article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "Bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF)-A, is currently used to treat patients with ovarian or colon cancer. While several cardiovascular toxicities related to bevacizumab-containing regimens have been reported, the effect of bevacizumab on the coronary microcirculation has not been fully elucidated. Here we report a case of 54-year-old female patient who developed microvascular angina after a series of bevacizumab-containing chemotherapeutic regimen. The discontinuation of bevacizumab and nicorandil administration was effective in alleviating her chest discomfort and the ischemic changes on her ECG. This highlights the possibility that coronary microvascular angina can be induced in patients treated with bevacizumab-containing chemotherapy. It should also be noted that nicorandil can be effective in managing microvascular angina.",
"affiliations": "Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.;Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.;Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo.;Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo.;Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.",
"authors": "Katoh|Manami|M|;Takeda|Norihiko|N|;Arimoto|Takahide|T|;Abe|Hajime|H|;Oda|Katsutoshi|K|;Osuga|Yutaka|Y|;Fujii|Tomoyuki|T|;Komuro|Issei|I|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D014665:Vasodilator Agents; D020108:Nicorandil; D000068258:Bevacizumab",
"country": "Japan",
"delete": false,
"doi": "10.1536/ihj.16-537",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1349-2365",
"issue": "58(5)",
"journal": "International heart journal",
"keywords": "Avastin; Chemotherapy; VEGF",
"medline_ta": "Int Heart J",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D017023:Coronary Angiography; D003326:Coronary Circulation; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D017566:Microvascular Angina; D008875:Middle Aged; D020108:Nicorandil; D010051:Ovarian Neoplasms; D014665:Vasodilator Agents",
"nlm_unique_id": "101244240",
"other_id": null,
"pages": "803-805",
"pmc": null,
"pmid": "28966326",
"pubdate": "2017-10-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bevacizumab-Related Microvascular Angina and Its Management with Nicorandil.",
"title_normalized": "bevacizumab related microvascular angina and its management with nicorandil"
} | [
{
"companynumb": "JP-ROCHE-2014913",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "Atypical femoral fracture (AFF) often appears with bisphosphonate use. Teriparatide (TPTD) treatment may promote AFF healing, but few controlled or comparative studies have examined the effects of TPTD on healing of bisphosphonate-associated AFF. We retrospectively reviewed the medical records of 45 consecutive AFFs in 34 Japanese patients who had received oral bisphosphonates (alendronate or risedronate) for osteoporosis before AFF and had been followed for ≥12 months (range, 12-90 months). Thirty-seven complete or incomplete AFFs (82 %) were treated surgically and eight incomplete AFFs (18 %) were treated conservatively. Bisphosphonates were stopped at diagnosis. Based on TPTD use after fracture, AFFs were divided into non-TPTD (n = 24) and TPTD (n = 21) groups. Time to fracture-healing and frequency of delayed healing or non-union were compared between groups. Because fracture type (complete or incomplete) differed significantly between groups, only subanalyses for all surgically treated AFFs (complete and incomplete), surgically treated complete AFFs, and conservatively treated incomplete AFFs were performed. In subanalyses for all AFFs treated surgically, mean (± standard deviation) time to fracture healing was significantly better in the TPTD group (5.4 ± 1.5 months) than in the non-TPTD group (8.6 ± 4.7 months; P = 0.012), and the frequency of delayed healing or non-union was significantly lower in the TPTD group than in the non-TPTD group (P = 0.014). Subanalyses for surgically treated complete AFFs yielded similar results, but subanalyses for incomplete AFFs treated conservatively showed no significant differences between groups. TPTD treatment appears to significantly shorten the postoperative time to fracture healing and reduce rates of delayed healing or non-union after bisphosphonate-associated AFF.",
"affiliations": "Department of Orthopedic Surgery, Akita University School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan, miyakosh@doc.med.akita-u.ac.jp.",
"authors": "Miyakoshi|Naohisa|N|;Aizawa|Toshiaki|T|;Sasaki|Satoshi|S|;Ando|Shigeru|S|;Maekawa|Shigeto|S|;Aonuma|Hiroshi|H|;Tsuchie|Hiroyuki|H|;Sasaki|Hiroshi|H|;Kasukawa|Yuji|Y|;Shimada|Yoichi|Y|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D019379:Teriparatide; D019386:Alendronate",
"country": "Japan",
"delete": false,
"doi": "10.1007/s00774-014-0617-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0914-8779",
"issue": "33(5)",
"journal": "Journal of bone and mineral metabolism",
"keywords": null,
"medline_ta": "J Bone Miner Metab",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D019386:Alendronate; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D005264:Femoral Fractures; D017102:Fracture Healing; D006801:Humans; D010024:Osteoporosis; D012189:Retrospective Studies; D019379:Teriparatide",
"nlm_unique_id": "9436705",
"other_id": null,
"pages": "553-9",
"pmc": null,
"pmid": "25227287",
"pubdate": "2015-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "23671316;11685647;19594305;20872215;23365544;22610061;23177553;23604648;15320749;23775464;22371548;21104227;20427833;10468993;22968250;15949481;23311861;23351873;23874247;21430030;21085935;21610533;17878149;23072919;23712442;23135345",
"title": "Healing of bisphosphonate-associated atypical femoral fractures in patients with osteoporosis: a comparison between treatment with and without teriparatide.",
"title_normalized": "healing of bisphosphonate associated atypical femoral fractures in patients with osteoporosis a comparison between treatment with and without teriparatide"
} | [
{
"companynumb": "JP-CIPLA LTD.-2014JP01454",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISEDRONATE SODIUM"
},
"drugadditional": null... |
{
"abstract": "OBJECTIVE\nThe use of antipsychotics to treat the behavioral symptoms of dementia is associated with greater mortality. The authors examined the mortality risk of individual agents to augment the limited information on individual antipsychotic risk.\n\n\nMETHODS\nThe authors conducted a retrospective cohort study using national data from the U.S. Department of Veterans Affairs (fiscal years 1999-2008) for dementia patients age 65 and older who began outpatient treatment with an antipsychotic (risperidone, olanzapine, quetiapine, or haloperidol) or valproic acid and its derivatives (as a nonantipsychotic comparison). The total sample included 33,604 patients, and individual drug groups were compared for 180-day mortality rates. The authors analyzed the data using multivariate models and propensity adjustments.\n\n\nRESULTS\nIn covariate-adjusted intent-to-treat analyses, haloperidol was associated with the highest mortality rates (relative risk=1.54, 95% confidence interval [CI]=1.38-1.73) followed by risperidone (reference), olanzapine (relative risk=0.99, 95% CI=0.89-1.10), valproic acid and its derivatives (relative risk=0.91, 95% CI=0.78-1.06), and quetiapine (relative risk=0.73, 95% CI=0.67-0.80). Propensity-stratified and propensity-weighted models as well as analyses controlling for site of care and medication dosage revealed similar patterns. The mortality risk with haloperidol was highest in the first 30 days but decreased significantly and sharply thereafter. Among the other agents, mortality risk differences were most significant in the first 120 days and declined in the subsequent 60 days during follow-up.\n\n\nCONCLUSIONS\nThere may be differences in mortality risks among individual antipsychotic agents used for treating patients with dementia. The use of valproic acid and its derivatives as alternative agents to address the neuropsychiatric symptoms of dementia may carry associated risks as well.",
"affiliations": "Ann Arbor VA Center for Clinical Management Research, Serious Mental Illness Treatment, Resource, and Evaluation Center, Ann Arbor, Mich., USA. kales@umich.edu",
"authors": "Kales|Helen C|HC|;Kim|Hyungjin Myra|HM|;Zivin|Kara|K|;Valenstein|Marcia|M|;Seyfried|Lisa S|LS|;Chiang|Claire|C|;Cunningham|Francesca|F|;Schneider|Lon S|LS|;Blow|Frederic C|FC|",
"chemical_list": "D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D014635:Valproic Acid; D006220:Haloperidol; D018967:Risperidone; D000077152:Olanzapine",
"country": "United States",
"delete": false,
"doi": "10.1176/appi.ajp.2011.11030347",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-953X",
"issue": "169(1)",
"journal": "The American journal of psychiatry",
"keywords": null,
"medline_ta": "Am J Psychiatry",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D003704:Dementia; D003987:Dibenzothiazepines; D005260:Female; D006220:Haloperidol; D006801:Humans; D008297:Male; D000077152:Olanzapine; D057216:Propensity Score; D000069348:Quetiapine Fumarate; D012189:Retrospective Studies; D012306:Risk; D018967:Risperidone; D013997:Time Factors; D014635:Valproic Acid",
"nlm_unique_id": "0370512",
"other_id": null,
"pages": "71-9",
"pmc": null,
"pmid": "22193526",
"pubdate": "2012-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "19138567;16286437;12641371;16319382;16035128;3558716;19897178;16505124;11156753;20224520;12556574;17325327;16816009;21300946;16234500;12453674;17975326;20487081;19173375;16434113;17548409;16848653;16103729;17898349",
"title": "Risk of mortality among individual antipsychotics in patients with dementia.",
"title_normalized": "risk of mortality among individual antipsychotics in patients with dementia"
} | [
{
"companynumb": "US-JNJFOC-20170600916",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": null,
... |
{
"abstract": "Isoniazid preventive therapy (IPT) is a key component of TB/HIV control, but few countries achieve high IPT coverage.\n\n\n\nUsing a behavioural COM-B design approach, the intervention consisted of a training on IPT guidelines and tuberculin skin testing (TST), identification of the optimal IPT implementation strategy by the health care workers (HCWs) of 3 primary care clinics, and a 2-month mentoring period. Using routine register data, TST and IPT uptake was determined 3 months before and 5 months after the intervention. Records were reviewed to identify factors associated with IPT initiation and HCW fidelity to the guidelines. A survey among HCWs was conducted to determine barriers to IPT.\n\n\n\nTwo clinics implemented TST-guided IPT for all clients receiving HIV care, one clinic decided against use of TST. According to routine register data, the proportion of clients initiating IPT increased substantially at the clinic not opting for TST (6% vs 36%), but minimally (34% vs 37% and 0.7% vs 3%) in the two other clinics. TST uptake did not increase (0 vs 0% and 0.5%). In addition to poor IPT uptake, HCW fidelity to investigation for TB and timing of IPT initiation was poor, with only 68% of symptomatic patients investigated and IPT initiation delayed to a median of 374 days post-ART initiation. In multivariate analysis, pregnancy (aOR 18.62, 95% CI 6.99-53.46), recent HIV diagnosis (aOR 3.65, 95% CI 1.73-7.41), being on ART (aOR 9.44, 95% CI 3.05-36.17), and CD4 <500 cells/mm3 (aOR 2.19, 95% CI 1.22-4.18) were associated with IPT initiation. Time needed to perform a TST, motivating patients to return for TST reading, and low IPT patient awareness were the main barriers to IPT implementation.\n\n\n\nDespite using a behavioural intervention framework including training and participatory development of the clinic IPT strategy, HCW fidelity to the guidelines was poor, resulting in low TST coverage and low IPT uptake under primary care conditions. To achieve the benefits of IPT, health system level approaches including TST-free guidelines and sensitization are needed.",
"affiliations": "Witkoppen Health and Welfare Centre, Johannesburg, South Africa.;Witkoppen Health and Welfare Centre, Johannesburg, South Africa.;Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States.;Witkoppen Health and Welfare Centre, Johannesburg, South Africa.;Department of Epidemiology and Social Medicine (ESOC), University of Antwerp, Antwerp, Belgium.",
"authors": "Van Ginderdeuren|Eva|E|0000-0001-8621-7718;Bassett|Jean|J|;Hanrahan|Colleen|C|;Mutunga|Lillian|L|0000-0001-8184-3701;Van Rie|Annelies|A|",
"chemical_list": "D000995:Antitubercular Agents; D007538:Isoniazid",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0212035",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0212035PONE-D-18-22947Research ArticleMedicine and Health SciencesInfectious DiseasesBacterial DiseasesTuberculosisMedicine and Health SciencesTropical DiseasesTuberculosisMedicine and health sciencesDiagnostic medicineHIV diagnosis and managementBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesWomen's HealthMaternal HealthPregnancyMedicine and Health SciencesWomen's HealthObstetrics and GynecologyPregnancyMedicine and Health SciencesHealth CarePrimary CareMedicine and Health SciencesPharmacologyDrugsIsoniazidBiology and Life SciencesOrganismsBacteriaActinobacteriaMycobacterium TuberculosisMedicine and Health SciencesHealth CareHealth Care PolicyScreening GuidelinesHealth system barriers to implementation of TB preventive strategies in South African primary care facilities Barriers to TB preventive strategieshttp://orcid.org/0000-0001-8621-7718Van Ginderdeuren Eva ConceptualizationData curationFormal analysisFunding acquisitionInvestigationMethodologyProject administrationWriting – original draftWriting – review & editing12*Bassett Jean ConceptualizationFunding acquisitionMethodologyProject administrationWriting – review & editing1Hanrahan Colleen ConceptualizationFunding acquisitionMethodologyProject administrationWriting – review & editing3http://orcid.org/0000-0001-8184-3701Mutunga Lillian ConceptualizationFunding acquisitionMethodologyProject administrationWriting – review & editing1Van Rie Annelies ConceptualizationFunding acquisitionMethodologyWriting – original draftWriting – review & editing21 \nWitkoppen Health and Welfare Centre, Johannesburg, South Africa2 \nDepartment of Epidemiology and Social Medicine (ESOC), University of Antwerp, Antwerp, Belgium3 \nDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United StatesDaftary Amrita EditorMcGill University Faculty of Medicine, CANADACompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: eva.vanginderdeuren@gmail.com14 2 2019 2019 14 2 e02120353 8 2018 26 1 2019 © 2019 Van Ginderdeuren et al2019Van Ginderdeuren et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background\nIsoniazid preventive therapy (IPT) is a key component of TB/HIV control, but few countries achieve high IPT coverage.\n\nMethods\nUsing a behavioural COM-B design approach, the intervention consisted of a training on IPT guidelines and tuberculin skin testing (TST), identification of the optimal IPT implementation strategy by the health care workers (HCWs) of 3 primary care clinics, and a 2-month mentoring period. Using routine register data, TST and IPT uptake was determined 3 months before and 5 months after the intervention. Records were reviewed to identify factors associated with IPT initiation and HCW fidelity to the guidelines. A survey among HCWs was conducted to determine barriers to IPT.\n\nResults\nTwo clinics implemented TST-guided IPT for all clients receiving HIV care, one clinic decided against use of TST. According to routine register data, the proportion of clients initiating IPT increased substantially at the clinic not opting for TST (6% vs 36%), but minimally (34% vs 37% and 0.7% vs 3%) in the two other clinics. TST uptake did not increase (0 vs 0% and 0.5%). In addition to poor IPT uptake, HCW fidelity to investigation for TB and timing of IPT initiation was poor, with only 68% of symptomatic patients investigated and IPT initiation delayed to a median of 374 days post-ART initiation. In multivariate analysis, pregnancy (aOR 18.62, 95% CI 6.99–53.46), recent HIV diagnosis (aOR 3.65, 95% CI 1.73–7.41), being on ART (aOR 9.44, 95% CI 3.05–36.17), and CD4 <500 cells/mm3 (aOR 2.19, 95% CI 1.22–4.18) were associated with IPT initiation. Time needed to perform a TST, motivating patients to return for TST reading, and low IPT patient awareness were the main barriers to IPT implementation.\n\nConclusion\nDespite using a behavioural intervention framework including training and participatory development of the clinic IPT strategy, HCW fidelity to the guidelines was poor, resulting in low TST coverage and low IPT uptake under primary care conditions. To achieve the benefits of IPT, health system level approaches including TST-free guidelines and sensitization are needed.\n\nThis study was funded by the United States Agency for International Development (USAID, https://www.usaid.gov) under award number AID-674-A-12-00033 (EV, JB, CH, LM, AV), with additional funding from Vlaamse Interuniversitaire Raad (VLIR, https://www.vliruos.be) under award number NDOC2016PR001 (EV). The content is solely the responsibility of the authors and does not necessarily represent the official views of USAID or VLIR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityAll research related files are available from the Zenodo database (accession number 10.5281/zenodo.1325042, http://doi.org/10.5281/zenodo.1325042).Data Availability\nAll research related files are available from the Zenodo database (accession number 10.5281/zenodo.1325042, http://doi.org/10.5281/zenodo.1325042).\n==== Body\nIntroduction\nTB continues to be a major public health problem with 10 million new TB cases and 1.4 million deaths worldwide in 2015 [1]. Isoniazid preventive therapy (IPT) reduces the progression of latent Mycobacterium tuberculosis infection to TB disease in those at high risk [2, 3]. The Global Plan to STOP TB aims to initiate IPT in 90% of all people living with HIV and 90% of all children in contact with TB by 2025 [4].\n\nSouth Africa carries one of the world’s highest TB/HIV burdens, with close to one in every 100 South Africans developing active TB disease each year, and over 60% of all TB cases occurring in people living with HIV. The continued high TB notification rate highlights that the South African TB control strategy, which is mainly focused on passive case finding, fails to control the TB epidemic in South Africa [1]. Scaling up TB preventive strategies among people living with HIV, including early initiation of antiretroviral treatment (ART) and high uptake of IPT, may be essential to reduce the TB incidence in South Africa. While 56% of people living with HIV in South Africa are initiated on ART, less than 10% start IPT [5, 6].\n\nRecent qualitative work assessing barriers to IPT implementation from the point of view of South African HIV care providers has suggested that the primary barrier to IPT use was lack of knowledge and experience [7]. Other barriers reported in the literature were inaccuracy of TB screening tools to exclude active TB, fear of isoniazid resistance, isoniazid and tuberculin shortage, and lack of clear guidance [8, 9]. Moreover, the reintroduction of TST as well as the complex stratification by ART status and TST status in the national 2014 South African IPT guidelines for people living with HIV likely poses logistical and human resource challenges to IPT implementation in already overburdened primary health care clinics (Box 1) [10, 11].\n\nBox 1. Overview of the WHO and South African IPT policy for people living with HIV\n10.1371/journal.pone.0212035.t001\tWHO* [10]\tSouth Africa [11]\t\nIPT eligibility\tAll people living with HIV with negative symptom-based TB screening\tAll people living with HIV with negative symptom-based TB screening\t\nTST provision\tUse of TST where feasible.\tUse of TST where available.\t\nIPT duration\t• TST positive or unknown: at least 36 months (as proxy for lifelong IPT), irrespective of ART\n• TST negative: assessed on a case-by-case basis for their individual risk of TB exposure\t• TST positive: 36 months\n• TST negative: 0 (pre-ART) and 12 months (ART)\n• TST not available: start IPT and do TST after 1 m\n• TST not available by 6 months (pre-ART) or 12 months (ART): stop IPT\t\n*in resource constrained settings with high TB prevalence\n\nImproving the implementation of an evidence-based practice such as IPT necessitates successful behaviour change at the patient, provider and health system levels. The COM-B framework identifies three main components of behavioural change (‘Capability’, ‘Opportunity’, and ‘Motivation’) which can be targeted by interventions [12]. We used the COM-B model to identify barriers to IPT implementation in our setting, and to design an intervention to improve IPT uptake in three primary care clinics. This intervention included training to enhance capability, a participatory design to create opportunities for IPT initiation, and mentored implementation and feedback to increase motivation. Following implementation, we evaluated IPT and TST uptake, determined health care worker (HCW) fidelity to the 2014 South African IPT guidelines, and identified remaining barriers for IPT and TST implementation as perceived by HCWs.\n\nMethods\nStudy setting\nThe study was performed in three primary care health facilities serving the Diepsloot community in Northern Johannesburg from August 2015 to November 2016. Diepsloot is a poor, densely populated, urban informal settlement of approximately 12 km2 with an estimated population of 138,329 [13]. The clinics routinely provide HIV and TB care in line with the South African guidelines but, at time of the study, the 2014 IPT guidelines were not yet implemented. Two clinics are DOH-funded without any history of implementation research, one clinic receives NGO and DOH funding and has participated in implementation research on TB, HIV and antenatal care. The South African Department of Health (DOH) issued new IPT guidelines in December 2014, which stratify eligibility and duration of IPT by TST and ART status [11]. According to these guidelines, TST-positive individuals are IPT eligible regardless of ART status and should receive isoniazid for 36 months (Box 1). TST negative individuals are only IPT eligible if on ART and should receive 12 months of isoniazid. If the TST is not done within one month of IPT-initiation, isoniazid should be administered for 6 months in people not on ART or for 12 months in people on ART.\n\nStudy design\nWe used a before-after design to evaluate the change in uptake of IPT and TST following an intervention that consisted of (1) training, (2) participatory identification of the optimal IPT implementation strategy for each clinic, and (3) mentored implementation of the chosen strategy, followed by routine implementation.\n\nTraining of clinic staff\nAt each clinic, a 4-hour training session was organized for all clinic staff working with TB and HIV patients, with separate sessions tailored for clinicians, auxiliary nurses, counsellors and community health workers. The training was given by a study clinician in English, the language used by DOH for all staff training. The training covered the evidence on IPT effectiveness in people living with HIV and an in-depth overview of the 2014 South African DOH IPT guidelines. The theoretical knowledge covered was then applied to practical case studies to assure in-depth apprehension among all HCWs. During the last interactive session, all HCWs were encouraged to express concerns related to the IPT clinic flow and propose solutions. Clinicians were trained in TST placement using PPD RT/23 (2UT/0.1ml) and all relevant clinic staff were trained in TST reading. TST training was based on the Center for Disease Control and Prevention (CDC) TST training video and the TST training guide of the New Jersey Medical School Global Tuberculosis Institute [14, 15]. After the training, performance of TST placement and TST reading was assessed by the study staff.\n\nParticipatory development of IPT implementation strategy at each clinic\nThe clinic flow and clinic environment were mapped and reviewed by the clinic manager and the clinician(s) in charge of TB and HIV care taking into account all concerns and solutions identified during the training. Using a participatory and iterative process, options for sustainable integration of IPT and its documentation were identified at each of the three clinics. Solutions to create a facilitating environment included a fast-track system for TST reading visits, full integration of IPT visits (except for TST reading visit) in the normal HIV care program, cooperation with local clinics for TST reading and documentation of IPT and TST results on hand-held patient cards. Options were discussed until a consensus on the optimal and feasible strategy at each of the three clinics was reached.\n\nMentored IPT implementation\nTo support IPT implementation and enhance treatment literacy, each clinic was given educational materials including patient TST cards, pamphlets and posters (developed by the South African DOH in English and Zulu, the two most commonly spoken languages in South Africa), and a poster with instructions for TST reading and placement (developed by CDC).\n\nTo assure that the IPT strategy selected by the clinic was being implemented as intended, a study staff member was present to assist with IPT-related activities and monitor the relevant clinics’ processes and their documentation during the first 2 months of implementation. Study staff support was withdrawn after two months. Quarterly feedback on IPT uptake was given to the clinic managers.\n\nData collection\nData on IPT uptake and TST placement was collected using routine clinic registers in paper and/or electronic format. These registers collected information on IPT initiation in all people newly diagnosed with HIV (clinic 1 and 2) or in all clients receiving HIV care (clinic 3). The number of people initiated on IPT and number of TSTs placed was extracted from these registers for the three months prior to the intervention and 5 months after completion of the 2-month mentored IPT implementation.\n\nTo assess the quality of the data collected in routine registers, data on IPT uptake was also collected through review of pharmacy reports of isoniazid mono-therapy prescriptions. This validation was only performed at one of the three clinics as detailed pharmacy records were not available at the other two clinics.\n\nTo determine HCW fidelity to the guidelines and identify factors associated with IPT initiation, we reviewed the records (paper medical files and electronic laboratory databases) of all clients receiving HIV care at one of 8 a priori selected days distributed throughout the 5 months following the 2-month mentored IPT implementation. This record review was only performed at two clinics as medical files are kept by patients in the third clinic. We extracted information on age and gender, CD4 count, viral load, IPT initiation prior to the day of record review, presence of contra-indications for IPT (current TB treatment, active liver disease, peripheral neuropathy, excessive alcohol use, history of adverse reactions to isoniazid, history of treatment for multidrug resistant TB), presence of symptoms suggestive of active TB (cough, fever >2 weeks, weight loss, night sweats), and results of sputum Xpert MTB/RIF, M. tuberculosis culture, and chest X-ray. We also documented whether TST was placed at that visit (and results thereof), whether IPT was initiated, and if so, its intended duration.\n\nTo identify important barriers to the IPT program, a survey was done during the last two months of the observation period among all HCWs involved in IPT prescription using a structured questionnaire based on the COM-B model. The survey enquired about competency (‘Capability’), habitual attitudes (‘Motivation’), and hurdles related to the clinic flow (‘Opportunity’).\n\nData analysis\nTo assess IPT and TST uptake before and after the intervention, the proportion of clients initiated on IPT were compared using either all clinic clients newly diagnosed with HIV or any clinic client presenting for HIV care as the denominator for the population of interest, depending on the data routinely collected by the clinic. Chi-square was used to compare proportions.\n\nTo identify patient-level factors associated with initiation of IPT among those eligible, we performed a logistic regression analysis. Variables with a p-value ≤0.20 in the bivariate analysis were included and a backward selection method was employed to identify those factors independently associated with IPT initiation. The goodness-of-fit of the stepwise logistic regression model was assessed using the Hosmer-Lemeshow test.\n\nTo assess implementation fidelity, a descriptive analysis was performed by comparing the decisions made by the HCWs to the ones expected when guidelines would have been followed accurately.\n\nTo evaluate barriers to IPT implementation, frequencies and proportions were used to summarize the responses to closed survey questions.\n\nAll analyses were performed in R.\n\nEthics approval\nEthical approval was obtained from the Health Research Ethics Committee of the University of the Witwatersrand (M150782, M160910). All identifying patient details were removed at time of data collection, recorded data were anonymous and securely stored. Waiver of consent was given by the ethics committee for review of routine clinic registers (clinic 1) and retrospective record review (clinic 2); all participants at clinic 3 gave written permission for use of routine data for research purposes.\n\nResults\nSelection of implementation strategies\nAll three clinics opted to implement IPT for all clients receiving HIV care, but only two clinics opted to implement TST (Table 1). Two different TST implementation strategies were used: a single nurse placing all TSTs (antenatal care service of clinic 3) or all clinicians placing TSTs in their patients (clinic 1 and general adult service of clinic 3).\n\n10.1371/journal.pone.0212035.t002Table 1 IPT and TST uptake during a 3-month period before and 5 months after an intervention consisting of training and a 2-month mentored implementation.\nClinic\tAverage monthly number of new HIV diag-noses\tIPT strategy pre-intervention\tIPT strategy identified through participatory process\tTST placements\tAverage monthly proportion of IPT initiations*\t\n\t\tTST screening\tIPT eligi-bility\tTST screening\tIPT eligi-bility\tBefore inter-vention\tAfter inter-vention\tBefore inter-vention\tAfter inter-vention\t\n1\t68\tNo\tAll PLWH emphasis on pregnant women\tYes\tAll PLWH\t0%\t0%\t34%\t37%\t\n2\t38\tNo\tAll PLWH emphasis on pregnant women\tNo\tAll PLWH\tNA\tNA\t6%\t36%\t\n3\t208\tNo\tAll PLWH emphasis on pregnant women\tYes\tAll PLWH\t0%\t0.5%\t0.7%\t3.0%\t\n*Routine registers collected information on IPT initiation in all people newly diagnosed with HIV (clinic 1 and 2) or in all clients receiving HIV care (clinic 3).\n\nIPT uptake\nIPT uptake increased in all clinics, but the increase was only substantial in one and statistically significant in two clinics. The proportion of clients newly diagnosed with HIV initiated on IPT increased from 6% before to 36% after the intervention in clinic 2 (p<0.01), the proportion of clients living with HIV initiated on IPT increased from 0.7% to 3% (p<0.01) in clinic 3 (Table 1), and the proportion of clients newly diagnosed with HIV initiated on IPT increased from 34% to 37% thereafter in clinic 1 (p = 0.57). At each of the clinics, there was large month-to-month variability in IPT uptake, which could, at least in part, be due to operational issues that clinics encountered during the post-intervention period such as isoniazid stock out, human resources shortages, and high staff turnover.\n\nReview of the pharmacy records (in clinic 3) suggested potential underreporting of IPT in routine registers, with 5% of all 23,452 clients receiving HIV care being prescribed isoniazid monotherapy during 5 months post mentoring compared to 3% of these clients recorded in the registers to having been initiated on IPT during the same period (p<0.01).\n\nTST uptake\nFor patients receiving antenatal care, TSTs were–as intended- mostly (74%) done by 1 nurse. At the general adult HIV care and treatment clinic, all 22 clinicians were responsible for performing TST in their patients but only 12 placed one or more TSTs. The intervention failed to increase TST uptake, with no (0%) TST placement in the pre-intervention period and 0% (clinic 1) and 0.5% (clinic 3) of clients assessed by TST in the post-intervention period (Table 1). Of the 106 individuals in whom a TST was placed, most 89/106 (84%) returned for the reading between 48–72 hours and 21/89 (24%) were positive (≥ 5 mm induration).\n\nHealthcare worker fidelity to the guidelines\nAmong the 1522 clients receiving HIV care during the a priori selected 8 days, 1395 (92%) had a medical file available for record review (Fig 1). Among these, IPT was not started in 63 (4.5%) patients because they were on TB treatment, in 253 (18%) because they were already on IPT, and in 5 patients because of a contra-indication for IPT (active liver disease n = 3, history of adverse reactions to isoniazid n = 1, or history of treatment for multidrug resistant TB n = 1). None of the records reviewed noted presence of peripheral neuropathy or excessive alcohol use as a contra-indication for IPT.\n\n10.1371/journal.pone.0212035.g001Fig 1 Flowchart of patients included in review.\nAmong the remaining 1074 individuals, TB symptom screening was done in almost all (1056 or 98%) patients. Among the 1056 patients screened, 131 (12%) were classified to have presumptive TB. Overall, any investigation for active TB was performed in only 68% (89/131) of patients with presumptive TB, with large variability between clinics (22% in clinic 2 vs 71% in clinic 3, p<0.01). The most frequent initial diagnostic used was sputum Xpert MTB/RIF (in 80 of the 89 patients evaluated). The remaining 9 patients with presumptive TB were assessed by other investigations including sputum culture (n = 1), blood culture (n = 2), urinary LAM (n = 3), fine needle aspiration of lymph nodes (n = 3), chest X-ray (n = 3) and abdominal US (n = 1). Of the 68 Xpert MTB/RIF negative patients, 37 (54%) were assessed by culture, all of which was negative for M. tuberculosis. A TB diagnosis was made in 17 patients, based on sputum Xpert MTB/RIF (n = 10), AFB sputum (n = 1), chest X-ray (n = 1), blood culture (n = 1), and urinary LAM (n = 4). IPT was started in 6 patients with presumptive TB, five of whom had not been evaluated for TB and one patient whose chest X-ray and abdominal ultrasound were not suggestive of TB.\n\nAmong the 925 IPT eligible clinic clients (i.e. not on TB treatment, not receiving IPT and without TB symptoms), median age was 39 years (IQR 32–46) and two thirds (627 or 68%) were female, of which 24 (3.8%) were pregnant (Table 2). Most (805 or 87%) had been diagnosed with HIV more than 90 days prior to the record review visit and most (814 or 88%) were on ART. The most recent median CD4 count was 423 cells/mm3 (IQR 267–612) with a median time of 215 days (IQR 56–420) prior to the record review visit. Viral load suppression was present in half (52%) of the 736 clinic clients that had a viral load measurement available with a median time of 84 days (IQR 0–197) prior to the record review visit. A TST was performed at time of the record review visit in five of the 925 (0.5%) IPT eligible individuals. One TST was positive (14 mm), two were negative, and 2 patients did not return for TST reading. The TST result did not influence IPT eligibility as the two TST negative individuals were on ART. IPT was started in 76 of the 925 (8.2%) IPT eligible clinic clients, 63 of the 901 non-pregnant adults and 13 of the 24 pregnant women. Among non-pregnant adults, the median time from ART initiation to IPT initiation was 374 days (IQR 84–917) and the median CD4 count at IPT initiation was 374 cells/mm3. Among the 13 pregnant women started on IPT, two were not yet on ART at time of IPT initiation, six were on ART for more than one month, and five were on ART for less than 30 days. The intended IPT duration was specified in only 25 of 76 (33%) patients started on IPT but was according to the guidelines in all 25.\n\n10.1371/journal.pone.0212035.t003Table 2 Uni- and multivariate analysis of patient-level factors associated with IPT initiation among eligible patients.\n \t\tIPT started\nn = 76\tIPT not started\nn = 849\tOR (95% CI)\taOR (95% CI)\t\nGender\tFemale\t52 (68%)\t575 (68%)\t1.03 (0.63–1.74)\t\t\n\tMale\t24 (32%)\t274 (32%)\t\t\t\nAge in years (median (IQR))\t\t34 (31–43.25)\t 39 (32–46)\t0.96 (0.94–0.99)\t\t\nTiming of HIV diagnosis compared to IPT eligibility assessment\t<90 days\t19 (25%)\t101 (12%)\t2.47 (1.38–4.25)\t3.65 (1.73–7.41)\t\n\t≥90 days\t57 (75%)\t748 (88%)\t\t\t\nART status at time of IPT eligibility assessment\tOn ART\t71 (93%)\t743 (87%)\t2.03 (0.88–5.87)\t9.44 (3.05–36.17)\t\n\tNot on ART\t5 (7%)\t106 (12%)\t\t\t\nPregnancy status\tPregnant\t13 (17%)\t 11 (1%)\t15.72 (6.77–37.20)\t18.62 (6.99–53.46)\t\n\tNot pregnant\t63 (83%)\t838 (99%)\t\t\t\nHIV viral load*\tSuppressed (<50 copies/ml)\t28 (56%)\t353 (51%)\t1.20 (0.68–2.16)\t\t\n\tNot suppressed\t22 (44%)\t333 (49%)\t\t\t\nMost recent CD4**\t<500 cells/mm3\t61 (80%)\t509 (60%)\t2.68 (1.54–4.97)\t2.19 (1.22–4.18)\t\n\t≥500 cells/mm3\t15 (20%)\t336 (40%)\t\t\t\nClinic\tClinic 2\t12 (16%)\t185 (22%)\t0.67 (0.34–1.23)\t\t\n\tClinic 3\t64 (84%)\t664 (78%)\t\t\t\n*viral load missing in 26 patients who started IPT and 163 patients not started on IPT\n\n**most recent CD4 count missing in 4 patients not started on IPT\n\nTaken together, these data show that, except for screening for TB symptoms of all clinic clients living with HIV, HCW fidelity to the IPT guidelines was low, with only two-thirds (68%) of symptomatic patients investigated for TB, TST not implemented as intended (<1% coverage), low (8.2%) IPT initiation rate, and delayed initiation of IPT instead of as soon as “stable on ART” for non-pregnant adults or one month after ART initiation for pregnant women.\n\nFactors associated with IPT initiation\nAge (OR 0.96, 95% CI 0.94–0.99), pregnancy (OR 15.72, 95% CI 6.77–37.20), recent (<90 days prior) HIV diagnosis (OR 2.47, 95% CI 1.38–4.25), ART status (OR 2.03, 95% CI 0.88–5.87) and CD4 <500 cells/mm3 (OR 2.68, 95% CI 1.54–4.97) were associated with IPT initiation in bivariate analysis. In multivariate analysis, pregnancy (aOR 18.62, 95% CI 6.99–53.46), recent HIV diagnosis (aOR 3.65, 95% CI 1.73–7.41), CD4 <500 cells/mm3 (aOR 2.19, 95% CI 1.22–4.18), and being on ART (aOR 9.44, 95% CI 3.05–36.17) remained independently associated with a higher odds of being initiated on IPT. Even among the patient groups where HCWs were more likely to initiate IPT, coverage of IPT was low: 54% of pregnant women, 16% of individuals with a recent HIV diagnosis, 11% of individuals with a CD4 count <500 cells/mm3, and 9% of people on ART.\n\nBarriers to IPT implementation as perceived by HCWs\nThe main barriers to IPT implementation reported by HCWs were low patient awareness of IPT, time needed to counsel patients on IPT, burden to document IPT-related activities, and concerns regarding exclusion of active TB (Table 3). Regarding TST, HCWs reported that the time needed to perform a TST and the difficulty to motivate patients to return for TST reading were important barriers to the use of TST.\n\n10.1371/journal.pone.0212035.t004Table 3 Self-reported barriers to IPT implementation among health care workers (HCWs).\n \tHCW (n = 25)\t\nSystematic screening for IPT-eligibility is difficult to implement\t1 (4%)\t\nCurrent TB-screening is not sufficient to rule out TB\t7 (28%)\t\nCounseling patients about IPT is difficult/time consuming\t7 (28%)\t\nPatients not knowledgeable about IPT\t18 (72%)\t\nDocumentation of IPT activities is difficult/time consuming\t8 (32%)\t\nFollow up of patients on IPT is difficult/time consuming$\t4 (17%)\t\nMotivating patients to adhere to IPT is difficult/time consuming\t3 (12%)\t\nNot enough training in IPT guidelines¥\t0 (0%)\t\nNot enough experience with prescribing IPT\t0 (0%)\t\nIPT not part of routine practice\t1 (4%)\t\nTST placement procedure is complex¶,£\t2 (10%)\t\nHCW not comfortable placing TST¶,£\t0 (0%)\t\nHCW has no time to perform TST¶,§\t18 (86%)\t\nTST is limiting factor in decision to place patient on IPT¶,§\t0 (0%)\t\nTST reading is time consuming¶\t3 (14%)\t\nDifficult to motivate patients to return for TST reading¶\t15 (68%)\t\n$1 HCW excluded as didn´t follow up patients on IPT\n\n¥2 HCWs excluded as they started after training\n\n¶denominator for TST only 2 clinics (n = 22), TST not performed in clinic 2 (n = 3)\n\n£2 HCWs excluded as they referred for TST\n\n§1 missing answer\n\nDiscussion\nDespite comprehensive training, participation by health care workers in the identification of the most sustainable IPT strategy for each clinic, post-training mentoring and feedback on performance, we observed poor fidelity to the IPT guidelines under routine primary care conditions resulting in low IPT uptake and almost non-existent use of TST. Pregnancy, recent HIV diagnosis, CD4 <500 cells/mm3, and being on ART were independently associated with higher IPT initiation, but even among those groups, IPT initiation remained low. The main barriers experienced among HCWs were concerns regarding exclusion of active TB, burden to document IPT-related activities, and operational issues with TST.\n\nThe low (8.2%) uptake of IPT was similar to the national IPT uptake estimates of approximately 10% [5] but far below the 80% target of the South African 2016 national strategic plan to scale up IPT implementation and far removed from the STOP TB target of 90% of people living with HIV initiating IPT [4, 16]. Our study highlighted potential inaccuracies in estimates of IPT uptake based on data recorded in routine public primary care clinic registers. This is important as register-based data on IPT uptake forms the basis for evaluation and strategic action by Departments of Health and WHO. In 2015, WHO changed the IPT denominator from all people living with HIV to only those newly enrolled in HIV care. WHO acknowledged that due to data quality issues, figures may not exclusively include number of people newly enrolled into HIV care, confounding interpretation and inter-country comparison of IPT uptake [1]. The use of different denominators across clinics (all clinic clients living with HIV or all patients newly enrolled in HIV care) may further complicate the collection of accurate summary estimates of IPT uptake at regional, provincial or national level. Finally, the observation that 18% of patients were on IPT at the time of file review but only 8.2% initiated IPT highlights the difficulty in interpretation of register-based estimates for IPT uptake. Register data provides a snapshot of IPT initiation at a particular clinic visit but fails to inform on the cumulative number of people living with HIV ever initiated on IPT. Reporting on cumulative indicators of “ever on IPT” may be required to evaluate progress towards the 90% IPT coverage target.\n\nTo date, few studies have assessed the operational feasibility, health systems aspects, HCW fidelity to IPT guidelines and resulting IPT coverage under real-life conditions. One study assessing IPT implementation in 49 South African health care facilities in 2010, when TST and ART status were not yet part of IPT eligibility assessment [17] found that IPT training was poor among clinic staff, IPT was only partly implemented in 71% of the facilities, and only half of eligible newly HIV diagnosed patients had been initiated on IPT. The TST requirement and the complex stratification by ART and TST status in the 2014 IPT guidelines may have contributed to the even lower (8.2%) IPT uptake observed in our study [11]. The finding that the only clinic to report a substantial and clinical relevant increase opted not to implement TST, supports this assumption. Two observational cohort studies in Médecins Sans Frontières (MSF) clinics in Kenya and Swaziland demonstrated that, in contrast to our finding of almost non-existent uptake of TST, the implementation of TST is feasible in an urban and rural resource-constrained settings [18]. The challenge in TST implementation we observed may have been due to greater human resource challenges in public sector clinics compared to MSF clinics. We could not compare our observation of low implementation fidelity to the 2014 IPT guidelines to findings in other studies as we could not identify any published reports. The low implementation fidelity resulted not only in poor uptake but also delayed IPT initiation, which results in missed opportunities to prevent TB among people living with HIV as the incidence of TB is the highest in individuals with low CD4 count and during the first months after ART initiation [19,20].