture after treatment with rituximab a case series"
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{
"companynumb": "US-ROCHE-1924877",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "PREDNISONE"
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"abstract": "BACKGROUND\nThe use of biologic agents has become an important option in treating patients with rheumatoid arthritis. However, these drugs have been associated with an increased risk of tuberculosis (TB) reactivation. Local guidelines for TB screening prior to the use of biologic agents were developed to address this issue.\n\n\nOBJECTIVE\nThis study is a survey describing the compliance of Filipino rheumatologists to these guidelines.\n\n\nMETHODS\nEighty-seven rheumatologists in the Philippines were given the questionnaire and responses from 61 rheumatologists were included in the analysis.\n\n\nRESULTS\nAll respondents agree that patients should be screened prior to giving the biologic agents. Local guidelines recommend screening with tuberculin skin test (TST) and chest radiograph. However, cut-off values considered for a positive TST and timing of initiation of biologic agents after starting TB prophylaxis and treatment varied among respondents. In addition, screening of close household contacts were only performed by 41 (69.5%) respondents. There were 11 respondents who reported 16 patients developing TB during or after receiving biologic agents, despite adherence to the guidelines.\n\n\nCONCLUSIONS\nThis survey describes the compliance rate of Filipino rheumatologists in applying current local recommendations for TB screening prior to initiating biologic agents. The incidence of new TB cases despite the current guidelines emphasizes the importance of compliance and the need to revise the guidelines based on updated existing literature.",
"affiliations": "Section of Rheumatology, Department of Medicine, St. Luke's Medical Center, Quezon City, Metro Manila.;Section of Rheumatology, Department of Internal Medicine, Cardinal Santos Medical Center, San Juan, Metro Manila, Philippines.;Section of Rheumatology, Department of Medicine, St. Luke's Medical Center, Quezon City, Metro Manila.",
"authors": "Aquino-Villamin|Melissa|M|;Tankeh-Torres|Sandra|S|;Lichauco|Juan Javier|JJ|",
"chemical_list": "D000995:Antitubercular Agents; D001688:Biological Products",
"country": "England",
"delete": false,
"doi": "10.1111/1756-185X.12656",
"fulltext": null,
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"issn_linking": "1756-1841",
"issue": "19(11)",
"journal": "International journal of rheumatic diseases",
"keywords": "TB screening; biologic agents; guidelines; rheumatoid arthritis (clinical aspects, education, and drug treatment)",
"medline_ta": "Int J Rheum Dis",
"mesh_terms": "D000995:Antitubercular Agents; D001291:Attitude of Health Personnel; D001688:Biological Products; D019983:Guideline Adherence; D019538:Health Care Surveys; D007722:Health Knowledge, Attitudes, Practice; D006801:Humans; D016867:Immunocompromised Host; D015994:Incidence; D008403:Mass Screening; D010679:Philippines; D017410:Practice Guidelines as Topic; D010818:Practice Patterns, Physicians'; D011237:Predictive Value of Tests; D013902:Radiography, Thoracic; D000072140:Rheumatologists; D016896:Treatment Outcome; D014374:Tuberculin Test; D014376:Tuberculosis",
"nlm_unique_id": "101474930",
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"pages": "1126-1131",
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"pmid": "26545293",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Survey of rheumatologists on the use of the Philippine Guidelines on the Screening for Tuberculosis prior to use of Biologic Agents.",
"title_normalized": "survey of rheumatologists on the use of the philippine guidelines on the screening for tuberculosis prior to use of biologic agents"
} | [
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"companynumb": "PH-JNJFOC-20170201544",
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{
"abstract": "Continuous hiccups during surgery not only affect the surgical procedure, they can also cause adverse effects for the patient. Apart from active investigation of the cause of the hiccups, their timely termination is also necessary.\n\n\n\nWe reported a case of a 70-year-old woman with continuous intraoperative hiccups that appeared during vaginal hysterectomy under low continuous epidural anesthesia. After the ineffectiveness CO2 repeated inhalation and intravenous administration of chlorpromazine and methoxychlorpromide, we performed unilateral phrenic nerve block under ultrasound guidance. Hiccups were terminated without any related complications.\n\n\n\nDuring intraoperative continuous hiccups, ultrasound guided phrenic nerve block may be a suitable treatment option when physical methods and drug therapy are not effective. However, given the absence of a vital risk related to hiccups, this block should imply the complete absence of any respiratory contraindication and a prolonged postoperative respiratory monitoring.",
"affiliations": "Department of Anesthesiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, 16# Jichang Road, Guangzhou, 510405, China. xbtdfh@163.com.;Department of MRI, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, China.;Department of Anesthesiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, 16# Jichang Road, Guangzhou, 510405, China.",
"authors": "Zhang|Yong|Y|0000-0001-9737-2166;Duan|Fuhong|F|;Ma|Wuhua|W|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12871-018-0589-2",
"fulltext": "\n==== Front\nBMC AnesthesiolBMC AnesthesiolBMC Anesthesiology1471-2253BioMed Central London 58910.1186/s12871-018-0589-2Case ReportUltrasound-guided phrenic nerve block for intraoperative persistent hiccups: a case report http://orcid.org/0000-0001-9737-2166Zhang Yong +86 020 36591231xbtdfh@163.com 1Duan Fuhong fuhongduan@sina.com 2Ma Wuhua Dr_wuhuama@163.com 11 grid.412595.eDepartment of Anesthesiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, 16# Jichang Road, Guangzhou, 510405 China 2 grid.412633.1Department of MRI, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052 China 5 9 2018 5 9 2018 2018 18 12323 3 2018 28 8 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\nContinuous hiccups during surgery not only affect the surgical procedure, they can also cause adverse effects for the patient. Apart from active investigation of the cause of the hiccups, their timely termination is also necessary.\n\nCase presentation\nWe reported a case of a 70-year-old woman with continuous intraoperative hiccups that appeared during vaginal hysterectomy under low continuous epidural anesthesia. After the ineffectiveness CO2 repeated inhalation and intravenous administration of chlorpromazine and methoxychlorpromide, we performed unilateral phrenic nerve block under ultrasound guidance. Hiccups were terminated without any related complications.\n\nConclusions\nDuring intraoperative continuous hiccups, ultrasound guided phrenic nerve block may be a suitable treatment option when physical methods and drug therapy are not effective. However, given the absence of a vital risk related to hiccups, this block should imply the complete absence of any respiratory contraindication and a prolonged postoperative respiratory monitoring.\n\nKeywords\nHiccupUltrasound-guidedNerve blockissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nHiccups are an unpleasant experience; they usually last for a short duration of time and do not cause any harm. However, long-term hiccupping can cause serious complications such as dehydration, weight loss, fatigue, insomnia, psychosis, depression, arrhythmia [1]. Persistent hiccups rarely occur during an ongoing operation. However, when they do, the hiccups affect not only the patient’s respiratory and circulatory function, they also interfere with the surgical procedure. Under these circumstances, it is necessary to interrupt the hiccups as soon as possible. A phrenic nerve block may be a suitable treatment choice because it can quickly and effectively terminate hiccups when physical or medical treatments are not effective. An ultrasound-guided block can improve the success rate and reduce the potential for complications [2]. The effects of surgery and anesthesia on the patient’s respiratory system should be highly considered when performing an intraoperative phrenic nerve block. Here, we report a case of an intraoperative persistent hiccups that appeared during vaginal hysterectomy performed under low continuous epidural anesthesia. We administered a unilateral phrenic nerve block under ultrasound guidance, and the hiccups were terminated successfully without any related complications.\n\nCase presentation\nThe patient involved has consented to the publication of her case and signed the consent form. A 70-year-old woman was hospitalized for third degree uterine prolapse in the First Affiliated Hospital of Guangzhou University of Chinese Medicine on February 10, 2016. Vaginal hysterectomy under continuous epidural anesthesia was indicated. She was rated class I risk using the American Society of Anesthesiologists (ASA) criteria and did not have any cardiopulmonary dysfunction or gastrointestinal disease. The preoperative blood tests were normal. The arterial blood pressure (ABP) was 145/85 mmHg. The peripheral oxygen saturation (SpO2) measured using pulse oximetry was 98%. The heart rate (HR) was 70 beats per minute. The results of the blood gas analysis, performed after the patient entered the operating room, were as follows: arterial partial pressure of oxygen (PaO2), 90 mmHg; and arterial partial pressure of carbon dioxide (PaCO2), 39 mmHg. The patient was placed in the left lateral position, and a continuous epidural anesthesia was performed in the L2 – L3 space. After successful puncture, a catheter was inserted in cephalad direction 4 cm beyond the tip of the needle. The patient was then placed in a supine position and given oxygen continuously via nasal catheter with an oxygen flow rate of 2 L/minute. A test dose of 3 mL 1.5% lidocaine was administered through the epidural catheter, followed by 8 ml of a 1.5% lidocaine-0.5% bupivacaine mixture. Sensory block was shown to be complete within 10 min, and the upper level of the block was at the level of T8. At this time, ABP was 130/70 mmHg, SPO2 was 99%, and HR was 82 beats per minute. A continuous intravenous infusion of dexmedetomidine 0.3 μg/kg/h was administered. The patient developed hiccups approximately 30 min after the start of surgery, about 10 times per minute at first, gradually increasing to 30 times per minute, 10 min later. At this time, ABP was 150/90 mmHg, SPO2 was 98%, and HR was 90 beats per minute. The persistent hiccups interrupted the operation. In order to terminate the hiccups, we first used repeated CO2 inhalation for 5 min, followed by intravenous injection of 25 mg chlorpromazine and 20 mg metoclopramide. There was no effect after 20 min. The abnormal movement of the diaphragm was confirmed using an ultrasound examination. It showed a spastic contraction of the patient’s right diaphragm. We decided to block the right phrenic nerve under the guidance of a high resolution portable ultrasound unit (Italy, Yum Mylab One). With the patient’s head towards the left, the ultrasound probe (frequency, 8 MHz) was placed on the right side of the neck. The axial scanning of the neck along the surface of the anterior scalene muscle, showed that the phrenic nerve rounded the anterior scalene muscle from the outside to the inside, and coursed through the trench between the common carotid artery and anterior scalene muscle (Fig. 1). Using an in-plane technique, when the needle was close to the phrenic nerve, 5 ml 0.4% ropivacaine was injected around the phrenic nerve. The hiccups gradually stopped after approximately 5 min. At this time, ABP was 135/75 mmHg, SPO2 was 99%, HR was 72 beats per minute, PaO2 was 88 mmHg, and PaCO2 was 41 mmHg. The patient reported no discomfort, and no related complications were observed. The operation resumed and ended 80 min later. The patient was kept in the intensive care unit for 24 h and was discharged 7 days after the surgery. No hiccups or phrenic nerve block-related complications were observed after the operation. No related complications were reported on the telephonic follow-up one month after being discharged.Fig. 1 The phrenic nerve ultrasonography of the right neck\n\n\n\nDiscussion and conclusions\nA hiccup is an involuntary spasmodic contraction of the diaphragm, which is an unconscious spinal reflex and has a complete reflex arc. The afferent nerves are the phrenic nerve, vagus nerve, and sympathetic nerve (T6 – T12), and the reflex center consists of the brainstem, phrenic nucleus, medullary reticular formation, and hypothalamus. The efferent nerves are the phrenic nerve and intercostal nerves, and the effectors comprise of the diaphragm, intercostal muscle, and anterior scalene muscle [3]. There are various causes of hiccups, and the most common are diseases located in the central nervous system and peripheral nervous pathways and digestive system diseases [4].\n\nIn the current patient, who had continuous hiccups during surgery, the cause may be related to uterine stretching during gynecological surgery, which caused stretching of other organs and tissues in the abdominal cavity and stimulation of the phrenic nerve leading to causing spasm of the diaphragm. In addition, hiccups may occur when, as a result of anxiety, a patient swallows a lot of cold air into the stomach before surgery [5]. It has been reported that bupivacaine epidural anesthesia could also induce hiccups [6].\n\nContinuous hiccups during surgery is a rare phenomenon; however, it can severely influence both the patient and the surgical procedure. Stuth et al. [7] reported a case where continuous hiccups induced pulmonary edema, and Rullo et al. [8] reported a case in which continuous hiccups caused left common iliac artery perforation. Therefore, timely termination of continuous hiccups during surgery is essential.\n\nVarious methods can be used for treating hiccups [6], including physical treatment (rebreathing carbon dioxide), drug treatment (chlorpromazine), and nerve block. When physical and pharmacological treatments are not successful, a phrenic nerve block may be a good option; it can quickly block the hiccup reflex pathway and terminate the hiccups. As the phrenic nerve is thin, blind puncture has a higher failure rate, and may easily damage the nerve, blood vessels, and peripheral tissues. A high-resolution ultrasound scan can accurately distinguish the phrenic nerve and its surrounding anatomy. As a result, phrenic nerve block under ultrasound guidance has an improved success rate and can also decrease the damage to nearby nerves and blood vessels [2]. Furthermore, it has been reported that five cancer patients with intractable hiccups underwent unilateral phrenic nerve block under ultrasound guidance and all patients had satisfactory results without any complications [9].\n\nWhile phrenic nerve block can effectively treat hiccups, it may also affect respiratory function [10]. Renes et al. [11] performed a phrenic nerve block for a patient with intractable hiccups under ultrasound guidance and subsequently found that the three parameters of FEV1, FVC, and PEF decreased by 12%, 13%, and 12%, respectively. A phrenic nerve block can highly impact the respiratory function; however, for patients with normal respiratory function, it should not cause adverse clinical consequences [3]. Wilkins et al. [12] suggested that for patients without respiratory insufficiency, paralysis of one side of the diaphragm can be compensated by the other side of the diaphragm and intercostal muscles, the SPO2 will not decrease, and patients will not develop dyspnea.\n\nIn this case, the patient was a 70-year-old woman, so we monitored the invasive arterial blood pressure and blood gas analysis. The patient was administered a low segmental epidural anesthesia with anesthesia reaching the level of T8 without involving the respiratory muscles, and the patient’s respiratory function was not affected. Therefore, it seemed safe to perform the unilateral phrenic nerve block using ultrasound guidance. Considering the long operation condition and to avoid recurring hiccup, we chose a long-acting local anesthetic with less cardiotoxicity, ropivacaine. Kang et al. [2] used ropivacaine to effectively block the phrenic nerve conduction and stop hiccups. In this case, the patient’s hiccups stopped immediately after the injection of ropivacaine and there was no desaturation or symptoms of dyspnea. However, when preoperative respiratory insufficiency or using a high segmental epidural anesthesia, as a result of inhibition of the patient’s respiratory function, the risks of dyspnea should be taken into account when administering a phrenic nerve block.\n\nSeveral limitations of the current case report should be considered. First, we did not report information on the recovery of phrenic nerve function and the timing of hemi-diaphragm movement. Second, we did not observe the spread of local anesthetics and its effect on brachial plexus under ultrasound. In addition, we did not pay attention to the effect of phrenic nerve block on other organ functions.\n\nContinuous hiccup during surgery is a rare occurrence that can lead to severe outcomes. Hence, when choosing the methods to treat hiccups, we should consider the causes of hiccups, the surgery, and the anesthesia. This article described only one case, which was successfully treated with phrenic nerve block, a technique which may not be suitable for all cases with hiccups during surgery. Nevertheless, this case may provide relevant evidence for selecting suitable treatment strategies for treating continuous hiccups that develop during surgery.\n\nAbbreviations\nABPArterial blood pressure\n\nHRHeart rate\n\nPaCO2Partial pressure of carbon dioxide\n\nPaO2Partial pressure of oxygen\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nYZ contributed study concepts and design, Literature research, Data acquisition and analysis, Manuscript writing and review; FHD contributed Literature research, Clinical studies, Manuscript writing; WHM contributed study concepts, Clinical studies, Data acquisition, Manuscript editing. All authors have read and approved the final version.\n\nEthics approval and consent to participate\nThis study was approved by the Institutional Review Board of The First Affiliated Hospital of Guangzhou University of Chinese Medicine. Written informed consent was obtained from the subject.\n\nConsent for publication\nThe patient involved has consented to the publication of her case and signed the consent form.\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. Homer JR Davies JM Amundsen LB Persistent hiccups after attempted interscalene brachial plexus block Reg Anesth Pain Med 2005 30 574 576 10.1097/00115550-200511000-00012 16326344 \n2. Kang KN Park IK Suh JH Leem JG Shin JW Ultrasound-guided pulsed radiofrequency lesioning of the phrenic nerve in a patient with intractable hiccup Korean J Pain 2010 23 198 201 10.3344/kjp.2010.23.3.198 20830266 \n3. Ong AM Tan CS Foo MW Kee TY Gabapentin for intractable hiccups in a patient undergoing peritoneal dialysis Perit Dial Int 2008 28 667 668 18981399 \n4. Becker DE Nausea, vomiting, and hiccups: a review of mechanisms and treatment Anesth Prog 2010 57 150 156 10.2344/0003-3006-57.4.150 21174569 \n5. Wilcox SK Garry A Johnson MJ Novel use of amantadine: to treat hiccups J Pain Symptom Manag 2009 38 460 465 10.1016/j.jpainsymman.2008.10.008 \n6. Chang FY Lu CL Hiccup: mystery, nature and treatment J Neurogastroenterol Motil 2012 18 123 130 10.5056/jnm.2012.18.2.123 22523721 \n7. Stuth EA Stucke AG Berens RJ Negative-pressure pulmonary edema in a child with hiccups during induction Anesthesiology 2000 93 282 284 10.1097/00000542-200007000-00046 10861177 \n8. Rullo S Ticconi C Marchetti AA Grande M Common iliac artery injury during the abdominal entry phase of gynecologic laparoscopy: a case report J Reprod Med 2007 52 1052 1054 18161405 \n9. Calvo E Fernandez-La Torre F Brugarolas A Cervical phrenic nerve block for intractable hiccups in cancer patients J Natl Cancer Inst 2002 94 1175 1176 10.1093/jnci/94.15.1175 12165648 \n10. Mak PH Irwin MG Ooi CG Chow BF Incidence of diaphragmatic paralysis following supraclavicular brachial plexus block and its effect on pulmonary function Anaesthesia 2001 56 352 356 10.1046/j.1365-2044.2001.01708-2.x 11284823 \n11. Renes SH van Geffen GJ Rettig HC Gielen MJ Scheffer GJ Ultrasound-guided continuous phrenic nerve block for persistent hiccups Reg Anesth Pain Med 2010 35 455 457 10.1097/AAP.0b013e3181e8536f 20830872 \n12. Wilkins IA Menon DK Matta BF Management of comatose head-injured patients: are we getting any better? Anaesthesia 2001 56 350 352 10.1046/j.1365-2044.2001.01708.x 11284822\n\n",
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"keywords": "Hiccup; Nerve block; Ultrasound-guided",
"medline_ta": "BMC Anesthesiol",
"mesh_terms": "D000368:Aged; D001340:Autonomic Nerve Block; D005260:Female; D006606:Hiccup; D006801:Humans; D007431:Intraoperative Complications; D010791:Phrenic Nerve; D018084:Ultrasonography, Interventional",
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"title": "Ultrasound-guided phrenic nerve block for intraoperative persistent hiccups: a case report.",
"title_normalized": "ultrasound guided phrenic nerve block for intraoperative persistent hiccups a case report"
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"abstract": "We herein report a 46-year-old man with diabetes who developed acute kidney injury and oliguria after receiving vancomycin to treat his foot infection. Renal biopsy revealed typical features of advanced diabetic nephropathy as well as features of acute vancomycin nephrotoxicity. Several changes typical for acute vancomycin nephrotoxicity, but hitherto not adequately described, were seen. There was an element of acute tubulointerstitial injury associated with frequent tubular casts consisting of typical hyaline casts, pale glassy material suggestive of uromodulin, and distinctive features suggestive of vancomycin deposition. Coprecipitation of vancomycin and uromodulin was confirmed by immunostain. Electron microscopic study showed features supportive for the diagnosis of diabetic nephropathy and distinctive concentric appearance of vancomycin tubular casts within the fibrillary background of uromodulin. The patient's renal function improved rapidly after cessation of vancomycin and initiation of steroid therapy, suggesting that vancomycin-associated tubular injury is potentially reversible over time with proper management.",