\n\nRecent qualitative work suggested that lack of knowledge and experience were important barriers to IPT implementation [7]. In our study, where HCWs were competently trained, we confirmed findings from other studies that low patient awareness of IPT and concern regarding exclusion of active TB posed barriers to IPT implementation [8, 9, 18]. Studies showed that increasing capability via knowledge transfer is not enough but needs to be complemented with supervisory mentored visits, staff motivation and a participatory environment [21]. To facilitate effective implementation of IPT, successful behaviour change of all 3 main B-COM components (‘Capability’, ‘Opportunity´, and ‘Motivation’) on patient, provider and system level will be mandatory. Our intervention showed that this may still not be sufficient and that additional approaches from a health system level are essential to create a facilitating environment that supports patient and care providers capability and motivation. Health system level approaches such as sensitization, political commitment, investment in human resources and continuous training, simplified guidelines and use of short regimens (such as one month rifapentine plus isoniazid [22]) may be needed to ultimately achieve high IPT coverage among people living with HIV.\n\nOur study had multiple strengths, including the use of a behavioural framework for intervention design and evaluation, the participation of health care workers in the design of the IPT implementation strategy at each clinic, the mixed methods approach, rigorous file review, large sample size, and evaluation of three primary care clinics under routine conditions. Our study also suffered from limitations. First, all clinics serve the same community, limiting generalizability to other urban and rural areas. Second, patient refusal can contribute to low IPT uptake, but we lacked sufficient data to assess this. Third, the study was conducted before South Africa implemented ART for all, limiting generalizability of our findings to the current situation.\n\nConclusion\nThe global call for TB elimination underpins the urgent need to scale-up TB preventive therapy. IPT implementation under routine primary care conditions is challenging due to numerous barriers related to concerns regarding exclusion of active TB, logistical and human resource challenges. To assure sustainable high uptake of IPT, simplified guidelines, HCW and patient sensitization on the benefit of IPT, and political commitment are needed to scale-up of IPT. Reporting on accurate standardized indicators on cumulative IPT uptake will be required to evaluate the success of the IPT program. Continued research towards shorter, better-tolerated regimens might be needed to ultimately achieve the 90% IPT coverage target.\n\nWe are grateful to the District of Health Johannesburg, the Witkoppen Health and Welfare Centre team, the clinic staff and survey participants for their time and for making this study possible.\n==== Refs\nReferences\n1 World Health Organization . Global tuberculosis report \n2016 \nGeneva : World Health Organization ;2016. Available from: http://apps.who.int/iris/bitstream/handle/10665/250441/97?sequence=1 (Accessed 14 July 2018.)\n2 Samandari T , Agizew TB , Nyirenda S , Tedla Z , Sibanda T , Shang N , et al\n6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial . The Lancet . 2011 ;377 (9777 ):1588 –98 .\n3 Rangaka MX , Wilkinson RJ , Boulle A , Glynn JR , Fielding K , van Cutsem G , et al\nIsoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial . The Lancet . 2014 ;384 (9944 ):682 –90 .\n4 Stop TB Partnership . Global Plan to End TB 2016–2020.\nGeneva : Stop TB Partnership ;2015 Available from: http://www.stoptb.org/global/plan/plan2/ (Accessed 14 July 2018.)\n5 World Health Organization . Global Tuberculosis Report 2015\nGeneva : World Health Organization ;2015 Available from: http://apps.who.int/iris/bitstream/handle/10665/191102/9789241565059_eng.pdf?sequence=1 (Accessed 14 July 2018.)\n6 Joint United Nations Programme on HIV/AIDS (UNAIDS) . Country factsheets South Africa 2016\nGeneva : Joint United Nations Programme on HIV/AIDS ;2016 Available from: http://www.unaids.org/en/regionscountries/countries/southafrica (Accessed 14 July 2018.)\n7 Lester R , Hamilton R , Charalambous S , Dwadwa T , Chandler C , Churchyard GJ , et al\nBarriers to implementation of isoniazid preventive therapy in HIV clinics: a qualitative study . AIDS . 2010 ;24 \nSuppl 5 :S45 –8 .\n8 Teklay G , Teklu T , Legesse B , Tedla K , Klinkenberg E . Barriers in the implementation of isoniazid preventive therapy for people living with HIV in Northern Ethiopia: a mixed quantitative and qualitative study . BMC public health . 2016 ;16 (1 ):840 \n10.1186/s12889-016-3525-8 \n27543096 \n9 Churchyard GJ , Chaisson RE , Maartens G , Getahun H . Tuberculosis preventive therapy: an underutilised strategy to reduce individual risk of TB and contribute to TB control . South African medical journal . 2014 ;104 (5 ):339 –43 . 10.7196/samj.8290 \n25212199 \n10 World Health Organization . Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings\nGeneva : World Health Organization ; 2011 Available from: https://www.who.int/hiv/pub/tb/9789241500708/en/ (Accessed 14 December 2018.)\n11 Department of Health . National consolidated guidelines for the prevention of mother-to-child transmission of HIV (PMTCT) and the management of HIV in children, adolescents and adults\nPretoria : Department of Health ; 2015 Available from: http://www.health.gov.za/index.php/2014-03-17-09-09-38/policies-and-guidelines/category/230-2015p# (Accessed 14 July 2018.)\n12 Michie S , van Stralen MM , West R . The behaviour change wheel: A new method for characterising and designing behaviour change interventions . Implementation Science . 2011 ;6 :42 \n10.1186/1748-5908-6-42 \n21513547 \n13 Statistics South Africa. Diepsloot. Pretoria: Statistics South Africa;2011. Available from: http://www.statssa.gov.za/?page_id=4286&id=11294 (Accessed 14 July 2018.)\n14 Centers for Disease Control and Prevention (CDC) . Mantoux Tuberculin Skin Test\nAtlanta: Centers for Disease Control and Prevention ; 2006 Available from: https://tools.cdc.gov/medialibrary/index.aspx#/media/id/302210 (Accessed 14 July 2018.)\n15 New Jersey Medical School Global Tuberculosis Institute. Mantoux Tuberculin Skin Testing training guide–appendix 8. New Jersey, New Jersey Medical School Global Tuberculosis Institute, 2007. Available from: http://globaltb.njms.rutgers.edu/downloads/products/CompleteTrainingGuide.pdf (Accessed 14 July 2018.)\n16 Department of Health . National Strategic Plan on HIV, STIs and TB 2012–2016\nPretoria : Department of Health ; 2012 Available from: http://www.gov.za/documents/national-strategic-plan-hiv-stis-and-tb-2012-2016 (Accessed 14 July 2018.)\n17 Chehab JC , Vilakazi-Nhlapo K , Vranken P , Peters A , Klausner JD . Survey of isoniazid preventive therapy in South Africa, 2011 . The international journal of tuberculosis and lung disease . 2012 ;16 (7 ):903 –7 . 10.5588/ijtld.11.0722 \n22583688 \n18 Huerga H , Mueller Y , Ferlazzo G , Mpala Q , Bevilacqua P , Vasquez B , et al\nImplementation and Operational Research: Feasibility of Using Tuberculin Skin Test Screening for Initiation of 36-Month Isoniazid Preventive Therapy in HIV-Infected Patients in Resource-Constrained Settings . Journal of acquired immune deficiency syndromes . 2016 ;71 (4 ):e89 –95 . 10.1097/QAI.0000000000000895 \n26910386 \n19 Van Rie A , Westreich D , Sanne I . Tuberculosis in patients receiving antiretroviral treatment: incidence, risk factors, and prevention strategies . Journal of acquired immune deficiency syndromes . 2011 ;56 (4 ):349 –55 . 10.1097/QAI.0b013e3181f9fb39 \n20926954 \n20 Moore D , Liechty C , Ekwaru P , Were W , Mwima G , Solberg P , et al\nPrevalence, incidence and mortality associated with tuberculosis in HIV-infected patients initiating antiretroviral therapy in rural Uganda . AIDS . 2007 ;21 (6 ):713 –9 . 10.1097/QAD.0b013e328013f632 \n17413692 \n21 Vanden Driessche K , Sabue M , Dufour W , Behets F , Van Rie A . Training health care workers to promote HIV services for patients with tuberculosis in the Democratic Republic of Congo . Human resources for health . 2009 ;7 :23 \n10.1186/1478-4491-7-23 \n19291327 \n22 Swindells S, Ramchandani R., Gupta A., Benson C., Leon-Cruz J., Omoz-Oarhe A., et al. One month of rifapentine/isoniazid to prevent TB in people with HIV: Brief-TB/A5279 [abstract]. Presented in 25th Annual Conference on Retroviruses and Opportunistic Infections;2018 March 4–7; Boston, MA. Abstract nr 37LB. Available from: http://www.croiconference.org/sessions/one-month-rifapentineisoniazid-prevent-tb-people-hiv-brief-tba5279 (Accessed 14 July 2018.)\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "14(2)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D005260:Female; D006078:Government Programs; D006268:Health Facilities; D006282:Health Personnel; D006801:Humans; D007538:Isoniazid; D008297:Male; D008875:Middle Aged; D017410:Practice Guidelines as Topic; D013019:South Africa; D014374:Tuberculin Test; D014376:Tuberculosis",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0212035",
"pmc": null,
"pmid": "30763378",
"pubdate": "2019",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "19291327;25212199;17413692;24835842;26910386;21492926;22583688;21513547;20926954;27543096;21079427",
"title": "Health system barriers to implementation of TB preventive strategies in South African primary care facilities.",
"title_normalized": "health system barriers to implementation of tb preventive strategies in south african primary care facilities"
} | [
{
"companynumb": "ZA-ALKEM LABORATORIES LIMITED-ZA-ALKEM-2019-01656",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugad... |
{
"abstract": "BACKGROUND\nIPF is a common form of interstitial lung disease for which there is no effective therapy and usually results in death. Two previous contradictory studies showed anticoagulant therapy to be associated with both improved and worsened survival, respectively.\n\n\nOBJECTIVE\nThe objective of this retrospective cohort study was to evaluate the effect of anticoagulant therapy on the survival and disease progression of patients with idiopathic pulmonary fibrosis (IPF) in real clinical practice.\n\n\nMETHODS\nWe compared the clinical characteristics, time to disease progression, incidence of acute exacerbation, and survival of 25 (20%) IPF patients receiving anticoagulant therapy to the remaining 97 IPF patients not receiving anticoagulant therapy. In addition we conducted a sensitivity analysis using as comparator a group of 25 patients matched by age, sex, functional impairment, cardiac comorbidities and pulmonary hypertension.\n\n\nRESULTS\nPatients on anticoagulant therapy had a worse 1- and 3-year survival (84% and 53% versus 89% and 64% in the non-anticoagulant group, respectively), a difference that persisted after adjusting for age and comorbidities (hazard ratio 3.1 - 95% confidence interval, 1.4 to 7.0; p=0.006) and after comparison with the matched group (adjusted HR=4.8, 95% CI: 1.8-12.8; p=0.002). IPF patients on anticoagulant therapy had a shorter interval to disease progression ( 0.7 years versus 1.6 years, adjusted HR 2.2 -95% CI, 0.96 to 5.1; p=0.063) confirmed also in the analysis with matched subgroups (HR=2.7 (95% CI: 1.2-6.5); p=0.023). The incidence of acute exacerbations did not differ in the two groups (22% versus 23%). Two patients (8%) experienced anticoagulant treatment related complications and included an episode of hemorrhagic shock.\n\n\nCONCLUSIONS\nIn this retrospective study patients treated with anticoagulants had a worse survival and a shorter interval to disease progression. This support the recent finding that warfarin worsen the respiratory status and survival of IPF patients.",
"affiliations": "GB Morgagni Hospital, Forlì, Italy. venerino.poletti@gmail.com",
"authors": "Tomassetti|S|S|;Ruy|J H|JH|;Gurioli|C|C|;Ravaglia|C|C|;Buccioli|M|M|;Tantalocco|P|P|;Decker|P A|PA|;Cavazza|A|A|;Dubini|A|A|;Agnoletti|V|V|;Gurioli|C|C|;Casoni|G L|GL|;Romagnoli|M|M|;Poletti|V|V|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1124-0490",
"issue": "30(2)",
"journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG",
"keywords": null,
"medline_ta": "Sarcoidosis Vasc Diffuse Lung Dis",
"mesh_terms": "D000925:Anticoagulants; D015331:Cohort Studies; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis; D012189:Retrospective Studies; D014859:Warfarin",
"nlm_unique_id": "9610928",
"other_id": null,
"pages": "121-7",
"pmc": null,
"pmid": "24071883",
"pubdate": "2013-08-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The effect of anticoagulant therapy for idiopathic pulmonary fibrosis in real life practice.",
"title_normalized": "the effect of anticoagulant therapy for idiopathic pulmonary fibrosis in real life practice"
} | [
{
"companynumb": "PHHY2015IT024217",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TICLOPIDINE"
},
"drugadditional": null,
"dru... |
{
"abstract": "BACKGROUND\nWe describe peripheral blood smear, bone marrow morphology, histopathology, immunohistochemistry, including BRAF V600E, and molecular testing results of patients with metastatic melanoma to the bone marrow.\n\n\nMETHODS\nWe performed a retrospective review for patients with metastatic melanoma to the bone marrow at our institution. Bone marrow morphology, histology, immunophenotyping, and cytogenetic/molecular genetic testing were reviewed, and BRAF V600E immunohistochemistry was performed. Results were compared to the literature.\n\n\nRESULTS\nWe identified four patients with metastatic melanoma to the bone marrow presenting with at least one cytopenia. Two of the four patients had leukoerythroblastosis, with three patients having atypical cells on bone marrow aspirate/touch preparation, and all patients had aggregates of atypical cells on biopsy. Immunohistochemistry for S100, Melan A, and HMB45 confirmed the diagnosis in all patients, and BRAF V600E immunohistochemistry was detected in two of four patients, which correlated with molecular testing findings. Review of the literature found 27 total patients, with normocytic anemia and leukoerythroblastosis as common peripheral blood smear findings.\n\n\nCONCLUSIONS\nFeatures including cytopenias (typically anemia), leukoerythroblastosis, and morphology of cohesive, large atypical cells in aspirate and biopsy, and immunohistochemical expression for S100, Melan A, and HMB45 were present in patients with metastatic melanoma. BRAF V600E immunohistochemistry is useful as a surrogate marker of molecular results. Regardless of clinical history, at the time of the bone marrow biopsies, hematologic malignancies are in the main differential diagnosis and very rarely included metastatic melanoma, likely due to the under-recognized metastatic potential of melanoma to the bone marrow.",
"affiliations": "University of Utah School of Medicine, Salt Lake City, Utah.;University of Utah School of Medicine, Salt Lake City, Utah.;University of Utah School of Medicine, Salt Lake City, Utah.;University of Utah School of Medicine, Salt Lake City, Utah.",
"authors": "Corean|Jessica L E|JLE|https://orcid.org/0000-0003-4340-6775;George|Tracy I|TI|;Patel|Jay L|JL|;Li|K David|KD|",
"chemical_list": "C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf",
"country": "England",
"delete": false,
"doi": "10.1111/ijlh.13051",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1751-5521",
"issue": "41(4)",
"journal": "International journal of laboratory hematology",
"keywords": "bone marrow; histopathology; melanoma; metastases; morphology",
"medline_ta": "Int J Lab Hematol",
"mesh_terms": "D001854:Bone Marrow Cells; D019046:Bone Marrow Neoplasms; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D020125:Mutation, Missense; D009362:Neoplasm Metastasis; D048493:Proto-Oncogene Proteins B-raf",
"nlm_unique_id": "101300213",
"other_id": null,
"pages": "550-560",
"pmc": null,
"pmid": "31112348",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bone marrow findings in metastatic melanoma, including role of BRAF immunohistochemistry.",
"title_normalized": "bone marrow findings in metastatic melanoma including role of braf immunohistochemistry"
} | [
{
"companynumb": "US-009507513-1908USA002498",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "A 75-year-old man with severe chronic obstructive pulmonary disease and epistaxis experienced progressive respiratory failure after receiving an injection of meperidine and hydroxyzine in preparation for nasal packing. The patient and his family refused endotracheal intubation; despite aggressive medical care, he continued to deteriorate toward an expected fatal outcome. An i.v. infusion of doxapram hydrochloride at 2 mg/min rapidly reversed his downhill course and hypercarbic coma. This case illustrates the potential usefulness of doxapram in the emergency setting. The mechanism of action, indications, dosing methods, and potential side effects of this agent are discussed.",
"affiliations": "Department of Emergency Medicine, Medical College of Pennsylvania, Philadelphia.",
"authors": "McNamara|R M|RM|;Euerle|B D|BD|",
"chemical_list": "D004315:Doxapram",
"country": "United States",
"delete": false,
"doi": "10.1016/s0196-0644(94)70289-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-0644",
"issue": "24(4)",
"journal": "Annals of emergency medicine",
"keywords": null,
"medline_ta": "Ann Emerg Med",
"mesh_terms": "D000368:Aged; D003131:Combined Modality Therapy; D004315:Doxapram; D004844:Epistaxis; D006801:Humans; D008297:Male; D012121:Respiration, Artificial; D012131:Respiratory Insufficiency; D016312:Treatment Refusal",
"nlm_unique_id": "8002646",
"other_id": null,
"pages": "751-4",
"pmc": null,
"pmid": "8092607",
"pubdate": "1994-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Doxapram reversal of respiratory failure in a patient refusing assisted ventilation.",
"title_normalized": "doxapram reversal of respiratory failure in a patient refusing assisted ventilation"
} | [
{
"companynumb": "US-PFIZER INC-2020489425",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "We report a rare case of aggressive plasmablastic lymphoma with an initial presentation of dermatomyositis. The challenges associated with the diagnosis and treatment approach are also highlighted in this case report.",
"affiliations": "Department of Haematology Royal Perth Hospital Perth WA Australia.;Department of Haematology Royal Perth Hospital Perth WA Australia.;Department of Haematology Royal Perth Hospital Perth WA Australia.;Department of Haematology Fiona Stanley Hospital Murdoch WA Australia.;Department of Haematology Royal Perth Hospital Perth WA Australia.",
"authors": "Chee|Ashlyn Rui Yin|ARY|https://orcid.org/0000-0003-0719-8569;Ng|Teng Fong|TF|;Lam|Stephanie Jin Ping|SJP|;Wright|Matthew|M|;Leahy|Michael F|MF|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.2787",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.2787\nCCR32787\nCase Report\nCase Reports\nAn unusual case of plasmablastic lymphoma presenting as dermatomyositis\nCHEE et al.Chee Ashlyn Rui Yin https://orcid.org/0000-0003-0719-8569\n1\nashchee@hotmail.com Ng Teng Fong \n1\n Lam Stephanie Jin Ping \n1\n\n3\n Wright Matthew \n2\n Leahy Michael F. \n1\n \n1 \nDepartment of Haematology\nRoyal Perth Hospital\nPerth\nWA\nAustralia\n\n\n2 \nDepartment of Haematology\nFiona Stanley Hospital\nMurdoch\nWA\nAustralia\n\n3 Present address:\nDepartment of Haematology\nSir Charles Gairdner Hospital\nNedlands\nWA\nAustralia\n\n* Correspondence\n\nAshlyn Rui Yin Chee, Department of Haematology, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, WA 6009, Australia.\n\nEmail: ashchee@hotmail.com\n\n10 3 2020 \n5 2020 \n8 5 10.1002/ccr3.v8.5843 847\n14 10 2019 14 1 2020 03 2 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nWe report a rare case of aggressive plasmablastic lymphoma with an initial presentation of dermatomyositis. The challenges associated with the diagnosis and treatment approach are also highlighted in this case report.\n\nWe report a rare case of aggressive plasmablastic lymphoma with an initial presentation of dermatomyositis. The challenges associated with the diagnosis and treatment approach are also highlighted in this case report.\n\n\nautologous stem cell transplantbortezomibdermatomyositisplasmablastic lymphoma source-schema-version-number2.0cover-dateMay 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.2 mode:remove_FC converted:26.05.2020\n\n\nChee \nARY \n, \nNg \nTF \n, \nLam \nSJP \n, \nWright \nM \n, \nLeahy \nMF \n. An unusual case of plasmablastic lymphoma presenting as dermatomyositis\n. Clin Case Rep . 2020 ;8 :843 –847\n. 10.1002/ccr3.2787\n==== Body\n1 BACKGROUND\nPlasmablastic lymphoma (PL) is a rare and aggressive disease with overlapping features of multiple myeloma and high‐grade B‐cell lymphomas. It is commonly associated with immunodeficiency disorders including the human immunodeficiency virus (HIV) infection.1 The disease has a male predominance, and the median age at presentation is 42 years in HIV‐infected patients and 55 years in non–HIV‐infected patients.1 The overall prognosis of PL is generally guarded with a reported median overall survival of 6‐19 months, without clear differences between HIV‐positive and HIV‐negative patients.2 Given its rarity, there is also currently no accepted treatment approach.1 Dermatomyositis is an inflammatory myopathy, which usually manifests as a subacute proximal myopathy, systemic inflammatory process, and a characteristic skin rash, with a 32% risk of cancer diagnosed within 3‐5 years after the onset of the disorder.3 Commonly associated cancers include carcinomas of the breast, colon, ovaries, nasopharynx, melanoma, and non‐Hodgkin's lymphoma.3 Histologically, it is characterized by atrophic fibers at the peripheral muscle fascicles due to microinfarcts and hypoperfusion, which is mediated by the early activation of the complement C5b‐9 membrane attack complex by antibodies.3 Steroids are typically the mainstay of treatment.\n\n2 CASE PRESENTATION\nA 52‐year‐old male presented with a 3‐week history of rash, which started in his right thigh and later evolved into an acute widespread eruption. This was associated with severe myalgias, arthralgias, lethargy, and chills. He also developed painful mouth ulcers resulting in reduced oral intake and a 6 kg weight loss over 3 weeks. His background medical history includes hypertension and type 2 diabetes, managed with ramipril and metformin, respectively. There was no history of autoimmune disorders, and he was a nonsmoker and nondrinker.\n\nOn examination, his rash was an erythematous papulosquamous eruption with desquamation, which was violaceous over his peripheries. Some areas appeared eczematous with serous crusting. Holster's sign was positive and a subtle shawl sign was present, but Gottron's papules and a heliotrope rash were not present.4 He had mild proximal myopathy with reduced power (grade 4/5) of his bilateral upper and lower limb proximal muscles. Apart from a tender left wrist, there were no other tender joints or evidence of synovitis. Cardiovascular, respiratory, and abdominal examination were unremarkable.\n\n3 INVESTIGATIONS\nHis initial full blood picture revealed a normal hemoglobin of 132 g/L, neutrophilia with white cell count of 15.7 × 109/L, and a thrombocytosis with a platelet count of 465 × 109/L. His inflammatory markers were elevated with a C‐reactive protein (CRP) of 220 mg/L and erythrocyte sedimentation rate (ESR) of 90 mm/h ANA was slightly elevated at 15 IU/mL with a speckled pattern. His serum creatinine kinase was extremely high at 10 300 U/L (ref interval 45‐250 U/L). Serum lactate dehydrogenase (LDH) was elevated at 1090 U/L (ref interval 120‐250 Us/L). Serum electrophoresis did not detect any paraprotein or elevated serum free light chains, and calcium and creatinine levels were within the normal range. HIV, hepatitis B, and C serologies were negative. A skin biopsy demonstrated an interface dermatitis, consistent with connective tissue disease/dermatomyositis (Figure 1). Magnetic resonance imaging (MRI) of his pelvic muscles was consistent with features of myositis, showing high‐intensity signal and patchy muscle edema of the hip adductors, iliopsoas, and gluteus minimus muscles in a bilateral symmetrical fashion. Lytic lesions were not identified on skeletal imaging. A myositis panel of associated autoantibodies returned negative, and EMG and muscle biopsy were not performed.\n\nFigure 1 (a) Mild keratosis. (b) Mild sperficial perivascular lymphocytic inflammation. (c) Cytoid bodies (necrotic keratinocytes) and basal vacuolar change. [As indicated by the red arrows]\n\nGiven the association between dermatomyositis and malignancy, a whole‐body computed tomography (CT) scan was performed, revealing multiple sites of lymphadenopathy. A percutaneous omental lymph node biopsy showed sheets of eccentric blastoid lymphocytes. Immunophenotype was positive for MUM1, CD79a, and CD138, with Ki67 proliferation index of 100%, and negative for leukocyte common antigen CD45, and B‐cell markers CD19 and CD20 (Figure 2). Immunohistochemistry was equivocal (30%) for C‐MYC expression and negative for the Epstein‐Barr encoding region (EBER), HHV8, cyclin D1, CD56, IgA, and IgM. Fluorescence in situ hybridization (FISH) analysis demonstrated a loss of TP53 and no MYC or IgM disruption. A monoclonal B‐cell population was not detected on flow cytometry. Cytogenetics and molecular studies were not performed on the lymph node biopsy. Positron emission tomography (PET) scan was consistent with stage IV disease, with significant small bowel and extranodal osseous involvement (Figure 3). Bone marrow and CSF staging were negative. Given the absence of myeloma‐defining signs, the presence of lymphadenopathy, and the morphological appearance of plasmablasts, a diagnosis of plasmablastic lymphoma was made despite the absence of EBER and negative HIV status.\n\nFigure 2 (a) Positive p53. (b) Positive MUM1. (c) Positive ki67. (d) Positive CD138. (f) Negative CD20. (g) H&E (×200). (h) H&E (×400)\n\n\nFigure 3 (a) The most active nodal disease is in the central small bowel mesentery (SUVmax 8.7). (b) Nodal involvement below and above the diaphragm and L3 bone involvement\n\n4 TREATMENT\nTreatment was started with the dose‐adjusted EPOCH chemotherapy regimen, which consisted of etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin.5 This was given in combination with bortezomib (V) at 1.3 g/m2 given on days 3 and 6 of each cycle. Six cycles of V‐DA‐EPOCH every 21 days were administered, with dose escalation up to the 2nd scale. The patient was also continued on a weaning dose of prednisolone for the treatment of dermatomyositis. As his CNS International Prognostic Index score for lymphoma6 was an intermediate risk, prophylactic intrathecal chemotherapy was not administered. His rash and myalgia improved with steroid use and chemotherapy, and LDH and CK levels normalized with treatment. He developed grade 2 peripheral neuropathy affecting his lower limbs by Common Terminology Criteria for Adverse Events (CTCAE) and expected myelosuppression due to the cytotoxic agents.\n\n5 OUTCOME AND FOLLOW‐UP\nThe patient achieved complete metabolic remission, evident on his interim and postinduction chemotherapy PET scans. The patient went on to have consolidation treatment with BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning protocol and autologous stem cell transplantation. Repeat PET scan at day 100 after his autologous stem cell transplantation showed continuing complete remission of the disease. Unfortunately, he developed florid relapse with brainstem and bone marrow involvement 16 months after his autologous stem cell transplant and was eventually palliated.\n\n6 DISCUSSION\nDermatomyositis as a presentation of PL has not been reported previously. More commonly, the site of disease involvement in both HIV‐positive and HIV‐negative patients diagnosed with PL is the oral cavity or jaw, followed by the gastrointestinal tract, lymph nodes, and skin.1, 7 Most cases present with advanced stage III or IV disease according to the Ann Arbor Staging.7 Analysis from the Lymphoma Study Association (LYSA), the largest cohort reported to date, has reported 7 of 58 non–HIV‐related PL cases to be associated with autoimmune conditions.8 These included sarcoidosis, inclusion body myositis, severe cutaneous psoriasis, graves’ disease, giant cell arteritis, and two cases of rheumatoid arthritis.8 Overall, there was a high incidence of immunosuppression among those with PL, with HIV‐positive patients being the most prevalent and only 5% not showing evidence of immune modulation.8 On the other hand, it has been well established that dermatomyositis is strongly associated with a variety of malignancies, which occur primarily as a paraneoplastic syndrome.9 The pathophysiologic mechanism linking systemic autoimmunity and malignancies is not well defined, but it has been postulated that antibodies produced against tumor antigens cross‐react with antigens temporarily expressed during normal muscle regeneration and cause muscle inflammation.9, 10\n\n\nImmunophenotypically, PL expresses plasma cell markers such as CD138, CD38, and IRF4/MUM1 and loses conventional B‐cell markers such as CD19 or CD20.1, 7, 11 The cell of origin is believed to be from a plasmablast, which is an activated B cell in the process of becoming a plasma cell.1 Although the pathogenesis of PL is not entirely known, the MYC gene rearrangement is commonly observed1, 7, 11 and identified in 50% of patients.11 In addition, in situ hybridization for EBER is also positive in up to 75% of cases.1, 11 The diagnosis of this disease is difficult not only due to its unique immunophenotype but also due to several overlapping morphological and phenotypical features with plasmacytoma, plasmablastic myeloma, or diffuse large B‐cell lymphoma (DLBCL). Although there may be several distinguishing features that aid in differentiating these lymphoid tumors, a specific histopathological diagnosis is not always straightforward.12, 13 Importantly, clinical correlation such as the presence of lymphadenopathy may favor the diagnosis of plasmablastic lymphoma over a plasma cell neoplasm and the presence of end‐organ damage; that is, CRAB criteria or plasma paraprotein may be more suggestive of multiple myeloma.12\n\n\nIn the WHO classification, PL has been classified as an aggressive subtype of DLBCL, but the National Comprehensive Cancer Network (NCCN) has reported that standard treatment with CHOP chemotherapy, consisting of cyclophosphamide, doxorubicin, vincristine, and prednisolone, is inadequate and associated with dismal outcomes.11, 14 Intensive regimens such as HyperCVAD, CODOX‐M/IVAC, and DA‐EPOCH that have higher doses and additional cytotoxic agents such as methotrexate, etoposide, or cytarabine have also not improved survival rates.11, 14 Majority of patients die within the first year after initial presentation.11, 14\n\n\nRecently, studies have shown that bortezomib, a proteasome inhibitor used in the treatment of multiple myeloma, has a therapeutic role in PL on the basis of the plasmacytic differentiation of the plasmablastic cells.1, 11 As the PL cells are characterized by the expression of plasma cell transcription factors such as XBP1 and BLIMP1, bortezomib may work by targeting these factors, which may have an effect on antibody production and unfolded protein response.14 Bortezomib, in combination with DA‐EPOCH, has been reported to induce a complete remission rate of >90% (n = 16) and a 65% 5‐year overall survival in the frontline setting in a retrospective case series published in 2018.15 A systematic review of bortezomib in plasmablastic lymphoma also reported that the overall response rate (ORR) to bortezomib‐based regimens was 100%, with complete remission (CR) in 89% of patients and a 2‐year overall survival rate of 55%.16\n\n\nHigh‐dose chemotherapy as myeloablative conditioning therapy supported by an autologous stem cell transplant has a role as a consolidative treatment1 and should be considered in the frontline setting in those who have a MYC gene rearrangement, TP53 gene deletion, age‐adjusted international prognostic index greater or equal to 2, and a partial response or refractory disease.17 Based on a review of 9 case reports of HIV‐negative patients with PL, BEAM was the most commonly used conditioning regimen prior to an autologous stem cell transplant.17 There is currently no report in the literature with regard to allogenic transplants in HIV‐negative patients with PL.17\n\n\nPlasmablastic lymphoma is a rare and aggressive hematological malignancy that affects both immunocompetent and immunocompromised patients, which often presents at a late stage and associated with poor outcomes. Not only is PL a difficult disease to diagnose, our patient also did not have the typical risk factors that are associated with this condition. This case illustrates the unique presentation of an uncommon disease and the complexities surrounding therapeutic management.\n\nCONFLICT OF INTEREST\nThe authors state that there are no conflicts of interest to disclose.\n\nAUTHOR CONTRIBUTION\nAC: wrote and edited the manuscript. TN: contributed to the editing of the manuscript and was involved in the patient's care. ML: was the lead physician and contributed to the editing of the manuscript. MW: was the transplant physician involved in the patient's care. SL: was involved in the patient's care.\n\nACKNOWLEDGMENTS\nDr Felicity Frost, Department of Anatomical Pathology, PathWest, Royal Perth Hospital, Perth, Western Australia; Dr Minh Lam, Cutaneous Pathology, East Perth, Western Australia.\n==== Refs\nREFERENCES\n1 \n\nCastillo \nJJ \n, \nBibas \nM \n, \nMiranda \nRN \n. The biology and treatment of plasmablastic lymphoma\n. Blood . 2015 ;125 (15 ):2323 ‐2330\n.25636338 \n2 \n\nLopez \nA \n, \nAbrisqueta \nP \n. Plasmablastic lymphoma: current perspectives\n. Blood Lymphat Cancer . 2018 ;8 :63 ‐70\n.31360094 \n3 \n\nDalakas \nMC \n. Inflammatory muscle diseases\n. N Engl J Med . 2015 ;372 :1734 ‐1747\n.25923553 \n4 \n\nMuro \nY \n, \nSugiura \nK \n, \nAkiyama \nM \n. Cutaneous manifestations in dermatomyositis and serological features – a comprehensive review\n. Clin Rev Allergy Immunol . 2016 ;51 :293 ‐302\n.26100618 \n5 \nEViQ (AU) \n. Non‐Hodgkin lymphoma DA‐R‐EPOCH (dose adjusted rituximab etoposide prednisolone, vincristine, cyclophosphamide, doxorubicin)\n [Internet]. NSW (Australia) : EViQ (AU) ; 2019 Sept. https://www.eviq.org.au/haematology-and-bmt/lymphoma/non-hodgkin-lymphoma/783-da-r-epoch-dose-adjusted-rituximab-etoposide. Accessed January 13, 2020.\n6 \n\nSchmitz \nN \n, \nZeynalova \nS \n, \nNickelsen \nM \n, et al. CNS International prognostic index: a risk model for CNS relapse in patients with diffuse large B‐cell lymphoma treated with R‐CHOP\n. J Clin Oncol . 2016 ;34 (26 ):3150 ‐3156\n.27382100 \n7 \n\nHarmon \nCM \n, \nSmith \nLB \n. Plasmablastic lymphoma\n. Arch Pathol Lab Med . 2016 ;140 :1074 ‐1078\n.27684979 \n8 \n\nTchernonog \nE \n, \nFaurie \nP \n, \nCoppo \nP \n, et al. Clinical characteristics and prognostic factors of plasmablastic lymphoma patients: analysis of 135 patients from the LYSA group\n. Ann Oncol . 2017 ;28 :843 ‐848\n.28031174 \n9 \n\nPark \nJK \n, \nSubhawong \nAP \n, \nZiminski \nCM \n, et al. Dermatomyositis as the initial presentation of a large anaplastic T‐cell Lymphoma\n. J Clin Oncol . 2011 ;29 (13 ):378 ‐380\n.21172877 \n10 \n\nSuber \nTL \n, \nCasciola‐Rosen \nL \n, \nRosen \nA \n. Mechanisms of disease: autoantigens as clue to the pathogenesis of myositis\n. Nat Clin Pract Rheumatol . 2008 ;4 (4 ):201 ‐209\n.18319710 \n11 \n\nDittus \nC \n, \nGrover \nN \n, \nEllsworth \nS \n, et al. Bortezomib in combination with dose‐adjusted EPOCH induces long‐term survival in patients with plasmablastic lymphoma: a retrospective analysis\n. Leuk Lymphoma . 2018 ;59 (9 ):2121 ‐2127\n.29303024 \n12 \n\nAhn \nJS \n, \nOkal \nR \n, \nVos \nJA \n, et al. Plasmablastic lymphoma versus plasmablastic myeloma: an ongoing diagnostic dilemma\n. J Clin Pathol . 2017 ;70 :775 ‐780\n.28249941 \n13 \n\nDiaz \nR \n, \nAmalaseelan \nJ \n, \nImlay‐Gillespie \nL \n. Plasmablastic lymphoma masquerading solitary plasmacytoma in an immunocompetent patient\n. BMJ Case Rep . 2018 ;2018 :1 ‐4\n.\n14 \n\nGuerrero‐Garcia \nTA \n, \nMogollon \nRJ \n, \nCastillo \nJJ \n. Bortezomib in plasmablastic lymphoma: a glimpse of hope for a hard‐to‐treat disease\n. Leuk Res . 2017 ;62 :12 ‐16\n.28963907 \n15 \n\nCastillo \nJJ \n, \nGuerrero‐Garcia \nT \n, \nBaldini \nF \n, et al. Bortezomib plus EPOCH is effective as frontline treatment in patients with plasmablastic lymphoma\n. Br J Haematol . 2018 ;184 (4 ):679 ‐682\n.29527667 \n16 \n\nCastillo \nJJ \n, \nReagan \nJL \n, \nSikov \nWM \n, et al. Bortezomib in combination with infusional dose‐adjusted EPOCH for the treatment of plasmablastic lymphoma\n. Br J Haematol . 2015 ;169 :352 ‐355\n.25612847 \n17 \n\nMonzr \nMA \n, \nCastillo \nJJ \n, \nSloan \nJM \n, et al. Hematopoietic cell transplantation for plasmablastic lymphoma: a review\n. Biol Blood Marrow Transplant . 2014 ;20 :1877 ‐1884\n.24946718\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "8(5)",
"journal": "Clinical case reports",
"keywords": "autologous stem cell transplant; bortezomib; dermatomyositis; plasmablastic lymphoma",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "843-847",
"pmc": null,
"pmid": "32477530",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports",
"references": "27684979;24946718;21343565;29527667;26100618;25636338;18319710;28031174;28963907;25612847;28249941;27382100;31360094;29303024;30344143;25923553",
"title": "An unusual case of plasmablastic lymphoma presenting as dermatomyositis.",
"title_normalized": "an unusual case of plasmablastic lymphoma presenting as dermatomyositis"
} | [
{
"companynumb": "AU-PFIZER INC-2020233567",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": "3",
... |
{
"abstract": "Lambert-Eaton myasthenic syndrome (LEMS) is an uncommon autoimmune idiopathic or paraneoplastic syndrome producing antibodies against voltage presynaptic calcium channels. According to previous studies, many patients with LEMS experience remission in both the clinical symptoms of muscle weakness and the electrophysiologic abnormalities after successful treatment of lung SCC. However, some patients might not respond to conventional therapy and eventually require palliative care. Hereby, we reported a LEMS patient with advanced lung malignancy was referred for palliative care. He was benefited from multidisciplinary approach even with limited survival. In this case, use of 3,4-diaminopyridine (3,4-DAP) had other roles apart from symptomatic treatment.",
"affiliations": "Palliative Medical Unit, Grantham Hospital, 125 Wong Chuk Hang, Hong Kong, China. cky842@yahoo.com.hk.;Division of Neurology, Department of Medicine, Queen Mary Hospital, Hong Kong, China.;Palliative Medical Unit, Grantham Hospital, 125 Wong Chuk Hang, Hong Kong, China.;Department of Psychiatry, Kowloon Hospital, Hong Kong, China.;Palliative Medical Unit, Grantham Hospital, 125 Wong Chuk Hang, Hong Kong, China.",
"authors": "Chan|Kwok-Ying|KY|;Chang|Richard Shek-Kwan|RS|;Lau|Vikki Wai-Kee|VW|;Chan|Man-Lui|ML|;Lai|Theresa|T|",
"chemical_list": "D026902:Potassium Channel Blockers; D015761:4-Aminopyridine; D000077770:Amifampridine",
"country": "China",
"delete": false,
"doi": "10.21037/apm.2016.06.01",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2224-5820",
"issue": "5(4)",
"journal": "Annals of palliative medicine",
"keywords": "3,4-diaminopyridine (3,4-DAP); Lambert-Eaton myasthenic syndrome (LEMS); palliative care; psycho-spiritual distress",
"medline_ta": "Ann Palliat Med",
"mesh_terms": "D015761:4-Aminopyridine; D000200:Action Potentials; D000077770:Amifampridine; D005260:Female; D006801:Humans; D015624:Lambert-Eaton Myasthenic Syndrome; D008297:Male; D008875:Middle Aged; D009431:Neural Conduction; D010166:Palliative Care; D026902:Potassium Channel Blockers; D019452:Terminally Ill; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101585484",
"other_id": null,
"pages": "311-314",
"pmc": null,
"pmid": "27506750",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Palliative care for a patient with Lambert-Eaton myasthenic syndrome: role of 3,4-diaminopyridine.",
"title_normalized": "palliative care for a patient with lambert eaton myasthenic syndrome role of 3 4 diaminopyridine"
} | [
{
"companynumb": "HK-BIOGEN-2017BI00368010",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IRINOTECAN HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\n5-Fluorouracil is an antineoplastic agent generally used to treat various types of solid tumors. The common adverse drug reaction associated with 5-fluorouracil are myelosuppression, mucositis, diarrhea, and hand-foot syndrome. Neurological side effects such as headache, dizziness, convulsion, encephalopathy, and acute cerebellar syndrome are rare in nature.\n\n\nMETHODS\nWe report a case of 5-fluorouracil induced cerebrovascular accident (CVA) in a patient with no risk factors for CVA before chemotherapy. A 37 years old female patient diagnosed with carcinoma rectum underwent six cycles of chemotherapy with 5- fluorouracil- calcium leucovorin- irinotecan (FOLFIRI regimen). After completing the last cycle, she developed headache, vomiting, and facial deviation along with high blood pressure (260/160 mmHg). MRI brain was done, and it revealed acute non-hemorrhagic lacunar infarct in the left half of pons. 5-fluorouracil induced CVA was suspected and was managed with dual antiplatelet, statin, and antihypertensives.\n\n\nCONCLUSIONS\nThe clinicians and clinical pharmacists must be aware about the potential of 5-FU to induce rare side effects such as CVA even in low risk patients in order to avoid permanent harm to the patient.",
"affiliations": "Department of Pharmacy Practice, St. Joseph's College of Pharmacy, Cherthala, India.;Department of Pharmacy Practice, St. Joseph's College of Pharmacy, Cherthala, India.;Department of Pharmacy Practice, St. Joseph's College of Pharmacy, Cherthala, India.;Department of Oncology, Lourdes Hospital, Kochi, India.;Department of Oncology, Lourdes Hospital, Kochi, India.",
"authors": "Karthikeyan|Kavya|K|https://orcid.org/0000-0002-1950-8280;Babu|Christy M|CM|;Shaji|Shintu|S|;Ashok|Ashwin M|AM|;Madhu|C S|CS|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D010975:Platelet Aggregation Inhibitors; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1177/1078155220954900",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "27(4)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "5-fluorouracil; antineoplastic agent; cerebrovascular accident",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000328:Adult; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D015179:Colorectal Neoplasms; D005260:Female; D005472:Fluorouracil; D006801:Humans; D010975:Platelet Aggregation Inhibitors; D020521:Stroke",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1016-1019",
"pmc": null,
"pmid": "32903144",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case report on 5-fluorouracil induced cerebrovascular accident.",
"title_normalized": "case report on 5 fluorouracil induced cerebrovascular accident"
} | [
{
"companynumb": "IN-ACCORD-202356",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"dr... |
{
"abstract": "Dantrolene is used for reversal of malignant hyperthermia and for improvement in spasticity following stroke which are Food and Drug Administration-approved indications. It is an infrequently used medication in the pediatric intensive care unit and is usually continued from the operating room or sedation suite after suspicion for malignant hyperthermia, secondary to other medications and anesthetic agents. Hepatitis has been described as a side effect of the medication after prolonged use and at doses of more than 100 mg/d mainly in adults. We described in this case report a patient in which the drug was used for sympathetic overactivity in the PICU and development of asymptomatic hepatitis on day 3 after starting the medication at a dose much lower than previously described.",
"affiliations": "Department of Pediatric Critical Care, Oishei Children's Hospital, University of Buffalo, Buffalo, New York, United States.;Department of Internal Medicine, Mercy Hospital of Buffalo, Buffalo, New York, United States.;Department of Pediatric Critical Care, Oishei Children's Hospital, University of Buffalo, Buffalo, New York, United States.",
"authors": "Pasrija|Divij|D|0000-0001-5826-0460;Gupta|Shilpi|S|;Hassinger|Amanda|A|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0040-1710496",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2146-4626",
"issue": "10(2)",
"journal": "Journal of pediatric intensive care",
"keywords": "dantrolene; hepatitis; spasticity; toxicity",
"medline_ta": "J Pediatr Intensive Care",
"mesh_terms": null,
"nlm_unique_id": "101592756",
"other_id": null,
"pages": "152-154",
"pmc": null,
"pmid": "33884217",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": "2392230;838213;761834;3527659;1107103;17302443;21878205",
"title": "Dantrolene-Induced Hepatitis: A Rare Culprit in the PICU.",
"title_normalized": "dantrolene induced hepatitis a rare culprit in the picu"
} | [
{
"companynumb": "US-EAGLE PHARMACEUTICALS, INC.-US-2021EAG000091",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DANTROLENE SODIUM"
},
"... |
{
"abstract": "Endogenous peritonitis resulting from inflammation or perforation of an abdominal viscus-a result, for example, of diverticulitis, cholecystitis, or acute appendicitis-can be a complication in patients undergoing peritoneal dialysis (PD), with significant morbidity and a high incidence of catheter loss.Here, we describe an end-stage renal disease patient on PD who presented with acute abdominal pain and who was diagnosed with uncomplicated PD peritonitis. His clinical course was complicated by development of eosinophilic peritonitis because of an allergy to vancomycin. Subsequently, when he failed to show clinical improvement, abdominal and pelvic imaging revealed severe appendicitis, which necessitated emergent surgical intervention.",
"affiliations": "Division of Nephrology, University of Missouri-Columbia, Columbia, Missouri, U.S.A.;Division of Nephrology, University of Missouri-Columbia, Columbia, Missouri, U.S.A.;Division of Nephrology, University of Missouri-Columbia, Columbia, Missouri, U.S.A.",
"authors": "Edo-Ohonba|Osaze|O|;Khanna|Ramesh|R|;Misra|Madhukar|M|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1197-8554",
"issue": "33(2017)",
"journal": "Advances in peritoneal dialysis. Conference on Peritoneal Dialysis",
"keywords": null,
"medline_ta": "Adv Perit Dial",
"mesh_terms": "D006801:Humans; D015994:Incidence; D007676:Kidney Failure, Chronic; D008297:Male; D010530:Peritoneal Dialysis; D010538:Peritonitis",
"nlm_unique_id": "9104803",
"other_id": null,
"pages": "47-49",
"pmc": null,
"pmid": "29668431",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Diagnostic Dilemma: A Case of Endogenous Peritonitis.",
"title_normalized": "diagnostic dilemma a case of endogenous peritonitis"
} | [
{
"companynumb": "US-AXELLIA-002417",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": "1",
"drug... |
{
"abstract": "BACKGROUND\nSalmonella is a notorious pathogen that causes gastroenteritis in humans and the emergence of resistance to third-generation cephalosporins and azithromycin have raised concern. There has been rare case of Salmonella Paratyphi A infection accompanied by spondylitis. Here, we report a case of initial antibiotic treatment failure in a Korean man with Salmonella Paratyphi A infection and conducted next-generation sequencing (NGS) to determine the cause of failure of initial treatment for Salmonella Paratyphi A infection.\n\n\nMETHODS\nA 70-year-old man was admitted to Chosun University Hospital with reported consistent low back pain with a history of having 5 days of chills and fever in another hospital a month ago. He was administered ceftriaxone (2 g daily) for 18 days including initial treatment to cover Salmonella enterica. The antimicrobial susceptibility test using MIC plate, found that the identified organism was resistant to ciprofloxacin and nalidixic acid. Moreover, the Salmonella Paratyphi A isolates were found to have an MIC > 16 mg/L for azithromycin, as he had resistance to both azithromycin and nalidixic acid, the treatment was switched to a combination of ciprofloxacin and cefotaxime. We carried out next-generation sequencing (NGS) to determine the cause of failure of initial treatment for Salmonella Paratyphi A infection. NGS showed that the amino acid substitution GyrA S83F and the expression of multiple RNA-family efflux pumps led to a high-level resistance to quinolone. No genes related to ceftriaxone resistance, such as CTX-M, CMY-2, or other extended-spectrum beta-lactamases were identified in Salmonella enterica Paratyphi A using NGS. The GyrA S83F mutation and the expression of multiple RNA-family efflux pumps may have contributed to the treatment failure of ceftriaxone, even though the MIC of the isolate to ceftriaxone was less than 1.\n\n\nCONCLUSIONS\nThis case involved a Salmonella Paratyphi A infection accompanied by spondylitis. To our knowledge, this is the first report to elucidate the mechanism underlying antimicrobial resistance using NGS.",
"affiliations": "Department of Internal Medicine, College of Medicine, Chosun University, 588 Seosuk-dong, Dong-gu, Gwangju, 501-717, Republic of Korea.;Department of Internal Medicine, College of Medicine, Chosun University, 588 Seosuk-dong, Dong-gu, Gwangju, 501-717, Republic of Korea. drongkim@chosun.ac.kr.;Department of Internal Medicine, College of Medicine, Chosun University, 588 Seosuk-dong, Dong-gu, Gwangju, 501-717, Republic of Korea.;Department of Premedical Science, College of Medicine, Chosun University, Gwangju, Republic of Korea.",
"authors": "Park|Hye-Ran|HR|;Kim|Dong-Min|DM|http://orcid.org/0000-0001-6373-0922;Yun|Na-Ra|NR|;Kim|Choon-Mee|CM|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin; D002443:Ceftriaxone; D017963:Azithromycin; D027081:DNA Gyrase; D002439:Cefotaxime",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-019-3821-x",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 382110.1186/s12879-019-3821-xCase ReportIdentifying the mechanism underlying treatment failure for Salmonella Paratyphi A infection using next-generation sequencing – a case report Park Hye-Ran hyerong313@naver.com 1http://orcid.org/0000-0001-6373-0922Kim Dong-Min 82-62-220-3108drongkim@chosun.ac.kr 1Yun Na-Ra shine@chosun.ac.kr 1Kim Choon-Mee choonmee@chosun.ac.kr 21 0000 0000 9475 8840grid.254187.dDepartment of Internal Medicine, College of Medicine, Chosun University, 588 Seosuk-dong, Dong-gu, Gwangju, 501-717 Republic of Korea 2 0000 0000 9475 8840grid.254187.dDepartment of Premedical Science, College of Medicine, Chosun University, Gwangju, Republic of Korea 26 2 2019 26 2 2019 2019 19 19112 12 2018 15 2 2019 © The Author(s). 2019Open 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\nSalmonella is a notorious pathogen that causes gastroenteritis in humans and the emergence of resistance to third-generation cephalosporins and azithromycin have raised concern. There has been rare case of Salmonella Paratyphi A infection accompanied by spondylitis. Here, we report a case of initial antibiotic treatment failure in a Korean man with Salmonella Paratyphi A infection and conducted next-generation sequencing (NGS) to determine the cause of failure of initial treatment for Salmonella Paratyphi A infection.\n\nCase presentation\nA 70-year-old man was admitted to Chosun University Hospital with reported consistent low back pain with a history of having 5 days of chills and fever in another hospital a month ago. He was administered ceftriaxone (2 g daily) for 18 days including initial treatment to cover Salmonella enterica. The antimicrobial susceptibility test using MIC plate, found that the identified organism was resistant to ciprofloxacin and nalidixic acid. Moreover, the Salmonella Paratyphi A isolates were found to have an MIC > 16 mg/L for azithromycin, as he had resistance to both azithromycin and nalidixic acid, the treatment was switched to a combination of ciprofloxacin and cefotaxime. We carried out next-generation sequencing (NGS) to determine the cause of failure of initial treatment for Salmonella Paratyphi A infection. NGS showed that the amino acid substitution GyrA S83F and the expression of multiple RNA-family efflux pumps led to a high-level resistance to quinolone. No genes related to ceftriaxone resistance, such as CTX-M, CMY-2, or other extended-spectrum beta-lactamases were identified in Salmonella enterica Paratyphi A using NGS. The GyrA S83F mutation and the expression of multiple RNA-family efflux pumps may have contributed to the treatment failure of ceftriaxone, even though the MIC of the isolate to ceftriaxone was less than 1.\n\nConclusion\nThis case involved a Salmonella Paratyphi A infection accompanied by spondylitis. To our knowledge, this is the first report to elucidate the mechanism underlying antimicrobial resistance using NGS.\n\nKeywords\nSalmonella enterica Paratyphi AOsteomyelitisNext-generation sequencingAntibiotic resistanceissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nSalmonella is a notorious pathogen that causes gastroenteritis in humans, and 94 million cases of salmonellosis are reported globally every year [1]. Infections are systemic, characterized by fever and gastrointestinal symptoms, and are associated with significant morbidity [2]. Death can occur, especially if appropriate antimicrobial therapy is delayed [3]. Fluoroquinolones became the first-line antimicrobial therapy following their introduction in the 1980s, and they were initially associated with rapid fever clearance and low rates of both relapse and chronic faecal carriage [4]. However, reduced ciprofloxacin susceptibility (MIC 0.06–0.25 mg/L) has become increasingly prevalent in Salmonella enterica Typhi and Salmonella enterica Paratyphi A, and has been associated with clinical failure [5, 6]. Fluoroquinolone-resistant strains of Salmonella Typhi and Salmonella Paratyphi A have recently emerged in tropical and subtropical regions of the world, such as southeast Asia and Africa [7]. In the UK, > 90% of Salmonella Typhi and Salmonella Paratyphi A isolates acquired from India between 2006 and 2007 were found to be nalidixic acid-resistant [8]. Alternative antimicrobials, including third-generation cephalosporins and azithromycin, are now being increasingly used as first-line therapies [9]. Reports of emergence of resistance to third-generation cephalosporins and azithromycin have raised concern amongst clinicians [10, 11]. A case of clinical failure under azithromycin treatment in a case of bacteremia due to Salmonella enterica Paratyphi A was reported in 2014 [7].\n\nHere, we report a case of initial antibiotic treatment failure in a Korean man with Salmonella Paratyphi A infection and conducted next-generation sequencing (NGS) to determine the cause of failure of initial treatment for Salmonella Paratyphi A infection.\n\nCase presentation\nIn January 2018, a 70-year-old man residing in South Korea was admitted to Chosun University Hospital with reported consistent low back pain. At first, he had been admitted to a local hospital on 24 November 2017, a month before visiting Chosun University Hospital with a history of 5 days of chills and fever. In the local hospital, in view of the possibility of acute pyelonephritis, he was first treated with intravenous ceftriaxone at a dosage of 2 g daily. Two days after admission, back pain started. During antibiotic treatment, blood cultures taken on admission yielded Salmonella enterica. He remained on ceftriaxone (2 g daily) for 18 days including initial treatment to cover S. enterica. Upon follow-up blood culture, no bacteria were detected on the 8th and 25th days after starting treatment, and the patient no longer had fever; he was subsequently discharged from the local hospital on 19 December 2017. However, he consistently suffered from lower back pain, nausea, and vomiting; he was re-admitted to the same local hospital 9 days after his discharge. When he was re-admitted to the local hospital again on 30 December 2017, magnetic resonance imaging (MRI) was performed and L1 spondylitis was demonstrated. MRI revealed whole bone marrow oedema with endplate lytic changes in the L1 body and focal marrow oedema in the upper endplate of L2 bodies. Additionally, mild destruction of intervertebral disc at L1–2 was shown. These findings were considered to be indicative of pyogenic spondylitis (Fig. 1a, b, c). He was empirically treated with cefazolin (1 g, 3 times a day) for 10 days to cover the possibility of Staphylococcus aureus infection, which is a common cause of pyogenic spondylitis. Then, blood cultures were tested and yielded S. enterica again. Finally, he was transferred to Chosun University Hospital, and bone biopsy of L spine was performed on 3 January 2018. He had no fever, and the initial blood test was generally unremarkable except that his erythrocyte sedimentation rate (ESR) level was 108 mm/h. After 7 days, the biopsy results of bone and blood cultures were positive for Salmonella enterica. Cultures of bone and blood obtained during biopsy at the Chosun University Hospital grew O:2-positive Salmonella. The organism was serotyped to be serovar Paratyphi A ([1],2,12:a:-) by the tube agglutination method combining Salmonella O and H (flagella) antigens according to the Antigenic Formulae of the Salmonella serovars.Fig. 1 a L-spine T2_tse_sagittal, b L-spine T1_tse_sagittal, and c L-spine T1_tse_sagittal_fat suppressed. MRI of the lumbosacral spine shows altered signals in the L1 vertebral body (in the local clinic on 30 December 2017). MRI revealed whole bone marrow oedema with endplate lytic changes in the L1 body and focal marrow oedema in the upper endplate of L2 bodies. Additionally, it showed mild destruction of intervertebral disc at L1–2. Adjacent paravertebral soft tissue thickening and small abscess in left psoas muscle were found. These findings are considered to be indicative of pyogenic spondylitis\n\n\n\nAfter the bacteria were identified, with suspicions of metastatic spondylitis, he was treated with ciprofloxacin for 13 days. Computed tomography (CT) was performed for further evaluation. CT scans revealed L1–2 spondylitis spreading to the left psoas muscle. Fluorodeoxyglucose positron emission tomography (FDG PET) was performed to detect clinically undetected diseases in different sites, and it showed hypermetabolism and bone destruction in L1 and L2 vertebral bodies, as well as mild hypermetabolism in the right facet joint between L4 and L5 vertebral bodies. The antimicrobial susceptibility test using MIC plate by the Chosun University Hospital and Health and Environment Research Institute of Gwangju City found that the identified organism was resistant to ciprofloxacin and nalidixic acid (Table 1). Since susceptibility tests for macrolides could not be carried out due to unavailability of the disc, the specimen was sent for testing to Korea Centers for Disease Control and Prevention. While waiting for results, the antibiotic used in the treatment of the patient was changed from ciprofloxacin to azithromycin due to the identified resistance to ciprofloxacin and nalidixic acid. While he was treated with azithromycin for 15 days, C-reactive ptrotein (CRP) gradually decreased to the normal value of 0.09 mg/dL; ESR level decreased as well, but not to normal levels (CRP: 0.09 mg/dL, ESR: 44 mm/h on the 20th day of admission). He was discharged and followed up through an outpatient clinic. Seven days later, the Salmonella Paratyphi A isolates were found to have an MIC > 16 mg/L for azithromycin. As he had resistance to both azithromycin and nalidixic acid, the treatment was switched to a combination of ciprofloxacin and cefotaxime. While he was treated with combination therapy for 2 months, his clinical symptoms such as back pain reduced, and the ESR level gradually decreased to normal (ESR: 20 mm/h on the 64th day of combination therapy).Table 1 Antimicrobial susceptibility test using MIC plate performed in Chosun University Hospital and Health and Environmental Research Institure of Gwangju City\n\nNo.\tSample\tAN\tAM\tCZ\tCTX\tCAZ\tTGC\tGM\tTZP\tAMC\tAZM\tFEP\tFOX\tETP\tCIP\tIPM\tSXT\tNAL\t\n2017-12-30\tblood\t<=2\t4\t<=4\t<=1\t<=1\t1\t<=1\t<=4\t<=2\t<=1\t<=1\t<=4\t<=0.5\t1\t<=0.25\t<=20\t128<\t\ninterpretations\tR\tS\tR\tS\tS\tS\tR\tS\tS\tS\tS\tR\tS\tR\tS\tS\tR\t\n2018-01-03\tbone Biopsy\t<=2\t4\t<=4\t<=1\t<=1\t2\t<=1\t<=4\t<=2\t<=1\t<=1\t<=4\t<=0.5\t1\t<=0.25\t<=20\t128<\t\ninterpretations\tR\tS\tR\tS\tS\tS\tR\tS\tS\tS\tS\tR\tS\tR\tS\tS\tR\t\nNalidixic acid was tested at the Health and Environment Research Institute, and the remaining interpretations were obtained at Chosun University Hospital\n\nAN Amikacin, AM Ampicillin, CZ Cefazolin, CTX Cefotaxime, CAZ Ceftazidime, TGC Tigecycline, GM Gentamicin, TZP Piperacillin/Tazobactam, AMC Amoxicillin/ClavulanicAcid, AZM Aztreonam, FEP Cefepime, FOX Cefoxitin, ETP Ertapenem, CIP Ciprofloxacin, IPM Imipenem, SXT Trimethoprim/Sulfamethoxazole, NAL Nalidixic acid\n\n\n\nWe carried out NGS to determine the cause of failure of the initial treatment for Salmonella Paratyphi A infection and elucidate the mechanism underlying antimicrobial resistance in Salmonella Paratyphi A.\n\nPurified genomic DNA was randomly sheared to yield DNA fragments approximately 350 bp in size using a Covaris S2 Ultrasonicator. Library preparation was performed using the Illumina TruSeq DNA PCR-free Preparation Kit following the manufacturer’s instructions. Adaptor enrichments were performed using PCR according to the manufacturer’s instructions. The final library size and quality were evaluated electrophoretically with an Agilent High Sensitivity DNA Kit. The 100-bp paired-end reads were sequenced on the Illumina HiSeq 2500 platform. Further image analysis and base calling were performed with RTA 2.7.3 (Real Time Analysis) and bcl2fastq v2.17.1.14.\n\nThe draft genome was assembled using A5 pipeline ver. 20,160,825 with paired-end reads. For annotation of the prokaryotic genome, Prokka v1.1.0 was used. The gene models were predicted through the open reading frame (ORF) finding method using prodigal v2.6.2. Then, tRNA, rRNA, and repetitive sequences were identified using Aragon v1.2.36, barrnap v0.6, and minced v0.2.0, respectively. For functional annotation, genes were searched against the UniProt and NCBI RefSeq databases using BLASTP v2.2.29+ with an E-cutoff value of 1 × 10− 6. Protein domains were also searched against Pfam using HMMER 3.1b1.\n\nResistance genes were identified using Resistance Gene Identifier (RGI) in the Comprehensive Antibiotic Resistance Database (CARD, http://arpcard.mcmaster.ca) using predicted peptide sequences. All sequences were run through all databases in CARD with a selected threshold of ID = 98.00%.\n\nThe clinical isolates were identified with a VITEK II automated system (bioMérieux, Marcy-l’Etoile, France). Tests for antimicrobial susceptibility including MIC were performed with the VITEK II system. In Chosun University Hospital, we cultured the blood collected on 30 December 2017 in the local hospital and conducted antimicrobial susceptibility tests using Clinical and Laboratory Standards Institute (CLSI) guideline (Table 1).\n\nThe antimicrobial susceptibility test performed by the Health and Environment Research Institute of Gwangju City showed that the identified organism from the closed pus taken from bone biopsy when the patient was admitted to Chosun University Hospital on 3 January 2018 exhibited resistance to ciprofloxacin (MIC = 1 mg/L) and nalidixic acid (MIC> 128 mg/L) (Table 1). The antibiotic resistance test results for the blood samples obtained on December 30, 2017 and the biopsy samples obtained on January 3, 2018 were the same. The isolate also presented resistance to macrolides (MIC> 16 mg/L) in a test performed by the Korea Centers for Disease Control and Prevention. We carried out NGS to determine the cause of failure of the initial treatment for Salmonella Paratyphi A infection and elucidate the mechanism underlying antimicrobial resistance in Salmonella Paratyphi A. The isolate used for NGS was taken in the local hospital when he was readmitted in 30 December 2017.\n\nNext-generation sequencing results for Salmonella Paratyphi A with a selected threshold of ID = 98.00% showed that there are antimicrobial resistance gene families present in the isolate, including resistance-nodulation-cell division (RND) antibiotics efflux pumps such as mdsC, CRP, and sdiA; gyrA associated with fluoroquinolone resistance such as Salmonella enterica gyrA; and MATE transporters such as MdtK and AAC (6′)-ly (Table 2). Based on the results, the most likely cause of treatment failure was a RND antibiotic efflux pump. Meanwhile azithromycin resistance genes such as mph and mef were not identified (Table 2). There were also no resistance genes related to ceftriaxone, such as CTX-M, CMY-2, or other extended-spectrum beta-lactamases.Table 2 NGS (next-generation sequencing) of Salmonella Paratyphi\n\nBest_Hit_ARO\tDrug class\tBest_Identities\tAMR gene family\tSNPs_in_Best_Hit_ARO\t\nSalmonella enterica gyrA conferring resistance to fluoroquinolones\tnybomycin; fluoroquinolone antibiotic\t99.89\tfluoroquinolone resistant gyrA\tS83F\t\nmdsC\tcarbapenem; monobactam; cephamycin; penam; penem ;phenicol antibiotic; cephalosporin\t100\tRND antibiotic efflux pump\t\t\t\t\nCRP\tmacrolide antibiotic; fluoroquinolone antibiotic; penam\t98.57\tRND antibiotic efflux pump\t\t\t\t\nMdtK\tfluoroquinolone antibiotic\t98.95\tMATE transporter\t\t\t\t\nAAC(6′)-Iy\taminoglycoside antibiotic\t98.62\tAAC(6′)\t\t\t\t\nsdiA\ttriclosan; glycylcycline; rifamycin antibiotic; phenicol antibiotic ;fluoroquinolone antibiotic; cephalosporin; tetracycline antibiotic; penam\t99.17\tRND antibiotic efflux pump\t\t\t\t\nAll sequences were run out through all databases in ResFinder with a selected threshold of ID = 98.00%\n\nRND resistance-nodulation-cell division, ABC ATP-binding cassette, MFS major facilitator superfamily, MATE multidrug and toxic compound extrusion\n\n\n\nDiscussion and conclusion\nIn 2008, a case of L3/4 vertebral osteomyelitis due to Salmonella Paratyphi A was first reported with bacteriological confirmation in Dubai, United Arab Emirates [12]; however, it was not described if the isolate exhibited resistance to nalidixic acid and macrolides.\n\nIn this case, we carried out NGS to elucidate the mechanism underlying antibiotic resistance in Salmonella Paratyphi A due to the emerging development of osteomyelitis during intravenous ceftriaxone treatment. As of late, there have been no studies involving the use of NGS in identifying the mechanism underlying treatment failure for Salmonella Paratyphi A.\n\nA recent study reported that 40% of Salmonella isolates in Chennai, India have an MIC of > 0.5 uL/mL against ceftriaxone [13].\n\nThere is a wide variety of serotypes and susceptibility results among Salmonella spp. isolated from clinical specimens in Korea [14]. The three most common Salmonella serotypes are Enteritidis, Typhimurium, and Infantis. These Salmonella strains had resistance rates of 38.7% to ampicillin, 23.0% to chloramphenicol, 8.2% to cefotaxime, 8.6% to ceftriaxone, and 6.3% to trimethoprim-sulfamethoxazole [14]. Another study showed the same result, where the major serotypes isolated in Jeollanam-do, Korea, were Salmonella Enteritidis and Salmonella Typhimurium, where a total of 22 different serotypes were identified, and the major serotypes were Salmonella Enteritidis (116 strains, 42.0%) and Salmonella Typhimurium (60 strains, 21.7%). The highest resistance was observed in response to nalidixic acid (43.4%), followed by ampicillin (40.5%) and tetracycline (31.6%) [15]. Resistance to nalidixic acid was detected in 81.0% of Salmonella Enteritidis isolates. Multidrug resistance was detected in 43.3% of Salmonella spp. Salmonella Enteritidis and Salmonella Typhimurium presented the highest resistance (98.3%) and multidrug resistance (73.3%) rates, respectively [15]. A recent report similar to our case showed that a patient infected with Salmonella Paratyphi A was treated with ceftriaxone, but his symptoms remained; therefore, his treatment was changed to azithromycin [7]. Even though the MIC of azithromycin was not elevated (8 mg/L), azithromycin treatment failed. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) states that the wild-type isolates of Salmonella Typhi have an MIC ≤16 mg/L. In our case, the MIC of the isolate showed that it was azithromycin-resistant (MIC > 16 mg/L) (Table 2).\n\nBased on our NGS results, azithromycin resistance genes such as mph and mef were not found; however, it was suggested that the mechanism of resistance to azithromycin was due to a RND antibiotic efflux pump.\n\nIn our previous study, a combination of ciprofloxacin and cefotaxime showed synergistic effects against nalidixic acid-resistant Salmonella Paratyphi A and B. This combination appears to be more effective than monotherapy and may help reduce the chances that fluoroquinolone-resistant mutants will emerge in patients with severe typhoid fever [16, 17]. In this case, we treated with ciprofloxacin and cefotaxime, and the patient’s clinical features including back pain and ESR level decreased.\n\nOlaquindox-resistant isolates were found to contain the gene combination oqxAB, which encodes an RND family efflux pump, confers resistance to olaquindox quinolones and chloramphenicol, and reduces susceptibility to other antibiotics [18]. OqxAB, a plasmid-mediated RND efflux pump conferring resistance to multiple antibiotics, was found in Salmonella isolates recovered from food samples. The overall OqxAB-positive rate of Salmonella typhimurium strains was 29% (159 out of 546 isolates), and the yearly rates were 0, 13, 26, 32, 36, 39, and 42% during the years 2005 to 2011, respectively. OqxAB was also found to be associated with multidrug resistance in S. typhimurium isolates from Hong Kong and from the Infectious Disease Prevention and Control, National Institute for Communicable Disease Control and Prevention (ICDC), Chinese Center for Disease Control and Prevention, Beijing, China. Among the S.typhimurium isolates of the OqxAB-positive group, 94% (Hong Kong) and 98% (ICDC) were resistant to ciprofloxacin (MIC = 2 mg/L); the corresponding resistance rate in the OqxAB-negative S. typhimurium isolates from Hong Kong and ICDC was only 11% [19].\n\nOur NGS study showed that expression of multiple RND family efflux pumps such as MdsC, CRP, and SdiA, which may be related to quinolone resistance, may have been responsible for the failure of ceftriaxone treatment (Table 2). The upregulation of endogenous SdeXY-HasF-mediated efflux has been reported to be associated with tigecycline resistance in Serratia marcescens, along with increases in MIC for tetracycline, ciprofloxacin, and cefpirome [20]. The overexpression of the BmeB efflux pump has also been reported to cause low-to-intermediate-level clinically relevant fluoroquinolone resistance and can be coupled with GyrA substitutions to cause high-level fluoroquinolone resistance. Finally, it also contributes to high-level clinically relevant resistance to beta-lactams [21]. Our case also showed that both the amino acid substitution GyrA S83F and the expression of multiple RND family efflux pumps led to high-level resistance to quinolone. No resistance genes in Salmonella Paratyphi A related to ceftriaxone, such as CTX-M, CMY-2, or other extended-spectrum beta-lactamases were identified using NGS. However, there was no response or even progression to vertebral osteomyelitis to treatment with third-generation cephalosporins after 18 days of the initial treatment. The GyrA S83F substitution and the expression of multiple RND family efflux pumps may have contributed to the failure of treatment with ceftriaxone, even though the MIC of the isolate to ceftriaxone was less than 1. In our case, there was a possibility that the early onset of metastatic spondylitis accounted for the failure of treatment with a third-generation cephalosporin because the treatment duration was not long enough. However, further studies on RND antibiotic efflux pumps are necessary to truly identify it as the cause of third-generation cephalosporin treatment failure.\n\nIn conclusion, this case involved a Salmonella Paratyphi A infection accompanied by spondylitis. To our knowledge, this is the first report to elucidate the mechanism underlying antimicrobial resistance using NGS.\n\nAbbreviations\nNGSNext-generation sequencing\n\nORFOpen reading frame\n\nPCRPolymerase chain reaction\n\nRGIResistance Gene Identifier\n\nAcknowledgements\nNot applicable.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nData and materials are available upon request to the corresponding author.\n\nAuthors’ contributions\nPHR and KCM equally contributed to this work; designed the study, proposal development, participated in data collection, laboratory analysis, performed statistical analysis and writing the first draft of manuscript and revision. YNR contributed in clinical evaluation and treatment of the patients: participated in study conduct and laboratory sample analysis and writing manuscript. KDM is the Principal advisor and corresponding author; idea conception, proposal development, study design and review final manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for the publication, of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\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. Majowicz SE Musto J Scallan E Angulo FJ Kirk M O’Brien SJ Jones TF Fazil A Hoekstra RM The global burden of nontyphoidal Salmonella gastroenteritis Clin Infect Dis 2010 50 882 889 10.1086/650733 20158401 \n2. Martin RD Michel D Vivienne DN Satheesh N Philip MA Claire J Timothy JD Flora JS Joanne F Katie LH Neil W Elizabeth MDP Gauri G Comparison of phenotypic and WGS-derived antimicrobial resistance profiles of Salmonella enteria serovars Typhi and Paratyphi J Antimicrob Chemother 2018 73 365 372 10.1093/jac/dkx379 29216342 \n3. Connor BA Schwartz E Typhoid and paratyphoid fever in travelers Lancet Infect Dis 2005 5 623 628 10.1016/S1473-3099(05)70239-5 16183516 \n4. Bhan MK Bahl R Bhatnagar S Typhoid and paratyphoid fever Lancet 2005 366 749 762 10.1016/S0140-6736(05)67181-4 16125594 \n5. Wain J Hoa NT Chinh NT Quinolone-resistant Salmonella typhi inViet Nam: molecular basis of resistance and clinical response to treatment Clin Infect Dis 1997 25 1404 1410 10.1086/516128 9431387 \n6. Threlfall EJ Ward LR Skinner JA Smith HR Lacey S Ciprofloxacin-resistant Salmonella typhi and treatment failure Lancet 1999 353 1590 1591 10.1016/S0140-6736(99)01001-6 10334265 \n7. Tetsuro K Kayoko H Momoko M Kazuhisa M Nozomi T Satoshi K Yoshihiro F Shuzo K Norio O Yasuyuki K Masatomo M Case report: failure under azithromycin treatment in a case of bacteremia due to Salmonella enterica Paratyphi A BMC Infect Dis 2014 14 404 10.1186/1471-2334-14-404 25041573 \n8. HPA Pilot of Enhanced Surveillance of Enteric Fever in England, Wales, and Northern Ireland, 1 May 2006 to 30 April 2007 2008 London HPA \n9. Wain J Hendriksen RS Mikoleit ML Keddy KH Ochiai RL Typhoid fever Lancet 2015 385 1136 1145 10.1016/S0140-6736(13)62708-7 25458731 \n10. Saha SK Talukder SY Islam M Saha S A highly ceftriaxone-resistant Salmonella typhi in Bangladesh Pediatr Infect Dis J 1999 18 387 10.1097/00006454-199904000-00018 10223698 \n11. Hassing RJ Goessens WH Pelt W Mevius DJ Stricker BH Molheok N Verbon A Genderen PJJ Salmonella subtypes with increased MICs for azithromycin in travelers returned to The Netherlands Emerg Infect Dis 2014 20 705 708 10.3201/eid2004.131536 24655478 \n12. Kumar P Mahmoodi SM Kalaparambil Moosa N Edgar M Samt HA Hussain RA Salmonella paratyphi spondylitis: a case report Eur Spine J 2008 17 5 756 10.1007/s00586-008-0614-0 \n13. Sekar U Srikanth P Kindo AJ Babu VP Ramasubramanian V Increase in minimum inhibitory concentration to quinolones and ceftriaxone in salmonellae causing enteric fever J Commun Dis 2003 35 3 162 169 15796408 \n14. Lee JY Kim JA Jeong HS Shin JH Chang CL Jeong J Cho JH Kim MN Kim SJ Kim YR Lee CH Lee KW Lee MA Lee WG Shin JH Lee JN Serotyping and antimicrobial susceptibility of Salmonella spp.: nationwide multicenter study in Korea Jpn J Infect Dis 2013 66 284 289 10.7883/yoken.66.284 23883837 \n15. Yoon KB Song BJ Shin MY Lim HC Yoon YH Jeon DY Hoon H Yang SI Kim JB Antibiotic resistance patterns and serotypes of Salmonella spp. isolated at Jeollanam-do in Korea Osong Public Health Res Perspect 2017 8 3 2118 10.24171/j.phrp.2017.8.3.08 \n16. Kim DM Neupane GP Jang SJ Kim SH Lee BK In vitro efficacy of the combination of ciprofloxacin and cefotaxime against nalidixic acid-resistant Salmonella enterica serotype Typhi Int J Antimicrob Agents 2010 36 2 155 158 10.1016/j.ijantimicag.2010.03.022 20478696 \n17. Neupane GP Kim DM Kim SH Lee BK In Vitro Synergism of Ciprofloxacin and Cefotaxime against Nalidixic Acid Resistant Salmonella enterica Serotypes Paratyphi A and B Antimicrob Agents Chemother 2010 54 9 3696 3701 10.1128/AAC.00988-09 20566759 \n18. Marcus H Yin W Sheng C First detection of oqxAB in Salmonella spp. isolated from food Antimicrob Agents Chemother 2013 57 658 660 10.1128/AAC.01144-12 23147728 \n19. Marcus H Meiying Y Edward WC Li ZL Biao K Sheng C Expansion of Salmonella enterica serovar Typhimurium ST34 clone carrying multiple resistance determinants in China Antimicrob Agents Chemother 2013 57 9 4599 4601 10.1128/AAC.01174-13 23796940 \n20. Hornsey M Ellington MJ Doumith M Hudson S Livermore DM Woodford N Tigecycline resistance in Serratia marcescens associated with up-regulation of the SdeXY-HasF efflux system also active against ciprofloxacin and cefpirome J Antimicrob Chemother 2010 65 3 479 482 10.1093/jac/dkp475 20051474 \n21. Pumbwe L Chang A Smith RL Wexler HM Clinical significance of overexpression of multiple RND-family efflux pumps in Bacteroides fragilis isolates J Antimicrob Chemother 2006 58 3 543 548 10.1093/jac/dkl278 16840432\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "19(1)",
"journal": "BMC infectious diseases",
"keywords": "Antibiotic resistance; Next-generation sequencing; Osteomyelitis; Salmonella enterica Paratyphi A",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000368:Aged; D019943:Amino Acid Substitution; D000900:Anti-Bacterial Agents; D017963:Azithromycin; D002439:Cefotaxime; D002443:Ceftriaxone; D002939:Ciprofloxacin; D027081:DNA Gyrase; D024881:Drug Resistance, Bacterial; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D010284:Paratyphoid Fever; D012482:Salmonella paratyphi A; D017211:Treatment Failure",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "191",
"pmc": null,
"pmid": "30808284",
"pubdate": "2019-02-26",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10223698;10334265;15796408;16125594;16183516;16840432;18008092;20051474;20158401;20478696;20566759;23147728;23796940;23883837;24655478;25041573;25458731;28781944;29216342;9431387",
"title": "Identifying the mechanism underlying treatment failure for Salmonella Paratyphi A infection using next-generation sequencing - a case report.",
"title_normalized": "identifying the mechanism underlying treatment failure for salmonella paratyphi a infection using next generation sequencing a case report"
} | [
{
"companynumb": "KR-BAYER-2019-054248",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nTo present a series of patients with bisphosphonate induced orbital inflammation, and to review the clinical presentation, radiological features, treatment options and outcomes.\n\n\nMETHODS\nWe present a multicentre, retrospective case series review of patients with a clinico-radiological diagnosis of bisphosphonate induced orbital inflammation and review all the reported cases of this complication in the literature.\n\n\nRESULTS\nFour new patients with bisphosphonate induced orbital inflammation were added to the 25 cases in the literature. Intravenous zoledronate was the commonest precipitant (22/29, 75.9%) and inflammation occurred 1-28 (mean 3) days post-infusion. Orbital imaging identified orbital inflammation in 22/29 cases and extra-ocular muscle enlargement in 8/29. Five patients presented with reduced vision of which one - with anterior ischaemic optic neuropathy - did not resolve. The vision resolved in all except one patient, with most requiring steroid treatment.\n\n\nCONCLUSIONS\nBisphosphonates have a pro-inflammatory effect, which can precipitate orbital inflammation. This rare, but potentially serious complication of bisphosphonate treatment should be considered by clinicians using bisphosphonate treatment and by ophthalmologists seeing patients with orbital inflammatory disease.",
"affiliations": "a South Australian Institute of Ophthalmology, Royal Adelaide Hospital , Adelaide , South Australia .;a South Australian Institute of Ophthalmology, Royal Adelaide Hospital , Adelaide , South Australia .;a South Australian Institute of Ophthalmology, Royal Adelaide Hospital , Adelaide , South Australia .;c Save Sight Institute, Sydney Eye Hospital , Sydney , NSW , Australia , and.;c Save Sight Institute, Sydney Eye Hospital , Sydney , NSW , Australia , and.;c Save Sight Institute, Sydney Eye Hospital , Sydney , NSW , Australia , and.;d Division of Oculoplastic and Orbital Surgery , Department of Ophthalmology, Tel Aviv Medical Centre, Tel-Aviv University , Tel Aviv , Israel.;a South Australian Institute of Ophthalmology, Royal Adelaide Hospital , Adelaide , South Australia .",
"authors": "Pirbhai|Adnan|A|;Rajak|Saul N|SN|;Goold|Lucy A|LA|;Cunneen|Thomas S|TS|;Wilcsek|Geoff|G|;Martin|Peter|P|;Leibovitch|Igal|I|;Selva|Dinesh|D|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D000077268:Pamidronate; D019386:Alendronate",
"country": "England",
"delete": false,
"doi": "10.3109/01676830.2015.1078380",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6830",
"issue": "34(6)",
"journal": "Orbit (Amsterdam, Netherlands)",
"keywords": "Bisphosphonate; complication; orbital inflammation; orbital inflammatory syndrome; side effect; zolendronate",
"medline_ta": "Orbit",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D019386:Alendronate; D050071:Bone Density Conservation Agents; D001851:Bone Diseases, Metabolic; D004164:Diphosphonates; D005260:Female; D006801:Humans; D007093:Imidazoles; D008297:Male; D008875:Middle Aged; D054517:Orbital Cellulitis; D055622:Orbital Myositis; D000077268:Pamidronate; D011859:Radiography; D012189:Retrospective Studies; D000077211:Zoledronic Acid",
"nlm_unique_id": "8301221",
"other_id": null,
"pages": "331-5",
"pmc": null,
"pmid": "26540241",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016448:Multicenter Study; D016454:Review",
"references": null,
"title": "Bisphosphonate-Induced Orbital Inflammation: A Case Series and Review.",
"title_normalized": "bisphosphonate induced orbital inflammation a case series and review"
} | [
{
"companynumb": "AU-MYLANLABS-2016M1000904",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PAMIDRONATE DISODIUM"
},
"drugadditional": nu... |
{
"abstract": "Didanosine, a purine analogue with antiretroviral activity, is used in the treatment of human immunodeficiency virus disease. Associated toxic effects of didanosine include pancreatitis, peripheral neuropathy, and retinopathy. The retinal lesions associated with didanosine therapy were studied in a 6-year-old girl with acquired immunodeficiency syndrome. Gross examination disclosed multiple well-circumscribed depigmented lesions in the midperipheral retina. Microscopic examination of these lesions showed multiple areas of retinal pigment epithelial (RPE) loss, some surrounded by areas of hypertrophy or hypopigmentation of the RPE. Partial loss of the choriocapillaris and neurosensory retina were also noted in areas of diseased RPE. Transmission electron microscopy showed numerous membranous lamellar inclusions and cytoplasmic bodies in the RPE cells. These data show that didanosine primarily affects the RPE and that the choriocapillaris and overlying neurosensory retina are also dystrophic in areas of RPE loss.",
"affiliations": "National Eye Institute, National Institutes of Health, Bethesda, Md.",
"authors": "Whitcup|S M|SM|;Dastgheib|K|K|;Nussenblatt|R B|RB|;Walton|R C|RC|;Pizzo|P A|PA|;Chan|C C|CC|",
"chemical_list": "D016049:Didanosine",
"country": "United States",
"delete": false,
"doi": "10.1001/archopht.1994.01090240100033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-9950",
"issue": "112(12)",
"journal": "Archives of ophthalmology (Chicago, Ill. : 1960)",
"keywords": null,
"medline_ta": "Arch Ophthalmol",
"mesh_terms": "D002675:Child, Preschool; D015862:Choroid Diseases; D016049:Didanosine; D005260:Female; D015658:HIV Infections; D006801:Humans; D006984:Hypertrophy; D010857:Pigment Epithelium of Eye; D012164:Retinal Diseases",
"nlm_unique_id": "7706534",
"other_id": null,
"pages": "1594-8",
"pmc": null,
"pmid": "7993216",
"pubdate": "1994-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A clinicopathologic report of the retinal lesions associated with didanosine.",
"title_normalized": "a clinicopathologic report of the retinal lesions associated with didanosine"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-070801",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DIDANOSINE"
},
"drugadd... |
{
"abstract": "We report a case of a 67-year-old man with type 2 diabetes presented with diabetic ketoacidosis, two weeks after his first dose of nivolumab therapy for non-small-cell lung carcinoma. He was started on empagliflozin two days prior in the setting of hyperglycaemia after the initiation of nivolumab therapy. Laboratory evaluation revealed an undetectable C-peptide and a positive anti-glutamic acid decarboxylase (GAD) antibody. He was treated with intravenous fluids and insulin infusion and was subsequently transitioned to subcutaneous insulin and discharged home. He subsequently has developed likely autoimmune thyroiditis and autoimmune encephalitis.\nGlycemic surveillance in patients receiving immune checkpoint inhibitors is recommended.Early glycemic surveillance after commencement of anti-programmed cell death-1 (PD-1) inhibitors may be indicated in selected populations, including patients with underlying type 2 diabetes mellitus and positive anti-glutamic acid decarboxylase (GAD) antibody.Sodium-glucose co transporter-2 (SGLT2) inhibitors should be used with caution in patients on immunotherapy.",
"affiliations": "Department of Endocrinology, Monash Health, Clayton, Victoria, Australia.;Department of Endocrinology, Monash Health, Clayton, Victoria, Australia.;Department of Endocrinology, Monash Health, Clayton, Victoria, Australia.;Department of Endocrinology, Monash Health, Clayton, Victoria, Australia.",
"authors": "Lee|Senhong|S|;Morgan|Aparna|A|;Shah|Sonali|S|;Ebeling|Peter R|PR|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1530/EDM-18-0021",