"affiliations": "Department of Pathology, The Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, USA.;Department of Medicine, Renal Section, The Houston Methodist Hospital, Houston, TX, USA, and.;Department of Nephrology and Transplantation, Tenon Hospital, Paris, France.;Department of Pathology, The Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, USA.",
"authors": "Tantranont|Ngoentra|N|;Obi|Chizoba|C|;Luque|Yosu|Y|;Truong|Luan D|LD|",
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"fulltext": "\n==== Front\nClin Nephrol Case StudDustriClinical Nephrology. Case Studies2196-5293Dustri-Verlag Dr. Karl Feistle 10.5414/CNCS109817Case ReportNephrologyVancomycin nephrotoxicity: Vancomycin tubular casts with characteristic electron microscopic findings Tantranont Ngoentra 12Obi Chizoba 3Luque Yosu 4Truong Luan D. 11 Department of Pathology, The Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, USA, 2 Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, 3 Department of Medicine, Renal Section, The Houston Methodist Hospital, Houston, TX, USA, and 4 Department of Nephrology and Transplantation, Tenon Hospital, Paris, FranceCorrespondence to: Ngoentra Tantranont, MD Department of Pathology and Genomic Medicine, The Houston Methodist Hospital and Weill Cornell Medical College, 6565 Fannin Street, Houston, TX 77030, USA ngoentramink@ gmail.com2019 12 12 2019 7 66 72 13 3 2019 6 11 2019 © Dustri-Verlag Dr. K. Feistle2019 This is an open-access article distributed under the terms of the Creative\nCommons Attribution License, which permits unrestricted use, distribution, and\nreproduction in any medium, provided the original work is properly cited.We herein report a 46-year-old man with diabetes who developed acute kidney injury and oliguria after receiving vancomycin to treat his foot infection. Renal biopsy revealed typical features of advanced diabetic nephropathy as well as features of acute vancomycin nephrotoxicity. Several changes typical for acute vancomycin nephrotoxicity, but hitherto not adequately described, were seen. There was an element of acute tubulointerstitial injury associated with frequent tubular casts consisting of typical hyaline casts, pale glassy material suggestive of uromodulin, and distinctive features suggestive of vancomycin deposition. Coprecipitation of vancomycin and uromodulin was confirmed by immunostain. Electron microscopic study showed features supportive for the diagnosis of diabetic nephropathy and distinctive concentric appearance of vancomycin tubular casts within the fibrillary background of uromodulin. The patient’s renal function improved rapidly after cessation of vancomycin and initiation of steroid therapy, suggesting that vancomycin-associated tubular injury is potentially reversible over time with proper management. \n\nvancomycinnephrotoxicitytubular castsimmunostainelectron microscopybiopsy\n==== Body\nIntroduction \n\nStaphylococcus aureus infection is often successfully controlled by methicillin or penicillin. \n\nHowever, the occurrence of methicillin-resistant Staphylococcus aureus infection is increasing worldwide. Vancomycin is the drug of choice in this situation and increased use has led to increased frequency of vancomycin-related renal complication. The incidence of vancomycin-related nephrotoxicity ranges from 12 to 43% [1, 2]. Many risk factors are known, including vancomycin concentration of > 20 mg/mL, admission to critically ill, ICU patients, higher cumulative number of organ failures, and cirrhosis [1, 3]. Currently, the mechanism of vancomycin nephrotoxicity is not well established. \n\nWe wish to report a case of vancomycin nephrotoxicity and describe the renal biopsy in this condition including the novel electron microscopic findings. Previously reported cases of biopsy-documented vancomycin nephrotoxicity are also reviewed. \n\nCase description \nA 46-year-old man with poorly controlled diabetes was admitted with a left great toe wound with serous drainage and progressive swelling. Past medical history included hypertension, diabetes, and hyperlipidemia. Home medication included metformin, lisinopril, and lovastatin, last taken 2 weeks prior to this admission. Physical examination showed a well-developed man, with a blood pressure of 154/98 mmHg, normal temperature, left foot and leg covered with dressing. His serum creatine before this hospitalization was normal at ~ 0.9 mg/dL. Laboratory studies at admission showed a serum creatinine of 1.0 mg/dL, blood glucose of 408 mg/dL, and HbA1c of 16.6 mg/dL. Serum electrolytes and liver function tests were normal. Additional studies during hospitalization to evaluate the acute kidney injury included a urine protein excretion of 950 mg/day without urine eosinophil and normal serologic studies (antinuclear antibody, rheumatoid factor, and complement levels). A normal renal ultrasound MRI showed left first toe with enhancing edematous changes at the distal phalanx. Insulin, piperacillin/tazobactam (3.4 g every 6 hours), and vancomycin (1 g every 8 hours) were started at day 1 of admission. Wound culture grew methicillin-resistant staphylococcus. Left big toe amputation was done at post-admission day 4. There was no perioperative hemodynamic instability. Vancomycin trough levels were 17.5 mg/L at day 1 and 29.1 mg/L at day 5. Serum creatinine progressively increased from 0.8 mg/dL at day 1 to 1.9 mg/dL at day 5, with no associated change in urine output (1,000 – 1,800 mL per 24 hours, respectively). Oliguria and volume overload developed at day 6, with serum creatinine increasing progressively to a peak of 7.6 mg/dL at day 12. Vancomycin and lisinopril were discontinued at day 7. Renal biopsy was done on day 13. After the renal biopsy diagnosis, steroid was started at day 15 (intravenous solumedrol 250 mg/daily for 2 days, followed by oral prednisone 40 mg/day for 2 weeks, and then tapered by 20 mg every 2 weeks). The patient was discharged on day 19, at which time serum creatine was 3.9 mg/dL. At most recent follow-up at day 75, serum creatine was 3.1 mg/dL. The patient was lost for long-term follow-up. \n\nRenal biopsy findings \nThe renal biopsy was submitted to routine light microscopic, immunofluorescent, and electron microscopic studies. It was also submitted to immunostain for Mib-1 (a marker for cell division), myoglobin, vancomycin, and uromodulin. Light microscopic findings included diffuse mesangial matrix expansion with some nodular sclerotic lesions (Figure 1). Few segmentally sclerotic glomeruli were identified. There was chronic tubulointerstitial injury characterized by tubular atrophy and interstitial fibrosis, involving ~ 50% of cortical tissue area (Figure 2). The interstitium was focally infiltrated by lymphocytes, plasma cells, some eosinophils and neutrophils (Figure 2). There was diffuse tubular basement membrane thickening (Figure 1). Many clusters of tubules displayed reactive epithelial changes with sloughing of cells into lumen and dystrophic calcification. Tubular casts were frequent and displayed various morphologies (Figure 3). Some appeared as typical hyaline casts or casts with features suggestive of uromodulin accumulation (Figures 4, 5). Some tubular casts displayed distinctive features suggestive of vancomycin deposition as packed clusters of spherules with central clearing, imparting a “bubble” appearance (Figure 4), or ill-defined or nodular collections of pale eosinophilic material, which were isolated or formed contiguous aggregates (Figure 5). A background of pale glassy material characteristic of uromodulin was noted in some of these casts, suggesting vancomycin/uromodulin coprecipitation (Figures 4, 5). Structures suggestive of necrotic cells were also noted in some of these casts. The arteries showed severe intimal fibrosis, and many arterioles showed severe hyalinosis. Immunostain for uromodulin or vancomycin confirmed the presence of these molecules in different tubular casts. In addition, their coprecipitation was also noted in some of these tubular casts (Figures 3, 4, 5). Mib-1 immunostain revealed multifocal staining of tubular cell nuclei supporting the presence of acute tubular injury. Immunostain for myoglobin was negative. Immunofluorescent study showed no staining for immunoglobulins or complement components for any renal compartment. Electron microscopic study showed diabetic glomerulosclerosis including diffuse thickening of the lamina densa of the glomerular basement membrane and mesangial matrix expansion corresponding to the light microscopic findings. Vancomycin tubular casts displayed distinctive ultrastructural features as electron-dense or variegated granular material forming concentric laminar globular structures consistent with vancomycin aggregates. These structures maintained an amorphous core (Figure 6A, B) or were entirely crystalized (Figures 6C, D). These casts were set against a background of pale granular or fibrillary material suggestive of uromodulin. \n\nThe renal biopsy diagnoses included changes consistent with acute vancomycin nephrotoxicity (acute tubular necrosis, acute interstitial nephritis, and vancomycin tubular casts) against a background of advanced diabetic nephropathy and severe arterial nephrosclerosis. \n\nDiscussion \nUp to the present, there have been 19 individual case reports of vancomycin-related nephrotoxicity, with renal biopsy results summarized in Table 1. Seven showed acute tubular necrosis (ATN), 8 showed acute tubulointerstitial nephritis (TIN), 2 showed acute TIN with predominant ATN features, and 2 showed granulomatous TIN. The morphologic changes in cases with ATN were consistent with nonspecific nephrotoxic type, which are necrosis of tubular cells, predominantly proximal tubules, and mild interstitial inflammation. One case showed allergic features that were consistent with drug rash with eosinophilia and systemic symptoms (DRESS). All 4 cases that received piperacillin/tazobactam developed features of ATN; 2 isolated ATN and 2 acute TIN with ATN. In most of the cases with acute TIN, the changes were consistent with nonspecific allergic type, as there was significant interstitial inflammation with eosinophils. Three cases had systemic allergic symptoms (2 DRESS and 1 rash). One out of 2 cases of granulomatous TIN was associated with rash. According to a report of 9 cases by Luque et al. [2], vancomycin casts were first described as granular proteinaceous casts appearing as non-crystalline spherical formations, 100 – 900 nm in size by scanning electron microscopy. The casts were confirmed by immunohistochemistry, infrared spectroscopy, and electron microscopy with immunogold labeling. In addition, the vancomycin casts are entangled with uromodulin indicating the obstructive nature of vancomycin-associated casts. \n\nIn our case, the patient developed acute TIN with predominant ATN, which was most probably due to vancomycin nephrotoxicity. The development of nonoliguric acute kidney injury subsequently progressing to oliguric acute kidney injury with volume overload argues against volume depletion as a cause of acute kidney injury. The interstitial infiltrate is composed of mixed inflammatory cells with eosinophils, which are consistent with nonspecific allergic type TIN. The renal biopsy in the current case helps illustrate several novel and distinctive changes that may be of both diagnostic and pathogenetic significance. There are tubular casts with characteristic features that may imply vancomycin deposition with or without associated uromodulin. These findings are indeed confirmed by immunostain for vancomycin and uromodulin done for the same casts on consecutive tissue sections. In addition, these vancomycin casts display characteristic ultrastructural features revealed by transmission electron microscopy: electron-dense or variegated concentric laminated structures. These are seen against a fibrillary background, consistent with uromodulin fibrils, in keeping with the immunohistochemical findings. These findings expand the ultrastructural morphologic spectrum of vancomycin casts as originally depicted by scanning electron microscopy [2]. Indeed, tubular casts with the same characteristic ultrastructural appearance have been noted in most of the other renal biopsies with features of vancomycin nephrotoxicity that we have encountered. The significance of vancomycin deposition in tubular lumens is not clear. This finding raises the possibility of a direct tubulotoxicity of vancomycin. Alternatively, this accumulation may be of a secondary nature and may merely reflect an unrelated pre-existing chronic/acute tubulointerstitial injury that led to a failure to clear a therapeutically acceptable renal load of vancomycin. Although the pathogenesis remains unclear, a coprecipitation of vancomycin and uromodulin suggests that vancomycin accumulation may be facilitated at least at the single nephron level by urine obstruction and the in situ presence of uromodulin. \n\nPatients treated with vancomycin are often affected by other conditions or treated with other medications that by themselves can cause acute kidney injury. Confirming vancomycin nephrotoxicity would be instrumental for management, since aside from cessation of vancomycin, treatment may include steroids, leading to a favorable outcome noted in the current case and in several previous reports. The current case also helps illustrate the diagnostic utility of renal biopsy, which shows characteristic findings including typical vancomycin tubular casts and the coexistence of acute tubular necrosis and acute interstitial nephritis. The unique ultrastructural features of vancomycin tubular casts are also demonstrated. \n\nFunding \nThe authors received no specific funding for this work. \n\nConflict of interest \nAll authors have no conflict of interest to declare. \n\nFigure 1. Diabetic nephropathy is noted including mesangial sclerosis, thickened glomerular capillary wall, and thickened tubular basement membrane (Periodic acid-Schiff, × 200). \nFigure 2. Tubulointerstitial nephritis including tubular atrophy, interstitial fibrosis, and interstitial inflammation with few eosinophils (H & E, × 200). \nFigure 3. Tubular casts of different appearance are noted on consecutive tissue sections (A and B; (square and circle)), displaying partial overlapped staining for vancomycin (C) and uromodulin (D) (H & E for A, periodic acid-Schiff for B, and immunostain for C and D; × 100 for all panels).\nFigure 4. A and B: A tubular cast (v) with changes characteristic for vancomycin deposition: packed aggregation of spherules with central clearing, imparting a “bubble” appearance. Another tubular cast with a hyaline appearance (h). C: Both types of casts are stained positive for vancomycin (H & E for A, periodic acid-Schiff for B, immunostain for C; × 400 for all panels). \nFigure 5. Consecutive tissue sections (H & E in A, periodic acid-Schiff in B, vancomycin immunostain in C, and uromodulin immunostain in D) show different types of tubular casts. Type V seems to represent pure vancomycin cast characterized by aggregated or individual eosinophilic globules, stained strongly for vancomycin, but also weakly for uromodulin. Type V+U seems to display features of both vancomycin deposit against a background of uromodulin, which is confirmed by immunostain. Type U seems to represent pure uromodulin cast, which is positive in PAS and uromodulin immunostain, but negative for vancomycin (× 200 for all panels). \nFigure 6. Vancomycin tubular casts display distinctive ultrastructural features: electron-dense or variegated granular material forming concentric laminar globular structures that are isolated or form aggregates. These structures maintain an amorphous core (A and B) or are entirely crystalized (C and D). These casts are set against a background of pale granular or fibrillary material suggestive of uromodulin (electron microscopy; × 12,000 for A and C, × 25,000 for B and D). \n\nTable 1. Previous case reports of vancomycin-related nephrotoxicity that had renal biopsies. \n\tAuthor, year\tAge, gender\tIndication for therapy\tOther disease\tOther nephrotoxins\tLM findings\t\n1\tCodding et al. 1989 [4]\t\tEndocarditis\tRash\tNot known\tGranulomatous TIN\t\n2\tMichail et al. 1998 [5]\t\tChest infection\t\tNot known\tAcute TIN\t\n3\tWai et al. 1998 [6]\t64, M\tWound infection, endocarditis\tDRESS syndrome\t\tAcute TIN\t\n4\tHsu, 2001 [7]\t70, M\tIliopsoas abscess\tDRESS syndrome\tOxacillin, metronidazole, ceftriaxone\tAcute TIN\t\n5\tSokol et al. 2004 [8]\t71, F\tPneumonia\tHypertension\tPiperacillin/tazobactam, amikacin\tATN\t\n6\tWicklow et al. 2006 [9]\t8, M\tVP shunt infection\tObstructive hydrocephalus\tCeftriaxone, cefotaxime, cloxacillin\tATN\t\n7\tWu et al. 2007 [10]\t13, M\tSkin infection\tSLE\tNone\tATN, LN class V\t\n8\tHong et al. 2007[11]\t44, M\tOsteomyelitis\t\tNot known\tGranulomatous TIN\t\n9\tSalazar et al. 2010 [12]\t51, M\tOsteomyelitis\tRash\tNot known\tAcute TIN\t\n10\tSha-Khan et al. 2011 [13]\t23\tIV line infection\tAcute leukemia in remission\tPiperacillin/tazobactam\tATN\t\n11\tHtike et al. 2012 [14]\t\tBacteremia\t\tNot known\tAcute TIN\t\n12\tGelfnad et al. 2014 [15]\t45, F\tOsteomyelitis\tHypertension, type II DM\tNone\tAcute TIN, moderate DN\t\n13\tGelfnad et al. 2014 [15]\t61, M\tWound infection\tHypertension, gout\tNone\tAcute TIN, IgA nephropathy\t\n14\tKim et al. 2016 [16]\t11, M\tParotitis\tDRESS syndrome\tCeftriaxone\tATN, postinfectious GN\t\n15\tKatikaneni et al. 2016 [17]\t53, M\tLung abscess\t\tPiperacillin/tazobactam\tAcute TIN, ATN\t\n16\tKatikaneni et al. 2016 [17]\t57, F\tOsteomyelitis\t\tCefepime\tATN\t\n17\tKatikaneni et al. 2016 [17]\t64, M\tInfected knee\tHypertension, type II DM\tNone\tATN\t\n18\tPingili and Emmanuel, 2017 [18]\t79, M\tBacteremia\tLeukocytoclastic vasculitis of skin\tNone\tAcute TIN\t\n19\tSawada et al. 2018 [19]\t41, M\tGenital infection\t\tPiperacillin/tazobactam\tAcute TIN, ATN\t\nATN = acute tubular necrosis; DM = diabetes mellitus; DN = diabetic nephropathy; DRESS = drug reaction with eosinophilia and systemic symptoms; GN = glomerulonephritis; IV = intravenous; LM = light microscopic; SLE = systemic lupus; TIN = tubulointerstitial nephritis; VP = ventriculoperitoneal.\n==== Refs\nReferences\n1 \nLacave G \nCaille V \nBruneel F \nPalette C \nLegriel S \nGrimaldi D \nEurin M \nBedos JP \nIncidence and risk factors of acute kidney injury associated with continuous intravenous high-dose vancomycin in critically ill patients: A retrospective cohort study. \nMedicine (Baltimore) .\n2017 ;\n96 : e6023 .\n28207512 \n2 \nLuque Y \nLouis K \nJouanneau C \nPlacier S \nEsteve E \nBazin D \nRondeau E \nLetavernier E \nWolfromm A \nGosset C \nBoueilh A \nBurbach M \nFrère P \nVerpont MC \nVandermeersch S \nLangui D \nDaudon M \nFrochot V \nMesnard L \nVancomycin-Associated Cast Nephropathy. \nJ Am Soc Nephrol .\n2017 ;\n28 :\n1723 –1728 .\n28082518 \n3 \nPark SJ \nLim NR \nPark HJ \nYang JW \nKim MJ \nKim K \nIn YW \nLee YM \nEvaluation of risk factors for vancomycin-induced nephrotoxicity. \nInt J Clin Pharm .\n2018 ;\n40 :\n1328 –1334 .\n29744794 \n4 \nCodding CERL \nRamseyer L \nAllon M \nPitha J \nRodriguez M \nTubulointerstitial nephritis due to vancomycin. \nAm J Kidney Dis .\n1989 ;\n14 :\n512 –515 .\n2596477 \n5 \nMichail S \nVaiopoulos G \nNakopoulou L \nRevenas C \nAroni K \nKaram P \nStathakis C \nThosios T \nHenoch-Schoenlein purpura and acute interstitial nephritis after intravenous vancomycin administration in a patient with a staphylococcal infection. \nScand J Rheumatol .\n1998 ;\n27 :\n233 –235 .\n9645421 \n6 \nWai AO \nLo AM \nAbdo A \nMarra F \nVancomycin-induced acute interstitial nephritis. \nAnn Pharmacother .\n1998 ;\n32 :\n1160 –1164 .\n9825081 \n7 \nHsu SI \nBiopsy-proved acute tubulointerstitial nephritis and toxic epidermal necrolysis associated with vancomycin. \nPharmacotherapy .\n2001 ;\n21 :\n1233 –1239 .\n11601669 \n8 \nSokol H \nVigneau C \nMaury E \nGuidet B \nOffenstadt G \nBiopsy-proven anuric acute tubular necrosis associated with vancomycin and one dose of aminoside. \nNephrol Dial Transplant .\n2004 ;\n19 :\n1921 –1922 .\n15199201 \n9 \nWicklow BA \nOgborn MR \nGibson IW \nBlydt-Hansen TD \nBiopsy-proven acute tubular necrosis in a child attributed to vancomycin intoxication. \nPediatr Nephrol .\n2006 ;\n21 :\n1194 –1196 .\n16721580 \n10 \nWu CY \nWang JS \nChiou YH \nChen CY \nSu YT \nBiopsy proven acute tubular necrosis associated with vancomycin in a child: case report and literature review. \nRen Fail .\n2007 ;\n29 :\n1059 –1061 .\n18067058 \n11 \nHong S \nValderrama E \nMattana J \nShah HH \nWagner JD \nEsposito M \nSinghal PC \nVancomycin-induced acute granulomatous interstitial nephritis: therapeutic options. \nAm J Med Sci .\n2007 ;\n334 :\n296 –300 .\n18030187 \n12 \nSalazar MN \nMatthews M \nPosadas A \nEhsan M \nGraeber C \nBiopsy proven interstitial nephritis following treatment with vancomycin: a case report. \nConn Med .\n2010 ;\n74 :\n139 –141 .\n20391819 \n13 \nShah-Khan F \nScheetz MH \nGhossein C \nBiopsy-proven acute tubular necrosis due to vancomycin toxicity. \nInt J Nephrol .\n2011 ;\n2011 : 436856 .\n21716699 \n14 \nHtike NL \nSantoro J \nGilbert B \nElfenbein IB \nTeehan G \nBiopsy-proven vancomycin-associated interstitial nephritis and acute tubular necrosis. \nClin Exp Nephrol .\n2012 ;\n16 :\n320 –324 .\n22086124 \n15 \nGelfand MS \nCleveland KO \nMazumder SA \nVancomycin-induced interstitial nephritis superimposed on coexisting renal disease: the importance of renal biopsy. \nAm J Med Sci .\n2014 ;\n347 :\n338 –340 .\n24646459 \n16 \nKim KM \nSung K \nYang HK \nKim SH \nKim HY \nBan GH \nPark SE \nLee HD \nKim SY \nAcute tubular necrosis as a part of vancomycin induced drug rash with eosinophilia and systemic symptoms syndrome with coincident postinfectious glomerulonephritis. \nKorean J Pediatr .\n2016 ;\n59 :\n145 –148 .\n27186222 \n17 \nKatikaneni M \nLwin L \nVillanueva H \nYoo J \nAcute kidney injury associated with vancomycin when laxity leads to injury and findings on kidney biopsy. \nAm J Ther .\n2016 ;\n23 :\ne1064 –e1067 .\n26035034 \n18 \nPingili CS \nOkon EE \nVancomycin-induced leukocytoclastic vasculitis and acute renal failure due to tubulointerstitial nephritis. \nAm J Case Rep .\n2017 ;\n18 :\n1024 –1027 .\n28943633 \n19 \nSawada A \nKawanishi K \nMorikawa S \nNakano T \nKodama M \nMitobe M \nTaneda S \nKoike J \nOhara M \nNagashima Y \nNitta K \nMochizuki T \nBiopsy-proven vancomycin-induced acute kidney injury: A case report and literature review. \nBMC Nephrol .\n2018 ;\n19 : 72 .\n29587650\n\n",
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"journal": "Clinical nephrology. Case studies",
"keywords": "biopsy; electron microscopy; immunostain; nephrotoxicity; tubular casts; vancomycin",
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"title": "Vancomycin nephrotoxicity: Vancomycin tubular casts with characteristic electron microscopic findings.",