"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepEDMEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol 10.1530/EDM-18-0021EDM180021Unique/Unexpected Symptoms or Presentations of a DiseaseRapid-onset diabetic ketoacidosis secondary to nivolumab therapy S Lee and othersNivolumab-induced diabeticLee Senhong 1Morgan Aparna 1Shah Sonali 1Ebeling Peter R 121 Department of Endocrinology, Monash Health, Clayton, Victoria, Australia2 Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, AustraliaCorrespondence should be addressed to S Lee Email senhonglee@hotmail.com27 4 2018 2018 2018 18-002107 3 2018 06 4 2018 © 2018 The authors2018The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.Summary\nWe report a case of a 67-year-old man with type 2 diabetes presented with diabetic ketoacidosis, two weeks after his first dose of nivolumab therapy for non–small-cell lung carcinoma. He was started on empagliflozin two days prior in the setting of hyperglycaemia after the initiation of nivolumab therapy. Laboratory evaluation revealed an undetectable C-peptide and a positive anti-glutamic acid decarboxylase (GAD) antibody. He was treated with intravenous fluids and insulin infusion and was subsequently transitioned to subcutaneous insulin and discharged home. He subsequently has developed likely autoimmune thyroiditis and autoimmune encephalitis.\n\nLearning points:\nGlycemic surveillance in patients receiving immune checkpoint inhibitors is recommended.\n\nEarly glycemic surveillance after commencement of anti-programmed cell death-1 (PD-1) inhibitors may be indicated in selected populations, including patients with underlying type 2 diabetes mellitus and positive anti-glutamic acid decarboxylase (GAD) antibody.\n\nSodium-glucose co transporter-2 (SGLT2) inhibitors should be used with caution in patients on immunotherapy.\n==== Body\nBackground\nThe rapid development of diabetic ketoacidosis after a single dose of an immune checkpoint inhibitor is extremely rare. This case highlights the importance of glycemic surveillance in patients receiving immune checkpoint inhibitors. We also highlight the risk factors for rapid development of diabetic ketoacidosis post-immunotherapy, which are not well established in the literature.\n\nCase presentation\nA 67-year-old man with a 40 pack-year smoking history was referred to the respiratory department in October 2016 for investigation of a persistent cough. His medical history was significant for hypertension, hypercholesterolemia, chronic obstructive pulmonary disease and a six-year history of presumed type 2 diabetes mellitus (T2DM) well managed on oral glucose-lowering agents. There was no known family history of diabetes or other autoimmune disease. He underwent bronchoscopy with biopsy of the left main bronchus revealing a diagnosis of squamous cell carcinoma (SCC). Further staging revealed unresectable T4N0M0 non–small-cell lung carcinoma (NSCLC). He subsequently received chemotherapy (6 cycles of weekly carboplatin and paclitaxel from December 2016 to January 2017) and radiotherapy. Follow-up CT chest in July 2017 revealed increased left hilar infiltrates and occlusion of left bronchus, consistent with local recurrence. Repeat bronchoscopic biopsy in August 2017 confirmed a left middle lobe SCC. He was then planned for nivolumab 312 mg (3 mg/kg) every two weeks, and he received his first dose on the 31st of August 2017.\n\nTwo weeks after the first dose of nivolumab, our patient presented to the chemotherapy day unit for his second dose of nivolumab therapy. A random blood glucose level (BGL) was 28.6 mmol/L and a ketone level was 7.0 mmol/L. A venous blood gas subsequently revealed a metabolic acidosis with a pH of 7.0 (7.32–7.42), partial pressure of carbon dioxide (pCO2) of 34 mmHg (41–51 mmHg), bicarbonate (HCO3−) of 8.3 mmol/L (21–30 mmol/L) with an increased anion gap of 36.7 mEq/L (8–16 mEq/L). On further questioning, he described two-day history of lethargy, polyuria and polydipsia associated with elevated BGL readings at home (between 20 and 30 mmol/L). In this setting, his local medical officer had commenced empagliflozin 12.5 mg twice a day (BD) two days prior to his presentation as third-line agent for treatment of diabetes in addition to metformin 850 mg BD and sitagliptin 50 mg BD. A diagnosis of diabetic ketoacidosis (DKA) was made, and patient was transferred to the Emergency Department for further management.\n\nInvestigation\nFurther laboratory evaluation revealed a C-peptide of <0.1 ng/mL (0.9–7 ng/mL) with a paired BGL of 15 mmol/L. He was found to have elevated anti-GAD antibody (glutamic acid decarboxylase) of >2000 U/mL (<5 U/mL) but was negative for anti-IA2 antibody (tyrosine phosphatase-related islet antigen 2) and anti-ZnT8 antibody (Zinc Transporter 8 antibody). His glycosylated hemoglobin (HbA1c) at presentation was 7.6%. His thyroid-stimulating hormone (TSH) was within the normal range. His septic screen including blood culture, urine culture and chest X-ray was negative.\n\nTreatment\nGiven the temporal relationship between the onset of symptoms and initiation of nivolumab therapy, a diagnosis of nivolumab-induced DKA was made. The undetectable C-peptide level and high-titre anti-GAD antibody (>2000 U/mL) were suggestive of underlying autoimmune diabetes. Unfortunately, in the absence of a pre-nivolumab C-peptide and anti-GAD antibody level, we were unable to establish whether our patient seroconverted prior or during nivolumab therapy. The initiation of empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) two days prior to his DKA may have contributed to his rapid development of DKA.\n\nHe was treated with intravenous fluids and insulin infusion and was subsequently transitioned to subcutaneous insulin and discharged home. His case was discussed with the oncology team, and the plan was to continue with nivolumab therapy.\n\nOutcome and follow-up\nThree months post discharge, he remained on insulin for his diabetes. He developed hyperthyroidism, likely secondary to autoimmune thyroiditis. His TSH was 0.07 mU/L (0.4–4.8 mU/L), free thyroxine (fT4) was 20.1 pmol/L (8–16 pmol/L) and thyroid autoantibodies were negative. Unfortunately, a thyroid uptake scan was unable to be performed due to recent contrast exposure. He also had developed recurrent seizures and was being investigated for suspected autoimmune encephalitis.\n\nDiscussion\nImmune checkpoint inhibitors (ICIs) are medications that activate anti-tumor responses by disrupting the inhibitory signaling to T cells (1). Nivolumab is an ICI that selectively blocks the programmed cell death-1 (PD-1) receptors found on the T cells (1). PD1-receptors inhibit kinase signaling pathways that normally lead to T-cell activation when bound to its ligands (PD-L1 and PD-L2) (1). Nivolumab has been approved by the Food and Drug Administration (FDA) for the treatment of multiple cancers – NSCLC, melanoma, renal cell carcinoma, Hodgkin’s lymphoma, SCC of head and neck, urothelial carcinoma and colorectal carcinoma (1). These medications can cause immune-related adverse events including colitis, pneumonitis, nephritis, hepatitis, encephalitis and endocrinopathies (1). Immune endocrinopathies include thyroid dysfunction, hypophysitis, adrenal insufficiency and autoimmune diabetes mellitus (1).\n\nOur current knowledge of DKA as a complication of anti-PD-1 antibody therapy is based on case reports and small case series. Most of these patients present in the setting of autoimmune diabetes induced by immunotherapy (2). The development of DKA associated with anti-PD1 antibody treatment typically presents after several doses of immunotherapy and that it is uncommon to develop after a single dose (2). In fact, our patient is only the fourth case of anti-PD1 antibody-induced DKA in the literature, to present within two weeks post treatment initiation (3, 4, 5).\n\nFour patients who presented with DKA within two weeks post anti-PD-1 antibody therapy were studied (Table 1). The mean age of presentation was 51 years (age range 31–67). Interestingly, three out of four of them received nivolumab for lung cancer, while the other one received pembrolizumab for melanoma. Half of the patients had a diagnosis of T2DM prior to receiving anti-PD-1 antibody therapy. However, it is noteworthy that 3 patients out of 4 had an HbA1c of ≥6.5% at presentation that may suggest undiagnosed diabetes prior to receiving pembrolizumab only two weeks earlier (patient 4). It is possible that patients with underlying T2DM present more rapidly with DKA due to their reduced islet beta cell reserve (6). Interestingly, all four patients were positive for anti-GAD antibodies. Gauci et al. identified that patients with anti-GAD antibodies had a more rapid onset of diabetes post-immunotherapy compared with those that were anti-GAD antibody negative; 3 weeks vs 12.5 weeks (2). The significance of anti-GAD positivity among these patients needs to be clarified with larger studies.\nTable 1 Summary of patients who presented with DKA within two weeks post anti-PD-1 antibody therapy.\n\nNo.\tReference\tAge\tGender\tCancer\tHistory of T2DM\tPD-1 inhibitor\tOnset to presentation (days)\tGlucose (mmol/L)\tC-peptide (ng/mL)\tHbA1c (%)\tAntibodies\t\n1\tOur case\t67\tM\tNSLCL\tYes\tNivolumab\t14\t28.6\t<0.10\t7.6\tPositive GAD\t\n2\t3\t58\tM\tSCLC\tYes\tNivolumab\t7\t39.9\t<0.10\t9.7\tPositive GAD65\t\n3\t4\t31\tM\tNSCLC\tNil\tNivolumab\t13\t38.4\t<0.03\t6.4\tPositive GAD\t\n4\t5\t48\tF\tMelanoma\tNil\tPembrolizumab\t14\t28.0\t<0.10\t8.0\tPositive GAD and insulin antibody\t\n\n\n\nIt is noteworthy that our patient was started on empagliflozin two days prior to his presentation with DKA. It has been reported in the literature that SGLT2 inhibitors may increase the risk of DKA shortly after their initiation (7). The initiation of empagliflozin may have accelerated the rapid development of DKA in addition to the patient’s pre-existing risk factors. This highlights the importance of avoiding SGLT2 in patients who are at risk of developing DKA, including concomitant use of anti-PD1-inhibitors.\n\nOur patient also developed likely autoimmune thyroiditis and autoimmune encephalitis. Our patient’s autoimmune diabetes may be a risk factor for him to develop other immune-related complications from nivolumab. Therefore, clinicians should remain vigilant in monitoring for other immune-related complications in patients with autoimmune diabetes and vice versa.\n\nDKA needs to be recognized as a rare, but important side effect of anti-PD-1 inhibitors. Early glycemic surveillance after commencement of this therapy is therefore recommended. Larger studies are needed to identify patients that are at increased risk of presenting with DKA and to better characterize the clinical course in this population.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nPatient consent\nWe confirm that written informed consent has been obtained from the patient for publication of the submitted article.\n\nAuthor contribution statement\nSenhong Lee: study conception, literature review, drafting of manuscript, critical revision; Aparna Morgan: study conception, literature review, critical revision; Sonali Shah: study conception, critical revision; Peter R Ebeling: study conception, critical revision.\n==== Refs\nReferences\n1 Godwin JL Jaggi S Sirisena I Sharda P Rao AD Mehra R Veloski C \nNivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer . Journal for Immunotherapy of Cancer \n2017 \n5 \n40 (10.1186/s40425-017-0245-2 )28515940 \n2 Gauci ML Laly P Vidal-Treecan T Baroudjian B Gottlieb J Madjlessi-Ezra N Da Meda L Madelaine-Chambrin I Bagot M Basset-Seguin N , et al\nAutoimmune diabetes induced by PD-1 inhibitor – retrospective analysis and pathogenesis: a case report and literature review . Cancer Immunology, Immunotherapy \n2017 \n66 \n1399 –1410 . (10.1007/s00262-017-2033-8 )28634815 \n3 Hughes J Vudattu N Sznol M Gettinger S Kluger H Lupsa B Herold KC \nPrecipitation of autoimmune diabetes with anti-PD-1 immunotherapy . Diabetes Care \n2015 \n38 \ne55 –e57 . (10.2337/dc14-2349 )25805871 \n4 Usui Y Udagawa H Matsumoto S Imai K Ishibashi M Kirita K Umemura S Yoh K Niho S Ohashi K , et al\nAssociation of serum anti-GAD antibody and HLA haplotypes with type 1 diabetes mellitus triggered by nivolumab in patients with non-small cell lung cancer . Journal of Thoracic Oncology \n2017 \n12 \ne41 –e43 . (10.1016/j.jtho.2016.12.015 )28017788 \n5 Abdul Aziz MH Fernando IP Lenkanpally A Fernando DJS. \nDiabetic ketoacidosis after treatment with pembrolizumab . Journal of Clinical and Translational Endocrinology: Case Reports \n2017 \n5 \n4 –5 . (10.1016/j.jecr.2017.05.002 )\n6 Cerf ME. \nBeta cell dysfunction and insulin resistance . Frontiers in Endocrinology \n2013 \n4 \n1 –12 . (10.3389/fendo.2013.00037 )23355833 \n7 Fralick M Scheeweiss S Patorno E. \nRisk of diabetic ketoacidosis after initiation of an SGLT2 inhibitor . New England Journal of Medicine \n376 \n2300 –2302 . (10.1056/NEJMc1701990 )\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2052-0573",
"issue": "2018()",
"journal": "Endocrinology, diabetes & metabolism case reports",
"keywords": null,
"medline_ta": "Endocrinol Diabetes Metab Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101618943",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29732161",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "28591538;28515940;23542897;28017788;25805871;28634815",
"title": "Rapid-onset diabetic ketoacidosis secondary to nivolumab therapy.",
"title_normalized": "rapid onset diabetic ketoacidosis secondary to nivolumab therapy"
} | [
{
"companynumb": "AU-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-025503",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
... |
{
"abstract": "We investigated long-term treatment outcomes and the feasibility of chemoradiotherapy consisting of daily-low-dose 5-fluorouracil and cisplatin (LDFP) chemotherapy plus radiotherapy for Stage I-II squamous cell esophageal cancer. Treatment records from the 2000 through 2008 period were reviewed retrospectively. Fractionated radiotherapy was performed with a total dose of 60 Gy delivered in 2 Gy per fraction. LDFP chemotherapy, as continuous infusion of 200 mg/m2 5-fluorouracil combined with one hour infusion of 4 mg/m2 cisplatin, was administered on the same days as radiotherapy. Survival was calculated by the Kaplan-Meier method. Survival, responses, failure patterns, and toxicities were evaluated. Seventy-six (47 stage I and 29 stage II) patients were analyzed with a median follow-up of 93.6 months. The 8-year overall survival (OS), progression-free survival (PFS) and cause-specific survival (CSS) rates were 63.4%, 49.8%, and 76.7%, respectively. The 8-year OS, PFS, and CSS for stage I and stage II patients were 71.0%/56.1%/82.9% and 45.2%/40.2%/66.6%, respectively. Sixty-eight patients (89.5%) completed the treatment regimen. A complete response (CR) was achieved in 68 patients (89.5%). Twenty-five patients (36.8%) experienced recurrence after CR. The failure patterns were (overlap included): local failure (n = 12), nodal metastasis (n = 12), distant metastasis (n = 3), details unknown (n = 2). Salvage therapy was performed for local failure; endoscopic therapy (n = 7) or surgery (n = 2). Six patients remain alive without relapse after salvage endoscopic therapy. Major Grade 3 or higher acute adverse events were leukopenia (22%), anorexia (17%), and esophagitis (11%). Major late toxicities (Grade 3 or 4) involved pericardial effusion (12%), pleural effusion (4%), and esophageal stenosis (3%). Chemoradiotherapy with LDFP provided favorable long-term survival with acceptable toxicity for Stage I-II squamous cell esophageal cancer. The tumor response was excellent, but close endoscopic follow-up is essential for detecting and treating local recurrence.",
"affiliations": "Department of Radiology and Department of Surgery, Keio University School of Medicine, Tokyo, Japan.;Department of Radiology and Department of Surgery, Keio University School of Medicine, Tokyo, Japan.;Department of Radiology and Department of Surgery, Keio University School of Medicine, Tokyo, Japan.;Department of Radiology and Department of Surgery, Keio University School of Medicine, Tokyo, Japan.;Department of Radiology and Department of Surgery, Keio University School of Medicine, Tokyo, Japan.;Department of Radiation Oncology, Saitama Medical University Hospital, Saitama, Tokyo, Japan.;Department of Radiology and Department of Surgery, Keio University School of Medicine, Tokyo, Japan.;Department of Surgery, Keio University School of Medicine, Tokyo, Japan.;Department of Radiology and Department of Surgery, Keio University School of Medicine, Tokyo, Japan.",
"authors": "Kumabe|A|A|;Fukada|J|J|;Kota|R|R|;Koike|N|N|;Shiraishi|Y|Y|;Seki|S|S|;Yoshida|K|K|;Kitagawa|Y|Y|;Shigematsu|N|N|",
"chemical_list": "D002945:Cisplatin; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1093/dote/dox138",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-8694",
"issue": "31(4)",
"journal": "Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus",
"keywords": null,
"medline_ta": "Dis Esophagus",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D002945:Cisplatin; D018572:Disease-Free Survival; D004938:Esophageal Neoplasms; D000077277:Esophageal Squamous Cell Carcinoma; D005240:Feasibility Studies; D005260:Female; D005472:Fluorouracil; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011879:Radiotherapy Dosage; D012074:Remission Induction; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "8809160",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29228166",
"pubdate": "2018-04-01",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Long-term results of concurrent chemoradiotherapy with daily-low-dose continuous infusion of 5-fluorouracil and cisplatin (LDFP) for Stage I-II esophageal carcinoma.",
"title_normalized": "long term results of concurrent chemoradiotherapy with daily low dose continuous infusion of 5 fluorouracil and cisplatin ldfp for stage i ii esophageal carcinoma"
} | [
{
"companynumb": "JP-HQ SPECIALTY-JP-2018INT000090",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": nul... |
{
"abstract": "MicroRNA-122 (miR-122) is the foremost liver-related micro-RNA, but its role in the hepatocyte is not fully understood. To evaluate whether circulating levels of miR-122 are elevated in chronic-HCV for a reason other than hepatic injury, we compared serum level in patients with chronic hepatitis C to other forms of liver injury including patients with acute liver failure and healthy controls. MiR-122 was quantitated using sera from 35 acute liver failure patients (20 acetaminophen-induced, 15 other etiologies), 39 chronic-HCV patients and 12 controls. In parallel, human genomic DNA (hgDNA) levels were measured to reflect quantitatively the extent of hepatic necrosis. Additionally, six HIV-HCV co-infected patients, who achieved viral clearance after undergoing therapy with interferon and ribavirin, had serial sera miR-122 and hgDNA levels measured before and throughout treatment. Serum miR-122 levels were elevated approximately 100-fold in both acute liver failure and chronic-HCV sera as compared to controls (P < 0.001), whereas hgDNA levels were only elevated in acute liver failure patients as compared to both chronic-HCV and controls (P < 0.001). Subgroup analysis showed that chronic-HCV sera with normal aminotransferase levels showed elevated miR-122 despite low levels of hepatocyte necrosis. All successfully treated HCV patients showed a significant Log10 decrease in miR-122 levels ranging from 0.16 to 1.46, after sustained viral response. Chronic-HCV patients have very elevated serum miR-122 levels in the range of most patients with severe hepatic injury leading to acute liver failure. Eradication of HCV was associated with decreased miR-122 but not hgDNA. An additional mechanism besides hepatic injury may be active in chronic-HCV to explain the exaggerated circulating levels of miR-122 observed.",
"affiliations": "Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Doris Duke Foundation, New York, New York.",
"authors": "Dubin|Perry H|PH|;Yuan|Hejun|H|;Devine|Robert K|RK|;Hynan|Linda S|LS|;Jain|Mamta K|MK|;Lee|William M|WM|;|||",
"chemical_list": "D015415:Biomarkers; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D000410:Alanine Transaminase",
"country": "United States",
"delete": false,
"doi": "10.1002/jmv.23987",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-6615",
"issue": "86(9)",
"journal": "Journal of medical virology",
"keywords": "HCV; acetaminophen; biomarker; liver injury; micro-RNA",
"medline_ta": "J Med Virol",
"mesh_terms": "D000410:Alanine Transaminase; D015415:Biomarkers; D016022:Case-Control Studies; D019698:Hepatitis C, Chronic; D006801:Humans; D017114:Liver Failure, Acute; D035683:MicroRNAs; D012720:Severity of Illness Index",
"nlm_unique_id": "7705876",
"other_id": null,
"pages": "1507-14",
"pmc": null,
"pmid": "24895202",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "22114337;20930130;2254635;16381609;15852042;16141076;21146248;19246379;19122656;15845854;23534542;18663219;23405269;19135886;15364969;22820288;23613588;21821155;18596100;18549828;21606975;19965718;22856605;23390034;16481640;20144731;19617899;21696309;23689081",
"title": "Micro-RNA-122 levels in acute liver failure and chronic hepatitis C.",
"title_normalized": "micro rna 122 levels in acute liver failure and chronic hepatitis c"
} | [
{
"companynumb": "US-JNJFOC-20140721116",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "We report our experience with a 34-year-old patient with schizophrenia, paranoid subtype, who demonstrated an elevation of clozapine serum levels subsequent to pregabalin comedication used for the treatment of schizophrenic anxiety. This observation turned to be dose-dependent. Although the pharmacokinetic profile of pregabalin suggests an exclusive renal elimination, our report supports the presumption of a possible direct or indirect hepatic \"effect\" of pregabalin.",
"affiliations": null,
"authors": "Gahr|M|M|;Schmid|M M|MM|;Schönfeldt-Lecuona|C|C|",
"chemical_list": "D014151:Anti-Anxiety Agents; D014150:Antipsychotic Agents; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D003024:Clozapine",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0032-1306312",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0176-3679",
"issue": "45(7)",
"journal": "Pharmacopsychiatry",
"keywords": null,
"medline_ta": "Pharmacopsychiatry",
"mesh_terms": "D000328:Adult; D014151:Anti-Anxiety Agents; D014150:Antipsychotic Agents; D003024:Clozapine; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D000069583:Pregabalin; D012563:Schizophrenia, Paranoid; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "8402938",
"other_id": null,
"pages": "297-9",
"pmc": null,
"pmid": "22473300",
"pubdate": "2012-11",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Pregabalin-associated elevation of clozapine serum levels.",
"title_normalized": "pregabalin associated elevation of clozapine serum levels"
} | [
{
"companynumb": "DE-MYLANLABS-2013S1001277",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "PREGABALIN"
},
"drugadditional": null,
... |
{
"abstract": "Linezolid, an oxazolidinone antibiotic, inhibits bacterial protein synthesis by binding to 23S ribosomal RNA (rRNA). We studied 3 patients who experienced lactic acidosis while receiving linezolid therapy. The toxicity may have been caused by linezolid binding to mitochondrial 16S rRNA. Genetic polymorphisms may have contributed to the toxicity in 2 patients.",
"affiliations": "Department of Neurology, Columbia University College of Physicians and Surgeons, New York, USA.",
"authors": "Palenzuela|Lluis|L|;Hahn|Noah M|NM|;Nelson|Robert P|RP|;Arno|Janet N|JN|;Schobert|Carol|C|;Bethel|Robert|R|;Ostrowski|Lisa A|LA|;Sharma|Manjuli R|MR|;Datta|Partha P|PP|;Agrawal|Rajendra K|RK|;Schwartz|Jennifer E|JE|;Hirano|Michio|M|",
"chemical_list": "D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D000069349:Linezolid",
"country": "United States",
"delete": false,
"doi": "10.1086/430441",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "40(12)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": null,
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000081:Acetamides; D000140:Acidosis, Lactic; D000368:Aged; D000900:Anti-Bacterial Agents; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D000069349:Linezolid; D008875:Middle Aged; D008928:Mitochondria; D023303:Oxazolidinones; D011110:Polymorphism, Genetic; D014176:Protein Biosynthesis",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "e113-6",
"pmc": null,
"pmid": "15909253",
"pubdate": "2005-06-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Does linezolid cause lactic acidosis by inhibiting mitochondrial protein synthesis?",
"title_normalized": "does linezolid cause lactic acidosis by inhibiting mitochondrial protein synthesis"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2022-01240",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugad... |
{
"abstract": "BACKGROUND\nLung cancer (LC) is frequently associated with idiopathic pulmonary fibrosis (IPF). Despite this well-known association, the outcome of LC in patients with IPF is unclear. The objective of this study was to evaluate the impact of LC on survival of patients with associated IPF.\n\n\nMETHODS\nA total of 260 patients with IPF were reviewed, and 186 IPF cases had complete clinical and follow-up data. Among these, five cases were excluded because LC was radiologically suspected but not histologically proven. The remaining 181 cases were categorized in two groups: 23 patients with biopsy-proven LC and IPF (LC-IPF) and 158 patients with IPF only (IPF). Survival and clinical characteristics of the two groups were compared.\n\n\nRESULTS\nPrevalence of histologically proven LC was 13%, and among those with LC-IPF cumulative incidence at 1 and 3 years was 41% and 82%. Patients with LC were more frequently smokers (91.3% vs 71.6%, P = .001), with combined pulmonary fibrosis and emphysema (52% vs 32%, P = .052). Survival in patients with LC-IPF was significantly worse than in patients with IPF without LC (median survival, 38.7 months vs 63.9 months; hazard ratio = 5.0; 95% CI, 2.91-8.57; P < .001). Causes of death in the study group were respiratory failure in 43% of patients, LC progression in 13%, and LC treatment-related complications in 17%.\n\n\nCONCLUSIONS\nIn patients with IPF, LC has a significant adverse impact on survival. Diagnosis and treatment of LC in IPF are burdened by an increased incidence of severe complicating events, apparently as lethal as the cancer itself.",
"affiliations": "Department of Diseases of the Thorax, G. B. Morgagni Hospital, Forlì, Italy.;Department of Diseases of the Thorax, G. B. Morgagni Hospital, Forlì, Italy.;Division of Pulmonary and Critical Care Medicine.;Biomedical Statistics and Informatics, Mayo Clinic, Mayo Foundation for Medical Education and Research, Rochester, MN.;Department of Diseases of the Thorax, G. B. Morgagni Hospital, Forlì, Italy.;Department of Diseases of the Thorax, G. B. Morgagni Hospital, Forlì, Italy.;Department of Diseases of the Thorax, G. B. Morgagni Hospital, Forlì, Italy.;Department of Radiology, G. B. Morgagni Hospital, Forlì, Italy.;Department of Radiology, Parma University, Parma, Italy.;Department of Pathology, G. B. Morgagni Hospital, Forlì, Italy.;Department of Radiology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (Forlì).;Department of Pathology, Verona University, Verona, Italy.;Department of Diseases of the Thorax, G. B. Morgagni Hospital, Forlì, Italy. Electronic address: venerino.poletti@gmail.com.",
"authors": "Tomassetti|Sara|S|;Gurioli|Christian|C|;Ryu|Jay H|JH|;Decker|Paul A|PA|;Ravaglia|Claudia|C|;Tantalocco|Paola|P|;Buccioli|Matteo|M|;Piciucchi|Sara|S|;Sverzellati|Nicola|N|;Dubini|Alessandra|A|;Gavelli|Giampaolo|G|;Chilosi|Marco|M|;Poletti|Venerino|V|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1378/chest.14-0359",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "147(1)",
"journal": "Chest",
"keywords": null,
"medline_ta": "Chest",
"mesh_terms": "D000368:Aged; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis; D015994:Incidence; D007558:Italy; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "157-164",
"pmc": null,
"pmid": "25166895",
"pubdate": "2015-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The impact of lung cancer on survival of idiopathic pulmonary fibrosis.",
"title_normalized": "the impact of lung cancer on survival of idiopathic pulmonary fibrosis"
} | [
{
"companynumb": "IT-TEVA-542207ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "BACKGROUND\nLapatinib, a dual EGFR and HER2 inhibitor has shown disappointing results in clinical trials of metastatic oesophago-gastric adenocarcinomas (OGAs), and in vitro studies suggest that MET, IGFR, and HER3 confer resistance. This trial applied Lapatinib in the curative neoadjuvant setting and investigated the feasibility and utility of additional endoscopy and biopsy for assessment of resistance mechanisms ex vivo and in vivo.\n\n\nMETHODS\nPatients with HER2 overexpressing OGA were treated for 10 days with Lapatinib monotherapy, and then in combination with three cycles of Oxaliplatin and Capecitabine before surgery. Endoscopic samples were taken for molecular analysis at: baseline including for ex vivo culture +/- Lapatinib to predict in vivo response, post-Lapatinib monotherapy and at surgery. Immunohistochemistry (IHC) and proteomic analysis was performed to assess cell kinetics and signalling activity.\n\n\nRESULTS\nThe trial closed early (n=10) due to an anastomotic leak in two patients for which a causative effect of Lapatinib could not be excluded. The reduction in Phosphorylated-HER2 (P-HER2) and P-EGFR in the ex vivo-treated biopsy demonstrated good correlation with the in vivo response at day 10. Proteomic analysis pre and post-Lapatinib demonstrated target inhibition (P-ERBB2, P-EGFR, P-PI3K, P-AKT, and P-ERK) that persisted until surgery. There was also significant correlation between the activation of MET with the level of P-Erk (P=0.0005) and P-PI3K : T-PI3K (total PI3K) ratio (P=0.0037). There was no significant correlation between the activation status of IGFR and HER3 with downstream signalling molecules.\n\n\nCONCLUSIONS\nAdditional endoscopy and biopsy sampling for multiple biomarker endpoints was feasible and confirmed in vitro data that MET is likely to be a significant mechanism of Lapatinib resistance in vivo.",
"affiliations": "MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.;MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.;MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.;Cambridge Clinical Trials Unit, Coton House, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.;Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.;Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK.;Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK.;Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK.;MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.;Glaxosmithkline, Stevenage SG1 2NY, UK.;University College Hospital, 235 Euston Road, London NW1 2BU, UK.;MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.;Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK.",
"authors": "De Silva|Nadeera|N|;Schulz|Laura|L|;Paterson|Anna|A|;Qain|Wendi|W|;Secrier|Maria|M|;Godfrey|Edmund|E|;Cheow|Heok|H|;O'Donovan|Maria|M|;Lao-Sirieix|Pierre|P|;Jobanputra|Minesh|M|;Hochhauser|Daniel|D|;Fitzgerald|Rebecca|R|;Ford|Hugo|H|",
"chemical_list": "D000970:Antineoplastic Agents; D011799:Quinazolines; D000077341:Lapatinib; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D018719:Receptor, ErbB-2; D020893:Receptor, ErbB-3; D051057:Proto-Oncogene Proteins c-akt",
"country": "England",
"delete": false,
"doi": "10.1038/bjc.2015.342",
"fulltext": "\n==== Front\nBr J CancerBr. J. CancerBritish Journal of Cancer0007-09201532-1827Nature Publishing Group bjc201534210.1038/bjc.2015.34226484410Translational TherapeuticsMolecular effects of Lapatinib in the treatment of HER2 overexpressing oesophago-gastric adenocarcinoma Lapatinib in Upper GI tumoursDe Silva Nadeera 1Schulz Laura 1Paterson Anna 1Qain Wendi 2Secrier Maria 3Godfrey Edmund 4Cheow Heok 4O'Donovan Maria 5Lao-Sirieix Pierre 1Jobanputra Minesh 6Hochhauser Daniel 7Fitzgerald Rebecca 1*Ford Hugo 81 MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK2 Cambridge Clinical Trials Unit, Coton House, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK3 Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK4 Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK5 Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK6 Glaxosmithkline, Stevenage SG1 2NY, UK7 University College Hospital, 235 Euston Road, London NW1 2BU, UK8 Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0QQ, UK* E-mail: rcf29@cam.ac.uk03 11 2015 20 10 2015 113 9 1305 1312 29 05 2015 20 08 2015 27 08 2015 Copyright © 2015 Cancer Research UK2015Cancer Research UKFrom twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/Background:\nLapatinib, a dual EGFR and HER2 inhibitor has shown disappointing results in clinical trials of metastatic oesophago-gastric adenocarcinomas (OGAs), and in vitro studies suggest that MET, IGFR, and HER3 confer resistance. This trial applied Lapatinib in the curative neoadjuvant setting and investigated the feasibility and utility of additional endoscopy and biopsy for assessment of resistance mechanisms ex vivo and in vivo.\n\nMethods:\nPatients with HER2 overexpressing OGA were treated for 10 days with Lapatinib monotherapy, and then in combination with three cycles of Oxaliplatin and Capecitabine before surgery. Endoscopic samples were taken for molecular analysis at: baseline including for ex vivo culture +/− Lapatinib to predict in vivo response, post-Lapatinib monotherapy and at surgery. Immunohistochemistry (IHC) and proteomic analysis was performed to assess cell kinetics and signalling activity.\n\nResults:\nThe trial closed early (n=10) due to an anastomotic leak in two patients for which a causative effect of Lapatinib could not be excluded. The reduction in Phosphorylated-HER2 (P-HER2) and P-EGFR in the ex vivo-treated biopsy demonstrated good correlation with the in vivo response at day 10. Proteomic analysis pre and post-Lapatinib demonstrated target inhibition (P-ERBB2, P-EGFR, P-PI3K, P-AKT, and P-ERK) that persisted until surgery. There was also significant correlation between the activation of MET with the level of P-Erk (P=0.0005) and P-PI3K : T-PI3K (total PI3K) ratio (P=0.0037). There was no significant correlation between the activation status of IGFR and HER3 with downstream signalling molecules.\n\nConclusions:\nAdditional endoscopy and biopsy sampling for multiple biomarker endpoints was feasible and confirmed in vitro data that MET is likely to be a significant mechanism of Lapatinib resistance in vivo.\n\nbiomarkerlapatinibHER2oesophageal /gastric cancer\n==== Body\nThe incidence of oesophago-gastric adenocarcinoma (OGA), has been increasing rapidly (CancerResearchUK, 2015), but 5 year overall survival remains poor, and it is the sixth most common cause of cancer related death. Locally advanced (non-metastatic) tumours are treated by surgery, and the addition of chemotherapy has improved 5 year overall survival from 23 to 36% (Cunningham et al, 2008). Oesophago-gastric adenocarcinoma (16.6%) overexpress HER2 (Van Cutsem et al, 2014) and data suggests that this upregulation occurs early in the process of carcinogenesis at the stage of pre-invasive Barrett's oesophagus and gastric intraepithelial neoplasia (Fassan et al, 2012; Paterson et al, 2013a). Trastuzumab, a monoclonal antibody to HER2, has shown significant activity in HER2 overexpressing gastric cancer, although the clinical use so far has been restricted to the metastatic setting (Bang et al, 2010). Lapatinib, a dual EGFR and HER2 receptor tyrosine kinase inhibitor (TKIs) has also been investigated in metastatic disease but response activity does not appear to be as great as for Trastuzumab. A Phase II monotherapy study showed a very modest response rate to single agent Lapatinib (Iqbal et al, 2011), and when used in combination with chemotherapy (paclitaxel) in the TyTan trial, only modest gains in survival were observed (11 m vs 8.9 m P=0.1044; Satoh et al, 2014). The TRIO-013/LOGiC trial, a randomised Phase III trial evaluating the combination of Capecitabine/Oxaliplatin with or without Lapatinib in the first-line treatment of metastatic OGAs demonstrated a non-significant increase in overall survival in the Lapatinib arm (overall survival of 12.2 m vs 10.5 m, P=0.35; Hecht et al, 2013) whilst the recent Phase II trial comparing Lapatinib with or without Capecitabine in the second line setting demonstrated a very modest response rates of 11% in combination with chemotherapy and no responders in the Lapatinib monotherapy arm (Lorenzen et al, 2015). These results point to significant primary resistance mechanisms.\n\nTargetting HER2 in gastric cancer cell lines and xenografts with TKIs or monoclonal antibodies results in inhibition of the phosphorylated receptor and downstream signalling through proliferative pathways such as PI3K (Wainberg et al, 2010; Chen et al, 2012). However, signalling through alternative receptor tyrosine kinases such as MET (Hepatocyte Growth Factor Receptor), HER3, and IGF1R (Insulin-like Growth Facotor Receptor-1) were noted to produce resistance to Lapatinib (Zhang et al, 2014). Inhibiting MET or IGFR activation with their corresponding TKI restored Lapatinib sensitivity, which was associated with a decrease in downstream activation of Akt and Erk in vitro. Similar work on cell lines demonstrated that the use of TKI combinations based on RTK activation status resulted in greater inhibition of proliferation of OGA cell lines (Paterson et al, 2013b). Though these in vitro studies shed some insight into the mechanisms of Lapatinib resistance, they may not represent the situation in vivo. Studies have explored the use of patient derived xenografts and organoids for drug sensitivity testing (Dobbin et al, 2014; Sachs and Clevers, 2014), but the major disadvantage with these methods is the time required to perform these assays, which means that that results cannot be delivered in a timely manner to inform patient management. Simple and rapid methods need to be developed to provide biomarker evidence to help guide clinical decision making. Options include the use of ex vivo-treated tumour biopsies, or repeat biopsies after window periods of therapy. This is particularly feasible for OGA that is accessible endoscopically. The Lapatinib in early oesophago-gastric cancer trial assessed Lapatinib as first-line therapy in the curative setting for OGA and aimed to:\nTo assess the safety and toxicity profile of Lapatinib with chemotherapy, when used peri-operatively for patients on a radical pathway.\n\nTo test whether an ex vivo assay examining the ability of Lapatinib to suppress HER2 and EGFR could predict in vivo response to 10 days of Lapatinib monotherapy.\n\nTo establish if assays of downstream signalling performed on biopsies taken before and after 10 days of Lapatinib monotherapy could indicate mechanisms of resistance/sensitivity to the drug\n\nCorrelate the molecular indicators of response to imaging criteria (functional18FDG-PET and CT imaging) along with clinical outcome measures such as R0 resection rate, complete pathological response and overall survival.\n\n\n\nMaterials and Methods\nTrial design\nThis was a two-centre open label trial of neoadjuvant treatment with Lapatinib alone and then in combination with Oxaliplatin and Capecitabine in HER2 expressing oesophageal or gastric cancers undergoing curative therapy.\n\nAll patients provided written informed consent before entry on the trial, and the study protocol was approved by a multi-centre research ethics committee, and a clinical trial authorisation was granted (number 12854/0235/001-0001) with Lapatinib, Capecitabine, and Oxaliplatin listed as Investigational Medicinal Products.\n\nPower calculation\nThis is a molecular biomarker study and thus designed to examine molecular rather than clinical endpoints. The primary objective was to compare the molecular response in biopsies taken pre-treatment, which were then treated with Lapatinib ex vivo with the molecular response in a biopsy taken after 10 days of oral Lapatinib. It was anticipated that concordant response outcomes (no change or decrease) would be observed for at least 80 to 85% patients, with a 5% significance (one-sided) level and 80% power, 13 patients would need to be recruited.\n\nPatient selection\nPatients were enroled with histologically confirmed OGA that over expressed HER2, defined as either 3+ staining intensity for HER2 on immunohistochemistry (IHC), or 2+ staining but shown to have HER2 amplification by FISH (Bang et al, 2010). All patients were deemed to have surgically resectable disease on presentation based on CT, PET CT, endoscopic ultrasound (oesophageal cases), and staging laparoscopy (gastric cases), and needed to be fit for both chemotherapy and surgery, with adequate haematological parameters (WBC⩾3.0 × 109 l−1, Plts⩾100 × 109 l−1, Hb⩾9 g dl−1), renal function (measured or calculated Cr clearance ⩾60 ml min−1) and liver function (Bilirubin⩽1.5 × ULN, ALT/AST⩽1.5 × ULN. ALP⩽2.5 × ULN). They needed to be able to swallow oral medication and be over 18 years of age. Patients with abnormal cardiac function determined by echocardiography/MUGA scan, or a history of interstitial lung disease were excluded. Those who had previously received chemotherapy or Lapatinib were excluded as were those with a known G6PD deficiency. Cases of known HIV, Hepatitis C or B infection were also excluded.\n\nTreatment\nPatients initially received 10 days of treatment with Lapitinib 1250 mg once a day. This period was used to assess the effect of Lapatinib alone on the tumour (Figure 1). From day 11, patients went on to receive three cycles of Oxaliplatin (130 mg m−2) and Capecitabine 1700 mg m−2 whilst continuing Lapatinib. On completion of neoadjuvant therapy, the patient went on to have definitive surgery in the form of an oesophagectomy or gastrectomy depending on the location of the tumour.\n\nAssessment\nToxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. Survival was determined by either confirmed date of death, or censored at the last recorded trial follow-up event. The Kaplan–Meier method was adopted for the survival analysis.\n\nThe PET CT scans were performed on day D0 and day D10 after treatment with Lapatinib monotherapy. The fall in the absolute maximum standard uptake value and for a region of interest of 1.5 cm diameter circle at D0 and D10 was reported by an Administration of Radioactive Substances Committee (ARSAC) accredited radiologist. A PET response was defined as a reduction of >35% in the standard uptake value (Lordick et al, 2007). The CT scans were performed on patients on D0 and on D72. Tumour response to therapy was evaluated between the two time points using RESCIST 1.1.\n\nBiopsy analysis\nBiopsies at baseline, D10 and surgery were taken and the specimen was split equally into two parts. One part was fresh frozen and stored in readiness for processing using the Collaborative Enzyme Enhanced Reactive Immunoassay (CEER; Prometheus Laboratories Inc, San Diego, USA) and the other part of the biopsy was formalin fixed for H&E and IHC analyses.\n\nAt baseline, a further tissue sample was treated with Lapatinib ex vivo. This was done by placing the biopsy tissue measuring ∼0.2 cm, on to a mesh placed in a well which was then filled with Dulbecco's Modified Eagles' Medium (Gibco, Invitrogen, Paisley, UK) medium and 10 uM Lapatinib (GlaxoSmithKline, Uxbridge, UK) or with a control DMSO (Fisher Scientific, Loughborough, UK) so as to provide an air–liquid interface. This was then incubated at 37 °C for 1 h, and then fixed in 10% neutral buffered formalin pots, to create paraffin blocks ready for IHC.\n\nAll samples were stained by IHC for P-HER2, HER2, P-EGFR, P-Erk, P-Akt, (Cell Signalling, Danvers, MA, USA), EGFR (Novacastra), and MET (Santa Cruz Biotechnology) using the Leica Bond Max Automated Immunohistochemistry System (Wetzlar, Germany). Staining was scored by two independent reviewers using intensity (0=no reactivity or membranous staining of tumour cell, 1=faint/barely perceptible membranous staining of ⩾10% of tumour cells, 2=weak to moderate complete, basolateral or lateral membranous reactivity in ⩾10% of tumour cells, 3=strong complete, basolateral or lateral membranous reactivity in ⩾10% of tumour cells; Koopman et al, 2015). Scores of 2 and 3 were considered positive whereas 0 and 1 were negative, and a response was defined as a positive score becoming negative (Zhang et al, 2014). A response was defined as a change from a positive IHC score (2+ or 3+) to a negative score (0+ or 1+) for P-HER2 and P-EGFR. Proliferation was assessed by staining for Ki67 (Leica, Wetzlar Germany), and apoptosis assessed by staining for cleaved caspase 3 (Cell Sginalling, Danvers, MA, USA) and by using the TUNEL assay (Millipore, Consett UK). A score of 1–5 was given based on the percentage of tumour cells staining for Ki67 (1=0–20%, 2=21–40%, 3=41–60%, 4=61–80%, 5=>81%). Scoring cleaved caspase 3 and the TUNEL assay was done my counting all positively staining cancer cells in 5 high-power (40 × ) fields of view by 2 independent scorers, and the average of all 10 scores was taken for the purposes of analysis (Li et al, 2008).\n\nAll frozen samples were assayed using the CEER platform (Prometheus Laboratories, San Diego, USA) for receptor tyrosine kinase activation (EGFR, HER2, p95, HER3, IGFR, and MET) and downstream signalling. This could not be done with the ex vivo biopsy as it was formalin fixed and further material was not available.\n\nGenomic analysis\nWhole genome sequencing was available for one patient's treatment naive tumour. DNA was extracted from fresh frozen tissue samples using the Qiagen DNA Mini Kit (Qiagen) as per protocol and sequenced on the Illumina HiSeq platform. Paired DNA from blood was sequenced to allow somatic variants to be distinguished from those in the germline. For alignment against GRCh37 reference from Ensembl v71 BWA was used. Variant calling was performed with Somatic Sniper (V1.0.2) and a variety of filters was used to exclude low quality calls (Larson et al, 2012; Weaver et al, 2014). The single nucleotide variation data was assessed using DAVID Bioinformatics resource Version 6.7 (National Institute of Allergy and Infectious Diseases). Functional annotation was assessed using the Gene Ontology tools and KEGG pathway analysis. ASCAT-NGS v.2.1 (Van Loo et al, 2010; Nik-Zainal et al, 2012) was used to infer tumour copy number data, and a combination of both copy number and single nucleotide variation data was analysed in cloneHD to assess clonality (Fischer et al, 2014).\n\nStatistical analysis\nFor the assessment of the ex vivo assay by IHC, a molecular response was defined as a positive P-HER2 or P-EGFR (2+ or 3+) becoming a negative score (0+ or 1+ Zhang et al, 2014). A Kappa correlation coefficient was calculated to assess agreement between ex vivo and D10 in vivo response, and between the two reviewers for these scores. Wilcoxon-Rank Sums analysis was performed, between baseline tumour IHC characteristics (HER2, EGFR, and MET) and predefined clinical outcome (RECIST response, complete pathological response, R0 resection).\n\nHER2, p95, and EGFR activation (phosphorylated to total protein ratio) using CEER data was assessed at baseline, D10 and surgery and the Wilcoxon-Signed Rank test was used to assess changes between baseline and D10 as well as baseline and surgery.\n\nCorrelation between MET, IGFR, and HER3 activation (phosphorylated to total protein ratio) was correlated with the PI3K, P-Erk, and P-Akt activation (absolute levels of P-Erk and P-Akt was used as the total protein level was not available for these two molecules) using the Spearman Rank Correlation.\n\nResults\nA total of 10 patients were recruited to the trial. The median age of the 10 patients was 61.7 years, with a preponderance for males (70%) which is in keeping with the epidemiology of the disease. Eight of the patients entering the trial had a performance status of 0, and the remaining two a performance status of 1. The primary site of disease was the gastro-oesophageal junction in six of the cases and the majority of these tumours were poorly differentiated (Table 1). All patients bar one had a HER2 IHC score of 3+ and only one patient had a tumour with an IHC score of 2, which was subsequently confirmed to be amplified by FISH.\n\nThe 10-day Lapatinib monotherapy window phase was well tolerated with 100% of patients receiving the intended Lapatinib dose with no ⩾grade 3 toxicity. With regards to the neoadjuvant period of chemotherapy with concurrent Lapatinib, 80% of patients received all three cycles of chemotherapy. These toxicities are summarised in Table 2.\n\nThe most common adverse effects noted were nausea and diarrhoea. These are in keeping with the known individual toxicities of the drugs, especially Capecitabine and Lapatinib. Three patients experienced grade 4 toxicity. This included two patients who experienced anastomotic leaks. One of these patients died after developing a chest infection. This leak rate of 20% was higher than expected given that both tertiary centres had leak rates in keeping with the national oesophago-gastric audit of 5%, and as a result the independent data monitoring committee agreed to suspend recruitment to the study after 10 patients had been enroled (Chadwick et al, 2013). Median overall survival was 32.4 months, and median progression free survival was 16.4 months. There were no responses by PET at D10 in the maximal standard uptake value of for the maximal region of interest (1.5 cm2 circle). Fifty per cent of patients had a partial response on CT after neoadjuvant therapy, and the rest had stable disease.\n\nMolecular analysis\nImmunohistochemistry\nTumour specimens were stained for HER2, EGFR, P-HER2, P-EGFR, and MET, as well as downstream targets including P-Erk, P-Akt and examples of staining patterns are demonstrated in Figure 2.\n\nAssessment of the ex vivo assay\nThe ex vivo assay was used to determine whether it is possible to predict in vivo response after 10 days of Lapatinib monotherapy.\n\nThere was good agreement between the two independent scorers. Three samples were inadequate specimens and so paired data was available for nine cases for P-HER2 and eight for P-EGFR. The ex vivo and D10 molecular response correlated 89% of the time for P-HER2 and 100% for P-EGFR that meets the predefined aim of 75% (Table 3).\n\nComparison of molecular and clinical outcomes\nAs an alternative to the ex vivo culture assay, the IHC results on biopsies sampled over time were correlated to clinical outcome measures to assess if any of these assays could be a potential biomarker for response to Lapatinib therapy.\n\nThe baseline score for HER2, EGFR, and MET (potential resistance mechanism) was related to clinical outcome measures. Our hypothesis was that stronger HER2 and EGFR staining tumours would be more responsive to Lapatinib, whereas tumours with strong MET expression would be resistant to therapy. Wilcoxon-Rank Sum Analysis failed to show any association between baseline HER2 scores and the clinical outcomes by RECIST response, R0 resection rate, or complete pathological response (P=1.000, P=0.660, and P=0.606, respectively). Nor was there any associations with baseline EGFR score (P=0.535, P=0.087, and P=0.702) or MET scores (P=0.399, P=0.615, 0.615, respectively). On-target response did not correlate with progression free survival or overall survival based on an IHC response (HER2-based response OS P=0.2278 PFS P=0.6650; EGFR-based response OS P=0.3938, PFS P=0.3173) or CEER response (HER2-based response OS P=0.4126, PFS P=0.2216; EGFR-based response OS P=0.2922, PFS P=0.1486).\n\nCEER proteomic analysis\nThe target effect of Lapatinib was examined at baseline, D10, and surgery using the CEER assay (Figure 3). There was a significant drop in the P-HER2 : T-HER2, and P-EGFR : T-EGFR ratios after only 10 days of Lapatinib monotherapy (P=0.0039 and P=0.0195, respectively). All 10 patients demonstrated reductions in HER2 activation by day 10 and 9 of 10 patients had a reduction in EGFR activation. This reduction in growth factor signalling persisted to the time of surgery and EGFR signalling remained significantly inhibited (P=0.0391), despite a 30 day wash out period between completing neoadjuvant therapy and surgery. HER2 signalling (PI3K, P-AKT, and P-ERK) continued to be lower at the time of surgery compared with baseline, although the difference did not reach significance (P=0.4961). The truncated form of HER2, p95HER2 lacks the extracellular domain, and significant inhibition was again noted at D10, which persisted through to surgery (P=0.0078 and P=0.0234, respectively).\n\nThere was a reduction in P-PI3K : T-PI3K activation that mirrors the response in HER2 and EGFR, with significant dampening in signalling between baseline and both D10 as well as surgery (P=0.03 and P=0.01, respectively). Only phosphorylated assays were available for Akt and Erk, and though there was a reduction in median levels, this did not reach significance. This may be because it was not possible to normalise the phosphorylated receptor level to the total protein content (assay not available at the time) and as such outliers tended to skew the data.\n\nThe correlation between the activation of RTKs and downstream signalling effectors was examined (Figure 4). There was a significant correlation between the activation of C-Met with the level of P-Erk (P=0.0005) and P-PI3K : T-PI3K ratio (P=0.0037). There was no significant correlation between the activation status of IGFR and HER3 with downstream signalling molecules, and no significant correlation was seen between the activation status of any receptor and P-Akt. This would suggest that activation of C-Met may be a mechanism of Lapatinib resistance in vivo with an R2 value of 0.914 for P-Erk (Figure 4Ai) and 0.84 for P-PI3K : T-PI3K (Figure 4Aii).\n\nWhole genome sequencing from a treatment naive sample was available for one of the four patients, with persistent MAPK and PI3K pathway activation, which was related to MET activation (Figure 4Ai and Aii). There were amplifications in EGFR and HER2 (total copy number 3 for both with a single copy in the minor allele), but the greatest copy number increase was seen with MET with a total copy number of 4. KEGG output using single nucleotide variation data revealed significant clustering in the Phosphotidylinositol signalling and Wnt pathways, although no mutations were observed in the growth proliferative canonical parts of these pathways.\n\nDiscussion\nThere are 7089 new cases of gastric cancer per year in the UK and 8332 for oesophageal cancer in the UK (http://info.cancerresearchuk.org/cancerstats/survival/latestrates/). In the ToGa trial, which is the largest assessment of HER2 positivity in this patient group, 16.6% of tumours were HER2 positive. This would mean that 2560 patients a year in the UK would be HER2 amplified. At present, the ToGa trial has established the use of Trastuzumab in the metastatic setting (Bang et al, 2010), but there is no trial evidence to support the use of HER2 targeted therapies in patients undergoing treatment with curative intent. The use of Lapatinib has been unsuccessful in prolonging survival in metastatic patients with HER2 overexpressing OGA (Iqbal et al, 2011; Hecht et al, 2013; Satoh et al, 2014; Lorenzen et al, 2015).\n\nThe Lapatinib in early oesophago-gastric cancer trial assessed the use of Lapatinib in the peri-operative setting where median overall survival was 32.4 months. This compares with previous trials where surgery alone and in combination with peri-operative chemotherapy demonstrated median overall survival rates of 18–24 months (Cunningham et al, 2006; Allum et al, 2009). Lapatinib monotherapy was well tolerated and the main grade 3 toxicity resulted from the combination with chemotherapy. Grade 3 toxicities such as nausea/vomiting and mucositis occurred at a similar rate between the Lapatinib in early oesophago-gastric cancer patients and those seen with ECX alone in the MAGIC trial at around 20% and 10%, respectively (Cunningham et al, 2006). Rates of grade ⩾3 diarrhoea was higher within the Lapatinib in early oesophago-gastric cancer trial which is in keeping with the fact that both Lapatinib and Capecitabine can induce diarrhoea individually, and was similar to the rates seen in the TRIO-013/LOGiC trial (Hecht et al, 2013). The most significant toxicities were the two anastomotic leaks, which is a much higher rate than observed in the UK national audit (Chadwick et al, 2013), which was 7.4% for oesophagectomies and 4.4% for gastrectomies. Although with such small numbers in the trial it is difficult to draw conclusions, a drug effect could not be excluded for this serious complication that resulted in death of one patient, especially in view of the persistent inhibition of HER2 and EGFR at the time of surgery.\n\nOne of the study endpoints was to examine if an ex vivo assay could help predict treatment response. This was done using an organ culture, in which a whole biopsy is treated with Lapatinib for an hour, and then fixed in formalin for IHC analysis. The ex vivo assay accurately predicted in vivo P-HER2 response in 88.9% of cases, and for 100% of the cases for P-EGFR. This met the predefined study target of concordance of 75%. This approach may warrant further consideration in other clinical trials.\n\nThe analysis comparing baseline predictors of sensitivity, namely IHC staining for HER2 and EGFR staining intensity, and biomarkers of resistance (C-MET staining) failed to show any correlation with clinical outcomes, namely CT response by RECIST criteria, R0 resection rates or complete pathological response. This is in keeping with the ToGa trial (Bang et al, 2010) where baseline HER2 scoring did not correlate with sensitivity to anti-HER2 directed therapy. The reasoning for this is thought to be the large amount of heterogeneity observed in staining patterns in Upper GI adenocarcinomas when compared with other cancers. Indeed, similar heterogeneity in staining was observed in this study, highlighting the need to use robust and validated scoring systems such as those used in this study (Koopman et al, 2015).\n\nFurther samples at baseline, D10 and surgery were analysed using the CEER assay, which has previously been shown to be much more sensitive for determining activation levels compared with IHC (Lee et al, 2013a). The window design of this trial also confirms that 10 days of monotherapy can give information of on-target effects of the drug, as well as assaying potential primary resistance mechanisms. Compared with other methods of assaying drug sensitivity, such as establishment of cell lines and organoids, repeat endoscopic biopsies after a window period is relatively simple, cheap, and effective method of getting molecular response data in a timeframe that can be clinically relevant for the patient. The effect of Lapatinib was first examined on its primary targets, namely HER2 and EGFR. After 10 days of Lapatinib monotherapy, there was a significant reduction in the proportion of activated receptors for both HER2 and EGFR. This is particularly important as it appears to precede any metabolic response as no response was observed by PET imaging over this same time period. There was also significant inhibition of p95, the truncated form of HER2 which lacks the extracellular domain. In breast cancer, resistance to Trastuzumab has been partly attributed to p95 (Duchnowska et al, 2014), as the antibody is unable to bind the protein due to the lack of an extracellular domain, but there was significant inhibition of p95 noted in this study by Lapatinib at day 10, which continued through to surgery. This highlights that repeat biopsy after a window period of monotherapy can provide the earliest evidence of on-target action for Lapatinib, and the drug also significantly inhibits p95.\n\nA 4–6 week wash out period before surgery was used to ensure that the patients had recovered fully from the neoadjuvant therapy before definitive surgery. This period has typically been used with cytotoxic chemotherapy as this usually allows for complete marrow recovery. Similar pre-operative wash out periods have also been used with anti-HER2 agents such as Trastuzumab in breast cancer, and have not been associated with an increased operative morbidity (Gianni et al, 2010). The CEER data demonstrated that despite a wash out period of several weeks, there was still significant reduction in EGFR signalling at the time of surgery, with a further non-significant reduction in HER2 signalling. Although the small numbers make it impossible to draw any definitive conclusion, it is possible that this persistent inhibition of growth factor signalling pathways at surgery may have contributed to the anastomotic leak rate. It should therefore be considered whether the wash out period required for neoadjuvant therapy using Lapatinib needs to be longer than typically used for traditional chemotherapeutics. This is particularly noteworthy given that there are current trials open to recruitment using Lapatinib in a similar context with a similar wash out period (Cunningham, 2012).\n\nNot only is there evidence of receptor deactivation in response to drug but a decrease in the activation of downstream molecules such as PI3K, P-Erk, and P-Akt. This supports the on-target action of Lapatinib on these tumours reducing EGFR and HER2 mediated signalling by PI3K and with a trend for reduction of the MAPK pathway.\n\nPreclinical studies have pointed to RTK crosstalk from MET as being an important mechanism of resistance to Lapatinib and other HER2 directed therapies (Shattuck et al, 2008; Chen et al, 2012; Lee et al, 2013b; Paterson et al, 2013b; Liu et al, 2014; Ha et al, 2014; Zhang et al, 2014). This study provides some of the first in vivo evidence that, MET appears to be the most important RTK in activating proliferative pathways (PI3K and MAPK) in the presence of Lapatinib inhibition of EGFR and HER2. This was demonstrated by the CEER assay where the activation of the MAPK and PI3K pathways after 10 days of Lapatinib monotherapy was significantly correlated with the activation of MET, but not with IGFR or HER3 (Figure 4). Larger studies would need to be undertaken to fully understand whether this molecular crosstalk has implications on clinical outcome as this trial was not powered to detect this. Our cohort is also not large enough to adequately correct for differences in staging, or to perform a multiple regression analysis to correlate clinical outcomes and molecular findings.\n\nWhole genome sequencing was available for one of the patients with persistent mitogenic signalling in the presence of Lapatinib, which appeared to be due to MET activation. The main canonical pathways for PI3K and MAPK were intact in keeping with previous genomic studies in OGA have suggested that point mutations do not tend to drive proliferation (Dulak et al, 2013; Weaver et al, 2014). Copy number data from this same patient-demonstrated HER2 and EGFR amplification (total copy number of 3 for each), but interestingly, the most amplified of the RTKs was MET. This supports the finding that activation of these mitogenic pathways at D10 is more likely to be due to RTK crosstalk from MET by amplification.\n\nThese in vivo findings suggests that MET mediates Lapatinib resistance and is particularly noteworthy given recent interest in using MET inhibitors. These trials have failed to demonstrate efficacy of single agent MET TKIs (Shah et al, 2013) and MET targeting antibodies (Cunningham et al, 2015), so it is likely that combination therapies should be considered with anti-HER2 therapies used in combination with anti-MET agents in the context of well designed stratified trials (Ha et al, 2014).\n\nThis study demonstrated that 10 days of monotherapy followed by CEER analysis can reveal in vivo evidence of target activity in a simple, rapid, and cheap manner, and in addition may provide clinically useful information about patients who may be resistant, providing the information for clinicians to make management decisions in real time, and to select appropriate targeted therapy in a truly personalised manner.\n\nThis work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License.\n\nThe authors declare no conflict of interest.\n\nFigure 1 Study design where patients undergo a baseline biopsy and ex vivo sample was taken at D0. Patients then received 10 days of Lapatinib monotherapy after which a repeat biopsy and functional imaging was performed. Patients went on to receive three cycles of Oxaliplatin and Capecitabine concurrent with Lapatinib on a 21-day cycle, followed by definitive surgery.\n\nFigure 2 Immunohistochemistry for the phosphorylated species for the RTKs P-HER2, P-EGFR and the downstream molecules P-Erk and P-Akt. Examples of staining performed using the Axio Slide Scanner (Oberkochen, Germany) at 40 × and images at a 35% digital zoom. No 3+ staining was observed for P-Akt.\n\nFigure 3 Phosphorylated:total (P : T) receptor ratios for HER2 (A), EGFR (B), and p95HER2 (C), along with the downstream molecules P-PI3K : T-PI3K ratio (D), P-Akt (E), and P-Erk (F) at baseline, D10 and surgery.\n\nFigure 4 The ratio of phosphorylated to total protein amount representing the activation status of c-met (A), IGFR (B), and HER3 (C), plotted against the activated downstream signalling molecules P-Erk (i), and P-PI3K : T-PI3K (ii) ratio.\n\nTable 1 Demographic data on patient cohort, with primary site, HER2 scoring, tumour differentiation and stage\nn=10\t\nAge (years)\t\nMean\t61.7\t\ns.d.\t9.4\t\nRange\t49.7–75.2\t\nSex\t\nMale\t7\t\nFemale\t3\t\nECOG performance status\t\n0\t8\t\n1\t2\t\nSite of primary\t\nOesophagus\t3\t\nStomach\t1\t\nGOJ type 1\t1\t\nGOJ type 2\t3\t\nGOJ type 3\t2\t\nHER2 staining\t\n3+\t9\t\n2+ with FISH amplification\t1\t\nTumour differentiation\t\nModerate\t4\t\nPoor\t6\t\nT stage\t\nT2\t1\t\nT3\t7\t\nN stage\t\nN0\t7\t\nN1\t2\t\nN2\t1\t\nM stage\t\nM0\t0\t\nAbbreviations: ECOG=Eastern Cooperative Oncology Group; FISH=fluorescence in situ hybridization; GOJ=gastro-oesophageal junction.\n\nTable 2 Adverse events of ⩾grade 3 experienced by patients during their monotherapy window, and concurrent chemotherapy treatment\nn=10\t\nLapatinib monotherapy\t\nLapatinib monotherapy toxicities\t0\t\nLapatinib and chemotherapy\t\nAnastomotic leak\t2\t\nFainting\t1\t\nMucositis\t1\t\nCandida infection\t1\t\nNausea\t2\t\nAtelectasis\t1\t\nDyspepsia\t1\t\nDiarrhoea\t2\t\nGastrointestinal Pain\t1\t\nSmall bowel obstruction\t1\t\nWeight loss\t1\t\nChest infection\t1\t\nHypoxia\t1\t\nNeutropenia\t1\t\nTable 3 Comparison of the ex vivo response to Lapatinib for P-HER2 and P-EGFR, with that seen after 10 days of in vivo Lapatinib monotherapy\n \t \tEx vivo\t\nP-HER2\tNo change\tResponse\t\nIn vivo\tNo change\t6\t0\t\n \tResponse\t1\t2\t\n \t \tEx vivo\t\nP-EGFR\tNo change\tResponse\t\nIn vivo\tNo Change\t7\t0\t\n \tResponse\t0\t1\t\nAbbreviation: IHC=immunohistochemistry.\n\nKappa score for P-HER2: between scorers (weighted)=0.5902; between ex vivo and D10 IHC score=0.7273; correlation between ex vivo and D10 in vivo=88.9%.\n\nKappa Score for P-EGFR: between scorers=0.832; between ex vivo and D10 IHC score=1; correlation between ex vivo and D10 in vivo=100.0%.\n==== Refs\nAllum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE (2009 ) Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer . J Clin Oncol \n27 : 5062 –5067.19770374 \nBang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang YK (2010 ) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial . Lancet \n376 : 687 –697.20728210 \nCancerResearchUK (2015 ) Oesophageal cancer incidence statistics Cancer Research UK. Available at: http://www.cancerresearchuk.org/cancer-info/cancerstats/types/oesophagus/incidence/ (accessed on 18 May 2015).\nChadwick G, Groene O, Cromwell D, Hardwich R, Riley S, Crosby T, Greenaway K (2013 ) National Oesophago-Gastric Audit 2013 In: England, T. R. C. O. S. O. (ed.) London.\nChen CT, Kim H, Liska D, Gao S, Christensen JG, Weiser MR (2012 ) MET activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells . Mol Cancer Ther \n11 : 660 –669.22238368 \nCRUK. Cancer survival rates for patients diagnosed 1996e1999 . Survival statistics for the most common cancers Available at http://info.cancerresearchuk.org/cancerstats/survival/latestrates/ (accessed 5 February 2009).\nCunningham D (2012 ) A Randomised Phase II/III trial of Perioperative Chemotherapy with or without Bevacizumab in Operable Oesophagogastric Adenocarcinoma. A Feasibility Study Evaluating Lapatinib in HER-2 Positive Oesophagogastric Adenocarcinomas. Protocol Version 6, 28 September 2012.\nCunningham D, Allum WH, Stenning SP, Thompson JN, Van De Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ, Participants MT (2006 ) Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer . N Engl J Med \n355 : 11 –20.16822992 \nCunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR (2008 ) Capecitabine and oxaliplatin for advanced esophagogastric cancer . N Engl J Med \n358 : 36 –46.18172173 \nCunningham D, Tebbutt NC, Davidenko I, Murad AM, Al-Batran S-E, Ilson DH, Tjulandin S, Gotovkin E, Karaszewska B, Bondarenko I, Tejani MA, Udrea AA, Tehfe MA, Baker N, Oliner KS, Zhang Y, Hoang T, Sidhu R, Catenacci DVT (2015 ) Phase III, randomized, double-blind, multicenter, placebo (P)-controlled trial of rilotumumab (R) plus epirubicin, cisplatin and capecitabine (ECX) as first-line therapy in patients (pts) with advanced MET-positive (pos) gastric or gastroesophageal junction (G/GEJ) cancer: RILOMET-1 study . ASCO Meet Abstr \n33 : 4000 .\nDobbin ZC, Katre AA, Steg AD, Erickson BK, Shah MM, Alvarez RD, Conner MG, Schneider D, Chen D, Landen CN (2014 ) Using heterogeneity of the patient-derived xenograft model to identify the chemoresistant population in ovarian cancer . Oncotarget \n5 : 8750 –8764.25209969 \nDuchnowska R, Sperinde J, Chenna A, Haddad M, Paquet A, Lie Y, Weidler JM, Huang W, Winslow J, Jankowski T, Czartoryska-Arlukowicz B, Wysocki PJ, Foszczynska-Kloda M, Radecka B, Litwiniuk MM, Zok J, Wisniewski M, Zuziak D, Biernat W, Jassem J (2014 ) Quantitative measurements of tumoral p95HER2 protein expression in metastatic breast cancer patients treated with trastuzumab: independent validation of the p95HER2 clinical cutoff . Clin Cancer Res \n20 : 2805 –2813.24668646 \nDulak AM, Stojanov P, Peng S, Lawrence MS, Fox C, Stewart C, Bandla S, Imamura Y, Schumacher SE, Shefler E, Mckenna A, Carter SL, Cibulskis K, Sivachenko A, Saksena G, Voet D, Ramos AH, Auclair D, Thompson K, Sougnez C, Onofrio RC, Guiducci C, Beroukhim R, Zhou Z, Lin L, Lin J, Reddy R, Chang A, Landrenau R, Pennathur A, Ogino S, Luketich JD, Golub TR, Gabriel SB, Lander ES, Beer DG, Godfrey TE, Getz G, Bass AJ (2013 ) Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity . Nat Genet \n45 : 478 –486.23525077 \nFassan M, Mastracci L, Grillo F, Zagonel V, Bruno S, Battaglia G, Pitto F, Nitti D, Celiento T, Zaninotto G, Fiocca R, Rugge M (2012 ) Early HER2 dysregulation in gastric and oesophageal carcinogenesis . Histopathology \n61 : 769 –776.22882541 \nFischer A, Vazquez-Garcia I, Illingworth CJ, Mustonen V (2014 ) High-definition reconstruction of clonal composition in cancer . Cell Rep \n7 : 1740 –1752.24882004 \nGianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, Zambetti M, Vazquez F, Byakhow M, Lichinitser M, Climent MA, Ciruelos E, Ojeda B, Mansutti M, Bozhok A, Baronio R, Feyereislova A, Barton C, Valagussa P, Baselga J (2010 ) Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort . Lancet \n375 : 377 –384.20113825 \nHa SY, Lee J, Jang J, Hong JY, Do IG, Park SH, Park JO, Choi MG, Sohn TS, Bae JM, Kim S, Kim M, Park CK, Kang WK, Kim KM (2014 ) HER2-positive gastric cancer with concomitant MET and/or EGFR overexpression: A distinct subset of patients for dual inhibition therapy . Int J Cancer \n136 : 1629 –1635.25157953 \nHecht JR, Bang YJ, Qin S, Chung HC, Xu JM, Park JO, Jeziorski K, Shparyk Y, Hoff PM, Sobrero AF, Salman P, Li J, Protsenko S, Buyse ME, Afenjar K, Kaneko T, Kemner A, Santillana S, Press MF, Slamon DJ (2013 ) Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): The TRIO–013/LOGiC Trial . J Clin Oncol \n31 : Abstract LBA4001 .\nIqbal S, Goldman B, Fenoglio-Preiser CM, Lenz HJ, Zhang W, Danenberg KD, Shibata SI, Blanke CD (2011 ) Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line therapy in patients with advanced or metastatic gastric cancer . Ann Oncol \n22 : 2610 –2615.21415234 \nKoopman T, Louwen M, Hage M, Smits MM, Imholz AL (2015 ) Pathologic diagnostics of HER2 positivity in gastroesophageal adenocarcinoma . Am J Clin Pathol \n143 : 257 –264.25596252 \nLarson DE, Harris CC, Chen K, Koboldt DC, Abbott TE, Dooling DJ, Ley TJ, Mardis ER, Wilson RK, Ding L (2012 ) SomaticSniper: identification of somatic point mutations in whole genome sequencing data . Bioinformatics \n28 (3): 311 –317.22155872 \nLee J, Kim S, Kim P, Liu X, Lee T, Kim KM, Do IG, Park JO, Park SH, Jang J, Hoe N, Harvie G, Kuller A, Jain A, Meyer G, Leesman G, Park YS, Choi MG, Sohn TS, Bae JM, Lim HY, Singh S, Kang WK (2013 a) A novel proteomics-based clinical diagnostics technology identifies heterogeneity in activated signaling pathways in gastric cancers . PLoS One \n8 : e54644 .23372746 \nLee YY, Kim HP, Kang MJ, Cho BK, Han SW, Kim TY, Yi EC (2013 b) Phosphoproteomic analysis identifies activated MET-axis PI3K/AKT and MAPK/ERK in lapatinib-resistant cancer cell line . Exp Mol Med \n45 : e64 .24263233 \nLi D, Wen X, Ghali L, Al-Shalabi FM, Docherty SM, Purkis P, Iles RK (2008 ) hCG beta expression by cervical squamous carcinoma—in vivo histological association with tumour invasion and apoptosis . Histopathology \n53 : 147 –155.18752498 \nLiu YJ, Shen D, Yin X, Gavine P, Zhang T, Su X, Zhan P, Xu Y, Lv J, Qian J, Liu C, Sun Y, Qian Z, Zhang J, Gu Y, Ni X (2014 ) HER2, MET and FGFR2 oncogenic driver alterations define distinct molecular segments for targeted therapies in gastric carcinoma . Br J Cancer \n110 : 1169 –1178.24518603 \nLordick F, Ott K, Krause BJ, Weber WA, Becker K, Stein HJ, Lorenzen S, Schuster T, Wieder H, Herrmann K, Bredenkamp R, Hofler H, Fink U, Peschel C, Schwaiger M, Siewert JR (2007 ) PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial . Lancet Oncol \n8 : 797 –805.17693134 \nLorenzen S, Riera Knorrenschild J, Haag GM, Pohl M, Thuss-Patience P, Bassermann F, Helbig U, Weissinger F, Schnoy E, Becker K, Stocker G, Ruschoff J, Eisenmenger A, Karapanagiotou-Schenkel I, Lordick F (2015 ) Lapatinib versus lapatinib plus capecitabine as second-line treatment in human epidermal growth factor receptor 2-amplified metastatic gastro-oesophageal cancer: a randomised phase II trial of the Arbeitsgemeinschaft Internistische Onkologie . Eur J Cancer \n51 : 569 –576.25694417 \nNik-Zainal S, Van Loo P, Wedge DC, Alexandrov LB, Greenman CD, Lau KW, Raine K, Jones D, Marshall J, Ramakrishna M, Shlien A, Cooke SL, Hinton J, Menzies A, Stebbings LA, Leroy C, Jia M, Rance R, Mudie LJ, Gamble SJ, Stephens PJ, Mclaren S, Tarpey PS, Papaemmanuil E, Davies HR, Varela I, Mcbride DJ, Bignell GR, Leung K, Butler AP, Teague JW, Martin S, Jonsson G, Mariani O, Boyault S, Miron P, Fatima A, Langerod A, Aparicio SA, Tutt A, Sieuwerts AM, Borg A, Thomas G, Salomon AV, Richardson AL, Borresen-Dale AL, Futreal PA, Stratton MR, Campbell PJ (2012 ) The life history of 21 breast cancers . Cell \n149 : 994 –1007.22608083 \nPaterson AL, O'Donovan M, Provenzano E, Murray LJ, Coleman HG, Johnson BT, Mcmanus DT, Novelli M, Lovat LB, Fitzgerald RC (2013 a) Characterization of the timing and prevalence of receptor tyrosine kinase expression changes in oesophageal carcinogenesis . J Pathol \n230 : 118 –128.22733579 \nPaterson AL, Shannon NB, Lao-Sirieix P, Ong CA, Peters CJ, O'Donovan M, Fitzgerald RC (2013 b) A systematic approach to therapeutic target selection in oesophago-gastric cancer . Gut \n62 : 1415 –1424.22773546 \nSachs N, Clevers H (2014 ) Organoid cultures for the analysis of cancer phenotypes . Curr Opin Genet Dev \n24 : 68 –73.24657539 \nSatoh T, Xu RH, Chung HC, Sun GP, Doi T, Xu JM, Tsuji A, Omuro Y, Li J, Wang JW, Miwa H, Qin SK, Chung IJ, Yeh KH, Feng JF, Mukaiyama A, Kobayashi M, Ohtsu A, Bang YJ (2014 ) Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN—a randomized, phase III study . J Clin Oncol \n32 : 2039 –2049.24868024 \nShah MA, Wainberg ZA, Catenacci DV, Hochster HS, Ford J, Kunz P, Lee FC, Kallender H, Cecchi F, Rabe DC, Keer H, Martin AM, Liu Y, Gagnon R, Bonate P, Liu L, Gilmer T, Bottaro DP (2013 ) Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089), cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer . PLoS One \n8 : e54014 .23516391 \nShattuck DL, Miller JK, Carraway KL 3rd, Sweeney C (2008 ) Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells . Cancer Res \n68 : 1471 –1477.18316611 \nVan Cutsem E, Bang YJ, Feng-Yi F, Xu JM, Lee KW, Jiao SC, Chong JL, Lopez-Sanchez RI, Price T, Gladkov O, Stoss O, Hill J, Ng V, Lehle M, Thomas M, Kiermaier A, Ruschoff J (2014 ) HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer . Gastric Cancer \n18 : 476 –484.25038874 \nVan Loo P, Nordgard SH, Lingjaerde OC, Russnes HG, Rye IH, Sun W, Weigman VJ, Marynen P, Zetterberg A, Naume B, Perou CM, Borresen-Dale AL, Kristensen VN (2010 ) Allele-specific copy number analysis of tumors . Proc Natl Acad Sci USA \n107 : 16910 –16915.20837533 \nWainberg ZA, Anghel A, Desai AJ, Ayala R, Luo T, Safran B, Fejzo MS, Hecht JR, Slamon DJ, Finn RS (2010 ) Lapatinib, a dual EGFR and HER2 kinase inhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is synergistic with trastuzumab in vitro and in vivo . Clin Cancer Res \n16 : 1509 –1519.20179222 \nWeaver JMJ, Ross-Innes CS, Shannon N, Lynch AG, Forshew T, Barbera M, Murtaza M, Ong C-AJ, Lao-Sirieix P, Dunning MJ, Smith L, Smith ML, Anderson CL, Carvalho B, O'Donovan M, Underwood TJ, May AP, Grehan N, Hardwick R, Davies J, Oloumi A, Aparicio S, Caldas C, Eldridge MD, Edwards PAW, Rosenfeld N, Tavare S, Fitzgerald RC, The OC (2014 ) Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis . Nat Genet \n46 : 837 –843.24952744 \nZhang Z, Wang J, Ji D, Wang C, Liu R, Wu Z, Liu L, Zhu D, Chang J, Geng R, Xiong L, Fang Q, Li J (2014 ) Functional genetic approach identifies MET, HER3, IGF1R, INSR pathways as determinants of lapatinib unresponsiveness in HER2-positive gastric cancer . Clin Cancer Res \n20 : 4559 –4573.24973425\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0007-0920",
"issue": "113(9)",
"journal": "British journal of cancer",
"keywords": null,
"medline_ta": "Br J Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000970:Antineoplastic Agents; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D004938:Esophageal Neoplasms; D004943:Esophagogastric Junction; D005260:Female; D006801:Humans; D000077341:Lapatinib; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D011799:Quinazolines; D018719:Receptor, ErbB-2; D020893:Receptor, ErbB-3; D015398:Signal Transduction; D013274:Stomach Neoplasms",
"nlm_unique_id": "0370635",
"other_id": null,
"pages": "1305-12",
"pmc": null,
"pmid": "26484410",
"pubdate": "2015-11-03",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": "22155872;23525077;24263233;24518603;24657539;24668646;24882004;24868024;24952744;24973425;17693134;16822992;25209969;18172173;18316611;18752498;19770374;20113825;25596252;25157953;25694417;25038874;20179222;20728210;20837533;21415234;22238368;22608083;22882541;23372746;23516391;22733579;22773546",
"title": "Molecular effects of Lapatinib in the treatment of HER2 overexpressing oesophago-gastric adenocarcinoma.",
"title_normalized": "molecular effects of lapatinib in the treatment of her2 overexpressing oesophago gastric adenocarcinoma"
} | [
{
"companynumb": "GB-SA-2015SA189144",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
"d... |
{
"abstract": "Autoimmune disease (AD) is common in patients with Wiskott-Aldrich syndrome (WAS) and patients with WAS who has an AD usually constitute a high-risk group with poor outcome. However, knowledge of AD in WAS is limited in China. In this study, medical records of 53 patients with WAS at Children´s Hospital of Chongqing Medical University from April 2004 to January 2014 were evaluated retrospectively and 14 patients (26%) had at least one AD. Autoimmune hemolytic anemia (AIHA) was the most common and detected in 12 patients (23%), other complications included immune thrombocytopenia (n = 1), immune neutropenia (n = 1), autoimmune arthritis (n = 1), and renal injury (n = 1). No significant differences were found in the level of serum immunoglobulins and lymphocyte subsets between the AD group and non-AD group. Although eight patients with AD received hematopoietic stem cell transplantation (HSCT), three patients died of pulmonary infection after HSCT.\n\n\nCONCLUSIONS\nAD is frequent in Chinese patients with WAS and AIHA was the most common. AD is a poor prognosis factor for WAS and should be treated as early as possible by HSCT.\n\n\nBACKGROUND\n• Autoimmune disease is common in patients with WAS. • Manifestations, follow-up finding, and treatment approaches of autoimmune disease in Chinese patients with WAS have received less attention in the literature. What is New: • This study is firstly intended for evaluation of the clinical and immune characteristics of autoimmune disease in a large series Chinese patients with WAS. • AD is frequent in Chinese patients with WAS and AIHA is the most common.",
"affiliations": "Division of Immunology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child, Development and Disorders, Chongqing, 400014, China. 664110431@qq.com.;Division of Immunology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child, Development and Disorders, Chongqing, 400014, China. zzy510214@126.com.;Division of Immunology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child, Development and Disorders, Chongqing, 400014, China. ldw8621@163.com.;Division of Immunology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child, Development and Disorders, Chongqing, 400014, China. 13228628556@126.com.;Division of Immunology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child, Development and Disorders, Chongqing, 400014, China. tangxuemei2008@sina.com.;Division of Immunology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child, Development and Disorders, Chongqing, 400014, China. zhaoxd@cqmu.edu.cn.",
"authors": "Chen|Nan|N|;Zhang|Zhi-Yong|ZY|;Liu|Da-Wei|DW|;Liu|Wei|W|;Tang|Xue-Mei|XM|;Zhao|Xiao-Dong|XD|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00431-015-2527-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-6199",
"issue": "174(10)",
"journal": "European journal of pediatrics",
"keywords": "Autoimmune disease; Autoimmune hemolytic anemia; Hematopoietic stem cell transplantation; Wiskott–Aldrich syndrome",
"medline_ta": "Eur J Pediatr",
"mesh_terms": "D015551:Autoimmunity; D002675:Child, Preschool; D002681:China; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D013601:T-Lymphocytes; D014923:Wiskott-Aldrich Syndrome",
"nlm_unique_id": "7603873",
"other_id": null,
"pages": "1311-8",
"pmc": null,
"pmid": "25877044",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "23107152;14981635;5948738;10968249;23264593;24104410;22982638;8279047;22079330;23527602;10622679;13133561;24217816;20571932;12969986;11309323;22426750;22036785;17296786;18043243;11420915;17498197;25363779;17703096;12819473;19351959;8582423;12728121",
"title": "The clinical features of autoimmunity in 53 patients with Wiskott-Aldrich syndrome in China: a single-center study.",
"title_normalized": "the clinical features of autoimmunity in 53 patients with wiskott aldrich syndrome in china a single center study"
} | [
{
"companynumb": "PHHY2015CN046501",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"drug... |
{
"abstract": "4-Aminopyridine (4-AP) is a recent treatment indicated to improve walking in patient with multiple sclerosis. We report the first case of pulmonary arterial hypertension (PAH) that we attribute to the use of 4-AP. A 64-year-old woman with multiple sclerosis presented with dyspnea. After excluding other secondary causes of pulmonary hypertension, a diagnosis of severe PAH due to 4-AP was made based on right heart catheterization. History revealed that the dyspnea began with the initiation of 4-AP. After discontinuation of 4-AP therapy and initiation of ambrisentan and tadalafil, dyspnea and pulmonary arterial pressure have improved significantly and one specific PAH treatment was stopped. 4-AP is an outward rectifying potassium channel blocker with a vasoconstrictor effect in animal's pulmonary artery. According to the chronological sequence of events, the lack of other etiology, and its pharmacological plausibility, 4-AP is highly suspected to have induced our patient's PAH.",
"affiliations": "Département de pneumologie, CHRU de Nancy, rue du Morvan, 54500, Vandœuvre-lès-Nancy, France.;Centre Régional de Pharmacovigilance, CHRU de Nancy, Hôpital Central, 29, avenue du Maréchal de Lattre de Tassigny, Nancy, France.;Département de pneumologie, CHRU de Nancy, rue du Morvan, 54500, Vandœuvre-lès-Nancy, France.;Centre Régional de Pharmacovigilance, CHRU de Nancy, Hôpital Central, 29, avenue du Maréchal de Lattre de Tassigny, Nancy, France.;Département de pneumologie, CHRU de Nancy, rue du Morvan, 54500, Vandœuvre-lès-Nancy, France.;Département de pneumologie, CHRU de Nancy, rue du Morvan, 54500, Vandœuvre-lès-Nancy, France.;Département de pneumologie, CHRU de Nancy, rue du Morvan, 54500, Vandœuvre-lès-Nancy, France.;Département de pneumologie, CHRU de Nancy, rue du Morvan, 54500, Vandœuvre-lès-Nancy, France.",
"authors": "Ribeiro Baptista|Bruno|B|http://orcid.org/0000-0003-0870-3352;Petitpain|Nadine|N|;Gomez|Emmanuel|E|;Yelehé-Okouma|Melissa|M|;Valentin|Simon|S|;Guillaumot|Anne|A|;Chabot|François|F|;Chaouat|Ari|A|",
"chemical_list": "D000959:Antihypertensive Agents; D010666:Phenylpropionates; D026902:Potassium Channel Blockers; D011724:Pyridazines; D000068581:Tadalafil; D015761:4-Aminopyridine; C467894:ambrisentan",
"country": "England",
"delete": false,
"doi": "10.1111/fcp.12396",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0767-3981",
"issue": "33(1)",
"journal": "Fundamental & clinical pharmacology",
"keywords": "4-aminopyridine; drug induced; multiple sclerosis; pulmonary hypertension",
"medline_ta": "Fundam Clin Pharmacol",
"mesh_terms": "D015761:4-Aminopyridine; D000959:Antihypertensive Agents; D004417:Dyspnea; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D008875:Middle Aged; D009103:Multiple Sclerosis; D010666:Phenylpropionates; D026902:Potassium Channel Blockers; D011724:Pyridazines; D000068581:Tadalafil",
"nlm_unique_id": "8710411",
"other_id": null,
"pages": "127-129",
"pmc": null,
"pmid": "29956855",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Pulmonary arterial hypertension in patient treated for multiple sclerosis with 4-aminopyridine.",
"title_normalized": "pulmonary arterial hypertension in patient treated for multiple sclerosis with 4 aminopyridine"
} | [
{
"companynumb": "FR-BIOGEN-2018BI00605179",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DALFAMPRIDINE"
},
"drugadditional": "3",
... |
{
"abstract": "We present three cases in which patients that had suffered polytrauma developed heparin-induced thrombocytopenia after the start of heparin treatment for thrombosis. All three patients had high injury severity scores and required major surgery. They all started receiving unfractionated heparin for deep venous thrombosis with or without an asymptomatic pulmonary embolism. The patients were clinically diagnosed with heparin-induced thrombocytopenia after their platelet counts fell or exhibited a delayed recovery.\n\n\n\nHeparin-induced thrombocytopenia and the associated thromboses were successfully treated by discontinuing all forms of heparin treatment and administering argatroban followed by warfarin.\n\n\n\nEarly recognition and clinical diagnosis of heparin-induced thrombocytopenia is necessary for clinicians in cases in which severely injured trauma patients show reductions or delayed recovery in their platelet counts in combination with thrombosis after starting heparin treatment.",
"affiliations": "Advanced Emergency and Critical Care Medical Center Okayama University Hospital Okayama Japan.;Advanced Emergency and Critical Care Medical Center Okayama University Hospital Okayama Japan.;Department of Hematology and Oncology Okayama University Hospital Okayama Japan.;Advanced Emergency and Critical Care Medical Center Okayama University Hospital Okayama Japan.;Advanced Emergency and Critical Care Medical Center Okayama University Hospital Okayama Japan.;Advanced Emergency and Critical Care Medical Center Okayama University Hospital Okayama Japan.;Advanced Emergency and Critical Care Medical Center Okayama University Hospital Okayama Japan.;Advanced Emergency and Critical Care Medical Center Okayama University Hospital Okayama Japan.",
"authors": "Yumoto|Tetsuya|T|;Sato|Keiji|K|;Fujii|Nobuharu|N|;Kinami|Yo|Y|;Tsukahara|Kohei|K|;Ugawa|Toyomu|T|;Ichiba|Shingo|S|;Ujike|Yoshihito|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/ams2.132",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2052-8817",
"issue": "3(1)",
"journal": "Acute medicine & surgery",
"keywords": "Argatroban; deep venous thrombosis; heparin‐induced thrombocytopenia; polytrauma; warfarin",
"medline_ta": "Acute Med Surg",
"mesh_terms": null,
"nlm_unique_id": "101635464",
"other_id": null,
"pages": "46-49",
"pmc": null,
"pmid": "29123749",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports",
"references": "16634744;19965682;20149589;20205800;21640991;22060821;22315270;23722881;29930820",
"title": "Three cases of heparin-induced thrombocytopenia associated with polytrauma.",
"title_normalized": "three cases of heparin induced thrombocytopenia associated with polytrauma"
} | [
{
"companynumb": "JP-TEVA-2018-JP-897896",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "Brimonidine eye drops are frequently prescribed for the treatment of glaucoma and ocular hypertension in adults. Systemic toxicities including neurological side effects have been reported with its use, especially in the paediatric population. In this report, we present a case of encephalopathy secondary to the use of brimonidine eye drops in a patient with underlying advanced chronic kidney disease, who recovered promptly after drug cessation. Herein, we also review the pharmacokinetics of eye drops leading to their systemic side effects, especially in the context of renal impairment. We also explore the possibility of extracorporeal treatment, such as by haemodialysis, for the treatment of these manifestations. This case demonstrates the need to clarify a patient's drug history and stop offending medications early on in a patient with delirium, while treatments such as antidotes or extracorporeal treatment are being considered.",
"affiliations": "Medicine, Queen Mary Hospital, Hong Kong, HKG.;Medicine, Queen Mary Hospital, Hong Kong, HKG.;Medicine, Queen Mary Hospital, Hong Kong, HKG.;Medicine/Nephrology, Tung Wah Hospital, Hong Kong, HKG.",