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"abstract": "Multiple intrahepatic arterio-portal fistulas are rare. The majority are isolated and occur secondary to liver trauma including iatrogenic interventions such as liver biopsy. Post-liver transplantation 18 cases have been reported, all secondary to an interventional radiological procedure. We report multiple bi-lobar arterio-portal fistulas in a liver transplant recipient recognized 1 year after transplantation. The donor died due to intracerebral bleeding following blunt head and abdominal trauma. In the present case, the etiology is not very clear. The patient was managed conservatively and to date has not required intervention.",
"affiliations": "Institute of Liver Studies, King's College Hospital, Denmark Hill, England. Electronic address: Yogesh.puri@nhs.net.;Institute of Liver Studies, King's College Hospital, Denmark Hill, England.;Institute of Liver Studies, King's College Hospital, Denmark Hill, England.;Institute of Liver Studies, King's College Hospital, Denmark Hill, England.",
"authors": "Puri|Y|Y|;Srinivasan|P|P|;Peddu|P|P|;Heaton|N|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2017.12.001",
"fulltext": null,
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"issn_linking": "0041-1345",
"issue": "50(3)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D001164:Arteriovenous Fistula; D000072700:Conservative Treatment; D006499:Hepatic Artery; D006801:Humans; D008099:Liver; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011169:Portal Vein; D011183:Postoperative Complications",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "920-924",
"pmc": null,
"pmid": "29661463",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Case Report of Multiple Bilobar Hepatic Arterio-Portal Fistulas Post-Liver Transplantation Managed Conservatively.",
"title_normalized": "case report of multiple bilobar hepatic arterio portal fistulas post liver transplantation managed conservatively"
} | [
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"abstract": "We report three cases of sacral and pelvic pain resistant to oral medications successfully managed with intraspinal drug delivery through a catheter placed at the intrathecal sacral space to deliver low doses of bupivacaine and fentanyl with local effects.",
"affiliations": null,
"authors": "Hochberg|Uri|U|;Perez|Jordi|J|",
"chemical_list": "D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D005283:Fentanyl; D002045:Bupivacaine",
"country": "England",
"delete": false,
"doi": "10.1080/15360288.2018.1491927",
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"issue": "32(2-3)",
"journal": "Journal of pain & palliative care pharmacotherapy",
"keywords": "cancer pain; drug delivery; intrathecal; retrograde",
"medline_ta": "J Pain Palliat Care Pharmacother",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D001416:Back Pain; D002045:Bupivacaine; D000072716:Cancer Pain; D016503:Drug Delivery Systems; D005260:Female; D005283:Fentanyl; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D017699:Pelvic Pain",
"nlm_unique_id": "101125608",
"other_id": null,
"pages": "149-154",
"pmc": null,
"pmid": "30589369",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Retrograde Intrathecal Drug Delivery: A Report of Three Cases for the Management of Cancer-Related Sacropelvic Pain.",
"title_normalized": "retrograde intrathecal drug delivery a report of three cases for the management of cancer related sacropelvic pain"
} | [
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"companynumb": "CA-PFIZER INC-2019029058",
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"abstract": "Bronchopleural fistulas (BPF) are abnormal sinus tracts connecting the bronchi and pleural cavity and form after surgical resection of a lung lobe. It is a complication with potentially disastrous sequelae including, failure of the bronchial stump to heal, ischemia of the affected area, and/or infection of the stump. Bronchopleural fistulas caused by surgical intervention most commonly present on the right side and within 7-12 days post-operatively, i.e., subacutely. While the fistula may initially be asymptomatic, they carry a mortality rate of 25-71% in the absence of other comorbidities.\nA 60-year-old female developed a BPF more than seven months after a left lower lobe lung lobectomy for non-small cell adenocarcinoma is presented. She was seen at our hospital on multiple occasions after her lobectomy with no evidence of a developing fistula on chest computer tomography (CT) during those visits. During her most recent presentation, roughly 7 months postoperatively, she was noted on imaging to have a new left-sided bronchopleural fistula. Bronchoscopy with lavage and culture of the fistula grew Pseudomonas Aeruginosa, for which she received appropriate treatment. Further surgical interventions were deferred due to poor prognosis. Her presentation differed from the typical BPF presentation in that it was left-sided and occurred out of the window of its usual occurrence.\nLate-onset BPF is an important diagnosis to consider in patients who have undergone lung resection, regardless of the type of surgery or postoperative duration, especially when patients are known to have multiple predisposing factors.",
"affiliations": "University of Central Florida, School of Medicine, 6850 Lake Nona Blvd, Orlando, FL, 32827, USA.;University of Central Florida, School of Medicine, 6850 Lake Nona Blvd, Orlando, FL, 32827, USA.;University of Central Florida, School of Medicine, 6850 Lake Nona Blvd, Orlando, FL, 32827, USA.;University of Central Florida, School of Medicine, 6850 Lake Nona Blvd, Orlando, FL, 32827, USA.;University of Central Florida, School of Medicine, 6850 Lake Nona Blvd, Orlando, FL, 32827, USA.;University of Central Florida, School of Medicine, 6850 Lake Nona Blvd, Orlando, FL, 32827, USA.",
"authors": "Fishman|Troy J|TJ|;Salabei|Joshua K|JK|;Zadeh|Cameron M|CM|;Malhi|Manjot S|MS|;Asnake|Zekarias T|ZT|;Bazikian|Yvette|Y|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2020.101056",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071 Elsevier \n\nS2213-0071(20)30139-8\n10.1016/j.rmcr.2020.101056\n101056\nCase Report\nAn atypical complicated left-sided bronchopleural fistula presenting more than seven months after lobectomy\nFishman Troy J. MDtroy.fishman@hcahealthcare.comab∗ Salabei Joshua K. MD, PhDab Zadeh Cameron M. MDab Malhi Manjot S. MDab Asnake Zekarias T. MDab Bazikian Yvette MDab a University of Central Florida, School of Medicine, 6850 Lake Nona Blvd, Orlando, FL, 32827, USA\nb North Florida Regional Medical Center, 6500 W Newberry Rd, Gainesville, FL, 32605, USA\n∗ Corresponding author. UCF College of Medicine/HCA GME Consortium, 6500 W Newberry Rd, Gainesville, FL, 32605, USA. troy.fishman@hcahealthcare.com\n19 4 2020 \n2020 \n19 4 2020 \n30 1010565 4 2020 9 4 2020 9 4 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/).Background\nBronchopleural fistulas (BPF) are abnormal sinus tracts connecting the bronchi and pleural cavity and form after surgical resection of a lung lobe. It is a complication with potentially disastrous sequelae including, failure of the bronchial stump to heal, ischemia of the affected area, and/or infection of the stump. Bronchopleural fistulas caused by surgical intervention most commonly present on the right side and within 7–12 days post-operatively, i.e., subacutely. While the fistula may initially be asymptomatic, they carry a mortality rate of 25–71% in the absence of other comorbidities.\n\nCase presentation\nA 60-year-old female developed a BPF more than seven months after a left lower lobe lung lobectomy for non-small cell adenocarcinoma is presented. She was seen at our hospital on multiple occasions after her lobectomy with no evidence of a developing fistula on chest computer tomography (CT) during those visits. During her most recent presentation, roughly 7 months postoperatively, she was noted on imaging to have a new left-sided bronchopleural fistula. Bronchoscopy with lavage and culture of the fistula grew Pseudomonas Aeruginosa, for which she received appropriate treatment. Further surgical interventions were deferred due to poor prognosis. Her presentation differed from the typical BPF presentation in that it was left-sided and occurred out of the window of its usual occurrence.\n\nConclusion\nLate-onset BPF is an important diagnosis to consider in patients who have undergone lung resection, regardless of the type of surgery or postoperative duration, especially when patients are known to have multiple predisposing factors.\n\nKeywords\nBronchopleural fistulaLobectomyAdenocarcinomaPulmonologyCase reportAbbreviations\nCT, computed tomographyCXR, chest x-rayBPF, Bronchopleural fistulaRVR, rapid ventricular rateED, emergency departmentBAL, bronchoalveolar lavageLAMP, loop-mediated isothermal DNA amplificationARDS, acute respiratory distress syndrome\n==== Body\n1 Background\nThe overall incidence of BPFs is between 4 and 20% post-pneumonectomy, with an even lower incidence of less than 1% post-lobectomy [1]. Unfortunately, BPFs carry a mortality rate of 25%–71% with the most common cause of mortality stemming from aspiration pneumonia and subsequent acute respiratory distress syndrome (ARDS) or tension pneumothorax [2]. Many factors increase the risk of developing BPFs, including superimposed lung infections, postoperative mechanical ventilation, chemotherapy, mediastinal lymph node resection, high-dose pre-operative radiation therapy, poor nutritional status, and the use of corticosteroids [3,4]. Specifically, regarding nutritional status, if not optimized, it can increase the chances of developing a BPF and increase closure duration once formed. Also, studies have demonstrated faster closure times of BPFs after a simple drainage when nutritional status is optimal as opposed to longer times seen when nutrition is suboptimal [4].\n\nParticularly, any right-sided pneumonectomy carries an increased risk for BPF formation when compared to left-sided procedures [3]. In addition to this location preference, the duration of onset of BPFs has been well documented. For instance, the majority of BPFs are known to occur as early as 1–7 days (acute BPF), between 8 and 30 days (subacute BPF), and >30 days (chronic BPF) [5], with almost all BPFs occurring within 3 months post-lobectomy. The acute form is almost always caused by surgical dehiscence and is the most lethal presentation, generally presenting with either tension pneumothorax or ARDS secondary to pulmonary flooding. The subacute and chronic forms are primarily related to infections and are more commonly seen in patients with multiple comorbidities [2]. Here, we report a case of a patient with a previous diagnosis of stage 4 non-small cell adenocarcinoma of the lung who developed a left-sided BPF more than seven months post lobectomy. We have highlighted the importance of considering BPF as one of the differentials, irrespective of the side of lobectomy or duration post lobectomy. Prompt diagnosis is important for expedited treatment, as such fistulas usually harbor disease-causing bacteria.\n\n2 Case presentation\nA 60-year-old female with a medical history significant for T3 N2 M1b left lung non-small cell adenocarcinoma was brought to our facility because of confusion, new-onset weakness, slurred speech, and disorientation. The patient was initially diagnosed with left lung non-small cell adenocarcinoma stage T3 N2 M0 following endobronchial ultrasound with fine-needle aspiration two years prior to her current presentation. She was immunohistochemistry positive for cytokeratin 7, cytokeratin 5/6, and TTF, and negative for p63, consistent with metastatic adenocarcinoma of the lung at the time of her initial diagnosis. She was started on Carboplatin and Paclitaxel as per loop-mediated isothermal DNA amplification protocol, however, she only received one dose before declining further treatment due to worsening side effects. The patient was lost to follow up for one year inbetween hospitalizations. When she re-presented to our hospital one year after her initial diagnosis, CT scan of her chest (Fig. 1A), showed an increasing left lower lobe spiculated lung mass. The patient then underwent an elective video-assisted thoracoscopic surgery for left lower lung lobectomy with an intercostal muscle flap and mediastinal lymph node dissection. Her postoperative course was complicated by the development of an empyema, secondary to Haemophilus influenza, that was subsequently treated with oral amoxicillin-clavulanic acid.Fig. 1 (A) Non-contrast CT scan of the chest two weeks after left lower lobe pneumonectomy. A representative image showing absence of a BPF. (B) Non-contrast CT of the chest 6 months after the first chest CT was obtained. Only post-surgical changes in the left lower lung field were noted. No visible BPF noted per the radiology report. (C) Non-contrast CT of the chest 7 months after the first chest CT scan. A notable development of a BPF in the left lower lung field (blue arrow). An air-filled thick-walled cavity in the lower left hemidiaphragm (not shown) was also seen.\n\nFig. 1\n\nApproximately six months after her video-assisted thoracoscopic surgery (i.e., two weeks before her current presentation), the patient presented to our facility again with complaints of not feeling well and a syncopal episode. A CT scan of the chest at that time (Fig. 1B) did not show any developing BPF per the radiology report. A brain MRI was also performed, which revealed multiple enhancing intracranial masses with significant edema. The patient underwent left occipital tumor resection because of the large size of the lesion with associated edema as seen on CT imaging. This resection was followed by adjuvant external beam radiation therapy. The pathology from the occipital lobe resection confirmed metastatic adenocarcinoma of pulmonary origin. She was started on Levetiracetam and a tapered dose of Dexamethasone post-resection and discharged home after stabilization of her condition. Two weeks later (i.e., during the current presentation), she presented with mental status changes and complaints of severe headaches and neck pain. The patient met the systemic inflammatory response syndrome criteria (i.e., pulse of 104 beats per minute and respiratory rate of 26 per minute) on admission for which she received appropriate antibiotics and fluid resuscitation. Initial work up in the emergency department (ED), including chest x-ray (CXR) and CT scan of the head, showed no evidence of acute disease; however, CT scan of the chest showed interval development of a bronchopleural fistula in the left lower lobe with minimal airspace disease and small amount of pleural fluid (Fig. 1C). Subsequent bronchoscopy with bronchoalveolar lavage (BAL) was performed with fluid cultures that subsequently grew Pseudomonas Aeruginosa, for which she received Pipercillin-Tazobactam that adequately controlled her infection resulting in only partial improvements in mentation. Thus, her altered mental status and lethargy were likely secondary to mass effect caused by cancer metastases and associated edema as seen on brain imaging. Given the patients poor prognosis, cardiothoracic surgery was deemed inappropriate, as the risks for complications were higher than the presumed benefits of surgery. Other forms of intervention to close the fistula were not considered because, as earlier mentioned, only mild improvements in mentation was noted upon treatment of her lung infection and, therefore, any further intervention to close the fistula was unlikely to improve her mental status. Even though the risk for fistula reinfection was high, management of her other comorbidities (such as brain metastasis) took precedence. The patient's respiratory status, as well as her functional status, continued to decline (laboratory values are visual in Table 1) throughout her hospitalization. During the remainder of her hospitalization, she also experienced atrial fibrillation with a rapid ventricular response for which she was treated with Amiodarone. She continued to decline and was later noted to have an acute change in mental status. New imaging of her brain showed a brain stem hemorrhage secondary to rupture of a berry aneurysm. The patient subsequently expired.Table 1 Pertinent laboratory data at the time of presentation and care transition.\n\nTable 1Complete Blood Count\tLevels on admission\tLevels at time of expiration\tNormal range\t\n White blood cells\t7.8\t11.5\t(4.5–11.0 thou/mm3)\t\n Neutrophils %\t91.3\t86.7\t(50.0–75.0%)\t\n Lymphocytes %\t5.7\t6.3\t(17.0–42.0%)\t\n Monocytes %\t2.7\t6.6\t(4.0–11.0%)\t\n Eosinophils %\t0.1\t0.1\t(0.4–6.0%)\t\n Basophils %\t0.2\t0.3\t(0.0–2.0%)\t\n Absolute Neut. Count\t7.1\t10\t(thousands/mm3)\t\n Red blood cells\t3.53\t4.38\t(3.80–5.20 million/uL)\t\n Hemoglobin\t11.2\t13.6\t(12.0–15.0 g/dL)\t\n Hematocrit\t33.4\t40.3\t(35.0–49.0%)\t\n Mean corpuscular volume\t94.4\t92.1\t(80.0–100.0 fL)\t\n Platelet Count\t157\t136\t(150–450 thousand/mm3)\t\nBMP\t\n Sodium\t133\t130\t(136–145 mmol/L)\t\n Potassium\t4.3\t4.2\t(3.5–5.1 mmol/L)\t\n Chloride\t103\t99\t(98–107 mmol/L)\t\n Carbon Dioxide\t22\t24\t(21–32 meq/L)\t\n Anion Gap\t12.3\t11.2\t(3.0–15.0 mEQ/L)\t\n Blood urea nitrogen\t21\t14\t(7–18 mg/dL)\t\n Creatinine\t0.76\t0.61\t(0.60–1.30 mg/dL)\t\n eGFR\t77\t100\t(=>90)\t\n Glucose\t112\t89\t(74–106 mg/dL)\t\n Calcium\t7.9\t8.5\t(8.5–10.1 mg/dL)\t\n\n\n3 Discussion and conclusion\nBPFs commonly occur after a right-sided lobectomy and are typically early-onset postoperatively. Our patient was found to have a rare presentation with a BPF developing more than seven months after a left-sided lobectomy. The diagnosis of BPF is typically made by combining clinical, radiographic, and bronchoscopic findings. Typically, patients present with symptoms that include fever, chills, purulent cough, and shortness of breath that could be secondary to pneumothorax formation, or an infectious process [2]. Our patient's presentation was atypical in that she did not present with any of these symptoms, although it was highly suspected that she had an infectious etiology despite a negative CXR. Our suspicion for an infectious etiology was based on the patient's initial presentation of encephalopathy with no identifiable cause in the setting of recent intracranial surgery for metastatic lung cancer [6]. A CT scan of the chest was ordered primarily to rule out interval development of other pathologies, which resulted in the diagnosis of a newly developed left-sided BPF.\n\nThe management of BPFs is highly case-dependent and involves conservative and/or surgical interventions, focusing on chest drainage in cases complicated by effusions and/or empyema [7]. In some cases, obliteration of the residual pleural cavity is recommended [8]. For cases of BPF with empyema, a multimodal approach including tracheobronchial conical stent insertion, open pleural packing, and omentoplastic closure of bronchial stump is known to be effective [3,4,9]. However, consideration for any further surgical intervention in a patient with BPF should always be approached with caution since success is dependent on the patient's overall health and physiological status. And given our patient's current presentation and poor prognosis, further surgical interventions were deferred. Of note, emergent intervention was also not warranted as she did not present with a pneumothorax nor was found to be aspirating (as she passed a bedside swallow test). Per recommendations from the infectious disease team, intravenous Piperacillin-Tazobactam and inhaled Tobramycin were deemed to be the best care option available for her.\n\nSeveral key points can be extracted from this case: (I) BPF should always be on the list of differential diagnoses in patients who have undergone pulmonary surgery (specifically pneumonectomy and lobectomy), irrespective of the lung side/lobe operated on and the time frame since surgery. (II) If a BPF is found on CT imaging, follow up bronchoscopy with BAL and culture should be performed since such fistulas are prone to infection, however, no clear-cut guidelines exist for treating this complex issue [10]. (III) Patients with poor clinical status presenting with late-onset BPFs, as highlighted in this case, generally carry poor prognoses. This should influence the choice of clinical decision and patient care. That is, such patients who are not fit to tolerate the stress of another surgical intervention are more likely to benefit from a more conservative management as opposed to aggressive surgical interventions. Minimally invasive procedures such as gluing (if the fistula size is within the appropriate recommendations), coiling, or stenting of the fistula can improve a patient's quality of life and should always be considered. Decisions on what treatment to pursue is highly case-dependent and must be clinically and ethically assessed. Lastly, physicians should note that the effectiveness of any treatment and the mortality associated with any intervention are strictly dependent on the size of the fistula, time of onset to time of diagnosis, and the baseline clinical condition of the patient.\n\nIn summary, late-onset BPF must be considered in patients who have undergone lung resection, irrespective of the lung region resected or postoperative duration. This should especially be considered in patients who have multiple predisposing factors, as highlighted in this case.\n\nDisclaimer\nThis research was supported (in whole or in part) by HCA Healthcare and/or an HCA healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities.\n\nDeclaration of competing interest\nThe authors of this paper have no conflicts of interest to diclose.\n==== Refs\nReferences\n1 Cooper W.A. Miller J.I. Jr. Management of bronchopleural fistula after lobectomy Semin. Thorac. Cardiovasc. Surg. 13 2001 8 12 10.1053/stcs.2001.22494 11309719 \n2 Salik I. Abramowicz A.E. Bronchopleural Fistula. [Updated 2019 Feb 28]. in: StatPearls [Internet] 2019 Jan StatPearls Publishing Treasure Island (FL) \n3 Sirbu H. Busch T. Aleksic I. Bronchopleural fistula in the surgery of non-small cell lung cancer: incidence, risk factors, and management Ann. Thorac. Cardiovasc. Surg. 7 2001 330 336 11888471 \n4 Asamura H. Naruke T. Tsuchiya R. Goya T. Kondo H. Suemasu K. Bronchopleural fistulas associated with lung cancer operations: univariate and multivariate analysis of risk factors, management, and outcome J. Thorac. Cardiovasc. Surg. 104 1992 1456 1464 10.1016/0169-5002(93)90415-t 1434730 \n5 Varoli F. Roviaro G. Grignani F. Endoscopic treatment of bronchopleural fistulas Ann. Thorac. Surg. 65 1998 807 809 10.1016/s0003-4975(97)01427-6 9527218 \n6 Rolston K.V. Bodey G.P. Pseudomonas aeruginosa infection in cancer patients Canc. Invest. 10 1992 43 59 10.3109/07357909209032787 \n7 Sarkar P. Chandak T. Shah R. Talwar A. Diagnosis and management bronchopleural fistula Indian J. Chest Dis. Allied Sci. 52 2010 97 104 20578402 \n8 Bribriesco A. Patterson G.A. Management of postpneumonectomy bronchopleural fistula: from thoracoplasty to transsternal closure Thorac. Surg. Clin. 28 2018 323 335 10.1016/j.thorsurg.2018.05.008 30054070 \n9 Andreetti C. Menna C. D'Andrilli A. Multimodal treatment for post-pneumonectomy bronchopleural fistula associated with empyema Ann. Thorac. Surg. 106 2018 e337 e339 10.1016/j.athoracsur.2018.05.094 30009802 \n10 Rakesh C.K. Madan A. Bhardwaj P.K. Bronchoscopic management of bronchopleural fistula with intrabronchial instillation of glue (N-butyl cyanoacrylate) Lung India 29 1 2012 11 14 10.4103/0970-2113.92350 22345907\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "30()",