"authors": "So|Benjamin Y F|BYF|;Lee|Kit Ming|KM|;Tang|Arthur H C|AHC|;Yip|Terence|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.17725",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.17725\nInternal Medicine\nOphthalmology\nNephrology\nBrimonidine Eye Drops Causing Encephalopathy in a Patient With Advanced Chronic Kidney Disease\nMuacevic Alexander\nAdler John R\nSo Benjamin Y.F. 1\nLee Kit Ming 1\nTang Arthur H.C. 1\nYip Terence 2\n1 Medicine, Queen Mary Hospital, Hong Kong, HKG\n2 Medicine/Nephrology, Tung Wah Hospital, Hong Kong, HKG\nBenjamin Y.F. So soyufaibenjamin@gmail.com\n5 9 2021\n9 2021\n13 9 e177255 9 2021\nCopyright © 2021, So et al.\n2021\nSo et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/70431-brimonidine-eye-drops-causing-encephalopathy-in-a-patient-with-advanced-chronic-kidney-disease\nBrimonidine eye drops are frequently prescribed for the treatment of glaucoma and ocular hypertension in adults. Systemic toxicities including neurological side effects have been reported with its use, especially in the paediatric population. In this report, we present a case of encephalopathy secondary to the use of brimonidine eye drops in a patient with underlying advanced chronic kidney disease, who recovered promptly after drug cessation. Herein, we also review the pharmacokinetics of eye drops leading to their systemic side effects, especially in the context of renal impairment. We also explore the possibility of extracorporeal treatment, such as by haemodialysis, for the treatment of these manifestations. This case demonstrates the need to clarify a patient’s drug history and stop offending medications early on in a patient with delirium, while treatments such as antidotes or extracorporeal treatment are being considered.\n\nbrimonidine\ndialysis\nchronic kidney disease\nencephalopathy\neye drops\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\npmcIntroduction\n\nBrimonidine, an α2-adrenergic agonist commonly prescribed for the treatment of glaucoma and ocular hypertension, is a lipid-soluble compound structurally related to clonidine. Systemic side effects have been reported after ocular administration of brimonidine, the most severe of which are neuropsychiatric manifestations [1]. While these cases seem more common in the paediatric population, there are only a few reports on brimonidine toxicity in adult patients. Here, we report on a case of acute encephalopathy attributed to the use of brimonidine tartrate eye drops in a 66-year-old woman with advanced chronic kidney disease (CKD). Her presentation was partly modified by the use of different modalities of renal replacement therapy (RRT) during her hospitalization. To the best of our knowledge, no reports have explored this clinical entity in the context of severe renal failure.\n\nCase presentation\n\nA 66-year-old woman was admitted to the intensive care unit (ICU) for acute diverticulitis with septic shock. Her past medical history was significant for hypertension, diabetes mellitus, hyperlipidaemia, gout, glaucoma, and stage 5 CKD. One month before admission, her creatinine was 395 μmol/L (4.47 mg/dL), corresponding to an estimated glomerular filtration rate of 10 mL/min/1.73 m2. She was a housewife who was cognitively intact and completely independent in her activities of daily living before admission.\n\nShe was conservatively managed with intravenous antibiotics and vasopressors. She also developed acute kidney injury with oliguria. RRT was initiated in view of uraemia, metabolic acidosis, and hyperkalaemia, and the patient received a prolonged session of continuous venovenous haemofiltration (CVVH) during her ICU stay. Upon resolution of sepsis, her renal function had recovered to its previous baseline, and RRT was discontinued.\n\nShe was noted to be increasingly confused and agitated in the days following discharge from the ICU. Her Montreal Cognitive Assessment (Hong Kong version) (HK-MoCA) score was 3/30. Computed tomography scan and magnetic resonance imaging of the brain showed age-related cerebral atrophy. Lumbar puncture was performed and cerebrospinal fluid analysis was grossly unremarkable. Septic screens including blood and urine cultures were negative. Her blood tests are presented in Table 1. There was a mild leukocytosis that was already significantly downtrend from previous values. There were no electrolyte disturbances that could account for her altered mental state. Her renal function was similar to the previous baseline. Vitamin B12, folate, ammonia, red cell transketolase levels, and thyroid function tests, were all within the normal range. Electroencephalogram showed generalized symmetrical moderate background slowing with intermittent frontal delta activity. The findings were non-specific and merely reflected underlying encephalopathy. In view of these findings, regular intermittent haemodialysis twice a week was resumed on suspicion of uraemic encephalopathy, but no improvement was seen after two weeks. The patient remained frankly delirious and pulled out her haemodialysis catheter, requiring limb restraints.\n\nTable 1 Blood results during an episode of delirium\n\nALT: alanine aminotransferase; AST: aspartate aminotransferase.\n\nVariable\tValue\tReference range\t\nHaemoglobin (g/dL)\t8.8\t11.5 – 14.8\t\nWhite blood cell (x 109/L)\t13.75\t3.89 – 9.93\t\nPlatelet (x 109/L)\t272\t167 – 396\t\nSodium (mmol/L)\t137\t136 – 148\t\nPotassium (mmol/L)\t4.1\t3.6 – 5.0\t\nChloride (mmol/L)\t97\t100 – 109\t\nBicarbonate (mmol/L)\t28\t21 – 31\t\nUrea (mmol/L)\t26.1\t2.9 – 8.0\t\nCreatinine (μmol/L)\t363\t49 – 82\t\nCalcium (albumin-adjusted) (mmol/L)\t2.51\t2.24 – 2.63\t\nPhosphate (mmol/L)\t0.92\t0.88 – 1.45\t\nAlbumin (g/L)\t32\t39 – 50\t\nGlobulin (g/L)\t30\t26 – 40\t\nBilirubin (μmol/L)\t11\t4 – 23\t\nAlkaline phosphatase (U/L)\t192\t47 – 124\t\nALT (U/L)\t23\t8 – 45\t\nAST (U/L)\t40\t15 – 37\t\n\nOn review of her medications, the patient had been started on 0.1% brimonidine tartrate eye drops, one drop twice a day to the right eye, for raised intraocular pressure one month before admission. The eye drops were stopped and her mental state improved markedly within one week. She became oriented to place and person. However, she was still lacking in motivation and complained of pervasive low mood, which was cautiously treated with a trial of the antidepressant vortioxetine. After a course of rehabilitation, she was discharged home with significantly improved cognition and was ambulatory with assistance.\n\nDiscussion\n\nBrimonidine normally undergoes hepatic metabolism via aldehyde oxidase to form oxo- and dioxo-brimonidine metabolites and is predominantly excreted in the kidney [2]. Brimonidine can cross the blood-brain barrier and cause central nervous system (CNS) depression via binding to α2-adrenergic receptors [1]. Delirium, psychosis, or even Charles-Bonnet syndrome has been reported in adults after ocular administration of brimonidine, and altered mental state has also been reported after topical use as a haemostatic agent in dermatologic surgery [1,3-5]. A variety of neuropsychiatric presentations, ranging from lethargy to coma, have been reported in neonates and children after administering brimonidine eye drops [6-8]. Depression has also been associated with increased α2-adrenoceptor activity in the brain in studies that used brimonidine as the detector ligand, and is a possible adverse effect of topical brimonidine; this may have been a contributing factor to the depressed mood and apathy observed in our patient [9]. Neurotoxicity is particularly common in elderly and paediatric age groups, and the effects are likely dose-dependent, extrapolating from early dose-response studies of brimonidine eye drops [2,10]. Reassuringly, as in our patient, complete neurological recovery was observed within days to weeks of drug cessation in most cases.\n\nFor lipophilic drugs, only around 10% of the active drug is absorbed into the eye via the cornea after topical administration of eye drops. Significant systemic drug absorption often occurs via the highly vascular nasal mucosa, after drainage through the nasolacrimal duct [11]. Importantly, such absorption bypasses hepatic first-pass metabolism and may increase the risk of systemic toxicities. Furthermore, for lipophilic drugs such as brimonidine, direct penetration into the CNS via the olfactory bulb after drainage into the nasal cavity has been demonstrated in animal studies [12]. In our case, neurotoxicity was evidently exacerbated by underlying advanced CKD with impaired drug excretion and systemic accumulation.\n\nTo reduce systemic absorption of topically administered eye drops, simple measures such as eyelid closure for up to five minutes and nasolacrimal duct occlusion may reduce systemic absorption by up to 67% and 65%, respectively [13,14]. Additionally, instillation of only one drop at a time is usually sufficient; whereas commercial eye drop dispensers often have a volume of 25-50 μL, the capacity of the conjunctival sac is only approximately 10 μL [15]. Unfortunately, dose adjustment of eye drops is logistically impossible even in patients with renal impairment. Brimonidine eye drops should therefore be used with caution in susceptible patients, including frail older adults and patients with impaired renal or liver function. Although alternative treatments may be available, ophthalmic preparations of beta-blockers and carbonic anhydrase inhibitors have also been associated with systemic side effects, including neuropsychiatric complications [16,17]. The smallest effective dose should be used, with vigilant monitoring for systemic toxicities.\n\nThere is no approved antidote for the treatment of brimonidine toxicity. Paediatric studies have described the use of activated charcoal after inadvertent oral ingestion of brimonidine eye drops, and also intravenous naloxone in established brimonidine toxicity, but no consistent benefit has been observed [8,18,19]. Conservative management with drug cessation and close monitoring was successful in most cases. Pertinent to our case, there are no data regarding whether haemodialysis may effectively remove the active compound from the circulation and facilitate recovery, especially in patients with severe acute or chronic renal impairment. Indeed, brimonidine does not have any safety data in advanced CKD. However, it is possible to predict from the known kinetics of brimonidine that it is probably poorly dialyzable; despite a relatively small molecular weight of 292.1 daltons, meaning that it can likely pass through the pores of a semi-permeable hemofilter membrane, brimonidine has a large volume of distribution of 10 L due to its lipid solubility [20]. Haemodialysis can only effectively remove drugs concentrated in the intravascular space. Significant redistribution of the active compound from the intracellular to the intravascular space is predicted to occur even in spite of removal during haemodialysis, by diffusion across cell membranes down a concentration gradient. An argument can be made for use of continuous renal replacement therapy, such as by CVVH, for continuous removal of redistributed brimonidine in oliguric patients, but no relevant reports were identified in the literature. Monitoring of drug levels will be helpful in case extracorporeal treatments are considered for reasons beyond standard indications for acute RRT. Given the above, it is plausible that the continuous removal of brimonidine by a prolonged session of CVVH given to our patient may have temporarily alleviated her symptoms, giving rise to the current, atypical presentation of delirium worsening after ICU discharge despite resolution of intercurrent sepsis. These symptoms were minimally improved even after the institution of regular intermittent haemodialysis, probably due to continuous administration of the offending eye drops and the inefficiency of intermittent RRT, with significant post-dialysis drug rebound with redistribution from other fluid compartments after each session of haemodialysis.\n\nConclusions\n\nWe have reported on a case of drug-induced encephalopathy in a patient with underlying advanced CKD, after administration of brimonidine eye drops. This case illustrates the need to pay close attention to the drug history, including topical medications, especially in patients with risk factors for systemic toxicity including abnormal end-organ function. The role of antidotes and extracorporeal treatments for various drug-induced encephalopathies, including those due to brimonidine, remains to be defined. Ultimately, a high index of suspicion and early cessation of offending medications remain the cornerstones of treatment, in order to prevent life-threatening complications and obviate the need for expensive and invasive investigations in the workup for delirium.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 A review of neuropsychiatric adverse events from topical ophthalmic brimonidine Hum Exp Toxicol Cimolai N 1279 1290 39 2020 32347114\n2 Brimonidine tartrate for the treatment of glaucoma Expert Opin Pharmacother Oh DJ Chen JL Vajaranant TS Dikopf MS 115 122 20 2019 30407890\n3 A case of suspected alphagan-induced psychosis Arch Ophthalmol Kim DD 1132 1133 118 2000 https://pubmed.ncbi.nlm.nih.gov/10922214/ 10922214\n4 Charles Bonnet syndrome precipitated by brimonidine tartrate eye drops Br J Ophthalmol Tomsak RL Zaret CR Weidenthal D 917 87 2003 12812898\n5 Association of central nervous system depression with topical brimonidine when used for hemostasis: a serious adverse event JAMA Dermatol Shagalov DR Taylor D Schleichert R Weiss J Weiss E 575 577 153 2017 28403392\n6 Apparent central nervous system depression in infants after the use of topical brimonidine Am J Ophthalmol Carlsen JO Zabriskie NA Kwon YH Barbe ME Scott WE 255 256 128 1999 10458196\n7 Ophthalmic drops causing coma in an infant J Pediatr Berlin RJ Lee UT Samples JR Rich LF Tang-Liu DD Sing KA Steiner RD 441 443 138 2001 11241061\n8 Brimonidine tartrate poisoning in children: frequency, trends, and use of naloxone as an antidote Pediatrics Lai Becker M Huntington N Woolf AD 0 11 123 2009\n9 Selective increase of alpha2A-adrenoceptor agonist binding sites in brains of depressed suicide victims J Neurochem Callado LF Meana JJ Grijalba B Pazos A Sastre M García-Sevilla JA 1114 1123 70 1998 9489732\n10 Brimonidine tartrate: a one-month dose response study Ophthalmology Derick RJ Robin AL Walters TR 131 136 104 1997 9022117\n11 Systemic side effects of eye drops: a pharmacokinetic perspective Clin Ophthalmol Farkouh A Frigo P Czejka M 2433 2441 10 2016 27994437\n12 Non-systemic delivery of topical brimonidine to the brain: a neuro-ocular tissue distribution study J Drug Target Abdulrazik M Tamilvanan S Benita S 670 679 14 2006 17162736\n13 Improving the therapeutic index of topically applied ocular drugs Arch Ophthalmol Zimmerman TJ Kooner KS Kandarakis AS Ziegler LP 551 553 102 1984 6704011\n14 The importance of eyelid closure and nasolacrimal occlusion following the ocular instillation of topical glaucoma medications, and the need for the universal inclusion of one of these techniques in all patient treatments and clinical studies Trans Am Ophthalmol Soc Flach AJ 138 145 106 2008 https://pubmed.ncbi.nlm.nih.gov/19277229/ 19277229\n15 Ocular anatomy and physiology: its relevance to transcorneal drug absorption and to vehicle effects Ophthalmic Drug Delivery: Biopharmaceutical, Technological and Clinical Aspects Peduzzi M Debbia A Monzani A 1 5 New York, NY Springer 11 1987\n16 Neuropsychiatric adverse events from topical ophthalmic timolol Clin Med Res Cimolai N 90 96 17 2019 31462538\n17 Acetazolamide toxicity and pharmacokinetics in patients receiving hemodialysis Pharmacotherapy Schwenk MH St Peter WL Meese MG Singhal PC 522 527 15 1995 https://pubmed.ncbi.nlm.nih.gov/7479208/ 7479208\n18 Unintentional ingestion of brimonidine antiglaucoma drops: a case report and review of the literature Pediatr Emerg Care Soto-Pérez-de-Celis E Skvirsky DO Cisneros BG 657 658 23 2007 17876259\n19 Failure of naloxone to reverse brimonidine-induced coma in an infant J Pediatr Sztajnbok J 485 486 140 2002 12006970\n20 Brimonidine. A review of its pharmacological properties and clinical potential in the management of open-angle glaucoma and ocular hypertension Drugs Aging Adkins JC Balfour JA 225 241 12 1998 9534022\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(9)",
"journal": "Cureus",
"keywords": "brimonidine; chronic kidney disease; dialysis; encephalopathy; eye drops",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e17725",
"pmc": null,
"pmid": "34659939",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": "32347114;19124581;10922214;28403392;10458196;17162736;12812898;12006970;27994437;9534022;11241061;6704011;30407890;7479208;31462538;9489732;19277229;17876259;9022117",
"title": "Brimonidine Eye Drops Causing Encephalopathy in a Patient With Advanced Chronic Kidney Disease.",
"title_normalized": "brimonidine eye drops causing encephalopathy in a patient with advanced chronic kidney disease"
} | [
{
"companynumb": "HK-ALLERGAN-2137536US",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BRIMONIDINE TARTRATE"
},
"drugadditional": "1",
... |
{
"abstract": "Primary focal segmental glomerulosclerosis recurrence occurs in 10% to 50% of recipients after kidney transplant and may affect both children and adults. Treatment after recurrence with plasma exchange and immunosuppression is quite variable and challenging, and those who do not respond usually progress to allograft failure. Podocyte injury and B7-1 expression and subsequently its blockade (abatacept) have been reported to be associated with complete remission of proteinuria in 4 patients with focal segmental glomerulosclerosis recurrence after kidney transplantation and in 1 patient with focal segmental glomerulosclerosis in native kidney. Here, we report our experience of successfully treating 3 consecutive patients with focal segmental glomerulosclerosis recurrence after kidney transplant with abatacept, which induced proteinuria remission.",
"affiliations": "From the Department of Adult Kidney and Pancreas Transplantation, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.",
"authors": "Shah|Yaser|Y|;Almeshari|Khalid|K|;Aleid|Hassan|H|;Broering|Dieter|D|;Alahmadi|Ibrahim|I|;Ali|Tariq|T|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069594:Abatacept",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.MESOT2018.P53",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "17(Suppl 1)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000069594:Abatacept; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental; D006801:Humans; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011507:Proteinuria; D012008:Recurrence; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "178-180",
"pmc": null,
"pmid": "30777550",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Treatment With Abatacept in Recurrent Focal Segmental Glomerulosclerosis After Kidney Transplant.",
"title_normalized": "successful treatment with abatacept in recurrent focal segmental glomerulosclerosis after kidney transplant"
} | [
{
"companynumb": "SA-ASTELLAS-2019US030358",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
... |
{
"abstract": "Pyogenic ventriculitis is an uncommon and potentially fatal central nervous system infection. Delayed treatment due to non specific clinical symptoms may lead to an unfavorable outcome. Brain magnetic resonance imaging (MRI) plays an important role in the diagnosis of pyogenic ventriculitis. We describe two patients with pyogenic ventriculitis presenting with a pathognomonic MRI finding. The first patient, a 77-year-old female, developed high fever and consciousness disturbance. MR images revealed hyperintense lesions with a fluid-fluid level in the bilateral lateral ventricles on diffusion-weighted images (DWIs) and hypointense lesions on T2-weighted images (T2WIs). MR images also revealed findings of left otitis media. The second patient, a 63-year-old male, who had a past history of multiple myeloma and had received chemotherapy, developed high fever and left hemiparesis. MR images revealed a hyperintense lesion with a fluid-fluid level in the right lateral ventricle on DWIs and a hypointense lesion on T2WIs, multiple ring-enhancing lesions on gadolinium enhanced T1-weighted images, and pontine infarction on DWIs. Chest computed tomography revealed an infiltrative shadow in the lower lobe of the left lung. On the basis of MRI findings, both patients were diagnosed as having pyogenic ventriculitis and were administered high-dose meropenem intravenously. The second patient was also administered sulfamethoxazole-trimethoprim orally. Intraventricular abnormalities disappeared and the patients achieved complete remission after the antibacterial treatment. Intraventricular hyperintense lesions on DWIs and hypointense ones on T2WIs with a fluid-fluid level is a pathognomonic finding of pyogenic ventriculitis and has not been previously reported in other diseases. Recognition of the characteristic MRI features and initiation of high-dose and appropriate antibiotics in an early stage may lead to a favorable outcome of the disease.",
"affiliations": "Department of Neurology, Brain Research Institute, Niigata University.",
"authors": "Hatakeyama|Masahiro|M|;Kanazawa|Masato|M|;Ishihara|Ayako|A|;Tanabe|Yoshinari|Y|;Shimohata|Takayoshi|T|;Nishizawa|Masatoyo|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem",
"country": "Japan",
"delete": false,
"doi": "10.5692/clinicalneurol.54.732",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-918X",
"issue": "54(9)",
"journal": "Rinsho shinkeigaku = Clinical neurology",
"keywords": null,
"medline_ta": "Rinsho Shinkeigaku",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D002552:Cerebral Ventricles; D058565:Cerebral Ventriculitis; D038524:Diffusion Magnetic Resonance Imaging; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D008297:Male; D000077731:Meropenem; D008875:Middle Aged; D020551:Pulse Therapy, Drug; D013492:Suppuration; D013845:Thienamycins; D016896:Treatment Outcome",
"nlm_unique_id": "0417466",
"other_id": null,
"pages": "732-7",
"pmc": null,
"pmid": "25283828",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pathognomonic magnetic resonance imaging (MRI) finding of fluid-fluid level in pyogenic ventriculitis: two case reports.",
"title_normalized": "pathognomonic magnetic resonance imaging mri finding of fluid fluid level in pyogenic ventriculitis two case reports"
} | [
{
"companynumb": "JP-CELGENE-087-21880-13013128",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE ACETATE"
},
"drugadditional... |
{
"abstract": "OBJECTIVE\nIt has been suggested that ingestion of even small amounts of minoxidil by young children may result in serious adverse effects. The intent of this study was to describe pediatric minoxidil exposures reported to a statewide poison center system.\n\n\nMETHODS\nCases were minoxidil exposures among patients 5 years or younger reported to Texas poison centers during 2000 to 2014. The distribution by various demographic and clinical factors was determined.\n\n\nRESULTS\nOf 125 total cases, 58% were male and 78% aged 1 to 2 years. Ingestion alone was reported in 92% of the exposures. Ninety-eight percent of the exposures were unintentional, and 94% occurred at the patient's own residence. Sixty-two percent of the patients were managed on site. The outcome was not serious (no effect, minor effect, not followed [nontoxic], not followed [minimal effects]) in 88% of the exposures. The most common adverse effect was vomiting, reported in 8% of the exposures. The most common treatments were dilution/irrigation/wash (53%), activated charcoal (18%), food/snack (17%), and intravenous fluids (8%).\n\n\nCONCLUSIONS\nFew pediatric minoxidil exposures were reported to Texas poison centers. Of these exposures, most involved ingestion, were unintentional, and involved patients who were male and aged 1 to 2 years. Although it has been suggested that pediatric minoxidil ingestions might result in serious adverse effects, this study suggests that most pediatric minoxidil exposures reported to poison centers are not likely to have serious outcomes and may be managed at home.",
"affiliations": "From the Environmental Epidemiology and Disease Registries Section, Department of State Health Services, Austin, TX.",
"authors": "Forrester|Mathias B|MB|",
"chemical_list": "D000959:Antihypertensive Agents; D008914:Minoxidil",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000001226",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "34(6)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000959:Antihypertensive Agents; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008914:Minoxidil; D011039:Poison Control Centers; D012189:Retrospective Studies; D013781:Texas",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "413-416",
"pmc": null,
"pmid": "29112111",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pediatric Minoxidil Exposures Reported to Texas Poison Centers.",
"title_normalized": "pediatric minoxidil exposures reported to texas poison centers"
} | [
{
"companynumb": "US-JNJFOC-20180716467",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MINOXIDIL"
},
"drugadditional": "3",
"d... |
{
"abstract": "BACKGROUND\nThe objective was to compare immediate and long-term results of systemic thrombolytic therapy (STT) and catheter-directed fragmentation (CDF) with local thrombolytic therapy (LTT) in patients with massive pulmonary embolism (PE).\n\n\nMETHODS\nAbout 209 patients with massive PE (the high risk of early death) were included in our study. From 2008 till 2010 in the first group (n = 102), STT was performed. From 2011 till 2013 in the second group (n = 107), CDF with LTT was carried out. Echocardiography and pulmonary arteriography were performed in all patients on admission to hospital and in 5 days after treatment. The patients of both groups were re-examined in 6 months, 1, 2, and 3 years after the operation.\n\n\nRESULTS\nIn the first group, there were 5 (4.9%) cases of in-hospital 30-day mortality. In the second group, there was 1 (0.9%) case of in-hospital 30-day mortality (P = 0.08). In the first group, a clinically significant bleeding was noted in 4 (3.9%) cases, but it caused mortality only in 1 case. In the second group, the clinically significant bleeding was not found (P = 0.038). Persistent postembolic pulmonary hypertension (PPPH) in 9.8% cases of patients in the first group and 2.9% cases of patients in the second group was determined (P = 0.048).\n\n\nCONCLUSIONS\nCDF combined with LTT is an effective minimal invasive treatment (helped us to reduce significantly the number of bleeding and PPPH cases), at least in the midterm, in patients with massive PE.",
"affiliations": "Academician E.N. Meshalkin Novosibirsk State Budget Research Institute of Circulation Pathology, Ministry for Public Health Care Russian Federation, Novosibirsk, Russian Federation.;Academician E.N. Meshalkin Novosibirsk State Budget Research Institute of Circulation Pathology, Ministry for Public Health Care Russian Federation, Novosibirsk, Russian Federation. Electronic address: starodub@mail.ru.;Academician E.N. Meshalkin Novosibirsk State Budget Research Institute of Circulation Pathology, Ministry for Public Health Care Russian Federation, Novosibirsk, Russian Federation.;Academician E.N. Meshalkin Novosibirsk State Budget Research Institute of Circulation Pathology, Ministry for Public Health Care Russian Federation, Novosibirsk, Russian Federation.;The Sobolev Institute of Mathematics SB RAS, Novosibirsk State University, Novosibirsk, Russian Federation.;Academician E.N. Meshalkin Novosibirsk State Budget Research Institute of Circulation Pathology, Ministry for Public Health Care Russian Federation, Novosibirsk, Russian Federation.",
"authors": "Klevanets|Julia|J|;Starodubtsev|Vladimir|V|;Ignatenko|Pavel|P|;Voroshilina|Olga|O|;Ruzankin|Pavel|P|;Karpenko|Andrey|A|",
"chemical_list": "D005343:Fibrinolytic Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.avsg.2017.05.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-5096",
"issue": "45()",
"journal": "Annals of vascular surgery",
"keywords": null,
"medline_ta": "Ann Vasc Surg",
"mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000792:Angiography; D004452:Echocardiography; D005260:Female; D005343:Fibrinolytic Agents; D006470:Hemorrhage; D017052:Hospital Mortality; D006801:Humans; D006976:Hypertension, Pulmonary; D015552:Injections, Intralesional; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011655:Pulmonary Embolism; D012720:Severity of Illness Index; D015912:Thrombolytic Therapy; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "8703941",
"other_id": null,
"pages": "98-105",
"pmc": null,
"pmid": "28501664",
"pubdate": "2017-11",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Systemic Thrombolytic Therapy and Catheter-Directed Fragmentation with Local Thrombolytic Therapy in Patients with Pulmonary Embolism.",
"title_normalized": "systemic thrombolytic therapy and catheter directed fragmentation with local thrombolytic therapy in patients with pulmonary embolism"
} | [
{
"companynumb": "RU-SHENZHEN TECHDOW PHARMACEUTICAL CO. LTD-RU-2018TEC0000003",
"fulfillexpeditecriteria": "1",
"occurcountry": "RU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
... |
{
"abstract": "The purpose of this study is to provide detailed data on treatment persistence and clinical outcomes in Chinese patients with nonvalvular atrial fibrillation (NVAF). A single-center retrospective observational study was conducted. A total of 26,663 NVAF patients were enrolled from January 1, 2014 to December 31, 2017, clinical information of whom were from inpatient and outpatients data system was collected. The 1-year treatment persistence rates of 11,350 dabigatran users were 24.5% in 2014, 36.6% in 2015, 37.7% in 2016 and 51.8% in 2017. The predominant reason of non-persistence patients was the cost of treatment. Incidence rates of all-cause death, ischemic stroke and embolism were 1.99/100 person-years, 2.56/100 person-years and 0.77/100 person-years, respectively. Incidence rates of minor bleeding events, intracranial hemorrhage and gastrointestinal hemorrhage were 10.05/100 person-years, 0.51/100 person-years and 0.85/100 person-years, respectively. In conclusion, it is of importance for Chinese clinicians to know about these information because dabigatran is a relatively new drug in China. Compared with other reported data, patients of this study have (1) lower dabigatran persistence and lower incident rates of all-cause death, systemic embolism, minor bleeding events and gastrointestinal hemorrhage and (2) higher incident rates of ischemic stroke and intracranial hemorrhage.",
"affiliations": "Department of Laboratory Medicine, Jiangsu, The First Affiliated Hospital of Nanjing Medical University, No 300 Guangzhou Road, Nanjing, 210029, People's Republic of China.;Department of Laboratory Medicine, Jiangsu, The First Affiliated Hospital of Nanjing Medical University, No 300 Guangzhou Road, Nanjing, 210029, People's Republic of China.;Department of Laboratory Medicine, Jiangsu, The First Affiliated Hospital of Nanjing Medical University, No 300 Guangzhou Road, Nanjing, 210029, People's Republic of China.;Department of Laboratory Medicine, Jiangsu, The First Affiliated Hospital of Nanjing Medical University, No 300 Guangzhou Road, Nanjing, 210029, People's Republic of China.;Department of Laboratory Medicine, Jiangsu, The First Affiliated Hospital of Nanjing Medical University, No 300 Guangzhou Road, Nanjing, 210029, People's Republic of China. 13851471182@163.com.",
"authors": "Rong|Guodong|G|;Huang|Yiling|Y|;Wang|Lin|L|;Liang|Hanyu|H|;Wang|Hong|H|http://orcid.org/0000-0002-7601-0614",
"chemical_list": "D000991:Antithrombins; D000069604:Dabigatran",
"country": "Japan",
"delete": false,
"doi": "10.1007/s00380-020-01565-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0910-8327",
"issue": "35(7)",
"journal": "Heart and vessels",
"keywords": "Atrial fibrillation; Bleeding events; Clinical outcomes; Dabigatran; Treatment persistence",
"medline_ta": "Heart Vessels",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000991:Antithrombins; D001281:Atrial Fibrillation; D002545:Brain Ischemia; D002681:China; D000069604:Dabigatran; D004617:Embolism; D005260:Female; D006470:Hemorrhage; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D020521:Stroke; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "8511258",
"other_id": null,
"pages": "977-984",
"pmc": null,
"pmid": "32006091",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Persistence, effectiveness and safety of dabigatran in \"real-world\" Chinese patients with nonvalvular atrial fibrillation.",
"title_normalized": "persistence effectiveness and safety of dabigatran in real world chinese patients with nonvalvular atrial fibrillation"
} | [
{
"companynumb": "CN-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-006485",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "Human T-cell lymphotropic virus type-1 (HTLV-1) is endemic in Japan, the Caribbean and in South American countries such as Ecuador. This virus is the cause of HTLV-1-associated myelopathy or tropical spastic paraparesis (HAM/TSP), a myelopathy characterised by chronic progressive paraparesis, spasticity and urinary symptoms. We report the case of a 40-year-old man who received a kidney transplant from a living donor and developed HAM/TSP, 24 months after transplant. The diagnosis was confirmed by detection of HTLV-1 in blood and cerebrospinal fluid by the ELISA and Western Blot tests. For myelopathy, the patient was treated with pulse methylprednisolone, but had poor response to treatment. We recommend that all patients receiving transplants and their donors who come from endemic countries be given a mandatory screening for HTLV-1 through an ELISA test, in an effort to inform candidates for renal transplantation of the potential risk of infection and the development of this disease.",
"affiliations": "Department of Nephrology, Hospital de Niños Baca Ortiz, Quito, Pichincha, Ecuador.;Department of Neurology, Hospital Carlos Andrade Marin, Quito, Pichincha, Ecuador.;Department of Neurology, Hospital Carlos Andrade Marin, Quito, Pichincha, Ecuador.",
"authors": "Montesdeoca Andrade|Maria Jose|MJ|;Correa Diaz|Edgar Patricio|EP|;Buestán|Maria Eugenia|ME|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D001921:Brain; D004484:Ecuador; D019353:Endemic Diseases; D015368:Human T-lymphotropic virus 1; D006801:Humans; D016030:Kidney Transplantation; D008279:Magnetic Resonance Imaging; D008297:Male; D015493:Paraparesis, Tropical Spastic; D066027:Transplant Recipients",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27268291",
"pubdate": "2016-06-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10980313;11762319;12876238;15346339;15834870;1634902;1639536;16482858;16984654;17081162;17101824;17239794;17376384;18160007;18657726;18981631;19155035;19628219;19839982;20411806;20565372;2139754;21743209;22300227;22405461;22460962;23060278;23198155;23465028;23689148;23945290;25320371;25742898;25760424;25772487;27500208;8780082",
"title": "HTLV-1-associated myelopathy in a solid organ transplant recipient.",
"title_normalized": "htlv 1 associated myelopathy in a solid organ transplant recipient"
} | [
{
"companynumb": "EC-TEVA-757921ROM",
"fulfillexpeditecriteria": "1",
"occurcountry": "EC",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "OBJECTIVE\nThe cutaneous adverse effects of the BRAF inhibitors vemurafenib and dabrafenib mesylate in the treatment of metastatic melanoma have been well reported. The addition of a MEK inhibitor to a BRAF inhibitor improves the blockade of the mitogen-activated protein kinase pathway. The combination of dabrafenib with the MEK inhibitor trametinib dimethyl sulfoxide (CombiDT therapy) increases response rate and survival compared with a BRAF inhibitor alone. Clinical trials have suggested that CombiDT therapy induces fewer cutaneous toxic effects than a single-agent BRAF inhibitor. To our knowledge, a direct comparison has not been performed before.\n\n\nOBJECTIVE\nTo compare the cutaneous toxic effects of BRAF inhibitor monotherapy and CombiDT therapy in a large cohort of patients.\n\n\nMETHODS\nWe performed a retrospective cohort study from September 1, 2009, through November 30, 2013. The study population included 185 Australian patients with unresectable stages IIIC and IV melanoma referred from Crown Princess Mary Cancer Care Centre who underwent review at the Department of Dermatology, Westmead Hospital. Of these, 119 patients received dabrafenib; 36, vemurafenib; and 30, CombiDT therapy. Data analysis were performed in December 2013.\n\n\nMETHODS\nMultiple cutaneous adverse effects between BRAF inhibitor monotherapy and CombiDT therapy were identified and compared in a cohort of patients who underwent the same dermatologic assessment.\n\n\nRESULTS\nThe most common cutaneous adverse effects seen in patients receiving the single-agent BRAF inhibitor dabrafenib or vemurafenib included Grover disease (51 patients [42.9%] and 14 [38.9%], respectively [P = .67]), plantar hyperkeratosis (47 [39.5%] and 14 [38.9%], respectively [P = .95]), verrucal keratosis (79 [66.4%] and 26 [72.2%], respectively [P = .51]), and cutaneous squamous cell carcinoma (31 [26.1%] and 13 [36.1%], respectively [P = .54]). Photosensitivity was more common with vemurafenib (14 patients [38.9%]) compared with dabrafenib (1 [0.8%]; P < .001). Compared with dabrafenib, CombiDT therapy showed a higher frequency of folliculitis (12 patients [40.0%] vs. 8 [6.7%]; P < .001) and a significant decrease of cutaneous squamous cell carcinoma (0 vs. 31 [26.1%]; P < .001), verrucal keratosis (0 vs. 79 [66.4%]; P < .001), and Grover disease (0 vs. 51 [42.9%]; P < .001).\n\n\nCONCLUSIONS\nThis study confirms that the prevalence of cutaneous toxic effects differs among vemurafenib, dabrafenib, and CombiDT therapies. Cutaneous squamous cell carcinoma is the most concerning cutaneous toxic effect related to BRAF inhibitor monotherapy that did not appear with CombiDT therapy. Although CombiDT therapy has an improved profile of cutaneous toxic effects, continuous dermatologic assessments should be provided for all patients when receiving these treatments.",
"affiliations": "Department of Dermatology, Westmead Hospital, Sydney, Australia2University of Sydney Medical Faculty, Sydney Medical School, University of Sydney, Sydney, Australia.;Department of Dermatology, Westmead Hospital, Sydney, Australia2University of Sydney Medical Faculty, Sydney Medical School, University of Sydney, Sydney, Australia.;University of Sydney Medical Faculty, Sydney Medical School, University of Sydney, Sydney, Australia3Westmead Institute for Cancer Research, Westmead Hospital, Westmead, Australia4Department of Medical Oncology, Westmead and Blacktown Hospitals, Sydney, A.;University of Sydney Medical Faculty, Sydney Medical School, University of Sydney, Sydney, Australia3Westmead Institute for Cancer Research, Westmead Hospital, Westmead, Australia4Department of Medical Oncology, Westmead and Blacktown Hospitals, Sydney, A.;University of Sydney Medical Faculty, Sydney Medical School, University of Sydney, Sydney, Australia3Westmead Institute for Cancer Research, Westmead Hospital, Westmead, Australia4Department of Medical Oncology, Westmead and Blacktown Hospitals, Sydney, A.;Department of Tissue Pathology and Diagnostic Oncology, Westmead Hospital, Westmead, Australia.;Department of Dermatology, Westmead Hospital, Sydney, Australia2University of Sydney Medical Faculty, Sydney Medical School, University of Sydney, Sydney, Australia.",
"authors": "Carlos|Giuliana|G|;Anforth|Rachael|R|;Clements|Arthur|A|;Menzies|Alexander M|AM|;Carlino|Matteo S|MS|;Chou|Shaun|S|;Fernandez-Peñas|Pablo|P|",
"chemical_list": "D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib",
"country": "United States",
"delete": false,
"doi": "10.1001/jamadermatol.2015.1745",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-6068",
"issue": "151(10)",
"journal": "JAMA dermatology",
"keywords": null,
"medline_ta": "JAMA Dermatol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007093:Imidazoles; D007211:Indoles; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010091:Oximes; D015995:Prevalence; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D011728:Pyridones; D011744:Pyrimidinones; D012189:Retrospective Studies; D012871:Skin Diseases; D012878:Skin Neoplasms; D013449:Sulfonamides; D000077484:Vemurafenib",
"nlm_unique_id": "101589530",
"other_id": null,
"pages": "1103-9",
"pmc": null,
"pmid": "26200476",
"pubdate": "2015-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Cutaneous Toxic Effects of BRAF Inhibitors Alone and in Combination With MEK Inhibitors for Metastatic Melanoma.",
"title_normalized": "cutaneous toxic effects of braf inhibitors alone and in combination with mek inhibitors for metastatic melanoma"
} | [
{
"companynumb": "AU-ROCHE-1656689",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VEMURAFENIB"
},
"drugadditional": null,
"dru... |
{
"abstract": "OBJECTIVE\nTo assess the impact of exposure to single-dose nevirapine (sdNVP) on virological response in young Ugandan/Zimbabwean children (<3 years) initiating antiretroviral therapy (ART), and to investigate other predictors of response.\n\n\nMETHODS\nObservational analysis within the ARROW randomized trial.\n\n\nMETHODS\nsdNVP exposure was ascertained by the caregiver's self-report when the child initiated non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART. Viral load was assayed retrospectively over a median 4.1 years of follow-up. Multivariable logistic regression models were used to identify independent predictors of viral load below 80 copies/ml, 48 and 144 weeks after ART initiation (backwards elimination, exit P = 0.1).\n\n\nRESULTS\nMedian (IQR) age at ART initiation was 17 (10-23) months in 78 sdNVP-exposed children vs. 21 (14-27) months in 289 non-exposed children (36 vs. 20% <12 months). At week 48, 49 of 73 (67%) sdNVP-exposed and 154 of 272 (57%) non-exposed children had viral load below 80 copies/ml [adjusted odds ratio (aOR) 2.34 (1.26-4.34), P = 0.007]; 79 and 77% had viral load below 400 copies/ml. Suppression was significantly lower in males (P = 0.009), those with higher pre-ART viral load (P = 0.001), taking syrups (P = 0.05) and with lower self-reported adherence (P = 0.04). At week 144, 55 of 73 (75%) exposed and 188 of 272 (69%) non-exposed children had less than 80 copies/ml [aOR 1.75 (0.93-3.29), P = 0.08]. There was no difference between children with and without previous sdNVP exposure in intermediate/high-level resistance to NRTIs (P > 0.3) or NNRTIs (P > 0.1) (n = 88) at week 144.\n\n\nCONCLUSIONS\nGiven the limited global availability of lopinavir/ritonavir, its significant formulation challenges in young children, and the significant paediatric treatment gap, tablet fixed-dose-combination NVP-based ART remains a good alternative to syrup lopinavir-based ART for children, particularly those over 1 year and even if exposed to sdNVP.",
"affiliations": "Baylor-Uganda, Paediatric Infectious Diseases Clinic, Mulago Hospital, Kampala, Uganda; Makerere University College of Health Sciences, Kampala, Uganda.;MRC Clinical Trials Unit at University College London, London, UK.;Joint Clinical Research Centre, Kampala, Uganda; Makerere University College of Health Sciences, Kampala, Uganda.;University of Zimbabwe College of Health Sciences, Harare, Zimbabwe.;Medical Research Council/Uganda Virus Research Institute Uganda Research Unit on AIDS, Entebbe, Uganda.;Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe.;Joint Clinical Research Centre, Kampala, Uganda.;Queen Mary University of London, London, UK.;MRC Clinical Trials Unit at University College London, London, UK.;MRC Clinical Trials Unit at University College London, London, UK.;MRC Clinical Trials Unit at University College London, London, UK.",
"authors": "Musoke|Philippa|P|;Szubert|Alexander J|AJ|;Musiime|Victor|V|;Nathoo|Kusum|K|;Nahirya-Ntege|Patricia|P|;Mutasa|Kuda|K|;Williams|David Eram|DE|;Prendergast|Andrew J|AJ|;Spyer|Moira|M|;Walker|A Sarah|AS|;Gibb|Diana M|DM|;|||",
"chemical_list": "D044966:Anti-Retroviral Agents; D019829:Nevirapine",
"country": "England",
"delete": false,
"doi": "10.1097/QAD.0000000000000749",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-9370",
"issue": "29(13)",
"journal": "AIDS (London, England)",
"keywords": null,
"medline_ta": "AIDS",
"mesh_terms": "D044966:Anti-Retroviral Agents; D002675:Child, Preschool; D005260:Female; D015658:HIV Infections; D006801:Humans; D007223:Infant; D008297:Male; D019829:Nevirapine; D012189:Retrospective Studies; D016896:Treatment Outcome; D014454:Uganda; D019562:Viral Load; D015030:Zimbabwe",
"nlm_unique_id": "8710219",
"other_id": "EMS67330",
"pages": "1623-1632",
"pmc": null,
"pmid": "26193705",
"pubdate": "2015-08-24",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": "23596273;22739394;23595153;25222305;24828266;23473847;15353977;8073200;17215531;17533166;18931630;19778270;19950430;20868279;20942666;20942667;21247884;22190066;22567139;22716976",
"title": "Single-dose nevirapine exposure does not affect response to antiretroviral therapy in HIV-infected African children aged below 3 years.",
"title_normalized": "single dose nevirapine exposure does not affect response to antiretroviral therapy in hiv infected african children aged below 3 years"
} | [
{
"companynumb": "GB-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-60632BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
... |
{
"abstract": "A 58-year-old woman with non-proliferative diabetic retinopathy presented with decreased visual acuity from chronic macular edema. She had undergone multiple treatments previously, including focal laser treatment and intravitreal triamcinolone acetonide. Within 2 days of treatment with intravitreal bevacizumab, the patient noted a significant decrease in visual acuity. Fluorescein angiogram demonstrated an enlargement of the foveal avascular zone and persistent late leakage following intravitreal bevacizumab; optical coherence tomography performed before and after treatment revealed persistent cystoid macular edema. The use of intravitreal bevacizumab in chronic, refractory diabetic macular edema may cause acute visual acuity loss by disrupting an already fragile vascular perfusion status, leading to macular ischemia.",
"affiliations": "Retina Service, Wills Eye Institute, Philadelphia, Pennsylvania, USA.",
"authors": "Chen|Eric|E|;Hsu|Jason|J|;Park|Carl H|CH|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab",
"country": "United States",
"delete": false,
"doi": "10.3928/15428877-20090101-04",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1542-8877",
"issue": "40(1)",
"journal": "Ophthalmic surgery, lasers & imaging : the official journal of the International Society for Imaging in the Eye",
"keywords": null,
"medline_ta": "Ophthalmic Surg Lasers Imaging",
"mesh_terms": "D000208:Acute Disease; D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D003930:Diabetic Retinopathy; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D007267:Injections; D008269:Macular Edema; D008875:Middle Aged; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A; D014786:Vision Disorders; D014792:Visual Acuity; D014822:Vitreous Body",