"journal": "Respiratory medicine case reports",
"keywords": "ARDS, acute respiratory distress syndrome; Adenocarcinoma; BAL, bronchoalveolar lavage; BPF, Bronchopleural fistula; Bronchopleural fistula; CT, computed tomography; CXR, chest x-ray; Case report; ED, emergency department; LAMP, loop-mediated isothermal DNA amplification; Lobectomy; Pulmonology; RVR, rapid ventricular rate",
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"title": "An atypical complicated left-sided bronchopleural fistula presenting more than seven months after lobectomy.",
"title_normalized": "an atypical complicated left sided bronchopleural fistula presenting more than seven months after lobectomy"
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"abstract": "Irinotecan hydrochloride (irinotecan) is a chemotherapeutic agent used in the treatment of solid tumors. In addition to severe neutropenia and delayed diarrhea, irinotecan causes cholinergic syndrome, characterized by abdominal pain and acute diarrhea. The latter symptoms are frequently observed during and after irinotecan treatment. Here, we have discussed the case of a patient who completely recovered from abdominal pain following the administration of loperamide hydrochloride (loperamide) at a dose of 2 mg, before infusing irinotecan. In contrast, anticholinergic drugs were not as effective in alleviating symptoms. A 28-year-old man with stage IV rectal cancer with peritoneal metastasis was prescribed with fluorouracil, irinotecan, and levofolinate calcium (FOLFIRI), in addition to cetuximab. Anticholinergic drugs, such as scopolamine butylbromide (scopolamine) or atropine sulfate (atropine), were administered to treat abdominal pain that was considered as irinotecan-induced cholinergic syndrome, but monotherapy was not effective. Thereafter, oral loperamide (2 mg) with atropine (0.25 mg) was prescribed before irinotecan infusion. Consequently, the patient did not experience any abdominal pain during and after irinotecan treatment. Loperamide is an opioid receptor agonist and decreases the activity of the myenteric plexus of the intestinal wall. It also inhibits the release of both acetylcholine and prostaglandins, resulting in decreased inhibition of peristaltic movement. We assumed that its mechanism solely or in combination contributed to symptom relief. We hypothesized that the synergistic anticholinergic interaction between loperamide and atropine resulted in marked suppression of irinotecan-induced cholinergic syndrome compared to loperamide alone. Thus, loperamide may improve abdominal pain attributed to irinotecan-induced cholinergic syndrome.",
"affiliations": "Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan.;Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan.;Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan.;Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan.;Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan.",
"authors": "Uchiyama|Kazuki|K|;Saito|Yoshitaka|Y|;Takekuma|Yoh|Y|;Yuki|Satoshi|S|;Sugawara|Mitsuru|M|",
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"doi": "10.1159/000516403",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575\nS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com\n\n10.1159/000516403\ncro-0014-0806\nCase Report\nAlleviation of Abdominal Pain due to Irinotecan-Induced Cholinergic Syndrome Using Loperamide: A Case Report\nUchiyama Kazuki a\nSaito Yoshitaka a\nTakekuma Yoh a\nYuki Satoshi b\nSugawara Mitsuru ac*\naDepartment of Pharmacy, Hokkaido University Hospital, Sapporo, Japan\nbDepartment of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan\ncLaboratory of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan\n*Mitsuru Sugawara, msuga@pharm.hokudai.ac.jp\nMay-Aug 2021\n10 6 2021\n10 6 2021\n14 2 806811\n29 3 2021\n1 4 2021\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.\nIrinotecan hydrochloride (irinotecan) is a chemotherapeutic agent used in the treatment of solid tumors. In addition to severe neutropenia and delayed diarrhea, irinotecan causes cholinergic syndrome, characterized by abdominal pain and acute diarrhea. The latter symptoms are frequently observed during and after irinotecan treatment. Here, we have discussed the case of a patient who completely recovered from abdominal pain following the administration of loperamide hydrochloride (loperamide) at a dose of 2 mg, before infusing irinotecan. In contrast, anticholinergic drugs were not as effective in alleviating symptoms. A 28-year-old man with stage IV rectal cancer with peritoneal metastasis was prescribed with fluorouracil, irinotecan, and levofolinate calcium (FOLFIRI), in addition to cetuximab. Anticholinergic drugs, such as scopolamine butylbromide (scopolamine) or atropine sulfate (atropine), were administered to treat abdominal pain that was considered as irinotecan-induced cholinergic syndrome, but monotherapy was not effective. Thereafter, oral loperamide (2 mg) with atropine (0.25 mg) was prescribed before irinotecan infusion. Consequently, the patient did not experience any abdominal pain during and after irinotecan treatment. Loperamide is an opioid receptor agonist and decreases the activity of the myenteric plexus of the intestinal wall. It also inhibits the release of both acetylcholine and prostaglandins, resulting in decreased inhibition of peristaltic movement. We assumed that its mechanism solely or in combination contributed to symptom relief. We hypothesized that the synergistic anticholinergic interaction between loperamide and atropine resulted in marked suppression of irinotecan-induced cholinergic syndrome compared to loperamide alone. Thus, loperamide may improve abdominal pain attributed to irinotecan-induced cholinergic syndrome.\n\nKeywords\n\nLoperamide\nIrinotecan\nAbdominal pain\nCholinergic syndrome\n==== Body\nIntroduction\n\nIrinotecan hydrochloride (irinotecan) is a chemotherapeutic agent used in the treatment of several solid tumors, such as colorectal cancer and lung cancer [1]. Irinotecan is a prodrug that is extensively metabolized in the liver by carboxylesterase to produce the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). It is then conjugated predominantly by liver UDP-glucuronosyltransferase (UGT) 1A1 to form inactive SN-38 glucuronide (SN-38G) and is categorized as a topoisomerase I inhibitor [1]. In addition to severe neutropenia and delayed diarrhea, which are known to be dose-limiting toxicities of irinotecan, cholinergic syndrome is frequently observed during and after infusion of the drug. The symptoms of cholinergic syndrome include acute diarrhea, abdominal pain (peristaltic pain), nausea, sweating, nasal discharge, and lacrimation [2] and have been reported in up to 30–50% of Japanese patients [3]. These symptoms often reduce the patients' quality of life. Anticholinergic drugs such as scopolamine and atropine are effective against acute diarrhea caused by cholinergic syndrome [4].\n\nWe observed that the administration of 2 mg loperamide hydrochloride (loperamide) plus 0.25 mg atropine before infusing irinotecan markedly attenuated irinotecan-induced cholinergic abdominal pain. The anticholinergic drug alone was not effective, and our recommended treatment process has been reported herein.\n\nCase Report\n\nA 28-year-old man was diagnosed with stage IV rectal cancer with peritoneal metastasis (BRAF wild V600E, RAS wild type, non-MSI-H, UGT1A1*6 wild, and UGT1A1*28 wild). He was a nonsmoker and a social drinker with normal liver and renal function. He was subjected to chemotherapeutic treatment using FOLFIRI (fluorouracil 400 mg/m2 on day 1 and 2,400 mg/m2 for 46 h from day 1, irinotecan 150 mg/m2 on day 1, and levofolinate calcium 200 mg/m2 on day 1, every 2 weeks) and cetuximab (400 mg/m2 for the first time, 250 mg/m2 in the subsequent injection, every week). Palonosetron (0.75 mg) and dexamethasone (9.9 mg) were intravenously administered on day 1 as antiemetic pre-medication for FOLFIRI administration, and chlorpheniramine maleate (10 mg) was intravenously administered to prevent an infusion reaction with cetuximab. The concomitant drug prescribed was oral minocycline hydrochloride (50 mg twice daily) for skin toxicity prevention. The patient did not present with cancer-associated pain, including abdominal pain, and did not consume any analgesic agents during chemotherapy.\n\nDetails of the therapeutic process and supportive care are presented in Table 1. The patient experienced perspiration and abdominal pain during administration of irinotecan in the first course but did not experience diarrhea. Scopolamine (20 mg) was intravenously administered because these symptoms were considered to be associated with cholinergic syndrome. Following treatment with scopolamine, the symptoms disappeared. During the second course, 20 mg scopolamine was administered prior to irinotecan administration, but abdominal pain and articulatory disorder were reported during irinotecan infusion. Accordingly, scopolamine (20 mg) was administered again after irinotecan infusion, and his symptoms improved. In the third course, scopolamine (20 mg) was intravenously administered before and after irinotecan infusion; however, the patient developed abdominal pain, and he claimed to experience palpitations during scopolamine administration. From the ninth course onward, we changed the pre-medication from scopolamine (20 mg) to atropine (0.5 mg) before and after irinotecan infusion. The patient's response seemed to support that atropine was superior to scopolamine in terms of attenuating symptoms of cholinergic syndrome. Nonetheless, the patient experienced palpitations and respiratory discomfort, which were more severe than those experienced when scopolamine was administered. Therefore, we injected atropine using approaches such as dose reduction from 0.5 to 0.25 mg with frequent administration in the range of a total daily dose of 1 mg; however, success was not achieved. In the fifteenth course, we administered oral loperamide (1 mg) with atropine (0.25 mg) before irinotecan treatment. As a result, the symptoms partially improved. Thereafter, we increased the dosage of loperamide to 2 mg while maintaining the atropine dose in the twentieth course. Following this regimen, the abdominal pain completely resolved, and administration of additional atropine was not necessary after irinotecan infusion.\n\nDiscussion\n\nTwo types of diarrhea reportedly occur following irinotecan treatment, namely acute and delayed diarrhea. Acute diarrhea occurs during or immediately after irinotecan infusion and is caused by increased cholinergic activity, which stimulates intestinal contractility and reduces the absorptive capacity of the mucosa [4]. The carbonyl group of irinotecan is considered to exert an inhibitory effect on acetylcholinesterase, and cholinergic syndrome may be caused by the stimulation of the muscarinic receptor due to excessive acetylcholine [5]. UGT1A1 is an important pharmacogenetic factor of irinotecan pharmacokinetics and affects the incidence and severity of delayed diarrhea [6]. Since the occurrence of acute diarrhea depends on irinotecan blood levels [7], no relationship exists between the UGT1A1 genotype and acute diarrhea caused by irinotecan-induced cholinergic syndrome. In general, anticholinergic agents such as scopolamine and atropine are used to treat this syndrome. In contrast, delayed diarrhea occurs approximately 8–10 days after irinotecan infusion and is probably caused by damage to the intestinal mucosa due to increased oxidative stress by biliary-secreted or intestinally deconjugated SN-38 [4]. Several guidelines recommend treatment of delayed diarrhea with loperamide or octreotide [8].\n\nThe predictive factors of irinotecan-induced cholinergic syndrome include irinotecan dose, gender (female), and combination chemotherapy [1, 5, 9]. Therefore, irinotecan dose reduction is one of the treatment strategies for preventing irinotecan-induced cholinergic syndrome; however, as easy dose reduction decreases the intensity of chemotherapy, alternative methods should be considered. In the previous studies, anticholinergic agents reportedly attenuated cholinergic syndrome [9]. Nevertheless, in the present study, the eventual addition of loperamide to an anticholinergic agent completely improved the patient's abdominal pain. The maximum plasma concentration of irinotecan is attained approximately 1 h after injection [10], and in the present study, the patient developed abdominal pain within 1 h of initiating irinotecan, which continued until day 2. However, administration of 2 mg loperamide suppressed not only immediate abdominal pain but also persistent pain. Since the half-life of loperamide is approximately 10 h [11], we assumed that loperamide contributed to the disappearance of abdominal symptoms considering its pharmacokinetics.\n\nWe formulated the following hypotheses on the mechanisms by which abdominal pain was alleviated following the administration of loperamide: (1) loperamide is an opioid receptor agonist that acts on the μ-opioid receptors in the myenteric plexus of the large intestine [12]. Similar to opioids, loperamide decreases the activity of the myenteric plexus and the tone of the longitudinal and circular smooth muscles of the intestinal wall [12]. (2) The anticholinergic activity of loperamide helps relieve abdominal pain. A previous report has suggested that loperamide inhibits acetylcholine release, resulting in decreased peristaltic movement during circumferential distension of the intestinal wall [13]. Therefore, the mechanism of anticholinergic activity is different for loperamide, scopolamine, and atropine, with loperamide demonstrating higher competitive inhibition of the muscarinic acetylcholine receptor [9]. Furthermore, Awouters et al. [14] reported that loperamide exerted a higher effect on the intestine than anticholinergics, and opioids resulted in higher antidiarrheal activity in rats. (3) Inhibition of prostaglandin (PG) release by loperamide is also related to antidiarrheal activity [13]. Kase et al. [15] reported that irinotecan increased the release of PGE2, which is related to the onset of diarrhea, within 1 h of irinotecan injection in rats. Therefore, it may be suggested that loperamide inhibits biologically active substances that are related to the occurrence of diarrhea via multiple mechanisms. We assumed that the abovementioned mechanism of loperamide solely or in combination contributed to symptom relief in our patient.\n\nMoreover, we consider that the synergistic anticholinergic interaction between loperamide and atropine facilitated further suppression of digestive disorders when compared to loperamide alone. In fact, since scopolamine or atropine dose escalation caused side effects such as palpitations and respiratory discomfort, we suggest that multidrug therapy is superior to monotherapy in certain cases.\n\nConclusion\n\nIn the present study, we demonstrated the effectiveness of loperamide when anticholinergic agents such as scopolamine and atropine alone were ineffective in alleviating abdominal pain attributed to irinotecan-induced cholinergic syndrome. However, further studies on the use and effectiveness of loperamide in symptomatic relief are warranted.\n\nStatement of Ethics\n\nWritten informed consent was obtained from the patient for the publication of this case report and any accompanying images.\n\nConflict of Interest Statement\n\nK.U., Y.S., Y.T., S.Y., and M.S. have no conflicts of interest.\n\nFunding Sources\n\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nAuthor Contributions\n\nK.U. contributed to the design of the report, collected the data, and drafted the manuscript. Y.S., Y.T., S.Y., and M.S. revised the manuscript. All the authors read and approved the final version of the manuscript.\n\nTable 1 Course details of symptoms and supportive care\n\nCourse\tDetails of symptoms and supportive care\t\nC1\tPerspiration and abdominal pain (peristaltic pain) were reported during administering irinotecan. Scopolamine (20 mg) injection attenuated these symptoms\t\nC2\tScopolamine (20 mg) injection was preventively administered prior to irinotecan infusion, but the effect was unsatisfactory. An additional injection of scopolamine (20 mg) successfully resolved the symptoms\t\nC3-C8\tScopolamine (20 mg) was intravenously administered before and after irinotecan infusion\t\nC9\tPalpitations in addition to abdominal pain occurred during irinotecan infusion. Regimen was changed from scopolamine (20 mg) to atropine (0.5 mg) injection before and after irinotecan infusion. Abdominal pain was mitigated, but palpitations and respiratory discomfort were reported\t\nC10–C14\tAtropine injection was performed, ensuring a restricted total daily dose of 1 mg, but all regimens failed\t\nC15\tLoperamide (1 mg) was orally administered before irinotecan infusion in addition to 0.25 mg of atropine. Abdominal pain was mitigated, but the treatment was unsatisfactory\t\nC20\tOral loperamide (2 mg) with atropine (0.25 mg) was administered before irinotecan infusion. Abdominal pain was completely resolved following treatment\t\nAfter C21\tNo symptoms were reported\t\nIrinotecan, irinotecan hydrochloride; scopolamine, scopolamine butylbromide; atropine, atropine sulfate; loperamide, loperamide hydrochloride.\n==== Refs\nReferences\n\n1 Tsuboya A Fujita KI Kubota Y Ishida H Taki-Takemoto I Kamei D Coadministration of cytotoxic chemotherapeutic agents with irinotecan is a risk factor for irinotecan-induced cholinergic syndrome in Japanese patients with cancer Int J Clin Oncol 2019 2 24 (2) 222 30 30244364\n2 Rougier P Bugat R Douillard JY Culine S Suc E Brunet P Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naïve patients and patients pretreated with fluorouracil-based chemotherapy J Clin Oncol 1997 1 15 (1) 251 60 8996150\n3 Pitot HC Goldberg RM Reid JM Sloan JA Skaff PA Erlichman C Phase I dose-finding and pharmacokinetic trial of irinotecan hydrochloride (CPT-11) using a once-every-three-week dosing schedule for patients with advanced solid tumor malignancy Clin Cancer Res 2000 6 6 (6) 2236 44 10873073\n4 de Man FM Goey AKL van Schaik RHN Mathijssen RHJ Bins S Individualization of irinotecan treatment: a review of pharmacokinetics, pharmacodynamics, and pharmacogenetics Clin Pharmacokinet 2018 10 57 (10) 1229 54 29520731\n5 Kanbayashi Y Ishikawa T Kanazawa M Nakajima Y Tabuchi Y Kawano R Predictive factors for the development of irinotecan-related cholinergic syndrome using ordered logistic regression analysis Med Oncol 2018 4 35 (6) 82 29705823\n6 Hu ZY Yu Q Zhao YS Dose-dependent association between UGT1A1*28 polymorphism and irinotecan-induced diarrhoea: a meta-analysis Eur J Cancer 2010 7 46 (10) 1856 65 20335017\n7 Hyatt JL Tsurkan L Morton CL Yoon KJ Harel M Brumshtein B Inhibition of acetylcholinesterase by the anticancer prodrug CPT-11 Chem Biol Interact 2005 12 157 247 52 16257398\n8 Benson AB 3rd Ajani JA Catalano RB Engelking C Kornblau SM Martenson JA Recommended guidelines for the treatment of cancer treatment-induced diarrhea J Clin Oncol 2004 7 22 (14) 2918 26 15254061\n9 Iihara H Fujii H Yoshimi C Kobayashi R Matsuhashi N Takahashi T Prophylactic effect of scopolamine butylbromide, a competitive antagonist of muscarinic acetylcholine receptor, on irinotecan-related cholinergic syndrome Cancer Chemother Pharmacol 2019 3 83 (3) 393 8 30564875\n10 Chabot GG Clinical pharmacokinetics of irinotecan Clin Pharmacokinet 1997 10 33 (4) 245 59 9342501\n11 Killinger JM Weintraub HS Fuller BL Human pharmacokinetics and comparative bioavailability of loperamide hydrochloride J Clin Pharmacol 1979 4 19 (4) 211 8 438356\n12 Hanauer SB The role of loperamide in gastrointestinal disorders Rev Gastroenterol Disord 2008 8 (1) 15 20 18477966\n13 Yagasaki O Suzuki H Sohji Y Effects of loperamide on acetylcholine and prostaglandin release from isolated guinea pig ileum Jpn J Pharmacol 1978 12 28 (6) 873 82 745310\n14 Awouters F Megens A Verlinden M Schuukes J Niemegeers C Janssen PA Loperamide. Survey of studies on mechanism of its antidiarrheal activity Dig Dis Sci 1993 6 38 (6) 977 95 8508715\n15 Kase Y Hayakawa T Togashi Y Kamataki T Relevance of irinotecan hydrochloride-induced diarrhea to the level of prostaglandin E2 and water absorption of large intestine in rats Jpn J Pharmacol 1997 12 75 (4) 399 405 9469646\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "14(2)",
"journal": "Case reports in oncology",
"keywords": "Abdominal pain; Cholinergic syndrome; Irinotecan; Loperamide",
"medline_ta": "Case Rep Oncol",
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"pubdate": "2021",
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"title": "Alleviation of Abdominal Pain due to Irinotecan-Induced Cholinergic Syndrome Using Loperamide: A Case Report.",
"title_normalized": "alleviation of abdominal pain due to irinotecan induced cholinergic syndrome using loperamide a case report"
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"abstract": "A 35-year-old woman with a 9-year history of Grave's disease delivered a male infant weighing 2,210 g at 32 weeks of gestation by caesarean section. The neonate developed thyrotoxicosis and, at the age of 24 h, was treated with oral carbimazole (500 µg every 8 h) and propranolol (2 mg/kg/day in two divided doses). He subsequently developed hypertension on day 4, which required therapy with amlodipine (0.1 mg once daily). Severe hypotension developed within 24 h and required discontinuation of amlodipine, with initiation of intravenous inotropic support with dopamine and dobutamine (at a rate of 20 µg/kg/min). The blood pressure rapidly normalized, and both dopamine and dobutamine infusions were stopped within 36 h. A Naranjo assessment score of 6 was calculated, indicating that the severe hypotension was a probable adverse drug reaction caused by the combination of amlodipine and propranolol therapy.",
"affiliations": "Jordan University of Science and Technology (JUST), PO Box 3030, Irbid 24166, Jordan. deema321@yahoo.com.;Jordan University of Science and Technology (JUST), PO Box 3030, Irbid 24166, Jordan.",
"authors": "Khassawneh|Mohammad|M|;Al-Ghazo|Nedaa|N|",
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"fulltext": "\n==== Front\nDrug Saf Case Rep\nDrug Saf Case Rep\nDrug Safety - Case Reports\n2199-1162\n2198-977X\nSpringer International Publishing Cham\n\n27747714\n4\n10.1007/s40800-015-0004-6\nCase Report\nSevere Hypotension After Amlodipine Use for Hypertension in a Newborn on Beta Blocker Therapy for Thyrotoxicosis\nKhassawneh Mohammad +971-3-7137296 deema321@yahoo.com\n\nAl-Ghazo Nedaa\nJordan University of Science and Technology (JUST), PO Box 3030, Irbid 24166, Jordan\n12 2 2015\n12 2 2015\n12 2015\n2 1 2© The Author(s) 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.\nA 35-year-old woman with a 9-year history of Grave’s disease delivered a male infant weighing 2,210 g at 32 weeks of gestation by caesarean section. The neonate developed thyrotoxicosis and, at the age of 24 h, was treated with oral carbimazole (500 µg every 8 h) and propranolol (2 mg/kg/day in two divided doses). He subsequently developed hypertension on day 4, which required therapy with amlodipine (0.1 mg once daily). Severe hypotension developed within 24 h and required discontinuation of amlodipine, with initiation of intravenous inotropic support with dopamine and dobutamine (at a rate of 20 µg/kg/min). The blood pressure rapidly normalized, and both dopamine and dobutamine infusions were stopped within 36 h. A Naranjo assessment score of 6 was calculated, indicating that the severe hypotension was a probable adverse drug reaction caused by the combination of amlodipine and propranolol therapy.\n\nissue-copyright-statement© The Author(s) 2015\n==== Body\nKey Points\n\nAntihypertensive medication combination therapy in neonates should be monitored closely for hypotension.\t\nThe interaction of a beta blocker and amlodipine therapy in the neonatal period needs to be studied further.\t\n\nIntroduction\n\nNeonatal hypertension secondary to renal, endocrine or other causes is commonly seen in sick newborn infants [1]. Its treatment may include use of beta blockers, vasodilators such as hydralazine, calcium channel blockers or alpha blockers. Although amlodipine has been shown to be effective and safe when used in children [2], its use has not been fully studied in neonates nor in combination with beta blockers in that age group. However, amlodipine was listed in a recent review article as one of the treatment options for hypertension in neonates [3].\n\nIn an infant born to a mother with Grave’s disease, we report the occurrence of severe hypotension, which developed after amlodipine was administered in addition to the beta blocker therapy already initiated for hypertension secondary to thyrotoxicosis. We describe the case and discuss the use of amlodipine in this age group.\n\nCase Report\n\nA male newborn infant, with a birth weight of 2,210 g, was born by caesarean section at 32 weeks of gestation to a 35-year-old mother with a 9-year history of Grave’s disease. He required mechanical ventilation for 3 days for respiratory distress syndrome. Thyrotoxicosis was confirmed by physical examination and laboratory investigations: his serum thyroxin (T4) level was 59 ng/dL and his thyroid stimulating hormone (TSH) level was 0.013 µIU/mL. Oral treatment with carbimazole 500 µg every 8 h and propranolol 2 mg/kg/day, divided into two doses, was started at 24 h after birth. On day 4, the infant developed hypertension, with a mean blood pressure ranging from 90 to 100 mmHg. On the recommendation of a paediatric nephrologist, therapy with amlodipine 0.1 mg orally once daily was started.\n\nTwenty hours after administration of the first dose of amlodipine, the child developed severe hypotension, with a mean blood pressure of 27 mmHg, and required supportive care with mechanical ventilation and intravenous inotropes (dopamine and dobutamine at a rate of 20 µg/kg/min). Amlodipine was stopped, propranolol therapy was continued, a full septic work-up was performed and all cultures showed no bacterial growth. Following the discontinuation of amlodipine, the blood pressure normalized, and the inotropes were stopped within 36 h. By day 8, propranolol was discontinued, as the blood pressure and serum T4 level (14.7 µg/dL) were normal.\n\nDiscussion\n\nThis case report aims to describe the occurrence of severe hypotension following amlodipine administration for hypertension developing in a preterm infant with thyrotoxicosis who was already receiving beta blocker. This is similar to the findings in an animal study by Ishizaka et al. [4], where more significant hypotension occurred when a beta blocker was added to amlodipine than when it was added to a newer calcium channel blocker.\n\nRecent research supports the use of amlodipine, a calcium channel blocker, in young children. Robinson et al. [5] described its use in 33 children aged 1.3–16.9 years and showed that it was well tolerated when used for 6 months. Lago Rivero et al. [6] reported its use in refractory hypertension in a 5-year-old girl with secondary hypertension. By contrast, there have been no good studies on the use of calcium channel blockers in neonates. One case report described the development of subcutaneous fat necrosis in a newborn whose mother had received a calcium channel blocker [7]. A case report of death caused by an amlodipine overdose recommended caution when using it in young infants [8].\n\nThe current report suggests that severe hypotension may result from combining amlodipine with beta blocker therapy in neonates. Combination antihypertensive therapy in this age group should be used only with caution.\n\nNo financial support was received for preparation of this manuscript. Mohammad Khassawneh and Nedaa Al-Ghazo declare that they have no relevant conflicts of interest.\n\nEthics\n\nInformed consent was obtained from both the infant’s father and his mother for the publication of this report.\n==== Refs\nReferences\n\n1. Seliem WA Falk MC Shadbolt B Kent AL Antenatal and postnatal risk factors for neonatal hypertension and infant follow-up Pediatr Nephrol 2007 22 12 2081 2087 10.1007/s00467-007-0603-2 17874136\n2. Flynn JT Efficacy and safety of prolonged amlodipine treatment in hypertensive children Pediatr Nephrol 2005 20 5 631 635 10.1007/s00467-004-1781-9 15785942\n3. Dionne JM Abitbol CL Flynn JT Hypertension in infancy: diagnosis, management and outcome Pediatr Nephrol 2012 27 1 17 32 10.1007/s00467-010-1755-z 21258818\n4. Ishizaka T Takahara A Iwasaki H Mitsumori Y Kise H Nakamura Y Sugiyama A Cardiovascular effects of azelnidipine in comparison with those of amlodipine assessed in the halothane-anaesthetized dog Basic Clin Pharmacol Toxicol 2010 106 2 135 143 10.1111/j.1742-7843.2009.00478.x 19906049\n5. Robinson RF Nahata MC Batisky DL Mahan JD Pharmacologic treatment of chronic pediatric hypertension Paediatr Drugs 2005 7 1 27 40 10.2165/00148581-200507010-00003 15777109\n6. Lago Rivero N, Arias Santos I, Paradela Carreiro A. Amlodipine in pediatric patient with uncontrolled multifactorial hypertension: formulation of amlodipine oral suspension. Eur Rev Med Pharmacol Sci. 2012;16(8):1117–9.\n7. Rosbotham JL Johnson A Haque KN Holden CA Painful subcutaneous fat necrosis of the newborn associated with intra-partum use of a calcium channel blocker Clin Exp Dermatol 1998 23 1 19 21 10.1046/j.1365-2230.1998.00290.x 9667103\n8. Spiller HA Milliner BA Bosse GM Amlodipine fatality in an infant with postmortem blood levels J Med Toxicol 2012 8 2 179 182 10.1007/s13181-011-0207-x 22271567\n\n",
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"title": "Severe Hypotension After Amlodipine Use for Hypertension in a Newborn on Beta Blocker Therapy for Thyrotoxicosis.",
"title_normalized": "severe hypotension after amlodipine use for hypertension in a newborn on beta blocker therapy for thyrotoxicosis"
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"abstract": "There is a growing interest in assessment of future remnant liver function with Tc-mebrofenin hepatobiliary scintigraphy before major hepatectomy to estimate the risk of posthepatectomy liver failure. We illustrate the case of a 42-year-old woman with liver metastasis from colorectal cancer who performed hepatobiliary scintigraphy. Tc-mebrofenin clearance rate of the total liver was considerably low. The patient recently started a treatment for active hepatitis C with a combination of 2 new direct-acting antiviral agents (grazoprevir, elbasvir). Apart from hypoalbuminemia or hyperbilirubinemia, physicians must be aware that drug interactions can interfere with Tc-mebrofenin liver uptake, thereby resulting in a dramatic underestimation of liver function.",
"affiliations": "Liver and Transplantation Unit, Montpellier School of Medicine and IRB-INSERM-1183.;Department of Surgical Oncology, ICM, Univ. Montpellier.;Radiology Department, Montpellier Saint Eloi University Hospital, Montpellier, France.",
"authors": "Deshayes|Emmanuel|E|;Fersing|Cyril|C|;Meunier|Lucy|L|;Quenet|François|F|;Guiu|Boris|B|",
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"keywords": null,
"medline_ta": "Clin Nucl Med",
"mesh_terms": "D000328:Adult; D000577:Amides; D000814:Aniline Compounds; D000998:Antiviral Agents; D001572:Benzofurans; D002219:Carbamates; D003521:Cyclopropanes; D004347:Drug Interactions; D005260:Female; D005998:Glycine; D016174:Hepacivirus; D006801:Humans; D007093:Imidazoles; D007098:Imino Acids; D017093:Liver Failure; D015609:Organotechnetium Compounds; D011810:Quinoxalines; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D013449:Sulfonamides",
"nlm_unique_id": "7611109",
"other_id": null,
"pages": "133-135",
"pmc": null,
"pmid": "31833927",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Antiviral (Hepatitis C Virus) Drug-Drug Interaction Leading to Dramatic Underestimation of Liver Function With 99mTc-Mebrofenin Hepatobiliary Scintigraphy.",
"title_normalized": "antiviral hepatitis c virus drug drug interaction leading to dramatic underestimation of liver function with 99mtc mebrofenin hepatobiliary scintigraphy"
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"companynumb": "FR-009507513-1912FRA012145",
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"abstract": "BACKGROUND\nRegional chemotherapy is used successfully in the treatment of both primary and secondary malignancies, in particular of the peritoneal surface and the liver, and is currently explored as an attractive approach for patients with locally advanced pancreatic ductal adenocarcinoma. To establish the feasibility and toxicity of regional intra-arterial gemcitabine delivered as a 24-h continuous infusion to the pancreas as a novel treatment option for patients with locally advanced PDAC a phase I clinical trial was conducted.\n\n\nMETHODS\nBetween April 2011 and September 2013 six patients with biopsy confirmed, borderline or unresectable pancreatic adenocarcinoma, and having received at least one line of systemic chemotherapy, underwent vascular redistribution of the inflow to the head of the pancreas by arterial coil embolization followed by perfusion catheter placement within the splenic artery. Patients were treated with increasing doses of gemcitabine administered by continuous splenic arterial infusion over 24 h with inter-patient and intra-patient dose escalation scheme. The primary endpoint was toxicity of the intra-arterial gemcitabine regimen and to establish the maximum tolerated dose.\n\n\nRESULTS\nCatheter placement and gemcitabine infusion was successful in all patients enrolled to date (n = 6). Four out of six patients experienced catheter tip migration requiring replacement or revision. Patients received a median of four doses of 24-h gemcitabine infusion. Two patients developed grade 3 and 4 duodenal ischemia and upper gastrointestinal bleeding. Median overall survival was 15.3 months and median time to progression was 3 months. Three patients (50 %, n = 3/6) progressed systemically. Two patients had stable disease >4 months following treatment and underwent pancreaticoduodenectomy.\n\n\nCONCLUSIONS\nWhile technically feasible to treat locally advanced pancreatic ductal adenocarcinoma, prolonged regional pancreatic perfusion with gemcitabine following pancreatic arterial redistribution carries a high risk for gastrointestinal toxicity. Shorter infusion schedules with frequent on treatment evaluations should be considered for future clinical trials.",
"affiliations": "Thoracic & GI Oncology Branch, National Cancer Institute, Hatfield Center, CCR - 4 West/5940 10 Center Drive, Bethesda, MD, 20892-0001, USA.",
"authors": "Beane|Joal D|JD|;Griffin|Kayla F|KF|;Levy|Elliot B|EB|;Pandalai|Prakash|P|;Wood|Bradford|B|;Abi-Jaoudeh|Nadine|N|;Beresnev|Tatiana|T|;Shutack|Yvonne|Y|;Webb|Carole C|CC|;Avital|Itzhak|I|;Rudloff|Udo|U|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "United States",
"delete": false,
"doi": "10.1007/s10637-014-0157-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6997",
"issue": "33(1)",
"journal": "Investigational new drugs",
"keywords": null,
"medline_ta": "Invest New Drugs",
"mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D021441:Carcinoma, Pancreatic Ductal; D002404:Catheterization; D003841:Deoxycytidine; D004378:Duodenal Diseases; D004386:Duodenum; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D007511:Ischemia; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010179:Pancreas; D010190:Pancreatic Neoplasms; D010477:Perfusion; D013157:Splenic Artery; D016896:Treatment Outcome",
"nlm_unique_id": "8309330",
"other_id": null,
"pages": "109-18",
"pmc": null,
"pmid": "25236592",
"pubdate": "2015-02",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": "11821447;11821446;20737218;7450406;8604906;10655437;10401733;11592607;21595953;1718594;16334117;12885837;8695365;2364394;12667396;16122282;24856119;18640930;9196156;9220290;18378536;10918160;22815840;23955427;8635074",
"title": "Duodenal ischemia and upper GI bleeding are dose-limiting toxicities of 24-h continuous intra-arterial pancreatic perfusion of gemcitabine following vascular isolation of the pancreatic head: early results from the Regional Chemotherapy in Locally Advanced Pancreatic Cancer (RECLAP) study.",
"title_normalized": "duodenal ischemia and upper gi bleeding are dose limiting toxicities of 24 h continuous intra arterial pancreatic perfusion of gemcitabine following vascular isolation of the pancreatic head early results from the regional chemotherapy in locally advanced pancreatic cancer reclap study"
} | [
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"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
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"abstract": "Drug-drug interactions with corticosteroids, causing Cushing's syndrome with secondary adrenal suppression, are well known in HIV patients. Corticosteroids are widely prescribed in the HIV-positive population. However, digoxin is rarely used in HIV patients; hence, digoxin toxicity due to drug-drug interaction is not widely recognised. Nevertheless, this practice might change in the future as HIV cohorts of patients are ageing, due to the successful treatment of HIV infection with combination antiretroviral therapy. We report a case of digoxin toxicity in an HIV-positive 51-year-old man, due to a combination of drug-drug interaction and renal impairment. The first case report of digoxin toxicity due to drug-drug interaction with ritonavir in an HIV-positive woman was published in 2003. To the best of our knowledge, no similar case report has since been published in the literature. This case alerts the profession to the importance of drug-drug interaction and highlights the clinical features of digoxin toxicity.",
"affiliations": "Singleton Hospital, Abertawe Bro Morgannwg University Health Board, Swansea, UK.;Singleton Hospital, Abertawe Bro Morgannwg University Health Board, Swansea, UK.;Singleton Hospital, Abertawe Bro Morgannwg University Health Board, Swansea, UK.",
"authors": "Yoganathan|Kathir|K|;Roberts|Beth|B|;Heatley|Martyn K|MK|",
"chemical_list": "D017320:HIV Protease Inhibitors; D004077:Digoxin; D019438:Ritonavir; D000069454:Darunavir",
"country": "England",
"delete": false,
"doi": "10.1177/0956462416661437",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0956-4624",
"issue": "28(3)",
"journal": "International journal of STD & AIDS",
"keywords": "HIV/AIDS; ageing HIV population; antiretroviral therapy; digoxin toxicity; drug–drug interaction; ritonavir",
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D000069454:Darunavir; D004077:Digoxin; D004347:Drug Interactions; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D006801:Humans; D008297:Male; D008875:Middle Aged; D051437:Renal Insufficiency; D019438:Ritonavir",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "297-301",
"pmc": null,
"pmid": "27440872",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Life-threatening digoxin toxicity due to drug-drug interactions in an HIV-positive man.",
"title_normalized": "life threatening digoxin toxicity due to drug drug interactions in an hiv positive man"
} | [
{
"companynumb": "GB-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-121608",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RITONAVIR"
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"druga... |
{
"abstract": "So far there have been no studies on Candida auris in Qatar. This study aimed to describe the clinical spectrum and outcome of C. auris infection in patients admitted to a general hospital in Qatar.\nWe conducted this descriptive observational study in a general hospital in Qatar. We have involved all patients with C. auris infection and colonization admitted to a general hospital from December 2018 to August 2019.\nWe identified 13 patients with confirmed C.auris infection/colonization, of which five cases represented an actual C. auris infection, while the remaining eight cases were considered as colonization. The mean age of the patients with infection was 76.6 ± 8.4 years, while the mean age of the patients with colonization was 66.4 ± 24.7 years. Among the individuals clinically infected with C. auris, two had urinary tract infections, one had candidemia, one acquired soft tissue infection, and one had a lower respiratory tract infection. All strains of C. auris were susceptible to echinocandins, flucytosine, and posaconazole while resistance to fluconazole and amphotericin B. Of the patients with C. auris infection who received systemic antifungal therapy, three (60%) died during antifungal therapy.\nOur study showed that C. auris can cause a wide variety of invasive infections, including bloodstream infection, urinary tract infection, skin infection, and lower respiratory tract infections, especially in critically ill patients. In addition, our isolates showed resistance to the most common antifungal agents such as fluconazole and amphotericin B.",
"affiliations": "Infectious Disease Section, Department of Medicine, Al Wakra Hospital, Hamad Medical Corporation (HMC), Qatar.;Infection Prevention and Control Department, Al Wakra Hospital, HMC, Qatar.;Department of Laboratory Medicine and Pathology, HMC, Qatar.;Critical Care Dept, Al Wakra Hospital, HMC, Qatar.;Medicine Division, Al Wakra Hospital-HMC, Qatar.;Pharmacy Department, Al Wakra Hospital, HMC, Qatar.;Department of Microbiology, HMC, Qatar.;Infection Prevention and Control Department, Al Wakra Hospital, HMC, Qatar.",
"authors": "Shaukat|Adila|A|;Al Ansari|Nasir|N|;Al Wali|Walid|W|;Karic|Edin|E|;El Madhoun|Ihab|I|;Mitwally|Hassan|H|;Hamed|Manal|M|;Alutra-Visan|Feah|F|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2020.e01007",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509 Elsevier \n\nS2214-2509(20)30315-2\n10.1016/j.idcr.2020.e01007\ne01007\nArticle\nExperience of treating Candida auris cases at a general hospital in the state of Qatar\nShaukat Adila Akashaf1@hamad.qaa⁎ Al Ansari Nasir b Al Wali Walid c Karic Edin d El Madhoun Ihab e Mitwally Hassan f Hamed Manal g Alutra-Visan Feah b a Infectious Disease Section, Department of Medicine, Al Wakra Hospital, Hamad Medical Corporation (HMC), Qatar\nb Infection Prevention and Control Department, Al Wakra Hospital, HMC, Qatar\nc Department of Laboratory Medicine and Pathology, HMC, Qatar\nd Critical Care Dept, Al Wakra Hospital, HMC, Qatar\ne Medicine Division, Al Wakra Hospital-HMC, Qatar\nf Pharmacy Department, Al Wakra Hospital, HMC, Qatar\ng Department of Microbiology, HMC, Qatar\n⁎ Corresponding author. Akashaf1@hamad.qa\n12 11 2020 \n2021 \n12 11 2020 \n23 e0100728 10 2020 9 11 2020 © 2020 The Authors2020This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• Candida. auris can cause invasive infections, including bloodstream, urinary tract, skin and ssoft tissue and lower respiratory tract infections.\n\n• Identification of C. auris requires specialized laboratory methods.\n\n• C. auris is associated with high morbidity and mortality.\n\n• C. auris isolates were resistant to the common antifungal agents such as fluconazole and amphotericin B.\n\n\n\nBackground and objectives\nSo far there have been no studies on Candida auris in Qatar. This study aimed to describe the clinical spectrum and outcome of C. auris infection in patients admitted to a general hospital in Qatar.\n\nMethods\nWe conducted this descriptive observational study in a general hospital in Qatar. We have involved all patients with C. auris infection and colonization admitted to a general hospital from December 2018 to August 2019.\n\nResults\nWe identified 13 patients with confirmed C.auris infection/colonization, of which five cases represented an actual C. auris infection, while the remaining eight cases were considered as colonization. The mean age of the patients with infection was 76.6 ± 8.4 years, while the mean age of the patients with colonization was 66.4 ± 24.7 years. Among the individuals clinically infected with C. auris, two had urinary tract infections, one had candidemia, one acquired soft tissue infection, and one had a lower respiratory tract infection. All strains of C. auris were susceptible to echinocandins, flucytosine, and posaconazole while resistance to fluconazole and amphotericin B. Of the patients with C. auris infection who received systemic antifungal therapy, three (60%) died during antifungal therapy.\n\nConclusion\nOur study showed that C. auris can cause a wide variety of invasive infections, including bloodstream infection, urinary tract infection, skin infection, and lower respiratory tract infections, especially in critically ill patients. In addition, our isolates showed resistance to the most common antifungal agents such as fluconazole and amphotericin B.\n\nKeywords\nCandida aurisCandidemiaUrinary tract infectionRespiratory tract infectionColonizationSkin infection.