"nlm_unique_id": "101155780",
"other_id": null,
"pages": "68-70",
"pmc": null,
"pmid": "19205502",
"pubdate": "2009",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute visual acuity loss following intravitreal bevacizumab for diabetic macular edema.",
"title_normalized": "acute visual acuity loss following intravitreal bevacizumab for diabetic macular edema"
} | [
{
"companynumb": "US-ROCHE-616266",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "2",
"druga... |
{
"abstract": "Osteonecrosis (ON) is a disabling complication of acute lymphoblastic leukemia (ALL) treatment in children and young adults. Isolated talus involvement is thought to be uncommon. A unique case of a 11-year-old female patient with ON in her left talus which developed six months after the completion of chemotherapy that she received for ALL is reported. A conservative treatment protocol was followed including activity modification, analgesia and prevention of weight-bearing. However, the disease significantly progressed during follow-up period. The present study makes an important contribution to the literature with unusual involvement pattern and location of ON after ALL treatment and with a long follow-up duration. LEVEL OF EVIDENCE: IV.",
"affiliations": "Istanbul University, Istanbul Medical Faculty, Orthopedics and Traumatology Department, Turkey. Electronic address: dr.serkanbayram89@gmail.com.;Istanbul University, Istanbul Medical Faculty, Orthopedics and Traumatology Department, Turkey.;Istanbul University, Istanbul Medical Faculty, Orthopedics and Traumatology Department, Turkey.",
"authors": "Bayram|Serkan|S|;Şahin|Koray|K|;Polat|Gökhan|G|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.foot.2019.10.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0958-2592",
"issue": "42()",
"journal": "Foot (Edinburgh, Scotland)",
"keywords": "Acute lymphoblastic leukemia; Ankle; Avascular necrosis; Talus",
"medline_ta": "Foot (Edinb)",
"mesh_terms": "D002648:Child; D000072700:Conservative Treatment; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D010020:Osteonecrosis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011859:Radiography; D012598:Sclerosis; D013628:Talus",
"nlm_unique_id": "9109564",
"other_id": null,
"pages": "101649",
"pmc": null,
"pmid": "32035403",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Osteonecrosis of the talus of a child with acute lymphoblastic leukemia: A case report.",
"title_normalized": "osteonecrosis of the talus of a child with acute lymphoblastic leukemia a case report"
} | [
{
"companynumb": "TR-ACCORD-174617",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DAUNORUBICIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND Leiomyosarcoma frequently occurs in patients who are on immunosuppressive therapy. It is the second most common sarcoma in this population and is often associated with Epstein-Barr virus (EBV) infection. We present a case of advanced leiomyosarcoma of the retroperitoneal space in a kidney transplant recipient and discuss additional risk factors for oncogenesis. CASE REPORT A 44-year-old woman with a history of peritoneal dialysis and kidney transplantation was diagnosed with multiple liver lesions. PET-CT scanning showed a metabolically active tumor in the left lumbar region with numerous liver focal lesions. The histological examination of the liver lesion biopsy identified advanced retroperitoneal leiomyosarcoma with a high proliferative index and liver involvement. Unexpectedly, the relation with EBV infection was not proven. The patient was treated with first-line doxorubicin, with the simultaneous reduction of immunosuppression. Owing to disease progression after 6 cycles, the patient received second-line chemotherapy based on gemcitabine and docetaxel, which was terminated owing to unacceptable toxicity, despite an observed response. Third-line trabectedin-based therapy with good tolerance and stabilization of disease after 20 months was being maintained at the time of this report. CONCLUSIONS The increased cancer mortality in solid-organ transplant recipients requires an individualized approach and increased post-transplantation screening according to additional specific cancer risk factors. A further consideration is the hypothetical relevance of long-term peritoneal membrane irritation in peritoneal dialysis patients.",
"affiliations": "Department of Internal Medicine and Oncological Chemotherapy, Medical University of Silesia, Katowice, Poland.;Department of Internal Medicine and Oncological Chemotherapy, Medical University of Silesia, Katowice, Poland.;Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, Katowice, Poland.;Department of Pathomorphology and Molecular Diagnostics, Medical University of Silesia, Katowice, Poland.;Department of Pathomorphology and Molecular Diagnostics, Medical University of Silesia, Katowice, Poland.;Department of Internal Medicine and Oncological Chemotherapy, Medical University of Silesia, Katowice, Poland.",
"authors": "Kaźmierczak|Olga|O|;Kozaczka|Anna|A|;Kolonko|Aureliusz|A|;Kajor|Maciej|M|;Pająk|Jacek|J|;Chudek|Jerzy|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.933267",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n34695070\n10.12659/AJCR.933267\n933267\nArticles\nAdvanced Leiomyosarcoma of the Retroperitoneal Space in a Kidney Transplant Recipient with a History of Peritoneal Dialysis: A Case Report\nKaźmierczak Olga A B C E F 1\nKozaczka Anna A B 1\nKolonko Aureliusz B D F 2\nKajor Maciej B C D 3\nPająk Jacek B C D 3\nChudek Jerzy A D E F 1\n1 Department of Internal Medicine and Oncological Chemotherapy, Medical University of Silesia, Katowice, Poland\n2 Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, Katowice, Poland\n3 Department of Pathomorphology and Molecular Diagnostics, Medical University of Silesia, Katowice, Poland\nCorresponding Author: Olga Kaźmierczak, e-mail: olgakudela@gmail.com\nAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nFinancial support: None declared\n\nConflict of interest: None declared\n\n2021\n25 10 2021\n22 e933267-1e933267-5\n24 5 2021\n11 9 2021\n25 9 2021\n© Am J Case Rep, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Female, 44-year-old\n\nFinal Diagnosis: Leiomyosarcoma • liver metastases\n\nSymptoms: Abdominal pain\n\nMedication:—\n\nClinical Procedure: Biopsy\n\nSpecialty: Nephrology • Oncology • Transplantology\n\nObjective:\n\nRare disease\n\nBackground:\n\nLeiomyosarcoma frequently occurs in patients who are on immunosuppressive therapy. It is the second most common sarcoma in this population and is often associated with Epstein-Barr virus (EBV) infection. We present a case of advanced leiomyosarcoma of the retroperitoneal space in a kidney transplant recipient and discuss additional risk factors for oncogenesis.\n\nCase Report:\n\nA 44-year-old woman with a history of peritoneal dialysis and kidney transplantation was diagnosed with multiple liver lesions. PET-CT scanning showed a metabolically active tumor in the left lumbar region with numerous liver focal lesions. The histological examination of the liver lesion biopsy identified advanced retroperito-neal leiomyosarcoma with a high proliferative index and liver involvement. Unexpectedly, the relation with EBV infection was not proven. The patient was treated with first-line doxorubicin, with the simultaneous reduction of immunosuppression. Owing to disease progression after 6 cycles, the patient received second-line chemo-therapy based on gemcitabine and docetaxel, which was terminated owing to unacceptable toxicity, despite an observed response. Third-line trabectedin-based therapy with good tolerance and stabilization of disease after 20 months was being maintained at the time of this report.\n\nConclusions:\n\nThe increased cancer mortality in solid-organ transplant recipients requires an individualized approach and increased post-transplantation screening according to additional specific cancer risk factors. A further consideration is the hypothetical relevance of long-term peritoneal membrane irritation in peritoneal dialysis patients.\n\nKeywords:\n\nCase Reports\nImmunosuppression\nKidney Transplantation\nLeiomyosarcoma\nPeritoneal Dialysis\n==== Body\npmcBackground\n\nLeiomyosarcoma is the second most common sarcoma after Kaposi sarcoma in patients undergoing maintenance of immunosuppressive treatment [1] and is one of the most common soft-tissue sarcomas in the general population [2]. It derives from smooth muscle cells of large veins or mesenchymal stem cells and is usually located in the retroperitoneal space. Of note, Epstein-Barr virus (EBV) infection in immunocompromised patients (including HIV-infected and organ transplant recipients) has been widely discussed as a potential risk factor for leiomyosarcoma [2,3] and its multifocal development [4]. Immunohistochemical assays fail to confirm the presence of viral genetic material in only 12% of cases [1].\n\nIt has been shown that the overall length and the net effect of immunosuppressive therapy increase the risk of carcinogenesis [5]. It is believed that increased gene expression for transforming growth factor beta-1 and vascular endothelial growth factor during therapy with certain immunosuppressive drugs, such as cyclosporine A and tacrolimus, can promote tumor invasiveness and metastatic dissemination [6].\n\nCase Report\n\nA 44-year-old woman was admitted to the nephrology department with multiple liver lesions of unknown origin, which were identified during an abdominal ultrasound in January 2019. She had a Zubrod performance status of 0 and had a history of kidney transplantation (KTx) from a deceased donor, with basiliximab induction in May 2016 on a 3-drug maintenance immunosuppressive regimen (tacrolimus, mycophenolate sodium, and prednisone). She had experienced mild right upper abdominal pain for a few months prior to her presentation, which did not require painkillers.\n\nThe patient had a medical history of right-sided nephrectomy and systemic therapy for nephroblastoma at the age of 6 years. She had chronic interstitial pyelonephritis of the remaining kidney, not associated with ureterovesical reflux and without confirmed immune deficiencies, which eventually led to end-stage kidney failure, with the initiation of automated peritoneal dialysis for 27 months before KTx. Comorbidity included type 2 diabetes and subtotal thyroidectomy, with parathyroidectomy performed in October 2015 owing to secondary hyperparathyroidism and a colloid goiter.\n\nThe patient’s laboratory tests performed on admission were within the reference range with optimal kidney graft function (serum creatinine concentration of 1.1 mg/dL; normal urinalysis).\n\nShe underwent an abdominal and pelvic computed tomography (CT) scan, which showed more than 25 poorly vascularized metastatic lesions in the liver. The lesions were an average diameter of 10 mm to 25 mm, and there was a 38-mm tumor in the small pelvis next to the left iliac vessel (adhered to the larger lumbar muscle on the left side, left iliac artery, and the small intestinal loop), with heterogeneous gaining after administration of contrast media. A similar lesion of 25×30 mm was found in the fundus of the uterus. We performed a PET-CT scan with 18F-FDG in search of the primary lesion. The scan revealed a metabolically active tumor in the left lumbar region, sized 49×41×44 mm (Figure 1A), and numerous liver focal lesions up to 22 mm (Figure 1B).\n\nThe patient underwent an ultrasound-guided core biopsy of the liver lesions.\n\nHistological examination revealed metastasis of sarcoma, which was composed of large atypical, elongated cells with abundant, fibrillary cytoplasm forming irregular cellular fascicles (Figure 1C). Immunohistochemical staining revealed extensive expression of smooth muscle actin (Figure 1D, 1F), desmin (Figure 1E, 1G), and high Ki67 proliferative index (Figure 1H) but did not detect any expression of ALK-1 protein, HMB45, neuron-specific enolase, DOG-1, S-100 protein, or cytokeratines 34 and 117. The specimens also stained negative for EBV.\n\nTherefore, a diagnosis of advanced retroperitoneal leiomyosarcoma with liver involvement was established (cT1N0M1 CS IV).\n\nThe patient started chemotherapy with doxorubicin 50 mg/m2 every 21 days. The dosage of mycophenolate sodium was reduced from 1260 to 540 mg daily, and trough levels of tacrolimus were maintained at approximately 6 ng/mL. The patient’s tolerance of the first-line chemotherapy was good and she received subsequent cycles without delay. She did not experience any adverse events, including infectious complications and neutropenic fever.\n\nUnfortunately, CT imaging after administration of 6 cycles showed progression in the primary retroperitoneal lesion and in the liver, with metastasis merging into a conglomerate of 64×51×50 mm. Owing to disease progression, the patient received a second-line chemotherapy based on gemcitabine (900 mg/m2 on days 1 and 8) and docetaxel (100 mg/m2 on day 8) every 3 weeks. Despite the use of adequate premedication, she presented significant toxicity that was aggravated with every administration of docetaxel, including subcutaneous edema of the upper and lower extremities, generalized sensory neuropathy (CTCAE G3), and erythematous-desquamative lesions on the face and neck. Despite a mild size reduction of the primary lesion (by 19%) and metastatic lesions in the liver (stable disease, according to RECIST 1.1), we terminated the second-line chemotherapy owing to unacceptable toxicity. The patient was referred to another oncology center with access to trabectedin-based therapy. Since January 2020, the patient has been continuing courses of trabectedin (1.5 mg/m2 every 21 days) with good tolerance and maintenance of stable disease status, reaching over 31 months of overall survival since the initial diagnosis. The kidney graft function is still excellent, despite a mycophenolate dosage reduction to 360 mg daily.\n\nDiscussion\n\nSoft-tissue sarcomas in patients after solid-organ transplantation usually have higher histological grading, and about 40% of patients are diagnosed in the metastatic phase of the disease [7]. Oncological treatment in patients with KTx should include all conventional pharmacological approaches, along with the concomitant consideration of the reduction of immunosuppression dosage. The median overall survival for advanced disease does not exceed 15 months [7].\n\nIncreased cancer risk is one of the major concerns in solid-organ transplant recipients. The 10-year risk of de novo cancer is twice as great in transplant recipients than in the general population [8]. De novo malignancies have tremendous impact on survival after solid-organ transplantation, as they have been reported as a leading cause of late mortality after transplantation [9]. One of the main causes of increased cancer incidence among patients with transplants is the common use of more intensive immunosuppressive therapies [10]. In KTx recipients, the use of tacrolimus and induction antibodies was proven to increase the risk of de novo post-transplantation malignancy [11]. It is worth noting that increased oncogenesis is observed already at the stage of chronic kidney disease and dialysis therapy [11,12]. Furthermore, the increasing age of the transplant population, longer organ survival, and exposure to oncogenic viruses also contribute to increased malignancy rates after transplantation [13,14].\n\nAlthough soft-tissue sarcomas remain a rare type of cancer in KTx recipients, soft-tissue sarcomas are significantly more common in KTx recipients than in the general population: the standardized incidence ratio is 14.4 (95% CI: 9.2–19.5) in male patients and 4.5 (95% CI: 0.6–8.5) in female patients [15]. The diagnosis of leiomyosarcoma is often accidental and can occur at any point after transplantation. Interestingly, a different pattern of the primary location has been observed in patients with KTx, with 33% occurring in the head and neck, compared with only 5% in the head and neck in the general population [7,16].\n\nIn the present case, the specimen derived from the tumor did not demonstrate EBV activity. However, pre-transplantation EBV-positive recipient status in itself has been demonstrated to increase the risk of post-transplantation malignancy [13]. Nevertheless, several circumstances can be identified as potential factors that were conducive to the development of sarcoma in our patient. Above all, was the immunosuppressive therapy she received. Second, we cannot exclude a hypothetical relevance of the long-term exposure to dialysis fluid as an additional risk factor for carcinogenesis. It has been demonstrated that the high-glucose load in peritoneal dialysis fluid increases the formation of advanced glycation end-products (AGEs). AGEs then exert cancer-promoting effects, mediated by an interaction with the receptor for AGEs and increased oxidative stress, in addition to chronic inflammatory responses [17], which have been shown to be strong contributors of carcinogenesis [18,19]. Moreover, metabolic complications such as insulin resistance and low plasma adiponectin levels have been associated with the increased risk of malignancy, even in nondiabetic peritoneal dialysis patients [20]. Hence, we cannot exclude that, in our patient, peritoneal dialysis treatment and diabetes alongside immunosuppression might have been involved in the pathogenesis of the retroperitoneal sarcoma.\n\nConclusions\n\nCertainly, substantially prolonged survival after KTx increases the cancer incidence and mortality in this cohort. According to a recent report, mortality attributable to cancer steadily increases after transplantation, reaching 15.7% of deaths in recipients that are more than 10 years past transplantation [21]. Despite regular ambulatory monitoring, cancers in KTx recipients are diagnosed in a more advanced stage as compared with those in the general population [22]. Importantly, imaging during this period is focused mainly on assessment of the graft and cirrhotic kidneys, and the guidelines for cancer screening vary greatly, depending on the screened organ, except for skin cancer [23]. Because patients after KTx present a markedly increased risk of malignancy complications, we strongly suggest individualizing post-transplantation screening, considering individual cancer risk, comorbidities, overall prognosis, and screening preferences.\n\nFigure 1. PET-CT with 18F-FDG showing a metabolically active tumor in the left lumbar region of 49×41×44 mm size (A) and numerous liver focal lesions up to 22 mm large (B). The histopathology of the tumor. Hematoxylin-eosin staining ×50 (C) showing metastasis of sarcoma to liver tissue (hepatocytes can be seen in the upper left corner) composed of large atypical, spindle cells with abundant, fibrillary cytoplasm and blunt-ended nuclei forming irregular chaotically arranged cellular fascicles. Immunohistochemical staining ×50 for SMA (D) and desmin (E). In the upper left corner, normal liver tissue can be seen between tumor cells. Tumor cells positively stained for SMA (D) and desmin (E). High-magnification images (×100) of immunohistochemical staining showing sarcoma cells spreading into the normal liver tissue and staining positively for SMA (F) and desmin (G). Ki-67 staining ×100 reflects a high proliferative index in sarcoma cells (H).\n\nDepartment and Institution Where Work Was Performed\n\nDepartment of Internal Medicine and Oncological Chemotherapy, Medical University of Silesia, Katowice, Poland.\n\nDeclaration of Figures’ Authenticity\n\nAll figures submitted have been created by the authors who confirm that the images are original with no duplication and have not been previously published in whole or in part.\n==== Refs\nReferences:\n\n1. Bhatia K Shiels MS Berg A Engels EA Sarcomas other than Kaposi sarcoma occurring in immunodeficiency: interpretations from a systematic literature review Curr Opin Oncol 2012 24 5 537 46 22729152\n2. Duffaud F Ray-Coquard I Salas S Pautier P Recent advances in understanding and managing leiomyosarcomas F1000Prime Rep 2015 7 55 26097728\n3. Shannon-Lowe C Rickinson A The global landscape of EBV-associated tumors Front Oncol 2019 9 713 31448229\n4. Deyrup AT Lee VK Hill CE Epstein-Barr virus-associated smooth muscle tumors are distinctive mesenchymal tumors reflecting multiple infection events: A clinicopathologic and molecular analysis of 29 tumors from 19 patients Am J Surg Pathol 2006 30 1 75 82 16330945\n5. Birkeland SA Hamilton-Dutoit S Is posttransplant lymphoproliferative disorder (PTLD) caused by any specific immunosuppressive drug or by the transplantation per se? Transplantation 2003 76 6 984 88 14508366\n6. Krisl JC Doan VP Chemotherapy and transplantation: The role of immunosuppression in malignancy and a review of antineoplastic agents in solid organ transplant recipients Am J Transplant 2017 17 8 1974 91 28394486\n7. Husted TL Buell JF Hanaway MJ De novo sarcomas in solid organ transplant recipients Transplant Proc 2002 34 5 1786 87 12176576\n8. Collett D Mumford L Banner NR Comparison of the incidence of malignancy in recipients of different types of organ: A UK Registry audit Am J Transplant 2010 10 8 1889 96 20659094\n9. Taborelli M Piselli P Ettorre GM Survival after the diagnosis of de novo malignancy in liver transplant recipients Int J Cancer 2019 144 2 232 39 30091809\n10. Martinez OM de Gruijl FR Molecular and immunologic mechanisms of cancer pathogenesis in solid organ transplant recipients Am J Transplant 2008 8 11 2205 11 18801025\n11. Maisonneuve P Agodoa L Gellert R Cancer in patients on dialysis for end-stage renal disease: An international collaborative study Lancet 1999 354 9173 93 99 10408483\n12. Lee YC Hung SY Wang HK Is there different risk of cancer among end-stage renal disease patients undergoing hemodialysis and peritoneal dialysis? Cancer Med 2018 7 2 485 98 29356425\n13. Sampaio MS Cho YW Qazi Y Posttransplant malignancies in solid organ adult recipients: An analysis of the U.S. National Transplant Database Transplantation 2012 94 10 990 98 23085553\n14. Huo Z Li C Xu X cancer risks in solid organ transplant recipients: Results from a comprehensive analysis of 72 cohort studies Oncoimmunology 2020 9 1 1848068 33299661\n15. Park B Yoon J Choi D De novo cancer incidence after kidney and liver transplantation: Results from a nationwide population based data Sci Rep 2019 9 1 17202 31748582\n16. D’Arcy ME Castenson D Lynch CF Risk of rare cancers among solid organ transplant recipients J Natl Cancer Inst 2021 113 2 199 207 32462187\n17. Schröter D Höhn A Role of advanced glycation end products in carcinogenesis and their therapeutic implications Curr Pharm Des 2018 24 44 5245 51 30706806\n18. Balkwill F Mantovani A Inflammation and cancer: Back to Virchow? Lancet 2001 357 9255 539 45 11229684\n19. Karin M Nuclear factor-kappaB in cancer development and progression Nature 2006 441 7092 431 36 16724054\n20. Park JT Yoo TH Chang TI Insulin resistance and lower plasma adiponectin increase malignancy risk in nondiabetic continuous ambulatory peritoneal dialysis patients Metabolism 2011 60 1 121 26 20303125\n21. Noone AM Pfeiffer RM Dorgan JF Cancer-attributable mortality among solid organ transplant recipients in the United States: 1987 through 2014 Cancer 2019 125 15 2647 55 31034602\n22. Au E Wong G Chapman JR Cancer in kidney transplant recipients Nat Rev Nephrol 2018 14 8 508 20 29802400\n23. Acuna SA Huang JW Scott AL cancer screening recommendations for solid organ transplant recipients: A systematic review of clinical practice guidelines Am J Transplant 2017 17 1 103 14 27575845\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "22()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000328:Adult; D020031:Epstein-Barr Virus Infections; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D016030:Kidney Transplantation; D007890:Leiomyosarcoma; D010530:Peritoneal Dialysis; D000072078:Positron Emission Tomography Computed Tomography; D012187:Retroperitoneal Space",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "e933267",
"pmc": null,
"pmid": "34695070",
"pubdate": "2021-10-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23085553;26097728;31448229;33299661;31034602;29802400;30706806;29356425;16724054;20303125;16330945;22729152;10408483;31748582;27575845;32462187;20659094;12176576;18801025;14508366;11229684;28394486;30091809",
"title": "Advanced Leiomyosarcoma of the Retroperitoneal Space in a Kidney Transplant Recipient with a History of Peritoneal Dialysis: A Case Report.",
"title_normalized": "advanced leiomyosarcoma of the retroperitoneal space in a kidney transplant recipient with a history of peritoneal dialysis a case report"
} | [
{
"companynumb": "PL-Accord-245072",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
"druga... |
{
"abstract": "The 2008 World Health Organization classification proposed a new entity in childhood myelodysplastic syndrome, refractory cytopenia of childhood. However, it is unclear whether this morphological classification reflects clinical outcomes. We retrospectively reviewed bone marrow morphology in 186 children (median age 8 years; range 1-16 years) who were enrolled in the prospective study and received horse antithymocyte globulin and cyclosporine between July 1999 and November 2008. The median follow-up period was 87 months (range 1-146 months). Out of 186 patients, 62 (33%) were classified with aplastic anemia, 94 (49%) with refractory cytopenia of childhood, and 34 (18%) with refractory cytopenia with multilineage dysplasia. Aplastic anemia patients received granulocyte colony-stimulating factor more frequently and for longer durations than other patients (P<0.01). After six months, response rates to immunosuppressive therapy were not significantly different among the 3 groups. Acquisition of chromosomal abnormalities was observed in 5 patients with aplastic anemia, 4 patients with refractory cytopenia of childhood, and 3 patients with refractory cytopenia with multilineage dysplasia. Although the cumulative incidence of total clonal evolution at ten years was not significantly different among the 3 groups, the cumulative incidence of monosomy 7 development was significantly higher in aplastic anemia than in the other groups (P=0.02). Multivariate analysis revealed that only granulocyte colony-stimulating factor administration duration of 40 days or more was a significant risk factor for monosomy 7 development (P=0.02). These findings suggest that even the introduction of a strict morphological distinction from hypoplastic myelodysplastic syndrome cannot eradicate clonal evolution in children with aplastic anemia.",
"affiliations": "Department of Pediatrics, Nagoya University Graduate School of Medicine, Kobe, Japan.;Department of Pediatrics, Nagoya University Graduate School of Medicine, Kobe, Japan.;Department of Pediatrics, Nagoya University Graduate School of Medicine, Kobe, Japan.;Department of Pathology, Japanese Red Cross Nagoya First Hospital, Kobe, Japan.;Department of Pediatrics, Nagoya University Graduate School of Medicine, Kobe, Japan.;Department of Pediatrics, Hyogo Children's Hospital, Kobe, Japan.;Department of Pediatrics, Ibaraki Children's Hospital, Isehara, Japan.;Department of Pediatrics, Sapporo Hokuyu Hospital, Isehara, Japan.;Department of Pediatrics, Hirosaki University Graduate School of Medicine, Isehara, Japan.;Department of Cell Transplantation and Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan.;Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Tokyo, Japan.;Department of Transfusion Medicine, Toho University School of Medicine, Tokyo, Japan.;Department of Pediatrics, Nagoya University Graduate School of Medicine, Kobe, Japan kojimas@med.nagoya-u.ac.jp.",
"authors": "Hama|Asahito|A|;Takahashi|Yoshiyuki|Y|;Muramatsu|Hideki|H|;Ito|Masafumi|M|;Narita|Atsushi|A|;Kosaka|Yoshiyuki|Y|;Tsuchida|Masahiro|M|;Kobayashi|Ryoji|R|;Ito|Etsuro|E|;Yabe|Hiromasa|H|;Ohga|Shouichi|S|;Ohara|Akira|A|;Kojima|Seiji|S|",
"chemical_list": "D000961:Antilymphocyte Serum; D016179:Granulocyte Colony-Stimulating Factor; D016572:Cyclosporine",
"country": "Italy",
"delete": false,
"doi": "10.3324/haematol.2015.128553",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0390-6078",
"issue": "100(11)",
"journal": "Haematologica",
"keywords": null,
"medline_ta": "Haematologica",
"mesh_terms": "D000741:Anemia, Aplastic; D000961:Antilymphocyte Serum; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D025063:Chromosome Disorders; D002897:Chromosomes, Human, Pair 7; D016572:Cyclosporine; D005260:Female; D005500:Follow-Up Studies; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009190:Myelodysplastic Syndromes; D011446:Prospective Studies",
"nlm_unique_id": "0417435",
"other_id": null,
"pages": "1426-33",
"pmc": null,
"pmid": "26273061",
"pubdate": "2015-11",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study",
"references": "12472591;16980411;21233311;22160017;22562435;23370706;24030381;23807769;24220272;24162791;24786393;24816243;25152119;25139356;25326804;22458667;10979946;12130487;17526862;17989314",
"title": "Comparison of long-term outcomes between children with aplastic anemia and refractory cytopenia of childhood who received immunosuppressive therapy with antithymocyte globulin and cyclosporine.",
"title_normalized": "comparison of long term outcomes between children with aplastic anemia and refractory cytopenia of childhood who received immunosuppressive therapy with antithymocyte globulin and cyclosporine"
} | [
{
"companynumb": "JP-AMGEN-JPNSP2017082649",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
... |
{
"abstract": "Bullous morphea is an uncommon form of localized scleroderma. The pathogenesis is unknown and treatment of coexistent ulcers is difficult. The pathogenesis of bullae formation in morphea is multifactorial, but reactive oxygen species production appears to play a key role. We report a patient with bullous morphea with long-standing ulcers whom we successfully treated with N-acetylcysteine and topical wound care. N-acetylcysteine, an antioxidant sulfhydryl substance, promotes the healing of ulcers in patients with bullous morphea.",
"affiliations": null,
"authors": "Rosato|E|E|;Veneziano|M L|ML|;Di Mario|A|A|;Molinaro|I|I|;Pisarri|S|S|;Salsano|F|F|",
"chemical_list": "D000975:Antioxidants; D007552:Isotonic Solutions; D000077325:Ringer's Lactate; D000111:Acetylcysteine",
"country": "England",
"delete": false,
"doi": "10.1177/039463201302600128",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0394-6320",
"issue": "26(1)",
"journal": "International journal of immunopathology and pharmacology",
"keywords": null,
"medline_ta": "Int J Immunopathol Pharmacol",
"mesh_terms": "D000111:Acetylcysteine; D000287:Administration, Topical; D000368:Aged; D000975:Antioxidants; D005260:Female; D006801:Humans; D007552:Isotonic Solutions; D000077325:Ringer's Lactate; D012594:Scleroderma, Localized; D017592:Skin Care; D014456:Ulcer; D014945:Wound Healing",
"nlm_unique_id": "8911335",
"other_id": null,
"pages": "259-62",
"pmc": null,
"pmid": "23527731",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Ulcers caused by bullous morphea: successful therapy with N-acetylcysteine and topical wound care.",
"title_normalized": "ulcers caused by bullous morphea successful therapy with n acetylcysteine and topical wound care"
} | [
{
"companynumb": "IT-TEVA-681325ACC",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIFEDIPINE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "A 77-year-old woman with rectal cancer and synchronous liver metastasis underwent a Hartmann operation with D3 lymph node dissection in June 2014. mFOLFOX6 plus bevacizumab(bev)was then administered to treat the liver metastasis.In February 2015, multiple liver metastases were detected and the regimen was changed to FOLFIRI plus bev.After 3 courses, peritonitis due to intestinal perforation around the descending colostomy occurred, and an emergency operation(partial resection of the descending colon and transverse colostomy)was performed.FOLFIRI was then administered from 2 months after the operation.After 3 courses of this regimen, a CT scan showed progression of the hepatic metastases.The regimen was therefore changed to mFOLFOX6.Five months later, another CT scan showed an intestinal perforation of the transverse colostomy at the abdominal wall, and an emergency cecostomy was performed.At this stage, chemotherapy was ceased.This case highlights the risk of intestinal perforation during chemotherapy, regardless of the use of bev.",
"affiliations": "Dept. of Surgery, Akita Kousei Medical Center.",
"authors": "Tamura|Hiroshi|H|;Otani|Ayaka|A|;Tsukui|Mizuki|M|;Toge|Koji|K|;Otani|Takahiro|T|;Hirose|Yuki|Y|;Morimoto|Yuta|Y|;Yoshino|Kei|K|;Kido|Tomoki|T|;Endo|Kazuhiko|K|;Kameyama|Hitoshi|H|;Kobayashi|Takashi|T|;Wakai|Toshifumi|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "43(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003125:Colostomy; D005260:Female; D006801:Humans; D007416:Intestinal Perforation; D008113:Liver Neoplasms; D064847:Multimodal Imaging; D012004:Rectal Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2172-2174",
"pmc": null,
"pmid": "28133259",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two Episodes of Colostomy-Associated Intestinal Perforation during Chemotherapy for Metastatic Rectal Cancer.",
"title_normalized": "two episodes of colostomy associated intestinal perforation during chemotherapy for metastatic rectal cancer"
} | [
{
"companynumb": "PHHY2017JP145702",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "1",
"drug... |
{
"abstract": "5-Fluorouracil (5-FU) is a chemotherapeutic agent frequently used for the treatment of solid tumors. In a few cases, 5-FU can be associated with coronary vasospasm, cardiac ischemia, or life-threatening arrhythmias. Recognition of 5-FU cardiotoxicity is clinically important as after the rapid sensation of therapy, cardiotoxicity can be completely reversible, and on the other hand, readministration may lead to serious damage of the heart and even death. A 70-year-old male came to the emergency department (ED) with chest pain which started while receiving an infusion of 5-FU. The patient did not have a personal history or risk factors of coronary artery disease and his electrocardiogram (ECG) before starting chemotherapy was completely normal. In the ED, his ECG had ischemic changes, troponin was elevated, and echocardiogram showed anterior wall hypokinesis. However, emergent coronary angiogram did not reveal any acute coronary occlusion. 5-FU-induced cardiotoxicity was suspected; the patient was admitted to a progressive care unit for close monitoring and infusion of calcium channel blockers was initiated. The patient's symptoms and ECG findings gradually resolved, and two days later on discharge, patient was chest pain free and ECG was normal. This case supports the vasospastic hypothesis of 5-FU cardiac toxicity, describes its clinical course, and emphasizes the importance of better awareness and early recognition of the rare side effect as it may allow physicians to reduce the risk of life-threatening complications.",
"affiliations": "Amita Saint Francis Hospital, Evanston, IL, USA.;Amita Saint Francis Hospital, Evanston, IL, USA.;Amita Saint Francis Hospital, Evanston, IL, USA.;Amita Saint Francis Hospital, Evanston, IL, USA.;Amita Saint Francis Hospital, Evanston, IL, USA.;Amita Saint Francis Hospital, Evanston, IL, USA.",
"authors": "Charkviani|Mariam|M|https://orcid.org/0000-0002-8854-8796;Murvelashvili|Natia|N|;Barrera|Francisco|F|;Sharma|Alisha|A|;Eldin|Randa Sharag|RS|;Nabil|Nur Un Nisa|NUN|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2020/4151474",
"fulltext": "\n==== Front\nCase Rep Oncol Med\nCase Rep Oncol Med\nCRIONM\nCase Reports in Oncological Medicine\n2090-6706 2090-6714 Hindawi \n\n10.1155/2020/4151474\nCase Report\nRare Presentation of Cardiotoxicity Related to 5-Fluorouracil\nhttps://orcid.org/0000-0002-8854-8796Charkviani Mariam charkvianimariami@gmail.com Murvelashvili Natia Barrera Francisco Sharma Alisha Eldin Randa Sharag Nabil Nur Un Nisa Amita Saint Francis Hospital, Evanston, IL, USA\nAcademic Editor: Mauro Cives\n\n\n2020 \n20 7 2020 \n2020 41514747 2 2020 1 6 2020 9 6 2020 Copyright © 2020 Mariam Charkviani et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.5-Fluorouracil (5-FU) is a chemotherapeutic agent frequently used for the treatment of solid tumors. In a few cases, 5-FU can be associated with coronary vasospasm, cardiac ischemia, or life-threatening arrhythmias. Recognition of 5-FU cardiotoxicity is clinically important as after the rapid sensation of therapy, cardiotoxicity can be completely reversible, and on the other hand, readministration may lead to serious damage of the heart and even death. A 70-year-old male came to the emergency department (ED) with chest pain which started while receiving an infusion of 5-FU. The patient did not have a personal history or risk factors of coronary artery disease and his electrocardiogram (ECG) before starting chemotherapy was completely normal. In the ED, his ECG had ischemic changes, troponin was elevated, and echocardiogram showed anterior wall hypokinesis. However, emergent coronary angiogram did not reveal any acute coronary occlusion. 5-FU-induced cardiotoxicity was suspected; the patient was admitted to a progressive care unit for close monitoring and infusion of calcium channel blockers was initiated. The patient's symptoms and ECG findings gradually resolved, and two days later on discharge, patient was chest pain free and ECG was normal. This case supports the vasospastic hypothesis of 5-FU cardiac toxicity, describes its clinical course, and emphasizes the importance of better awareness and early recognition of the rare side effect as it may allow physicians to reduce the risk of life-threatening complications.\n==== Body\n1. Background\n5-Fluorouracil (5-FU) is a chemotherapeutic agent that is frequently used in the treatment of solid tumors. Despite proven therapeutic efficiency, 5-FU can have some undesired side effects, and, in a few cases, it was found to be associated with cardiotoxicity [1–3]. The incidence is rare and according to different sources, it varies from 1 to 19% [4, 5]. The most common clinical manifestation is angina but asymptomatic electrocardiogram (ECG) changes, arrhythmias, myocardial infarction (MI), heart failure, and cardiac arrest have been also reported [3]. We will present the case of a 70-year-old male, who developed coronary vasospasm after starting chemotherapy with 5-FU for newly diagnosed colorectal cancer.\n\n2. Case Report\nA 70-year-old male with newly diagnosed colorectal carcinoma presented to the emergency department with chest pain which developed during the first course of chemotherapy treatment with FOLFOX (a combination of oxaliplatin, leucovorin, and 5-FU). The patient informed his oncologist about the chest pain, who stopped his 5-FU infusion and sent him to the Emergency Department (ED). The pain was described as severe, squeezing in nature, located in the middle of the chest, without aggravating and alleviating factors. The patient did not have any known cardiac history or its risk factors like hypertension, hypercholesterolemia, or diabetes. Family history was negative for coronary artery disease, social history was not significant for any cardiac risk factors, and he was not a smoker and was not using any illicit drugs. Vitals were stable and physical examination was unremarkable. On initial ECG in the ED, the patient was found to have ischemic changes with diffuse T wave inversions and ST depressions in V3, V4, V5, and V6 (Figure 1), and the cardiac troponin I (cTnI) was elevated to 0.06 ng/ml (reference range 0–0.03 ng/ml). Of note, patient had ECG done during his regular visit to primary care physician three days before starting chemotherapy which was completely normal (Figure 2). Two hours later after arrival to the ED, ECG showed new ST elevations on lead 1, V3, V4, and V5 (Figure 3). Troponin increased from 0.06 ng/ml to 2.49 ng/ml and bedside echocardiogram demonstrated anterior wall hypokinesis. The patient was taken for an emergent coronary angiogram which revealed mild to moderate proximal left anterior descending artery disease with no acute occlusion (Figure 4). Diagnosis of 5-FU-induced coronary vasospasm was made. The patient was started on nitroglycerin and calcium channel blocker and admitted to a progressive care unit. Repeated serial ECGs showed gradual normalization of ST segment and ST and T wave abnormalities (Figures 5 and 6), troponin started to trend down and chest pain resolved in 24 hours. Two days later, the patient was discharged with normal ECG (Figure 7).\n\n3. Discussion\nThe fluoropyrimidines, namely, 5-FU, is the third most commonly used chemotherapeutic agent for the treatment of solid tumors [6]. 5-FU is a pyrimidine analog that inhibits thymidylate synthase, an enzyme involved in DNA replication [7]. These agents function as S-phase antimetabolites, inducing double-strand DNA and single-strand DNA breaks and promote genomic instability; they interfere with DNA synthesis, repair, and elongation. 5-FU is the second most common agent after carboplatin which can cause cardiotoxicity [4]. Risk factors for 5-FU cardiotoxicity include older age, preceding history of cardiac disease, and concomitant use of cardiotoxic medications [8]. The most common clinical manifestation associated with cardiotoxicity is angina. Diagnosis of 5-FU cardiotoxicity mainly occurs during the first cycle of administration [9, 10], and it is mainly based on clinical presentation and symptoms, chest pain, elevated cardiac markers, electrocardiographic changes, changes of cardiac function by echocardiography, and results of coronary angiography. One prospective study [3] describes the cases of 5-FU-induced cardiotoxicity where the pain was the most common symptom, and serial cardiac enzyme levels were normal in all patients, also the symptoms immediately resolved after sensation of therapy and time to recovery was 5 to 60 minutes. In contrast, in our patient, we observed a significant elevation of troponin and the ECG changes resolved within 24 hours, which represents the different presentation of cardiac toxicity of 5-FU. The exact mechanism of cardiotoxicity is unknown; according to some theories, it can be due to coronary vasospasm, although myocardial infarction, arrhythmias, QT prolongation, heart failure, pericarditis, coronary dissection, and sudden cardiac death have also been reported [2, 5, 9]. In vitro models showed that 5-FU can cause concentration-dependent vasoconstriction of smooth muscle cells [11], but some studies have also shown that echocardiography demonstrated wall motion abnormalities in areas that do not correspond to the classic distribution of coronary arteries, that is, suggesting that a mechanism can be multifactorial [12]. For most patients with suspected fluoropyrimidine-induced chest pain, diagnostic coronary arteriography is indicated to exclude concomitant processes that account for acute coronary syndrome presentation and to guide treatment decisions. If coronary arteries are normal (or the extent of coronary artery disease is thought not to be clinically significant), a presumptive diagnosis of fluoropyrimidine cardiotoxicity can be made. Fluoropyrimidine treatment should be immediately discontinued if symptoms are suggestive of cardiotoxicity. Cardiac symptoms usually resolve, and cardiotoxicity appears to be completely reversible after cessation of therapy. Parenteral calcium channel blockers and long-acting nitrates can be used as a treatment if vasospasm is suspected. The presentation of cardiotoxicity in our patient also supports the vasospastic theory as the angiogram showed only mild clinically nonsignificant disease and the symptoms and ECG changes completely resolved after 24 hours of cessation of therapy and introduction of nitrates and calcium channel blockers. In general, the reintroduction of 5-FU after known cardiac toxicity is not recommended as the recurrence rate is as high as 90% and is associated with serious complications such as myocardial infarction, development of cardiogenic shock, and death [12, 13]; however, there are some exceptions when fluoropyrimidine challenge may be necessary for some patients in whom there are no alternative chemotherapy regiments or if the potential benefit is thought to outweigh the risk [14]. There is only limited literature available about rechallenging, and if this option is attempted, aggressive prophylaxis with aspirin, calcium channel blocker, and long-acting nitrates are required before administration of chemotherapy, along with informed consent, cardiology consultation, and close cardiac monitoring in an inpatient setting and immediate discontinuation if any sign of cardiotoxicity occurs. In 2015, FDA approved uridine triacetate for severe, life-threatening fluoropyrimidine toxicity; however, data is limited and there are only a few cases reports available when it was actually used [15, 16].\n\n4. Conclusion\nOur case emphasizes the importance of early recognition of the rare complication of the commonly used chemotherapeutic agent. In the majority of cases, 5-FU-induced coronary vasospasm is reversible; however, in view of the potentially lethal profile and successful clinical outcomes associated with early detection and intervention, physicians should be aware of its existence.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 12-lead electrocardiogram (ECG) obtained at the time of arrival of the patient to the ED. ECG shows diffuse T wave inversions (blue arrows) and ST depressions in V3, V4, V5, and V6 (red arrows).\n\nFigure 2 Patient's ECG three days before starting chemotherapy. ECG is normal with no ST segment or T wave abnormalities.\n\nFigure 3 Patient's ECG after 2 hours from arrival to the ED. ECG shows new ST elevations on lead 1, V3, V4, and V5 (red arrows).\n\nFigure 4 Pictures of emergent coronary angiogram after patient's arrival to the ED. Pictures show only mild focal left anterior descending artery disease.\n\nFigure 5 Patient's ECG after 6 hours of hospitalization. ECG shows that T waves are normalized in most of the leads, but it still remains inverted in lead II, III, aVF (blue arrows).\n\nFigure 6 Patient's ECG after 24 hours of hospitalization. CG shows that T waves are normalized in most of the leads and there are no ST segment abnormalities.\n\nFigure 7 Patient's ECG on discharge ECG is normal with no T wave or ST segment abnormalities.\n==== Refs\n1 Yuan C. Parekh H. Allegra C. George T. J. Starr J. S. 5-FU induced cardiotoxicity: case series and review of the literature Cardio-Oncology 2019 5 1, article 13 10.1186/s40959-019-0048-3 \n2 Stewart T. Pavlakis N. Ward M. Cardiotoxicity with 5-fluorouracil and capecitabine: more than just vasospastic angina Internal Medicine Journal 2010 40 4 303 307 10.1111/j.1445-5994.2009.02144.x 2-s2.0-77951096208 20529041 \n3 Akhtar S. S. Salim K. P. Bano Z. A. Symptomatic cardiotoxicity with high-dose 5-fluorouracil infusion: a prospective study Oncology 1993 50 6 441 444 10.1159/000227226 2-s2.0-0027496323 8233284 \n4 Sara J. D. Kaur J. Khodadadi R. 5-Fluorouracil and cardiotoxicity: a review Therapeutic Advances in Medical Oncology 2018 10 10.1177/1758835918780140 2-s2.0-85054601657 \n5 Wacker A. Lersch C. Scherpinski U. Reindl L. Seyfarth M. High incidence of angina pectoris in patients treated with 5-fluorouracil Oncology 2003 65 2 108 112 10.1159/000072334 2-s2.0-0042924424 12931015 \n6 Bartelink H. Roelofsen F. Eschwege F. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups Journal of Clinical Oncology 1997 15 5 2040 2049 10.1200/JCO.1997.15.5.2040 2-s2.0-0031004470 9164216 \n7 Curtin N. J. Harris A. L. Aherne G. W. Mechanism of cell death following thymidylate synthase inhibition: 2′-deoxyuridine-5′-triphosphate accumulation, DNA damage, and growth inhibition following exposure to CB3717 and dipyridamole Cancer Research 1991 51 9 2346 2352 2015598 \n8 Kosmas C. Kallistratos M. S. Kopterides P. Cardiotoxicity of fluoropyrimidines in different schedules of administration: a prospective study Journal of Cancer Research and Clinical Oncology 2008 134 1 75 82 10.1007/s00432-007-0250-9 2-s2.0-35848950726 17636329 \n9 Ng M. Cunningham D. Norman A. R. The frequency and pattern of cardiotoxicity observed with capecitabine used in conjunction with oxaliplatin in patients treated for advanced colorectal cancer (CRC) European Journal of Cancer 2005 41 11 1542 1546 10.1016/j.ejca.2005.03.027 2-s2.0-22144479717 15978800 \n10 Meyer C. C. Calis K. A. Burke L. B. Walawander C. A. Grasela T. H. Symptomatic cardiotoxicity associated with 5-fluorouracil Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 1997 17 4 729 736 \n11 Mosseri M. Fingert H. J. Varticovski L. Chokshi S. Isner J. M. In vitro evidence that myocardial ischemia resulting from 5-fluorouracil chemotherapy is due to protein kinase C-mediated vasoconstriction of vascular smooth muscle Cancer Research 1993 53 13 3028 3033 8391384 \n12 de Forni M. Malet-Martino M. C. Jaillais P. Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study Journal of Clinical Oncology 1992 10 11 1795 1801 10.1200/jco.1992.10.11.1795 2-s2.0-0027069532 1403060 \n13 Saif M. W. Shah M. M. Shah A. R. Fluoropyrimidine-associated cardiotoxicity: revisited Expert Opinion on Drug Safety 2009 8 2 191 202 10.1517/14740330902733961 2-s2.0-66949158016 19309247 \n14 Clasen S. C. Ky B. . O’Quinn R. Giantonio B. Teitelbaum U. Carver J. R. Fluoropyrimidine-induced cardiac toxicity: challenging the current paradigm Journal of Gastrointestinal Oncology 2017 8 6 970 979 10.21037/jgo.2017.09.07 2-s2.0-85036546466 29299356 \n15 Baldeo C. Vishnu P. Mody K. Kasi P. M. Uridine triacetate for severe 5-fluorouracil toxicity in a patient with thymidylate synthase gene variation: potential pharmacogenomic implications SAGE Open Medical Case Reports 2018 6 10.1177/2050313x18786405 \n16 Zurayk M. Keung Y.-K. Yu D. Hu E. H. L. Successful use of uridine triacetate (Vistogard) three weeks after capecitabine in a patient with homozygous dihydropyrimidine dehydrogenase mutation: a case report and review of the literature Journal of Oncology Pharmacy Practice 2019 25 1 234 238 10.1177/1078155217732141 2-s2.0-85057229220 28950804\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2020()",