\n==== Body\nIntroduction\nCandida auris is a novel multidrug-resistant yeast with high overall mortality that was first isolated from the external auditory canal of a patient in Japan in 2009 [1]. Since then, this fungal infection has been reported from various countries across the world [[2], [3], [4]], and over time it has become a serious global health concern as one of the most serious emerging pathogens that critical care physicians should be aware of [5].\n\nC. auris being resistant to major antifungal classes used to treat Candida including azole antifungal agents, poses a challenge to routine microbiology laboratories, as C. auris can be misidentified with standard laboratory techniques, and have a tendency to cause outbreaks in healthcare settings especially critical care areas despite adequate infection prevention and control measures [4,5].\n\nIn Qatar, there is no published data on Candida aurisso far. In this series, we reported the first outbreak of C. auris infection in Qatar, to describe the clinical spectrum and outcome of this infection in the affected patients.\n\nMethods and patients\nWe conducted this descriptive observational study in a general hospital in Qatar. We involved all patients with Candida Auris infection and colonization in the intensive care units and other wards from December 2018 to August 2019. This study was given ethical approval by the medical research committee at Hamad Medical Corporation, under number: MRC-01-19-503..\n\nDefinitions\nColonization is defined as isolation of C. auris from endotracheal aspiration fluid, throat swabs, sputum, urine, and samples from central venous catheters or other parts of the body in absence of clinical signs or symptomes of infection. C.auris infection is defined as the isolation of Cauris from clinical specimens with compatible clinical signs and symptoms of infection [5].\n\nCandida auris identification\nAll clinical specimens, from different sites, were cultured by quantitative technique on Sabouraud Dextrose Agar (OXOID, UK) and incubated at 35−37 °C for 48 h. Preliminary fungal strain identification was based on colony morphology on Chromogenic Candida Agar (OXOID, UK), while the identification to the species level was confirmed by Vitek 2 XL automated system (bioMerieux). Susceptibility of strains to Amphotericin B, Fluconazole, 5-fluorocytosine, and voriconazole was determined by using Sensititre™ YeastOne™ plate and by interpreting results according to closely related Candida species and on expert opinion. As per the Centers for Disease Control and Prevention (CDC), there are currently no established C. auris-specific susceptibility breakpoints [6].\n\nPulsed-field gel electrophoresis (PFGE) typing, which consisted of electrophoretic karyotyping (EK), was performed to compare the isolates from different sites. Following the results of the PFGE, an outbreak of C. auris infection in critical care unit and medical unit was confirmed by identifying five5 cases and patient screening revealed colonization of eight additional patients. Intensive efforts were done to find out the cause of cross-transmission and environmental and surface swabbing was done in affected areas, but all results were negative.\n\nData analysis\nThe results of analyses of continuous variables are expressed as means and standard deviations (SD) unless otherwise specified.\n\nResults\nDuring the study period, we identified 13 patients with confirmed C. auris infection/colonization, of which five cases represented an actual Candida infection, while the remaining eight cases were considered colonization. The mean age of the patients with infection was 76.6 ± 8.4 years (range: 65–90 years), while the mean age of the patients with colonization was 66.4 ± 24.7 years (range: 23–91 years). Table 1 describes the demographic characteristics of the patients involved in this study.Table 1 Candida auris infection/colonization patients details.\n\nTable 1Case/No\tAge\tSex\tSite of infection/ or site of Candida isolation\tType of infection\tPre or co-infection\tCo-morbidity\tTreatment provided\tOutcome\t\n1\t78 years\tMale\tTracheal aspirate and urine\tLower respiratory tract infection\tCorona virus 229 E PCR positive from nasal swab\tInterstitial lung disease\tAnidulafungin\tDied of hypoxic respiratory failure\t\n2\t79 years\tMale\tNose and decubitus ulcer\tSkin soft tissue infection\tPseudomonas MDR and Morganella morganii from decubitus ulcer\tDiabetes mellitus, sacral bed sores\tFlucytosine\tDied of bacterial/fungal sepsis\t\n3\t71 years\tMale\tNose, throat, tracheal aspirate, and decubitus ulcer\tCandidemia\tPseudomonas aeruginosa MDR and ESBL Klebsiella pneumoniae from sputum\tDiabetes mellitus, sacral bed sores\tAnidulafungin and posaconazole\tCured\t\n4\t90 years\tMale\turine, throat and nose\tUrinary tract infection\tKlebsiella pneumoniae and carbapenem resistant Pseudomonas aeruginosa from sputum, Pseudomonas aeruginosa MDR from a bedsore\tCerebrovascular accident, dementia\tAnidulafungin\tCured\t\n5\t65 years\tMale\tThroat, sputum, groin and urine\tUrinary tract infection\tPseudomonas aeruginosa multidrug resistant\tMotor neuron disease, hospital-acquired pneumonia\tAnidulafungin\tDied of bacterial pneumonia\t\n6\t29 years\tMale\tGroin\tColonization\tESBL Klebsiella\tAcute liver failure secondary to hepatitis C, acute kidney injury, critical care polyneuropathy\tTerbinafine spray\tDischarged home\t\n7\t86 years\tMale\tAxilla, urine\tColonization\tPseudomonas aeruginosa\tCOPD, vascular dementia, bedbound on tracheostomy to\tTerbinafine spray, nystatin application\tDied due to aspiration pneumonia and hypoxic respiratory failure\t\n8\t80 years\tFemale\tNose, tracheostomy site\tColonization\tESBL Klebsiella\tChronic kidney disease, coronary artery disease, on tracheostomy\tTerbinafine spray, nystatin application\tTransfer to geriatric ward\t\n9\t62 years\tFemale\tAxilla\tColonization\tPseudomonas multi drug-resistant\tChronic kidney disease, necrotizing fasciitis\tTerbinafine spray, nystatin application\tDied due to bacterial sepsis\t\n10\t91 years\tFemale\tGroin area\tColonization\tNone\tCOPD, hypertension\tTerbinafine spray, nystatin application\tDischarged home\t\n11\t23 years\tMale\tNose, axilla\tColonization\tEscherichia coli\tHypoxic brain injury, recurrent urinary tract infection\tTerbinafine spray, nystatin application\tTransfer to long-term unit\t\n12\t75 years\tMale\tNose, groin\tColonization\tPseudomonas aeruginosa\tDiabetes mellitus, chronic kidney disease, recurrent pneumonia\tTerbinafine spray, nystatin application\tDischarged home\t\n13\t85 years\tMale\turine\tColonization\tPseudomonas aeruginosa\tParkinson’s disease, cerebrovascular accident\tTerbinafine spray, nystatin application\tTransfer to geriatric unit\t\nPCR: polymerase chain reaction, MRD: multi-drug resiatant, ESBL: extended spectrum beta lactamase, COPD: chronic obstructive pulmonary disease.\n\n\n\nAmong the individuals clinically infected with C. auris, two had urinary tract infections, one had candidemia, one acquired soft tissue infection, and one had a lower respiratory tract infection. All patients had bacterial or viral infections prior to or concomitantly with C. auris infection/colonization, as shown in Table 1.\n\nFor the typing of C. auris isolates, the molecular technique PFGE, which consisted of electrophoretic karyotyping (EK), was utilized to compare the isolates from different sites. The PFGE karyotype of the outbreak isolates of C. auris in our series is shown in Fig. 1. Antifungal susceptibility tests were performed on isolates from infected subjects. All strains of C. auris shared the same susceptibility profile, being susceptible to echinocandins (especially anidulafungin), flucytosine, and posaconazole while resistance to fluconazole and amphotericin B. Table 2 shows the susceptibility pattern in the form of minimal inhibitory concentrations (MIC) of antifungal agents for the C. auris isolates. All patients with C. auris infection received systemic antifungal drugs, while the eight patients who were colonized were appropriately decolonized with topical nystatin and terbinafine as recommended by the CDC (Table 1).Fig. 1 Electrophoretic karyotypes of C. auris isolates. Karyotypes of representative outbreak isolates from five patients in the intensive care unit. Lane 1, 2 and 8 are control specimens which served as comparison for different genotypes. Lane 3 to 7 strains (specimens from the five C. auris cases) show no single band variation and are likely representing the same strain.\n\nFig. 1Table 2 Susceptibility pattern in the form of minimal inhibitory concentrations (MIC) of antifungal agents for the C. auris isolates from subjects with infection.\n\nTable 2Antifungal drugs\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\t\nAmphotericin\t4-R\t4-R\t2-R\t4-R\t2-R\t\nCaspofungin\t0.25\t8-R\t8\t0.5\t8\t\nFluconazole\t64\t128-R\t128-R\t128-R\t128-R\t\nFlucytocin\t0.125\t0.5-S\t0.12\t0.12\t0.12\t\nItraconazole\t0.125-R\t16-R\t0.12\t0.12\t16\t\nPosaconazole\t0.012\t8-R\t0.06\t0.06-S\t8\t\nVoriconazole\t0.25\t8-R\t0.25\t0.5\t8\t\nAnidulafungin\t0.125-S\t0.5-I\t0.25\t0.12-S\t0.5-I\t\nMicafungin\t\t\t0.25\t0.12\t0.25\t\nR: resistant, S: sensitive, I: intermediate.\n\n\n\nAmong the patients with C. auris infection who received systemic antifungal therapy, three (60 %) died during antifungal therapy. The other two patients were successfully treated and appropriately decolonized of C. auris (Table 1).\n\nDiscussion\nRecent reports showed that C. auris is an emerging yeast that has been identified worldwide as a cause of severe invasive healthcare infections, which mostly affect critically ill patients and cause substantial morbidity and mortality [7,8]. To our knowledge, our series is the first designed to study this infection in Qatar.\n\nMany C. auris outbreaks have been reported worldwide. In India, the first C. auris outbreak was reported in 2013 by Chowdhary et al. [9] who identified 12 patients with positive microbiological clinical specimens collected between 2009 and 2012. While Calvo et al. reported the first outbreak of C. auris infection in Venezuela between March 2012 and July 2013 [10]. All the isolates were initially identified as C. haemulonii. However, the isolation of C. auris was later confirmed by genome sequencing [9,10]. Similarly, we have reported the first outbreak of C. auris infection in Qatar, identifying 13 patients. The emergence of C. auris in our hospital raises concerns that this fungus may spread to other healthcare settings, particularly critical care facilities in Qatar, requiring intensified measures to control the spread of this infection. Therefore, knowing the source of infection and detection of possible routes of transmission can help in preventing the clonal spread of this infection and hospital outbreaks among various health facilities in Qatar [5,7,8]. Similarly, intensive efforts have been made in our hospital to find the cause of the cross-transmission. Environmental and surface swabs were carried out in the affected areas, but all results were negative.\n\nDiagnosing C. auris infection is difficult because the clinical presentation is non-specific or may not be recognizable since patients infected with C. auris often have another serious illness or condition. Moreover, C. auris can be misidentified with standard laboratory techniques as C. haemulonii [11,12]. As a result, a high index of suspicion is required to diagnose this infection. In addition, accurate identification of C. auris through specialized laboratory methods is required to avoid misidentification and inappropriate treatment that may make it difficult to control the spread of C. auris in the healthcare settings [10]. In this study, the diagnosis of C. auris infection was suspected because of the resistance of the isolates to fluconazole and amphotericin B. The diagnosis was confirmed by molecular methods.\n\nThe spectrum of C. auris infection ranges from superficial infections that affect the skin to widespread infections that affect the brain, heart, lungs, liver, spleen, and kidneys [5]. Antifungal therapy should be administered to eradicate and control C. auris infection. On the other hand, C. auris can be isolated from the skin, rectum, wounds or mouth of some patients who do not show symptoms of infection. This condition is referred to as asymptomatic colonization and treatment with antifungal drugs does not eradicate C. auris colonization. However, the identification of C. auris colonization is significant because it carries the risk of transmission, which requires the immediate implementation of adequate infection control measures [13]. Likewise, our patients showed different clinical presentations, and cases with colonization were identified and appropriately decolonized with topical nystatin and terbinafine as recommended by the CDC.\n\nIn agreement with other reports [[3], [4], [5],7,13], our isolates showed resistance to the most important antifungal agents such as fluconazole and amphotericin B. The all cause mortality among our patients was 60 % which is in line with the mortality rate seen in other studies ranging from 30 to 60% [3].\n\nOne of the limitations of this study is the retrospective nature of the research. In addition, the small sample size is another factor that limits the generalizability of these findings.\n\nConclusion\nC. auris can cause a wide variety of invasive infections, including bloodstream infections, urinary tract infection, skin infection, and lower respiratory tract infection, especially in critically ill patients. In addition, all isolates showed resistance to fluconazole and amphotericin B and were sensitive to echinocandins especially anidulafungin.\n\nAuthors contribution (Authorship)\nAdila Shaukat: Desgning, interpretation of data, revising and approving the final draft.\n\nNasir Al Ansari: conception of the study, revising and approving the final draft.\n\nWalid Al Wali: interpretation of data, revising and approving the final draft.\n\nEdin Karic: interpretation of data, revising and approving the final draft.\n\nIhab El Madhoun: acquisition of data, revising and approving the final draft.\n\nHassan Mitwally: interpretation of data, revising and approving the final draft.\n\nManal Hamed: acquisition of data, revising and approving the final draft.\n\nFeah Alutra- Visan: interpretation of data, drafting the article and approving the final draft.\n\nConflict of interest\nAll authors report no conflict of interest.\n\nAcknowledgement\nOpen Access funding provided by the Qatar National Library.\n\nWe are alsothankful for Dr Jameela Al Ajmi,from Corporate Infection prevention and control dept and Ms Tahani M. Al Saadi from Laboratory department for their corporation and support.\n==== Refs\nReferences\n1 Satoh K. Makimura K. Hasumi Y. Nishiyama Y. Uchida K. Yamaguchi H. Candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a Japanese hospital Microbiol. Immunol. 53 2009 41 44 19161556 \n2 Sears D. Schwartz B.S. Candida auris: an emerging multidrug-resistant pathogen Int J Infect Dis 63 2017 95 98 28888662 \n3 Lockhart S.R. Etienne K.A. Vallabhaneni S. Farooqi J. Chowdhary A. Govender N.P. Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses Clin Infect Dis 64 2 2017 134 140 27988485 \n4 Kordalewska M. Perlin D.S. Identification of drug resistant Candida auris Front Microbiol 10 2019 1918 31481947 \n5 Cortegiani A. Misseri G. Fasciana T. Giammanco A. Giarratano A. Chowdhary A. Epidemiology, clinical characteristics, resistance, and treatment of infections by Candida auris J Intensive Care 6 2018 69 30397481 \n6 Cdc website: https://www.cdc.gov/fungal/candida-auris/c-auris-antifungal.html (accessed 1 september 2020).\n7 Chowdhary A. Sharma C. Meis J.F. Candida auris: a rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally PLoS Pathog 13 2017 e1006290 \n8 Jeffery-Smith A. Taori S.K. Schelenz S. Jeffery K. Johnson E.M. Borman A. Candida auris: a review of the literature Clin Microbiol Rev 31 1 2017 e00029 17 29142078 \n9 Chowdhary A. Sharma C. Duggal S. New clonal strain of Candida auris, Delhi, India Emerg Infect Dis. 19 10 2013 1670 1673 24048006 \n10 Calvo B. Melo A.S.A. Perozo-Mena A. Hernandez M. Francisco E.C. Hagen F. First report of Candida auris in America: clinical and microbiological aspects of 18 episodes of candidemia J Inf Secur 73 2016 369 374 \n11 Tian S. Rong C. Nian H. First cases and risk factors of super yeast Candida auris infection or colonization from Shenyang, China Emerg Microbes Infect 7 1 2018 128 29992959 \n12 Virgin department of health: https://www.vdh.virginia.gov/epidemiology/epidemiology-fact-sheets/candida-auris-infection/ (Accessed 1 September 2020).\n13 Tsay S. Kallen A. Jackson B.R. Chiller T.M. Vallabhaneni S. Approach to the investigation and management of patients with Candida auris, an emerging multidrug-resistant yeast Clin Infect Dis 66 2 2018 306 311 29020224\n\n",
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"keywords": "Candida auris; Candidemia; Colonization; Respiratory tract infection; Skin infection.; Urinary tract infection",
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"title": "Experience of treating Candida auris cases at a general hospital in the state of Qatar.",
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"abstract": "We herein present three cases of locally advanced colon cancer (LACC) invading the urinary bladder, in whom combined neoadjuvant chemotherapy with surgical intervention was effective in disease control and preserving urinary function.\nBefore neoadjuvant chemotherapy, all three cases underwent loop transverse colostomy for symptomatic colonic obstruction. Case 1: after 6 courses of capecitabine plus oxaliplatin (CAPOX), we performed sigmoid colectomy and partial resection of the bladder. The histological examination revealed pathological complete response (pCR). The final diagnosis was ypStage 0 (ypT0ypN0M0). Case 2: after 13 courses of CAPOX plus bevacizumab, we performed Hartmann's operation with partial resection of the bladder. The histological examination revealed pCR. The final diagnosis was ypStage 0 (ypT0ypN0M0). Case 3: after 6 courses of chemotherapy with CAPOX plus bevacizumab, we performed sigmoid colectomy and partial resection of the bladder. The pathological response was grade 1a according to the Japanese Classification of Colorectal Carcinoma. The final diagnosis was ypStage IIC (ypT4bypN0M0). All three cases underwent capecitabine-based adjuvant chemotherapy after radical surgery and patients are alive without recurrence.\nNeoadjuvant chemotherapy with CAPOX with or without bevacizumab followed by radical surgery could be an effective treatment option for LACC invading the urinary bladder.",
"affiliations": "Department of Surgery, Saitama Medical Center, Jichi Medical University, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Japan.;Department of Pathology, Saitama Medical Center, Jichi Medical University, Japan.;Department of Surgery, Saitama Medical Center, Jichi Medical University, Japan.",
"authors": "Takenami|Tsutomu|T|;Tsujinaka|Shingo|S|0000-0002-8554-3869;Takahashi|Jun|J|;Tamaki|Sawako|S|;Maemoto|Ryo|R|;Fukuda|Rintaro|R|;Ishikawa|Hideki|H|;Kakizawa|Nao|N|;Hasegawa|Fumi|F|;Kikugawa|Rina|R|;Miyakura|Yasuyuki|Y|;Suzuki|Koichi|K|;Tanaka|Akira|A|;Rikiyama|Toshiki|T|",
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"doi": "10.1155/2019/8129358",
"fulltext": "\n==== Front\nCase Rep SurgCase Rep SurgCRISCase Reports in Surgery2090-69002090-6919Hindawi 10.1155/2019/8129358Case ReportEfficacy of Neoadjuvant Chemotherapy with Capecitabine plus Oxaliplatin in the Treatment of Locally Advanced Sigmoid Colon Cancer Invading the Urinary Bladder: A Report of Three Cases Takenami Tsutomu \n1\nhttp://orcid.org/0000-0002-8554-3869Tsujinaka Shingo tsujinakas@omiya.jichi.ac.jp\n1\nTakahashi Jun \n1\nTamaki Sawako \n1\nMaemoto Ryo \n1\nFukuda Rintaro \n1\nIshikawa Hideki \n1\nKakizawa Nao \n1\nHasegawa Fumi \n1\nKikugawa Rina \n1\nMiyakura Yasuyuki \n1\nSuzuki Koichi \n1\nTanaka Akira \n2\nRikiyama Toshiki \n1\n\n1Department of Surgery, Saitama Medical Center, Jichi Medical University, Japan\n2Department of Pathology, Saitama Medical Center, Jichi Medical University, JapanAcademic Editor: Frederique Marchal\n\n2019 27 3 2019 2019 81293583 2 2019 7 3 2019 Copyright © 2019 Tsutomu Takenami et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction\n We herein present three cases of locally advanced colon cancer (LACC) invading the urinary bladder, in whom combined neoadjuvant chemotherapy with surgical intervention was effective in disease control and preserving urinary function. \n\nCase Presentation\n Before neoadjuvant chemotherapy, all three cases underwent loop transverse colostomy for symptomatic colonic obstruction. Case 1: after 6 courses of capecitabine plus oxaliplatin (CAPOX), we performed sigmoid colectomy and partial resection of the bladder. The histological examination revealed pathological complete response (pCR). The final diagnosis was ypStage 0 (ypT0ypN0M0). Case 2: after 13 courses of CAPOX plus bevacizumab, we performed Hartmann's operation with partial resection of the bladder. The histological examination revealed pCR. The final diagnosis was ypStage 0 (ypT0ypN0M0). Case 3: after 6 courses of chemotherapy with CAPOX plus bevacizumab, we performed sigmoid colectomy and partial resection of the bladder. The pathological response was grade 1a according to the Japanese Classification of Colorectal Carcinoma. The final diagnosis was ypStage IIC (ypT4bypN0M0). All three cases underwent capecitabine-based adjuvant chemotherapy after radical surgery and patients are alive without recurrence. \n\nConclusion\n Neoadjuvant chemotherapy with CAPOX with or without bevacizumab followed by radical surgery could be an effective treatment option for LACC invading the urinary bladder.\n==== Body\n1. Introduction\nColon cancer is the third most common cancer and one of the leading causes of cancer-associated mortality worldwide [1, 2]. Locally advanced colon cancer (LACC) is defined as a primary colon cancer invading adjacent organs or involving extensive regional lymph nodes in patients with Union for International Cancer Control stage IIC or III [3, 4]. Clinical guidelines recommend adjuvant chemotherapy as an established treatment for patients with stages IIC and III colorectal cancer [5]. The current standard of treatment for LACC is complete surgical removal of the tumor followed by adjuvant chemotherapy; however, the 5-year overall survival for LACC patients ranges from 37.3% in stage IIC patients to 28% in stage IIIC [6]. Thus, the oncological outcome of those patients remains unsatisfactory.\n\nNeoadjuvant treatment before surgery has demonstrated oncological benefits in locally advanced rectal cancer [7, 8]. In contrast, the efficacy of neoadjuvant chemotherapy for LACC patients has been reported in limited case reports [9, 10]. Moreover, several studies have evaluated the feasibility and advantage of neoadjuvant treatment before surgery for LACC [3, 11–13]. Arredondo et al. investigated the midterm prognosis of LACC patients who underwent neoadjuvant chemotherapy followed by radical surgery, showing improved prognosis with a 5-year relapse-free survival of 85.6% and 5-year overall survival of 95.3% after the median follow-up of 40.1 months [13]. Furthermore, in terms of organ preservation, preoperative chemoradiotherapy for LACC involving adjacent organs could avoid extensive multivisceral resection and achieve an improved quality of life, especially in urinary function [14, 15]. However, the appropriate regimen for neoadjuvant chemotherapy for LACC patients has not been well-established.\n\nWe herein report three cases of locally advanced sigmoid colon cancer invading the urinary bladder in which neoadjuvant chemotherapy with capecitabine plus oxaliplatin (CAPOX) followed by surgery was effective in both improving oncological outcome and organ preservation.\n\n2. Case Presentation\n2.1. Case 1\nA 78-year-old man presented with constipation and abdominal distension. His medical history was remarkable for diabetes mellitus and dilated cardiomyopathy. Laboratory data were unremarkable except for a slightly increased level of cancer antigen 19-9 (45.8 U/ml). Colonoscopy revealed a circumferential impassable tumor located 28 cm from the anal verge. Contrast-enhanced computed tomography (CT) showed irregular colonic wall thickening with infiltration into the urinary bladder (Figure 1(a)). No lymph node enlargement or distant metastases were found. Histological examination of the biopsy revealed adenocarcinoma. The RAS/RAF mutational status was not investigated. The pretreatment diagnosis was LACC stage IIC (T4bN0M0). We surmised that immediate radical surgery would result in substantial bladder resection with impaired urinary function. Therefore, neoadjuvant chemotherapy before radical surgery was planned.\n\nFirstly, we performed loop transverse colostomy for symptomatic colonic obstruction. Secondly, we planned 6 courses of chemotherapy with CAPOX and the treatment was initiated 1 month after the loop colostomy. We did not add molecular targeted agents because of his reduced cardiac function (ejection fraction of 21%). Follow-up CT after 3 courses of CAPOX revealed significant tumor shrinkage (Figure 1(b)). However, after 5 courses of CAPOX, grade 1 neurotoxicity and grade 2 neutropenia were observed. As he did not wish to receive oxaliplatin, the 6th course comprised capecitabine alone. Follow-up CT after the treatment (5 courses of CAPOX and 1 course of capecitabine alone) showed tumor disappearance (Figure 1(c)).\n\nThereafter, we performed sigmoid colectomy, partial resection of the bladder, and diverting ileostomy. The postoperative course was uneventful, and he did not suffer from neurogenic voiding dysfunction or urinary incontinence. Well-tolerated pathological examination revealed no residual tumor cells in the resected specimen, which was consistent with pathological complete response (pCR) and grade 3 effect according to the Japanese Classification of Colorectal Carcinoma (Figure 2) [16]. The final pathological diagnosis was ypT0, ypN0, M0, ypStage 0. We then planned 8 courses of adjuvant chemotherapy with CAPOX. After 4 courses, he developed grade 2 neutropenia despite a dose reduction (70%) for oxaliplatin. Therefore, the following 4 courses of chemotherapy comprised capecitabine alone. Subsequently, he underwent ileostomy closure and had no recurrence at 25 months after the initial diagnosis.\n\n2.2. Case 2\nA 79-year-old man presented with abdominal pain. His medical history was significant for high blood pressure without the need for medication. Laboratory data revealed an increased level of carcinoembryonic antigen (77.5 ng/ml) and a normal level of cancer antigen 19-9 (33.7 U/ml). Colonoscopy revealed an advanced tumor with 80% of the circumference in the sigmoid colon. Histological examination of the biopsy revealed adenocarcinoma. The RAS/RAF mutational status was not investigated. Contrast-enhanced CT showed irregular colonic wall thickening with infiltration into the urinary bladder (Figure 3(a)). There were enlarged regional lymph nodes suggestive of metastases but no distant metastasis. The pretreatment diagnosis was LACC stage IIIC (T4bN2M0).\n\nSimilar to Case 1, we initially performed loop transverse colostomy. Subsequently, we planned 6 courses of neoadjuvant chemotherapy with CAPOX plus bevacizumab followed by surgery; however, the patient wished to continue chemotherapy rather than have surgery. No significant adverse events occurred. After 13 courses, CT showed significant tumor shrinkage and reduction of bladder wall thickening (Figure 3(c)). Colonoscopy revealed the disappearance of the primary tumor. Thereafter, he agreed to undergo surgery.\n\nWe performed Hartmann's operation with partial resection of the bladder. The postoperative course was uneventful, and he did not suffer from neurogenic voiding dysfunction or urinary incontinence. Pathological examination revealed no residual tumor cells in the resected specimen with foci of fibrotic tissue and inflammatory cell infiltration, which was consistent with pCR and grade 3 effect according to the Japanese Classification of Colorectal Carcinoma (Figure 4) [16]. The final pathological diagnosis was ypT0, ypN0, M0, ypStage 0. He then received 8 courses of adjuvant chemotherapy with CAPOX. Hartmann's reversal was not performed because he did not wish to do so. There was no recurrence at 65 months after the initial diagnosis.\n\n2.3. Case 3\nA 74-year-old woman presented with body weight loss. Her medical history included hypertension and diabetes mellitus, both of which were well-controlled by medication. Laboratory data were unremarkable except for decreased hemoglobin (9.1 g/dl). Tumor markers were within normal limits. Colonoscopy revealed a circumferential tumor in the sigmoid colon. Histological examination of the biopsy revealed RAS-mutant adenocarcinoma. The RAF mutational status was not investigated. Contrast-enhanced CT showed irregular colonic wall thickening with massive involvement of the urinary bladder (Figure 5(a)). There were enlarged regional lymph nodes suggestive of metastases but no distant metastasis. The pretreatment diagnosis was LACC stage IIIC (T4bN2M0).\n\nSimilar to Cases 1 and 2, we initially performed loop transverse colostomy. Subsequently, we planned 6 courses of chemotherapy with CAPOX plus bevacizumab. The patient eventually received 5 courses of CAPOX plus bevacizumab and the remaining 1 course without oxaliplatin due to grade 2 neurotoxicity. Follow-up CT after the neoadjuvant chemotherapy revealed significant tumor shrinkage (Figure 5(b)).\n\nThereafter, we performed sigmoid colectomy and partial resection of the bladder. The postoperative course was uneventful, and the patient did not suffer from neurogenic voiding dysfunction or urinary incontinence. Pathological examination revealed that tumor cells or degeneration was present in less than one third of the entire lesion, which was consistent with grade 1a effect according to the Japanese Classification of Colorectal Carcinoma (Figure 6) [16]. The final diagnosis was ypT4b, ypN0, M0, ypStage IIC. She subsequently received 8 courses of adjuvant chemotherapy with capecitabine alone. There was no recurrence at 16 months after the initial diagnosis.\n\n3. Discussion\nThe efficacy of neoadjuvant chemotherapy for potentially resectable LACC is uncertain. En bloc multivisceral resection is the standard surgical procedure for LACC invading adjacent structures [17, 18]. Although R0 resection rates ranged from 65.0% to 93.1%, postoperative rates of complications (25.8-33.0%) and mortality (6.9-7.5%) were high. In addition, aggressive surgical procedures may damage the function of adjacent organs when resected together. A previous study indicated that the urinary bladder is the most frequently involved organ in patients with LACC [19]. Therefore, oncologic clearance and organ preservation must be carefully balanced. Recently, several studies have shown the efficacy of neoadjuvant treatment followed by surgery for LACC [3, 11–13]. In this report, we suggested a new treatment strategy of neoadjuvant chemotherapy using CAPOX with or without bevacizumab to improve cancer prognosis and preserve urinary function for patients with T4b LACC involving the urinary bladder.\n\nIn our cases, CT scan showed substantial cancer invasion into the urinary bladder. At the pretreatment discussions, extensive resection of the bladder was deemed necessary in Cases 1 and 2, and subtotal or total cystectomy might be appropriate for curative resection in Case 3. The invasion to the urinary bladder prompted the administration of neoadjuvant chemotherapy, and this strategy successfully led to tumor shrinkage in all cases. The operative findings of Cases 1 and 2 showed spreading inflammation around the sigmoid colon, where the primary tumor was originally located. However, intraoperative discrimination of inflammatory adhesions from malignant invasion is extremely difficult; therefore, we performed combined resection of the affected area of the bladder including the detrusor muscle layer. On the other hand, in Case 3, CT scan after neoadjuvant chemotherapy still indicated the presence of communication between the sigmoid colon and the bladder. Therefore, we performed sigmoid colectomy with full-thickness resection (including mucosa) of the bladder. After successful en bloc resection of the primary lesion, the defect of the bladder was then closed in an interrupted layer-to-layer manner. Although partial cystectomy was necessary in all cases, they did not complain of any related symptoms such as pollakiuria, urinary urgency, urinary incontinence, and incomplete voiding after surgery. Thus, urinary function was well preserved in all cases. We assumed that our treatment strategy was effective in organ preservation.\n\nWith respect to the oncological outcome, Arredondo et al. reported good midterm prognosis for LACC patients with neoadjuvant chemotherapy followed by radical surgery [13]. They concluded that cancer survival of those patients was encouraging. A systemic review and meta-analysis demonstrated that patients with locally advanced rectal cancer who had complete response to neoadjuvant chemoradiotherapy exhibited excellent long-term survival and low local recurrence rates [20]. Another study indicated that locally advanced rectal cancer patients with pCR after chemoradiotherapy achieved improved disease-free survival and overall survival rates than those without pCR [21]. Currently, a phase II trial is ongoing which evaluates disease-free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy [22]. The results of this trial would certainly bring new insights to the field of neoadjuvant treatment for locally advanced rectal cancer.\n\nIn contrast, there are few studies investigating the survival rates of LACC patients with pCR. Nevertheless, it is conceivable that LACC patients with pCR might have improved prognosis and survival rates, similar to rectal cancer patients. In fact, in Case 2 of our report, the patient showed 61 months of recurrence-free survival after the initial treatment. This result supports the concept that LACC patients who achieved pCR after neoadjuvant chemotherapy followed by radical surgery can survive longer than patients without neoadjuvant chemotherapy.\n\nOne of the concerns with neoadjuvant chemotherapy for LACC is the choice of regimen. Pilot clinical trials adopted oxaliplatin, fluorouracil, and leucovorin (OxMdG) with or without panitumumab, CAPOX with or without panitumumab, and infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) without molecular agent [3, 11, 13]. To date, the standard neoadjuvant regimen for LACC patients has not been established. FOLFOX and CAPOX are the standard adjuvant chemotherapy regimens for high-risk stage II and III colorectal cancer patients and are also used as first-line chemotherapy for metastatic colorectal cancer (mCRC) [23, 24]. A phase III clinical trial is recently in progress to compare the efficacy and safety of the neoadjuvant and adjuvant CAPOX chemotherapy with the postoperative one for locally advanced resectable colon cancer [25]. Furthermore, CAPOX can be used as radiosensitizer for neoadjuvant chemoradiation in downstaging locally advanced rectal cancer [26]. We selected CAPOX as the neoadjuvant chemotherapy because we believed it was advantageous that the medications could be delivered without the use of a venous reservoir implant. Moreover, the addition of bevacizumab to an oxaliplatin-based regimen is the standard first-line chemotherapy for mCRC cancer patients; we thus added bevacizumab to the neoadjuvant chemotherapy regimen unless contraindicated [27]. In Case 1, the ejection fraction was 21% as determined by echocardiography; hence, we did not add bevacizumab to his neoadjuvant treatment. In this report, all three patients were elderly (in their 70s) with some comorbidities. Younger patients with fewer comorbidities could have benefited from other triplet regimens such as fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab [28].\n\nRecent reports suggested that primary tumor location in terms of right- versus left-sided cancer is associated with survival difference in mCRC patients [29–31]. Tejpar et al. investigated the prognostic relevance of primary tumor location in patients with RAS wild-type mCRC [32] and concluded that patients with left-sided mCRC have remarkably better prognosis than patients with right-sided mCRC. Moreover, they indicated that first-line infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab benefitted patients with left-sided cancer. Therefore, RAS testing is strongly recommended before the induction of neoadjuvant chemotherapy for LACC, for the choice of antiepidermal growth factor receptor (EGFR) agents in the treatment regimen. In our cases, the RAS mutation was positive in Case 3; however, it was not investigated in Cases 1 and 2. Currently, the RAS/RAF testing is universally available for LACC in our institution and the status of which would determine our therapeutic approach.\n\nAnother therapeutic option for obstructive sigmoid colon cancer is the self-expanding metallic stent (SEMS), which has been widely applied in patients with malignant large bowel obstruction [33]. The use of a SEMS as a bridge to surgery is advantageous as it avoids colostomy. However, as Lee et al. implied that chemotherapy after deploying a SEMS in mCRC patients might cause intestinal perforation, we opted for colostomy creation followed by neoadjuvant chemotherapy for safer administration during continuous chemotherapy [34]. Moreover, guidelines indicated that SEMS placement is not recommended in patients treated with antiangiogenic agents [35]. The optimal timing of radical surgery after neoadjuvant chemotherapy has never been investigated in LACC. Due to the potential outgrowth of the primary tumor during neoadjuvant chemotherapy, we might miss the appropriate timing for surgical intervention. Further prospective studies are required to evaluate the feasibility of this strategy.\n\nAlthough neoadjuvant chemotherapy regimens for LACC patients remain unknown, it is important to select the appropriate regimen depending on primary tumor location, RAS status, and comorbidity of the patients.\n\n4. Conclusion\nNeoadjuvant chemotherapy with CAPOX with or without bevacizumab followed by radical surgery could be an effective treatment option in terms of both improving oncological outcome and organ preservation for LACC invading the urinary bladder. Further prospective studies are needed to evaluate the feasibility of this treatment strategy.\n\nConflicts of Interest\nThe authors declare that there is no conflict of interests regarding the publication of this article.\n\nFigure 1 Coronal section of CT indicated the efficacy of neoadjuvant chemotherapy. Before chemotherapy (a). After 3 courses of CAPOX (b). After 5 courses, the tumor had disappeared (c).\n\nFigure 2 Pathological findings revealed no viable cells with collagen fibers. Original magnification: ×200.\n\nFigure 3 Before treatment, CT scan revealed a bulky mass in the sigmoid colon invading the bladder (a). After 6 courses of CAPOX (b). CT failed to detect the tumor after 13 courses of CAPOX plus bevacizumab (c).\n\nFigure 4 Microscopic findings showed no residual tumor cells with foci of fibrotic tissue and inflammatory cell infiltration. Original magnification: ×200.\n\nFigure 5 Contrast-enhanced CT showed an irregular mass with infiltration into the bladder. The arrow indicates the communication between the mass and the bladder (a). After 5 courses of neoadjuvant chemotherapy, CT scan revealed shrinkage of the primary tumor (b).\n\nFigure 6 Viable cells were observed in less than one third of the lesion. The histological effect was consistent with grade 1a. Original magnification: ×40.\n==== Refs\n1 Torre L. A. Bray F. Siegel R. L. Ferlay J. Lortet-Tieulent J. Jemal A. Global cancer statistics, 2012 CA: A Cancer Journal for Clinicians 2015 65 2 87 108 10.3322/caac.21262 2-s2.0-84924271853 25651787 \n2 Siegel R. L. Miller K. D. Jemal A. Cancer statistics, 2018 CA: A Cancer Journal for Clinicians 2018 68 1 7 30 10.3322/caac.21442 2-s2.0-85040049759 29313949 \n3 FOxTROT Collaborative Group Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: the pilot phase of a randomised controlled trial The Lancet Oncology 2012 13 11 1152 1160 10.1016/S1470-2045(12)70348-0 2-s2.0-84868206154 23017669 \n4 Smith N. J. 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Neoadjuvant FOLFOX chemotherapy combined with radiotherapy followed by radical resection in patients with locally advanced colon cancer Radiation Oncology 2017 12 1 p. 48 10.1186/s13014-017-0790-3 2-s2.0-85014657387 28270172 \n13 Arredondo J. Baixauli J. Pastor C. Mid-term oncologic outcome of a novel approach for locally advanced colon cancer with neoadjuvant chemotherapy and surgery Clinical and Translational Oncology 2017 19 3 379 385 10.1007/s12094-016-1539-4 2-s2.0-84983009851 27496023 \n14 Qiu B. Ding P. R. Cai L. Outcomes of preoperative chemoradiotherapy followed by surgery in patients with unresectable locally advanced sigmoid colon cancer Chinese Journal of Cancer 2016 35 1 p. 65 10.1186/s40880-016-0126-y 2-s2.0-85015355192 27389519 \n15 Chang H. Yu X. Xiao W. W. Neoadjuvant chemoradiotherapy followed by surgery in patients with unresectable locally advanced colon cancer: a prospective observational study OncoTargets and Therapy 2018 11 409 418 10.2147/OTT.S150367 2-s2.0-85040909577 29398921 \n16 Japanese Society of Cancer of the Colon and Rectum Japanese Classification of the Colorectal, Appendiceal, and Anal Carcinoma 2018 9th Tokyo, Japan Kanehara & Co., Ltd. \n17 Lehnert T. Methner M. Pollok A. Schaible A. Hinz U. Herfarth C. Multivisceral resection for locally advanced primary colon and rectal cancer: an analysis of prognostic factors in 201 patients Annals of Surgery 2002 235 2 217 225 10.1097/00000658-200202000-00009 2-s2.0-0036155028 11807361 \n18 Croner R. S. Merkel S. Papadopoulos T. Schellerer V. Hohenberger W. Goehl J. Multivisceral resection for colon carcinoma Diseases of the Colon and Rectum 2009 52 8 1381 1386 10.1007/DCR.0b013e3181ab580b 2-s2.0-68149148721 19617748 \n19 Talamonti M. S. Shumate C. R. Carlson G. W. Curley S. A. Locally advanced carcinoma of the colon and rectum involving the urinary bladder Surgery, Gynecology & Obstetrics 1993 177 5 481 487 8211600 \n20 Martin S. T. Heneghan H. M. Winter D. C. Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer British Journal of Surgery 2012 99 7 918 928 10.1002/bjs.8702 2-s2.0-84862775402 22362002 \n21 Maas M. Nelemans P. J. Valentini V. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data The Lancet Oncology 2010 11 9 835 844 10.1016/S1470-2045(10)70172-8 2-s2.0-77956185901 20692872 \n22 Aguilar J. G. Trial evaluating 3-year disease free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy and total mesorectal excision or non-operative management https://clinicaltrials.gov/ct2/show/NCT02008656 \n23 Cassidy J. Clarke S. Díaz-Rubio E. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer Journal of Clinical Oncology 2008 26 12 2006 2012 10.1200/JCO.2007.14.9898 2-s2.0-42949150908 18421053 \n24 André T. de Gramont A. Vernerey D. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study Journal of Clinical Oncology 2015 33 35 4176 4187 10.1200/JCO.2015.63.4238 2-s2.0-84957568046 26527776 \n25 Liu F. Tong T. Huang D. CapeOX perioperative chemotherapy versus postoperative chemotherapy for locally advanced resectable colon cancer: protocol for a two-period randomised controlled phase III trial BMJ Open 2019 9 1, article e017637 10.1136/bmjopen-2017-017637 30700474 \n26 Saha A. Ghosh S. Roy C. Saha M. Choudhury K. Chatterjee K. A randomized controlled pilot study to compare capecitabine-oxaliplatin with 5-FU-leucovorin as neoadjuvant concurrent chemoradiation in locally advanced adenocarcinoma of rectum Journal of Cancer Research and Therapeutics 2015 11 1 88 93 10.4103/0973-1482.150341 2-s2.0-84928633026 25879343 \n27 Saltz L. B. Clarke S. Díaz-Rubio E. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study Journal of Clinical Oncology 2008 26 12 2013 2019 10.1200/JCO.2007.14.9930 2-s2.0-42949149159 18421054 \n28 Loupakis F. Cremolini C. Masi G. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer The New England Journal of Medicine 2014 371 17 1609 1618 10.1056/NEJMoa1403108 2-s2.0-84908139591 25337750 \n29 Price T. J. Beeke C. Ullah S. Does the primary site of colorectal cancer impact outcomes for patients with metastatic disease? Cancer 2015 121 6 830 835 10.1002/cncr.29129 2-s2.0-84924106166 25377235 \n30 Brulé S. Y. Jonker D. J. Karapetis C. S. Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17 European Journal of Cancer 2015 51 11 1405 1414 10.1016/j.ejca.2015.03.015 2-s2.0-84930804509 25979833 \n31 Engstrand J. Nilsson H. Stromberg C. Jonas E. Freedman J. Colorectal cancer liver metastases - a population-based study on incidence, management and survival BMC Cancer 2018 18 1 p. 78 10.1186/s12885-017-3925-x 2-s2.0-85040663788 29334918 \n32 Tejpar S. Stintzing S. Ciardiello F. Prognostic and Predictive Relevance of Primary Tumor Location in Patients With RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses of the CRYSTAL and FIRE-3 Trials JAMA Oncology 2017 3 2 p. 194 10.1001/jamaoncol.2016.3797 2-s2.0-85018205885 \n33 Zhang Y. Shi J. Shi B. Song C. Y. Xie W. F. Chen Y. X. Self-expanding metallic stent as a bridge to surgery versus emergency surgery for obstructive colorectal cancer: a meta-analysis Surgical Endoscopy 2012 26 1 110 119 10.1007/s00464-011-1835-6 2-s2.0-84857215714 21789642 \n34 Lee W. S. Baek J. H. Kang J. M. Choi S. Kwon K. A. The outcome after stent placement or surgery as the initial treatment for obstructive primary tumor in patients with stage IV colon cancer American Journal of Surgery 2012 203 6 715 719 10.1016/j.amjsurg.2011.05.015 2-s2.0-84862776889 22265203 \n35 van Hooft J. van Halsema E. Vanbiervliet G. Self-expandable metal stents for obstructing colonic and extracolonic cancer: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline Endoscopy 2014 46 11 990 1053 10.1055/s-0034-1390700 2-s2.0-84911934818 25325682\n\n",
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"title": "Efficacy of Neoadjuvant Chemotherapy with Capecitabine plus Oxaliplatin in the Treatment of Locally Advanced Sigmoid Colon Cancer Invading the Urinary Bladder: A Report of Three Cases.",
"title_normalized": "efficacy of neoadjuvant chemotherapy with capecitabine plus oxaliplatin in the treatment of locally advanced sigmoid colon cancer invading the urinary bladder a report of three cases"
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"abstract": "BACKGROUND\nActive tuberculosis constitutes a relevant risk for kidney transplant recipients. In contrast to immunocompetent hosts, kidney transplant recipients often show atypical presentation and course of the disease impeding diagnosis. Especially extrapulmonary or disseminated infection is more frequent and can resemble malignant processes. However, reactivation of tuberculosis mostly develops within the early post-transplant course, whereas malignancies are predominantly long-term complications. We report a case of disseminated abdominal tuberculosis developing 10 years after kidney transplantation and review the underlying literature.\nA 51-year-old lady presented with epigastric pain, diarrhea, weight loss and night sweats 10 years after deceased-donor kidney transplantation. An epigastric as well as multiple peritoneal masses were found suspicious of a cancer of unknown primary. Colonoscopy revealed a colon tumor with the biopsy showing no dysplasia but histiocytic and granulomatous infiltration with acid-fast bacilli. Mycobacterium tuberculosis was detected in the biopsy and stool and disseminated abdominal tuberculosi was diagnosed.\n\n\nRESULTS\nWith anti-tuberculosis therapy, the masses regressed, and all cultures became sterile, sparing graft function.\n\n\nCONCLUSIONS\nThis case emphasizes how variable and unspecific the presentation of tuberculosis in kidney transplant recipients may be and that tuberculosis constitutes a relevant risk also in the long-term post-transplant course.",
"affiliations": "Department of Nephrology and Hypertension.;Department of Nephrology and Hypertension.;Department of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany.;Department of Nephrology and Hypertension.;Department of Nephrology and Hypertension.",
"authors": "Schmidt-Lauber|Christian|C|;Jacobi|Johannes|J|;Polifka|Iris|I|;Hilgers|Karl F|KF|;Wiesener|Michael S|MS|",
"chemical_list": "D000995:Antitubercular Agents",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31490381MD-D-19-0165210.1097/MD.0000000000016995169955200Research ArticleClinical Case ReportSuspected colonic cancer turns out to be disseminated tuberculosis in a kidney transplant recipient A case reportSchmidt-Lauber Christian MDa∗Jacobi Johannes MDaPolifka Iris MDbHilgers Karl F. MDaWiesener Michael S. MDaNA. a Department of Nephrology and Hypertensionb Department of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany.∗ Correspondence: Christian Schmidt-Lauber, Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Ulmenweg 18, D-91054 Erlangen, Germany (e-mail: christian.schmidt-lauber@uk-erlangen.de).9 2019 06 9 2019 98 36 e1699527 2 2019 7 7 2019 7 8 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nRationale:\nActive tuberculosis constitutes a relevant risk for kidney transplant recipients. In contrast to immunocompetent hosts, kidney transplant recipients often show atypical presentation and course of the disease impeding diagnosis. Especially extrapulmonary or disseminated infection is more frequent and can resemble malignant processes. However, reactivation of tuberculosis mostly develops within the early post-transplant course, whereas malignancies are predominantly long-term complications. We report a case of disseminated abdominal tuberculosis developing 10 years after kidney transplantation and review the underlying literature.\n\nPatient concerns and diagnoses:\nA 51-year-old lady presented with epigastric pain, diarrhea, weight loss and night sweats 10 years after deceased-donor kidney transplantation. An epigastric as well as multiple peritoneal masses were found suspicious of a cancer of unknown primary. Colonoscopy revealed a colon tumor with the biopsy showing no dysplasia but histiocytic and granulomatous infiltration with acid-fast bacilli. Mycobacterium tuberculosis was detected in the biopsy and stool and disseminated abdominal tuberculosi was diagnosed.\n\nInterventions and outcomes:\nWith anti-tuberculosis therapy, the masses regressed, and all cultures became sterile, sparing graft function.\n\nLessons:\nThis case emphasizes how variable and unspecific the presentation of tuberculosis in kidney transplant recipients may be and that tuberculosis constitutes a relevant risk also in the long-term post-transplant course.\n\nKeywords\nabdominal massescolon tumorkidney transplantationperitoneal carcinomatosistuberculosisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nInfections such as tuberculosis as well as malignancies are 2 major complications after kidney transplantation. Despite screening and prophylaxis programs for kidney transplant candidates, the risk for primary or reactivation of latent tuberculosis is highly increased after transplantation. Depending on the geographic region, the incidence of active tuberculosis after kidney transplantation varies from 1% in developed and up to 15% in highly endemic countries.[1] Furthermore, the presentation and course of the disease differ significantly from that in immunocompetent hosts.[2] About 30% to 40% of tuberculosis after kidney transplantation are disseminated when diagnosed and involvement of extra-pulmonary organs is much more frequent than in immunocompetent hosts.[3,4] The most common extrapulmonary site is the gastrointestinal tract.[3] Symptoms of abdominal and gastrointestinal tuberculosis are often unspecific and include abdominal pain, loss of weight, and appetite, as well as fever.[5] Given these unspecific symptoms, abdominal tuberculosis is not always easy to distinguish from other abdominal diseases such as malignancies. Diagnosis is further challenged by the fact that tuberculin skin tests and interferon-gamma release assays have lower sensitivities in solid-organ transplant recipients.[6] However, reactivation of tuberculosis mostly develops within the early post-transplant course, whereas malignancies are predominantly long-term complications.[4,7–10]\n\nHere we report a case of abdominal tuberculosis in a kidney transplant recipient resembling a metastatic colon cancer, which occurred in the long-term post-transplant course. We highlight the diagnostic challenge and review the underlying literature.\n\n2 Case presentation\nWe report a 51-year-old woman who was admitted to our hospital 10 years after a deceased-donor kidney transplantation with epigastric pain, intermittent non-bloody diarrhea, undefined weight loss, and night sweats. She was born in the Philippines and moved to Germany as a young adult. The last oversea travel to the Philippines was 3 years ago and she denied any animal contact or intake of raw meat or unpasteurized milk. Her medical history was remarkable for end-stage renal disease of unknown origin with a 7-year hemodialysis therapy. No biopsy of the native kidneys was performed. The pretransplant screening status of latent tuberculosis is unknown and there was no history of malignancies. Her post-transplant course was complicated by 2 cellular borderline rejections within the first post-transplant year and subsequent impaired allograft function as well as anemia with iron deficiency. Her kidney function was stable with creatinine values at admission of approximately 2.1 mg/dL (estimated glomerular filtration rate [eGFR] 30 mL/min MDRD). Current medication included cyclosporine (80 mg twice per day, target levels 50 to 70 ng/mL), mycophenolic acid (360 mg twice per day), prednisolone (5 mg once per day), fluvastatin, and oral iron. The patient was in good general condition; physical examination only revealed epigastric tenderness on palpation. Laboratory testing was evident for microcytic and hypochromic anemia (hemoglobin 10.6 g/dL) as well as elevated levels of white blood cells (23.4 × 103 cells/μL), lactate dehydrogenase (677 U/L), C-reactive protein (165 mg/L), and creatinine (2.6 mg/dL).\n\nThe patient developed low-grade fever and urine microscopy was positive for bacteria and white blood cells. A urinary tract infection was assumed, and antibiotic therapy initiated. The fever ceased but urinary culture only showed Escherichia coli in nonrelevant counts. An abdominal ultrasound was evident for an epigastric hyperechogenic mass infiltrating the pancreas and a subsequent computed tomography (CAT) scan revealed multiple peritoneal lesions. A tumor in the right adrenal gland was described as well as enlarged retroperitoneal lymph nodes highly susceptive for a malignant process of unknown origin (Fig. 1A). A chest CAT scan showed no pulmonary abnormalities. Further endoscopic evaluation found an exophytic and ulcerating tumor in the right transverse colon and a metastatic colon cancer was suspected (Fig. 1B). Surprisingly, the pathological result of the biopsy taken from the colonic mass showed no dysplasia but a histiocytic and granulomatous infiltration (Fig. 2A). Acid stains detected mycobacteria and finally mycobacterium tuberculosis was identified by polymerase chain reaction (PCR) and culture (Fig. 2B). Further analysis also revealed positive tests for mycobacterium tuberculosis in the stool and sputum. All other specimens were negative for acid-fast staining and cultures, but PCR for mycobacterium tuberculosis was positive in urine and blood. Disseminated tuberculosis was diagnosed and a therapy with rifampicin, isoniazid, pyrazinamide, and ethambutol was initiated. Immunosuppressive therapy was reduced as mycophenolic acid was stopped and cyclosporine was reduced to through levels of 25 to 45 ng/mL, prednisolone was increased to 15 mg/day in compensation.\n\nFigure 1 (A) Abdominal computed tomography scan showing multiple peritoneal lesions (white arrows) highly suspicious for a malignant process of unknown origin. (B) Colonoscopy showing an exophytic and ulcerating tumor in the right transverse colon.\n\nFigure 2 Colon biopsy. (A) Hematoxylin and eosin stain showing an ulcerating granulomatous inflammation (white arrows); original magnification 10×. (B) Ziehl-Neelsen stain revealing bright red acid-fast mycobacteria; original magnification 40×.\n\nOwing to liver toxicity with highly elevated liver function tests pyrazinamide had to be stopped and therapy was continued with rifampicin, isoniazid and ethambutol. Although all cultures became sterile after 1 month, a follow-up CAT scan showed persistent abdominal masses. Thus, triple therapy was extended to 3 months. A subsequent CAT scan showed remission of the abdominal masses and the kidney transplant function improved to a creatinine of 1.7 mg/dL at discharge (eGFR 39 mL/min MDRD). Also, anemia improved, and white blood cell count as well as lactate dehydrogenase decreased to normal range. Immunosuppressive therapy was slightly increased as mycophenolic acid was resumed at 180 mg twice per day, cyclosporine was continued with target levels of 30 to 50 ng/mL and prednisolone given at 5 mg/day. The patient was discharged, and intensive antibiotic therapy was followed by 8 months of rifampicin and isoniazid.\n\nOne year later, the patient was hospitalized again and died of severe cytomegalovirus pneumonia. All tests and cultures for mycobacterium tuberculosis were negative at that time.\n\n3 Discussion\nReactivation of latent and primary tuberculosis constitutes serious risks for immunosuppressed hosts such as kidney transplant recipients.[11] The exact frequency of active tuberculosis in kidney or other solid organ recipients is not well known and highly depends on the geographical tuberculosis prevalence.[3,12] Older studies suggest a 20- to 70-times increased risk of active tuberculosis for solid organ recipients compared to the general population.[3] A more recent meta-analysis found a prevalence of 0.6% in kidney transplant recipients from low prevalence countries, which translates into a 56-times increased absolute risk over the general population.[12] The risk for tuberculosis increases with the intensity of immunosuppression. Thus, previous rejections and coexisting infections such as cytomegalovirus or pneumocystis pneumonia infections are associated with an elevated risk for tuberculosis.[13] As different regimens, such as tacrolimus and cyclosporine-containing therapies, have been linked to the onset of tuberculosis it remains unclear which exact immunosuppressive regimen has the lowest risk for the development of active tuberculosis.[14,15] However, additional T-cell-depleting drugs certainly increase the risk.[13]\n\nDiagnosis of active tuberculosis in transplant recipients is complicated, as presentation is often atypical and unspecific. Whereas pulmonary tuberculosis is less frequent as compared to nontransplant recipients, extrapulmonary infection is more common. Disseminated disease is found in up to one-third of kidney transplant recipients.[4,16] Although fever occurs in as much as 70%, other symptoms such as weight loss and weakness are only present in <50% of kidney transplant recipients.[4] This is even more accentuated for abdominal tuberculosis where unspecific symptoms like abdominal pain, loss of weight, and appetite are the most common symptoms.[5] Therefore, the time from suspicion to diagnosis of tuberculosis is thus significantly longer in kidney transplant recipients compared to non-kidney transplant recipients.[16] The symptoms as well as the radiologic or endoscopic presentation of abdominal tuberculosis can resemble that of malignancies so that distinguishing between these entities is difficult and diagnosis commonly requires biopsies as illustrated in this case. As tuberculosis mostly occurs in the early post-transplant course and malignancies are predominantly late-course complications, the timing might help to distinguish between these diseases. However, this case shows that tuberculosis can also occur many years after transplantation.\n\nMost cases of post-transplant tuberculosis are thought to be owing to reactivation of latent tuberculosis.[11] This is supported by the fact that most cases occur within the first year after transplantation.[2] Thus, prevention with screening and treatment of latent tuberculosis is a key feature in impeding post-transplant tuberculosis. The American Society of Transplantation Guidelines as well as the European Best Practice Guidelines recommend screening all transplant candidates and consider prophylactic treatment upon positive results and risk factors.[17,18] However, screening is impaired by low sensitivities and specificities of available test in immunocompromised hosts. For hemodialysis patients, testing with interferon gamma release assays show 50% and the tuberculin skin test only 31% sensitivity.[19] Although prophylactic treatment is very effective in preventing early-onset tuberculosis, the underlying studies only had short follow-ups so that the long-term effectiveness is unknown.[20] In our case, active tuberculosis occurred 10 years after kidney transplantation, which is rather unusual. Although the screening history is unknown, and a new-onset infection cannot be excluded, the patient's origin, history, and presentation point toward a reactivation of latent tuberculosis. Perhaps regular testing of latent tuberculosis after transplantation as recommended for patients with ongoing risk factors for tuberculosis, such as those receiving biologicals for rheumatoid arthritis, could have identified active tuberculosis at an earlier stage.[21]\n\nFurthermore, the therapy in kidney transplant recipients is complicated by drug–drug interactions with immunosuppressive agents and is associated with the development of rejections.[11,22] Owing to the difficulties in diagnosis and treatment, the mortality of active tuberculosis in renal transplant recipients is still 6% to 10%[4,15] with about 15% graft loss and a median GFR decrease of 10 mL/min during therapy.[23] In our case, the kidney transplant function even improved with therapy. This can partially be attributed to the reduction in cyclosporine doses but might also be because of renal involvement of tuberculosis,[24] which is supported by the sterile pyuria.\n\nIn conclusion, this case demonstrates the variable and unspecific presentation of tuberculosis in kidney transplant recipients with its challenging diagnosis and illustrates that tuberculosis also constitutes a relevant complication in the later post-transplant course.\n\nAuthor contributions\nConceptualization: Christian Schmidt-Lauber, Johannes Jacobi, Karl Friedrich Hilgers, Michael Sean Wiesener.\n\nInvestigation: Christian Schmidt-Lauber, Johannes Jacobi, Iris Polifka, Karl Friedrich Hilgers, Michael Sean Wiesener.\n\nSupervision: Michael Sean Wiesener.\n\nValidation: Johannes Jacobi.\n\nWriting – original draft: Christian Schmidt-Lauber.\n\nWriting – review & editing: Christian Schmidt-Lauber, Michael Sean Wiesener.\n\nChristian Schmidt-Lauber orcid: 0000-0002-7864-0361.\n\nAbbreviations: CAT = computed tomography, eGFR = estimated glomerular filtration rate, MDRD = Modification of Diet in Renal Disease, PCR = polymerase chain reaction.\n\nHow to cite this article: Schmidt-Lauber C, Jacobi J, Polifka I, Hilgers KF, Wiesener MS. Suspected colonic cancer turns out to be disseminated tuberculosis in a kidney transplant recipient. Medicine 2019;98:36(e16995).\n\nThe authors report no conflicts of interest.\n\nConsent for publication: In her lifetime, the patient repeatedly signed for her approval of scientific workup and publication of her medical history.\n==== Refs\nReferences\n[1] Muñoz P Rodríguez C Bouza E \nMycobacterium tuberculosis infection in recipients of solid organ transplants . Clin Infect Dis \n2005 ;40 :581–7 .15712081 \n[2] Torre-Cisneros J Doblas A Aguado JM \nTuberculosis after solid-organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort . Clin Infect Dis \n2009 ;48 :1657–65 .19445585 \n[3] Singh N Paterson DL \nMycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management . Clin Infect Dis \n1998 ;27 :1266–77 .9827281 \n[4] Canet E Dantal J Blancho G \nTuberculosis following kidney transplantation: clinical features and outcome. A French multicentre experience in the last 20 years . Nephrol Dial Transplant \n2011 ;26 :3773–8 .21467129 \n[5] Rathi P Gambhire P \nAbdominal tuberculosis . J Assoc Physicians India \n2016 ;64 :38–47 .\n[6] Mazurek GH Jereb J Vernon A \nUpdated guidelines for using Interferon Gamma Release Assays to detect Mycobacterium tuberculosis infection—United States, 2010 . MMWR Recomm Rep \n2010 ;59 :1–25 .\n[7] Klote MM Agodoa LY Abbott K \nMycobacterium tuberculosis infection incidence in hospitalized renal transplant patients in the United States, 1998-2000 . Am J Transplant \n2004 ;4 :1523–8 .15307841 \n[8] Pedotti P Cardillo M Rossini G \nIncidence of cancer after kidney transplant: results from the North Italy transplant program . Transplantation \n2003 ;76 :1448–51 .14657684 \n[9] Miyazaki T Sato S Kondo T \nNational survey of de novo malignancy after solid organ transplantation in Japan . Surg Today \n2018 ;48 :618–24 .29380136 \n[10] Webster AC Craig JC Simpson JM \nIdentifying high risk groups and quantifying absolute risk of cancer after kidney transplantation: a cohort study of 15,183 recipients . Am J Transplant \n2007 ;7 :2140–51 .17640312 \n[11] Subramanian AK Morris MI \nAST Infectious Diseases Community of Practice . Mycobacterium tuberculosis infections in solid organ transplantation . Am J Transplant \n2013 ;13 suppl 4 :68–76 .23465000 \n[12] Reis-Santos B Gomes T Horta BL \nTuberculosis prevalence in renal transplant recipients: systematic review and meta-analysis . J Bras Nefrol \n2013 ;35 :206–13 .24100740 \n[13] John GT Shankar V Abraham AM \nRisk factors for post-transplant tuberculosis . Kidney Int \n2001 ;60 :1148–53 .11532111 \n[14] Ha YE Joo EJ Park SY \nTacrolimus as a risk factor for tuberculosis and outcome of treatment with rifampicin in solid organ transplant recipients . Transpl Infect Dis \n2012 ;14 :626–34 .22372581 \n[15] Ergun I Ekmekci Y Sengul S \nMycobacterium tuberculosis infection in renal transplant recipients . Transplant Proc \n2006 ;38 :1344–5 .16797298 \n[16] Benito N García-Vázquez E Horcajada JP \nClinical features and outcomes of tuberculosis in transplant recipients as compared with the general population: a retrospective matched cohort study . Clin Microbiol Infect \n2015 ;21 :651–8 .25882369 \n[17] Mycobacterium tuberculosis . Am J Transplant \n2004 ;4 suppl 10 :37–41 .15504210 \n[18] EBPG Expert Group on Renal Transplantation . European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.7.2. Late infections Tuberculosis . Nephrol Dial Transplant \n2002 ;17 suppl 4 :39–43 .\n[19] Ferguson TW Tangri N Macdonald K \nThe diagnostic accuracy of tests for latent tuberculosis infection in hemodialysis patients: a systematic review and meta-analysis . Transplantation \n2015 ;99 :1084–91 .25286055 \n[20] Kim S-H Lee S-O Park JB \nA prospective longitudinal study evaluating the usefulness of a T-cell-based assay for latent tuberculosis infection in kidney transplant recipients . Am J Transplant \n2011 ;11 :1927–35 .21749641 \n[21] Singh JA Saag KG Bridges SL \n2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis . Arthritis Rheumatol \n2016 ;68 :1–26 .\n[22] Aguado JM Torre-Cisneros J Fortún J \nTuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology . Clin Infect Dis \n2009 ;48 :1276–84 .19320593 \n[23] Costa SD de Sandes-Freitas TV Jacinto CN \nTuberculosis after kidney transplantation is associated with significantly impaired allograft function . Transpl Infect Dis \n2017 ;19 :e12750.\n[24] Eastwood JB Corbishley CM Grange JM \nTuberculosis and the kidney . J Am Soc Nephrol \n2001 ;12 :1307–14 .11373356\n\n",
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"mesh_terms": "D000995:Antitubercular Agents; D003110:Colonic Neoplasms; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008875:Middle Aged; D011183:Postoperative Complications; D014385:Tuberculosis, Gastrointestinal",
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"title": "Suspected colonic cancer turns out to be disseminated tuberculosis in a kidney transplant recipient: A case report.",
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