"journal": "Case reports in oncological medicine",
"keywords": null,
"medline_ta": "Case Rep Oncol Med",
"mesh_terms": null,
"nlm_unique_id": "101581035",
"other_id": null,
"pages": "4151474",
"pmc": null,
"pmid": "32774961",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "29977352;8233284;17636329;12931015;9164216;32154019;29299356;20529041;2015598;15978800;1403060;30013790;8391384;19309247;28950804;9250550",
"title": "Rare Presentation of Cardiotoxicity Related to 5-Fluorouracil.",
"title_normalized": "rare presentation of cardiotoxicity related to 5 fluorouracil"
} | [
{
"companynumb": "US-MYLANLABS-2020M1076673",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "1",
... |
{
"abstract": "is missing (Short communication).",
"affiliations": "Department of Dermatology, APHP, Hôpital Avicenne, FR-93000 Bobigny, France.",
"authors": "Delaleu|Jérémie|J|;Maubec|Eve|E|;Rodrigues|Francois|F|;Lévy|Annie|A|;Szablewski|Vanessa|V|;Laroche|Lilliane|L|;Dereure|Olivier|O|",
"chemical_list": "D008727:Methotrexate",
"country": "Sweden",
"delete": false,
"doi": "10.2340/00015555-3554",
"fulltext": "\n==== Front\nActa Derm Venereol\nActa Derm Venereol\nActaDV\nActa Dermato-Venereologica\n0001-5555\n1651-2057\nSociety for Publication of Acta Dermato-Venereologica\n\n32516423\nActaDV-100-15-5806\n10.2340/00015555-3554\nShort Communication\nMethotrexate-induced Primary Cutaneous Diffuse Large B-cell Lymphoma in Patients with Erythrodermic Cutaneous T-cell Lymphoma\nDELALEU Jérémie 12\nMAUBEC Eve 12\nRODRIGUES Francois 12\nLEVY Annie 3\nSZABLEWSKI Vanessa 4\nLAROCHE Lilliane 12\nDEREURE Olivier 5\n1 Department of Dermatology\n2 University of Paris XIII, Sorbonne Paris Cité, Bobigny\n3 Laboratory of Pathology, Assistance Publique – Hôpitaux de Paris, Hôpital Avicenne\n4 Laboratory of Pathology\n5 Department of Dermatology and INSERM U1058, University of Montpellier Montpellier France\nE-mail: o-dereure@chu-montpellier.fr\n\n17 8 2020\n2020\n100 15 580601 6 2020\n© 2020 Acta Dermato-Venereologica\n2020\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license\n==== Body\npmcSeveral studies have suggested a higher risk of occurrence of lymphoproliferative disorders (LPDs) in patients with rheumatoid arthritis (RA) treated with MTX, a subset of conditions overall known as MTX-associated LPDs and categorized by the WHO as “other iatrogenic immunodeficiency-associated LPDs” (OIIA-LPD) (1–3). Among them, diffuse large B cell lymphoma (DLBCL), either related to Epstein Barr virus (EBV) or not other-wise specified (NOS) and classical Hodgkin disease are the main subtypes, followed by polymorphic/lymphoplasmacytic infiltrates (P/L-I), Hodgkin-like lesions (HLL) and EBV+ mucocutaneous ulcer. MTX-associated LPDs initially presenting with skin lesions have been reported in a minority of cases, and mainly identified as primary cutaneous B-cell lymphoma in single case-reports or small series (1, 4, 5) with only 4 cases in patients with prior CTCL (6–9). We report here on 3 further cases of primary cutaneous B-cell LPD occurring in a setting of CTCL treated with MTX.\n\nCASE REPORTS\n\nPatient 1. An 80-year-old woman was diagnosed with erythrodermic mycosis fungoides (MF) stage IIIA (T4N1M0B0b). Ten months after MTX introduction as first-line treatment with an initial weekly dosage of 20 mg rapidly increased to 40 mg with a favourable response, she presented with a solitary ulcerated nodule of the upper back (Fig. 1) with no further LN enlargement or hepatosplenomegaly. Absolute total lymphocytes cells counts was 0.860 G/l. Skin biopsy of the nodule displayed scattered CD3+ CD4+ CD5+ CD7– CD8– T-cells documenting residual MF admixed with a heavy dermal infiltrate consisting of large atypical CD20+ Pax5+ lymphocytes with strong EBER expression on in situ hybridization (ISH) (Fig. S11) and B clonality. EBV viral load was also detected in peripheral blood (3.5 log). The diagnosis of EBV+ primary cutaneous diffuse large B-cell lymphoma (PCDLBCL) associated with MTX treatment of the underlying CTCL was considered, and MTX withdrawal resulted in a total disappearance of the skin nodule within one month. The patient remained relapse-free after a 6-year follow-up, but eventually died from a non-CTCL-related cause.\n\nFig. 1 Clinical presentation of patient 1. Solitary ulcerated nodule on the upper back 10 months after introduction of methotrexate.\n\nPatient 2. A 78-year-old man with Sézary syndrome (SS) developed twenty months after MTX implementation at a weekly dosage of 15 mg increased to 22.5 mg a 3-cm right temporal ulcerated nodule quickly developed, followed by occurrence of 4 similar but smaller, ulcerated nodules on the scalp with no general status alteration or LN changes. Absolute total lymphocytes and Sézary cells counts were 1.150 G/l and 0.770 G/l, respectively. Chest, abdomen and pelvis CT scan were unremarkable apart from a few moderately enlarged stable peripheral LN. Biopsy of a scalp nodule revealed a diffuse, dense and monotonous dermal infiltrate of large CD20+ Pax5+ B-cells with strong EBER expression on ISH. A dominant B clone was present in skin nodules, but not in peripheral blood. Bone marrow biopsy was normal. No Myd88 mutation was identified. A diagnosis of EBV+ PCDLBCL associated with MTX was retained. Replacement of MTX by bexarotene, topical superpotent dermocorticoids and extracorporeal photochemotherapy ECP resulted in a total disappearance of skin nodules in 3 months with no relapse of the B cell lymphoma after an 8-year follow-up.\n\nPatient 3. A 64-year-old woman treated for SS with MTX alone (15 then 22.5 mg weekly) subsequently associated with bexarotene and ECP suddenly developed after 5 years of this therapeutic regimen a relapsing pruritic erythroderma, massive infiltration of the right arm, multiple ulcerated nodules of the chest and the right axilla and multiple enlarged lymph nodes. No visceral involvement or deep LN enlargement was identified by imaging procedures, but haematological parameters worsened with 2.750 G/l of circulating Sézary cells for an absolute total lymphocyte count of 3.400 G/L and a CD4/CD8 ratio of 70. Multiple skin biopsies obtained from chest nodules and right arm revealed a diffuse, dense dermal infiltrate of small- and medium-size atypical CD3+ CD4+ CD5+ CD7– CD8– T cells admixed with large CD20+ Pax5+ atypical B cells. No EBV expression identified by both IHC and ISH. An identical dominant T clone was present in skin and peripheral blood, and a B clone was identified in skin nodular lesions, but absent in peripheral blood. LN biopsy of the axillary mass displayed the same T cell proliferation as in skin lesions, but not the B-cell proliferation identified in skin nodules. A diagnosis of MTX-induced PCDLBCL with no EBV reactivation in association with a severe relapse of SS was primarily considered. MTX was withdrawn and 6 courses of systemic chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) resulted in total clinical remission of chest nodules and partial remission of SS. Further CTCL progression occurred after a few months with no evidence of PCDLBCL recurrence and the patient eventually died from septic complications 17 months after diagnosis of B-cell lymphoma.\n\nDISCUSSION\n\nWe report 3 new cases of B-cell LPD occurring in patients with CTCL treated with MTX, all of them categorized as PCDLBCL either EBV+ or not with no evidence of systemic disease. In the literature, MTX-associated LPDs are predominantly of the B-cell subset (10) and clinically present as nodal systemic lymphoma with a histologically pattern of DLBCL and strong EBV expression in most cases (4, 5). In these patients, iatrogenic LPD occurrence is therefore presumed to be closely related to EBV reactivation secondary to MTX immunosuppressive effect (11). Treatment of systemic MTX-associated LPDs is primarily based on drug withdrawal, resulting in a favourable course in most cases (12, 13). Conversely, a combined rituximab and polychemotherapy (R-CHOP) regimen may be warranted in some cases owing to a more protracted outcome (10).\n\nFour similar cases of PCDLBCL occurring in MTX-treated CTCL have been previously reported in the literature (6–9). All 7 cases, including ours, were erythrodermic CTCL (4 SS and 3 erythrodermic MF; 5 males/2 females; median age 74 years) and the cutaneous B-cell LPD presented with rapidly evolving cutaneous papules and nodules occurring 2–66 months after MTX introduction (mean 22.8 months) with a close histological pattern of monotonous dermal infiltrate of diffuse large B-cells admixed with features reminiscent of the underlying CTCL in 3/7 cases and positive EBV markers in 6/7 cases (86%). Similarly to MTX-associated systemic LPDs, cutaneous lesions totally vanished in all cases in less than 3 months after MTX discontinuation alone (4/7 patients) or associated with a systemic treatment targeting malignant B cells (3/7 patients: R-CHOP in 2/7 and rituximab alone in 1/7). No relapse was observed after a mean follow-up of 35.8 months (range 3–96 months), but 3/7 patients eventually died from CTCL evolution. All patients’ characteristics and outcome are summarized in Table SI1. An additional role of lymphoma-related immunosuppression in LPD pathomechanisms cannot be ruled out especially in SS, as illustrated by our EBV negative case.\n\nLymphocytes have been suggested to play a key role in the pathogenesis of MTX-associated LPD, with a decrease in the absolute lymphocyte count in peripheral blood at the time of LPD development (14). Interestingly, the total count of normal lymphocytes was low in all our patients at the time of PCDLBCL diagnosis and increased rapidly after MTX discontinuation in patient 2 concomitantly with definitive regression of cutaneous lesions.\n\nIn conclusion, the onset of skin tumour(s) or nodule(s) in patients with CTCL treated with MTX should alert to the possibility of MTX-induced primary cutaneous B-cell lymphoma. Treatment is primarily based on drug withdrawal, resulting in a favourable course in most cases.\n\n1 https://doi.org/10.2340/00015555-3554\n==== Refs\nREFERENCES\n\n1 Mariette X, Cazals-Hatem D, Warszawki J, Liote F, Balandraud N, Sibilia J. Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France. Blood 2002; 99 : 3909–3915.12010788\n2 Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: The effect of methotrexate and anti–tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum 2004; 50 : 1740–1751.15188349\n3 Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al . The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016; 127 : 2375–2390.26980727\n4 Shimizu S, Inokuma D, Murata J, Kikuchi K, Ito T, Fukasawa Y, et al . Cutaneous manifestations of methotrexate-associated lymphoproliferative disorders: report of two cases and a review of the literature. Acta Derm Venereol 2015; 95 : 366–367.25138609\n5 Koens L, Senff NJ, Vermeer MH, Willemze R, Jansen PM. Methotrexate-associated B-cell lymphoproliferative disorders presenting in the skin: a clinicopathologic and immunophenotypical study of 10 cases. Am J Surg Pathol 2014; 38 : 999–1006.24805861\n6 Rausch T, Cairoli A, Benhattar J, Spring P, Hohl D, de Leval L. EBV+ cutaneous B-cell lymphoproliferation of the leg in an elderly patient with mycosis fungoides and methotrexate treatment. APMIS Acta Pathol Microbiol Immunol Scand 2013; 121 : 79–84.\n7 Curry JL, Prieto VG, Jones DM, Vega F, Duvic M, Diwan AH. Transient iatrogenic immunodeficiency-related B-cell lymphoproliferative disorder of the skin in a patient with mycosis fungoides/Sézary syndrome. J Cutan Pathol 2011; 38 : 295–297.19889052\n8 Ingen-Housz-Oro S, Ortonne N, Cordel N, Moroch J, Do-Pham G, Delfau MH, et al . Epstein-Barr virus-associated B-cell lymphoproliferative disorder in a patient with Sézary syndrome treated by methotrexate. Br J Dermatol 2016; 175 : 430–433.27031298\n9 Maderal AD, Malone JC, Callen JP. Methotrexate-associated B-cell lymphoproliferative disease in a patient with cutaneous T-cell lymphoma. JAMA Dermatol 2018; 154 : 490–492.29490369\n10 Yamakawa N, Fujimoto M, Kawabata D, Terao C, Nishikori M, Nakashima R et al . A clinical, pathological, and genetic characterization of methotrexate-associated lymphoproliferative disorders. J Rheumatol 2014; 41 : 293–299.24334644\n11 Feng W, Cohen JI, Fischer S, Li L, Sneller M, Goldbach-Mansky R, et al . Reactivation of latent Epstein-Barr virus by methotrexate: a potential contributor to methotrexate-associated lymphomas. J Natl Cancer Inst 2004; 96 : 1691–1702.15547182\n12 Rizzi R, Curci P, Delia M, Rinaldi E, Chiefa A, Specchia G, et al . Spontaneous remission of ‘methotrexate-associated lymphoproliferative disorders’ after discontinuation of immunosuppressive treatment for autoimmune disease. Review of the literature. Med Oncol Northwood Lond Engl 2009; 26 : 1–9.\n13 Ross Y, Kamran M. Treatment of advanced stage methotrexate-associated lymphoproliferative disorders (MTX-LPDs) with methotrexate discontinuation. BMJ Case Rep 2018; 11 .\n14 Tokuhira M, Tamaru JI, Kizaki M. Clinical management for other iatrogenic immunodeficiency-associated lymphoproliferative disorders. J Clin Exp Hematop 2019; 59 : 72–92.31257348\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0001-5555",
"issue": "100(15)",
"journal": "Acta dermato-venereologica",
"keywords": " B-cell lymphoma; Epstein barr virus ; T cell lymphoma; methotrexate",
"medline_ta": "Acta Derm Venereol",
"mesh_terms": "D020031:Epstein-Barr Virus Infections; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D016410:Lymphoma, T-Cell, Cutaneous; D008727:Methotrexate; D009182:Mycosis Fungoides; D012878:Skin Neoplasms",
"nlm_unique_id": "0370310",
"other_id": null,
"pages": "adv00226",
"pmc": null,
"pmid": "32516423",
"pubdate": "2020-08-17",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Methotrexate-induced Primary Cutaneous Diffuse Large B-cell Lymphoma in Patients with Erythrodermic Cutaneous T-cell Lymphoma.",
"title_normalized": "methotrexate induced primary cutaneous diffuse large b cell lymphoma in patients with erythrodermic cutaneous t cell lymphoma"
} | [
{
"companynumb": "FR-ENDO PHARMACEUTICALS INC-2020-006193",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugad... |
{
"abstract": "Neuromyopathy is a rare side effect of chronic colchicine therapy, especially without renal impairment. Drugs interacting with colchicine metabolism through CYP3A4 can accelerate accumulation and toxicity. We describe a case of an interaction between atorvastatin, clarithromycin and colchicine resulting in acute neuromyopathy.\nColchicine has a narrow therapeutic window, and therefore, often produces side effects.Special caution should be adopted if patients with renal disease and concomitant medications are given colchicine.Before prescribing colchicine, the clinical history, including previous medications and conditions, should be carefully considered.",
"affiliations": "Gastroenterology and Hepatology Department, Hospital Universitario Marqués de Valdecilla-IDIVAL, Universidad de Cantabria, Santander, Spain.;Department of Internal Medicine, Hospital Universitario Marqués de Valdecilla-IDIVAL, Universidad de Cantabria, Santander, Spain.;Department of Internal Medicine, Hospital Universitario Marqués de Valdecilla-IDIVAL, Universidad de Cantabria, Santander, Spain.;Department of Internal Medicine, Hospital Universitario Marqués de Valdecilla-IDIVAL, Universidad de Cantabria, Santander, Spain.;Department of Internal Medicine, Hospital Universitario Marqués de Valdecilla-IDIVAL, Universidad de Cantabria, Santander, Spain.",
"authors": "Olmos-Martínez|José M|JM|;Molina|Helena|H|;Salas|Cristina|C|;Olmos|José M|JM|;Hernández|José L|JL|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2019_001066",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2019_0010661066-1-7318-1-10-20190313ArticlesAcute Colchicine-induced Neuromyopathy in a Patient Treated with Atorvastatin and Clarithromycin Olmos-Martínez José M 1Molina Helena 2Salas Cristina 2Olmos José M 2Hernández José L 2\n1 Gastroenterology and Hepatology Department, Hospital Universitario Marqués de Valdecilla-IDIVAL, Universidad de Cantabria, Santander, Spain\n2 Department of Internal Medicine, Hospital Universitario Marqués de Valdecilla-IDIVAL, Universidad de Cantabria, Santander, Spain2019 18 3 2019 6 3 00106602 2 2019 05 2 2019 © EFIM 20192019This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseNeuromyopathy is a rare side effect of chronic colchicine therapy, especially without renal impairment. Drugs interacting with colchicine metabolism through CYP3A4 can accelerate accumulation and toxicity. We describe a case of an interaction between atorvastatin, clarithromycin and colchicine resulting in acute neuromyopathy.\n\nLEARNING POINTS\nColchicine has a narrow therapeutic window, and therefore, often produces side effects.\n\nSpecial caution should be adopted if patients with renal disease and concomitant medications are given colchicine.\n\nBefore prescribing colchicine, the clinical history, including previous medications and conditions, should be carefully considered.\n\nColchicineneuromyopathyatorvastatinclarithromycin\n==== Body\nINTRODUCTION\nColchicine has been synthesised for the treatment and prophylaxis of gout for centuries. It has a narrow therapeutic window, with common side effects such as gastroenteritis, blood dyscrasias, and dermatitis. Neuromuscular toxicity associated with colchicine is rare and under-recognised[1]. Although it is widely used, myopathy has not been reported frequently in the literature. When noticed, it has usually been associated with renal impairment (RI) and/or co-administration of cytochrome P450-metabolised drugs[2]. We report a patient with colchicine-induced neuromyopathy after an increased dosage due to an acute gout attack shortly after receiving clarithromycin.\n\nCASE DESCRIPTION\nA 78-year-old Caucasian man, with a history of hypertensive myocardiopathy and chronic gout, was admitted because of muscle pain and weakness in the lower extremities lasting for 15 days. One month before admission, he received intravenous ertapenem and oral clarithromycin due to orchitis. He developed acute arthritis in the right first metatarsophalangeal joint, and colchicine was increased from 1 to 4 mg per day. His current medications included: furosemide (40 mg qd), dutasteride/tamsulosin (0.5/0.4 qd), allopurinol (300 mg qd), omeprazole (20 mg qd), paracetamol (650 mg/t.i.d.), atorvastatin (40 mg qd), and verapamil (240 mg qd).\n\nAt admission, he complained about moderate to severe weakness starting in the legs progressing to the upper limbs, in addition to myalgia without paraesthesia or sensory loss.\n\nPhysical examination revealed gouty tophi in his left elbow and at the first right metatarsophalangeal joint and a slight bilateral hypothenar atrophy. Neurological examination did not reveal any cranial nerve palsy, back pain, bladder or bowel dysfunction. The weakness affected all limbs, mainly the lower ones, without great difference between proximal and distal muscle power. The Medical Research Council (MRC) grading for muscle power was as follows:\n\nTrapezius (left and right): 5/5; biceps (both): 4/5; triceps (both): 4/5; right psoas: 2/5; left psoas: 3/5; quadriceps (both): 3/5; right tibialis anterior: 2/5; left tibialis anterior: 4/5; right extensor hallucis longus: 2/5; left extensor hallucis longus: 3/5.\n\nHe had universal areflexia and he was unable to walk. No other relevant findings were found in the physical examination.\n\nMETHODS AND PROCEDURES\nSerum blood tests revealed a highly increased CK (2660 U/L), and increased LDH (457 U/L), and thyroxine levels (2.34 mUI/ml). Aminotransferases and GGT were also altered (ALT: 1238 U/L, AST: 488 U/L, FA: 83 U/L, GGT: 354 U/L) without any other abnormal parameters. Urinary tests revealed the presence of haemoglobin (+++), without red cells in the sediment, consistent with myoglobinuria.\n\nAntinuclear, antimyeloperoxidase, antiproteinase 3, antiganglionic and antineuronal antibodies were all negative. Immunoglobulin tests revealed lower levels of serum IgG and IgM (410 mg/dl and 17.3 mg/dl, respectively), consistent with a common variable immunodeficiency. A body CT scan was normal, and a spinal MRI study only showed slight multisegmental degenerative discopathy. Nerve conduction studies revealed low amplitude motor responses and low amplitude median sensory responses. Needle electrode examination showed long duration motor unit potentials, the recruitment phenomenon and diffuse fibrillation potentials most prominently in distal muscles.\n\nIn the absence of any other reasonable aetiology, and considering that the symptoms appeared right after the increase in the colchicine dosage and the introduction of clarithromycin, a diagnosis of colchicine-induced neuromyopathy was suspected. Colchicine, atorvastatin and clarithromycin were withdrawn, leading to a slow but continuous improvement in the patient’s weakness and serum CK levels. Rehabilitation therapy was started, and after a few months he was able to walk on his own again. A new electrophysiological study was performed, showing normal findings at the upper limbs and a clear improvement at the lower ones. No fibrillation potentials were detected, and motor unit potentials had normal amplitudes.\n\nDISCUSSION\nColchicine has been used for more than 200 years. Gastrointestinal side effects are quite common and often minor, whereas neuromuscular toxicity is rare and sometimes under-recognised[1,2]. The neuromyopathy associated with colchicine is usually painless, but in rare instances it can be a painful condition, as occurred in our patient. The time course is usually subacute (1–3 months) but can be acute (<4 weeks) or chronic (>3 months)[2]. The key clinical finding is proximal lower limb weakness, although distal weakness and sensory involvement have been reported[3]. Laboratory tests usually show mild to higher elevations of serum CK levels. Electrophysiological findings include myopathic motor unit potentials with features of membrane irritability as may be seen in inflammatory myopathy and a coexistent sensorimotor axonal polyneuropathy[6]. Although muscle biopsy is not always necessary, it uncovers highly specific abnormalities, revealing a vacuolar myopathy with autophagic vacuoles[2,5]. Chronic RI, hepatopathy or diuretic use have been reported to be predisposing factors for this side effect at the usual dose range[2,4,7]. Moreover, it has been widely reported that co-administration of drugs that are metabolised by the CYP450 system can induce colchicine toxicity, including myopathy[3,5,7,8]. This fact is explained by the inhibition of CYP3A4 by other drugs metabolised by the same route, leading to increased levels of colchicine despite normal dosage. Our patient was being treated with two drugs reported to interact with colchicine: clarithromycin and atorvastatin. He was on statin treatment for more than 3 years, but clarithromycin was prescribed 2 weeks before symptoms of myopathy began. Accordingly, the increased dose of colchicine in a patient receiving atorvastatin and clarithromycin at the same time could probably trigger the myoneuropathy in our case.\n\nCONCLUSIONS\nColchicine-induced myotoxicity is a rare adverse effect. Clinicians should recognise that RI is the primary risk factor for colchicine-induced myotoxicity, and that dosage adjustment or alternative therapy may be required if the patient is receiving other P450-metabolised medication at the same time. It should be suspected in elderly patients with RI who present with subacute proximal lower extremity weakness. Diagnosis may be confirmed by electromyography or muscle biopsy. Prompt discontinuation of the medication can reverse most of the clinical weakness and laboratory abnormalities. On the other hand, combined use of macrolides and colchicine should be cautioned.\n\nAcknowledgements\nI would like to express my gratitude to all the authors for their help gathering clinical data, manuscript redaction and review, with special thanks to Dr. Hernandez who guided us through the clinical diagnosis, management and the posterior preparation and subsequent redaction of this manuscript.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n==== Refs\nREFERENCES\n1 Kuncl RW Duncan G Watson D Alderson K Rogawski MA Peper M Colchicine myopathy and neuropathy N Engl J Med 1987 316 1562 1568 3035372 \n2 Wilbur K Makowsky M Colchicine myotoxicity: case reports and literature review Pharmacotherapy 2004 24 1784 1792 15585444 \n3 Ghosh PS Emslie-Smith AM Dimberg EL Colchicine-induced myoneuropathy mimicking polyradiculoneuropathy J Clin Neurosci 2014 21 331 332 24071053 \n4 Van der Velden W Huussen J Ter Laak H de Sévaux R Colchicine-induced neuromyopathy in a patient with chronic renal failure: the role of clarithromycin Neth J Med 2008 66 204 206 18490798 \n5 Goh IW How CH Tavintharan S Cytochrome P450 drug interactions with statin therapy Singapore Med J 2013 54 131 135 23546024 \n6 Kuncl RW Cornblath DR Avila O Electrodiagnosis of human colchicine myoneuropathy Muscle Nerve 1989 12 360 364 2725561 \n7 Mor A Wortmann RL Mitnick HJ Drugs causing muscle disease Rheum Dis Clin North Am 2011 37 219 231 21444021 \n8 McKinnell J Tayek JA Short term treatment with clarithromycin resulting in colchicine-induced rhabdomyolysis J Clin Rheumatol 2009 15 303 305 19734738\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2284-2594",
"issue": "6(3)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Colchicine; atorvastatin; clarithromycin; neuromyopathy",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "001066",
"pmc": null,
"pmid": "30931282",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "15585444;18490798;19734738;21444021;23546024;24071053;2725561;3035372",
"title": "Acute Colchicine-induced Neuromyopathy in a Patient Treated with Atorvastatin and Clarithromycin.",
"title_normalized": "acute colchicine induced neuromyopathy in a patient treated with atorvastatin and clarithromycin"
} | [
{
"companynumb": "ES-MYLANLABS-2019M1038646",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Extended-release naltrexone (XR-NTX) is associated with an increased number of opioid-free days, improved adherence rates in substance use disorder treatment programs, and reduced cravings and drug-seeking behaviors. There is little evidence on the predictive associations between baseline characteristics of opioid-dependent patients and XR-NTX utilization. Some studies have demonstrated better pharmacotherapy adherence and/or retention rates among non-heroin opioid users compared to heroin users. This study examines predictive associations between characteristics of patients and XR-NTX utilization, as well as participants' urge to use opiates. Our findings suggest that XR-NTX may contribute to decreases in urges to use among both heroin and non-heroin opioid users. Non-heroin opioid users and heroin users were retained in XR-NTX treatment for comparable periods of time. However, those who identified as homeless, injected opioids (regardless of opioid-type), or were diagnosed with a mental illness were less likely to be retained in treatment with XR-NTX.",
"affiliations": "University of California, Los Angeles, Integrated Substance Abuse Programs, 11075 Santa Monica Blvd., Suite 200, Los Angeles, CA, USA 90025. Electronic address: SarahJCousins@ucla.edu.;University of California, Los Angeles, Integrated Substance Abuse Programs, 11075 Santa Monica Blvd., Suite 200, Los Angeles, CA, USA 90025; Isfahan University of Medical Science, Hezar Jerib Avenue, Isfahan, Iran 81745.;University of California, Los Angeles, Integrated Substance Abuse Programs, 11075 Santa Monica Blvd., Suite 200, Los Angeles, CA, USA 90025.;University of California, Los Angeles, Integrated Substance Abuse Programs, 11075 Santa Monica Blvd., Suite 200, Los Angeles, CA, USA 90025.;University of California, Los Angeles, Integrated Substance Abuse Programs, 11075 Santa Monica Blvd., Suite 200, Los Angeles, CA, USA 90025.;University of California, Los Angeles, Integrated Substance Abuse Programs, 11075 Santa Monica Blvd., Suite 200, Los Angeles, CA, USA 90025.",
"authors": "Cousins|Sarah J|SJ|;Radfar|Seyed Ramin|SR|;Crèvecoeur-MacPhail|Desirée|D|;Ang|Alfonso|A|;Darfler|Kendall|K|;Rawson|Richard A|RA|",
"chemical_list": "D003692:Delayed-Action Preparations; D009292:Narcotic Antagonists; D009271:Naltrexone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0740-5472",
"issue": "63()",
"journal": "Journal of substance abuse treatment",
"keywords": "Extended-release naltrexone; Heroin; Medication-assisted treatment; Opioid use disorder; Opioids",
"medline_ta": "J Subst Abuse Treat",
"mesh_terms": "D000328:Adult; D066249:Craving; D003692:Delayed-Action Preparations; D005260:Female; D006556:Heroin Dependence; D006801:Humans; D015141:Los Angeles; D008297:Male; D008875:Middle Aged; D009271:Naltrexone; D009292:Narcotic Antagonists; D009293:Opioid-Related Disorders; D015819:Substance Abuse, Intravenous",
"nlm_unique_id": "8500909",
"other_id": null,
"pages": "66-71",
"pmc": null,
"pmid": "26823295",
"pubdate": "2016-04",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Predictors of Continued Use of Extended-Released Naltrexone (XR-NTX) for Opioid-Dependence: An Analysis of Heroin and Non-Heroin Opioid Users in Los Angeles County.",
"title_normalized": "predictors of continued use of extended released naltrexone xr ntx for opioid dependence an analysis of heroin and non heroin opioid users in los angeles county"
} | [
{
"companynumb": "US-ALKERMES INC.-ALK-2016-001143",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NALTREXONE"
},
"drugadditional": null,... |
{
"abstract": "Advanced maxillary medication-related osteonecrosis of the jaw can cause extensive hard and soft tissue destruction that results in long-term oroantral fistulae. The surgical treatment of medication-related osteonecrosis of the jaw may relieve acute symptoms and eliminate the signs of inflammation, but the primary and sustained plastic closure of these defects can challenge both the clinician and the patients. Although the use of obturator prostheses for maxillary defects after ablative oncologic surgery is well documented, studies about this treatment for similar medication-related osteonecrosis of the jaw-related defects are missing. This presentation of clinical situations describes the use of obturators as a conservative alternative to repetitive surgery for the rehabilitation of selected maxillary defects with oroantral communications.",
"affiliations": "Resident, Department of Oral and Maxillofacial Surgery, University of Munich, Munich, Germany. Electronic address: matthias_troeltzsch@hotmail.com.;Resident, Department of Oral and Maxillofacial Surgery, University of Munich, Munich, Germany.;Resident, Department of Oral and Maxillofacial Surgery, University of Göttingen, Göttingen, Germany.;Professor and Department Chair, Department of Oral and Maxillofacial Surgery, University of Munich, Munich, Germany.;Associate Professor, Department of Oral and Maxillofacial Surgery, University of Munich, Munich, Germany.",
"authors": "Troeltzsch|Matthias|M|;Probst|Florian|F|;Troeltzsch|Markus|M|;Ehrenfeld|Michael|M|;Otto|Sven|S|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3913",
"issue": "113(3)",
"journal": "The Journal of prosthetic dentistry",
"keywords": null,
"medline_ta": "J Prosthet Dent",
"mesh_terms": "D000273:Adipose Tissue; D000368:Aged; D000369:Aged, 80 and over; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D003646:Debridement; D003819:Denture Bases; D003779:Denture Design; D003832:Denture, Partial, Removable; D004164:Diphosphonates; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles; D008297:Male; D008439:Maxillary Diseases; D008875:Middle Aged; D009957:Oroantral Fistula; D010158:Palatal Obturators; D013529:Surgical Wound Dehiscence; D000077211:Zoledronic Acid",
"nlm_unique_id": "0376364",
"other_id": null,
"pages": "236-41",
"pmc": null,
"pmid": "25444286",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Conservative management of medication-related osteonecrosis of the maxilla with an obturator prosthesis.",
"title_normalized": "conservative management of medication related osteonecrosis of the maxilla with an obturator prosthesis"
} | [
{
"companynumb": "PHHY2016DE084531",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "Cyclophosphamide has been the mainstay of treatment of ANCA-associated vasculitis. However, cyclophosphamide has unfavorable side effects and alternatives are needed. Evidence suggests that mycophenolate mofetil can induce sustained remission in nonlife-threatening disease. The purpose of this study was to compare the efficacy and safety of mycophenolate mofetil versus cyclophosphamide for the induction treatment of nonlife-threatening relapses of proteinase 3-ANCA- and myeloperoxidase-ANCA-associated vasculitis.\n\n\n\nWe conducted a multicenter randomized, controlled trial. Participants with a first or second relapse of ANCA-associated vasculitis were randomized to induction treatment with cyclophosphamide or mycophenolate mofetil both in combination with glucocorticoids. Maintenance therapy consisted of azathioprine in both arms. Primary outcome was remission at 6 months, and secondary outcomes included disease-free survival at 2 and 4 years.\n\n\n\nEighty-four participants were enrolled, of whom 41 received mycophenolate mofetil and 43 received cyclophosphamide. Eighty-nine percent of participants were proteinase 3-ANCA positive. At 6 months, 27 (66%) mycophenolate mofetil-treated participants versus 35 (81%) cyclophosphamide-treated participants were in remission (P=0.11). Disease-free survival rates at 2 and 4 years were 61% and 39% for cyclophosphamide, respectively, and 43% and 32% for mycophenolate mofetil, respectively (at 4 years, log rank test, P=0.17).\n\n\n\nWe did not demonstrate mycophenolate mofetil to be similarly effective as cyclophosphamide in inducing remission of relapsed ANCA-associated vasculitis. However, mycophenolate mofetil might be an alternative to cyclophosphamide for the treatment of selected patients with nonlife-threatening relapses.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; j.tuin@umcg.nl.;Division of Acute Medicine, Department of Internal Medicine and.;Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.;Division of Nephrology, Department of Internal Medicine, Medisch Centrum Leeuwarden, Leeuwarden, The Netherlands; and.;Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.;Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.;Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.;Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.",
"authors": "Tuin|Janneke|J|;Stassen|Patricia M|PM|;Bogdan|Daria I|DI|;Broekroelofs|Jan|J|;van Paassen|Pieter|P|;Cohen Tervaert|Jan Willem|JW|;Sanders|Jan-Stephan|JS|;Stegeman|Coen A|CA|",
"chemical_list": "D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D009173:Mycophenolic Acid",
"country": "United States",
"delete": false,
"doi": "10.2215/CJN.11801018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1555-9041",
"issue": "14(7)",
"journal": "Clinical journal of the American Society of Nephrology : CJASN",
"keywords": "ANCA; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies; Antineutrophil Cytoplasmic; Mycophenolic Acid; Recurrence; Remission Induction; cyclophosphamide; mycophenolate mofetil; randomized controlled trials; relapse; vasculitis",
"medline_ta": "Clin J Am Soc Nephrol",
"mesh_terms": "D000328:Adult; D000368:Aged; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D003520:Cyclophosphamide; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D012008:Recurrence; D012074:Remission Induction",
"nlm_unique_id": "101271570",
"other_id": null,
"pages": "1021-1028",
"pmc": null,
"pmid": "31253599",
"pubdate": "2019-07-05",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "16052573;16188901;17179175;1739240;18065810;19451574;20093349;21311184;23045170;23902481;24304103;25805745;25956510;30612116;7820541;9041949",
"title": "Mycophenolate Mofetil Versus Cyclophosphamide for the Induction of Remission in Nonlife-Threatening Relapses of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Randomized, Controlled Trial.",
"title_normalized": "mycophenolate mofetil versus cyclophosphamide for the induction of remission in nonlife threatening relapses of antineutrophil cytoplasmic antibody associated vasculitis randomized controlled trial"
} | [
{
"companynumb": "NL-ALKEM LABORATORIES LIMITED-NL-ALKEM-2021-06391",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
... |
{
"abstract": "To compare the efficacy of sorafenib plus hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin to that of sorafenib alone in patients with advanced hepatocellular carcinoma (HCC).\nThis was a retrospective, single-center trial. Between April 3, 2017 and July 2, 2018, 104 patients with Child-Pugh A and advanced HCC received either 400 mg of sorafenib orally twice daily plus HAIC with oxaliplatin (oxaliplatin 85 mg/m2, every 3 weeks via repetitive catheterization) (n = 46, soraOXA group) or 400 mg of only sorafenib orally twice daily (n = 58, sorafenib group). Overall survival, progression-free survival, objective response rate, and treatment-related adverse events were compared.\nThe median overall survival was 9.37 months (95% CI, 7.05-11.68) in the soraOXA group versus 4.8 months (95% CI, 2.98-6.62) in the sorafenib group (HR 0.46 [95% CI, 0.29-0.72]; P < 0.001). The soraOXA group also showed a higher objective response rate (16 [34.8%] vs 1 [1.7%]; P < 0.001) and a longer progression-free survival rate (5.5 months [95% CI, 2.32-8.68] vs 2.4 months [95% CI, 1.65-3.15], HR 0.54 [95% CI, 0.36-0.81], P = 0.003) than the sorafenib group. There was no significant difference in the overall incidence of any grade adverse events, grade 3/4 adverse events, serious adverse events, or incidence of treatment termination due to adverse events between the two groups.\nCompared with sorafenib alone, sorafenib plus HAIC with oxaliplatin showed favorable treatment outcomes in patients with advanced HCC. The merits of this approach need to be established with a prospective trial.",
"affiliations": "Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.;HuiDong Senior Middle School, Huidong, Huizhou, China.;Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.;Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.;Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.",
"authors": "Zhao|Yang|Y|;Lai|JiaYing|J|;Liang|RunBin|R|;He|MinKe|M|;Shi|Ming|M|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.1016/j.jimed.2019.07.005",
"fulltext": "\n==== Front\nJ Interv Med\nJ Interv Med\nJournal of Interventional Medicine\n2096-3602\n2590-0293\nKeAi Publishing\n\nS2096-3602(19)30087-0\n10.1016/j.jimed.2019.07.005\nArticle\nSorafenib plus hepatic arterial infusion chemotherapy with oxaliplatin versus sorafenib alone for advanced hepatocellular carcinoma\nZhao Yang a\nLai JiaYing b\nLiang RunBin a\nHe MinKe a\nShi Ming shiming@mail.sysu.edu.cn\na∗\na Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China\nb HuiDong Senior Middle School, Huidong, Huizhou, China\n∗ Corresponding author. Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, PR China. shiming@mail.sysu.edu.cn\n31 7 2019\n5 2019\n31 7 2019\n2 2 7883\n© 2019 Shanghai Journal of Interventional Medicine Press. Production and hosting by Elsevier B.V. on behalf of KeAi.\n2019\nShanghai Journal of Interventional Medicine Press\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nObjective\n\nTo compare the efficacy of sorafenib plus hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin to that of sorafenib alone in patients with advanced hepatocellular carcinoma (HCC).\n\nMethods\n\nThis was a retrospective, single-center trial. Between April 3, 2017 and July 2, 2018, 104 patients with Child-Pugh A and advanced HCC received either 400 mg of sorafenib orally twice daily plus HAIC with oxaliplatin (oxaliplatin 85 mg/m2, every 3 weeks via repetitive catheterization) (n = 46, soraOXA group) or 400 mg of only sorafenib orally twice daily (n = 58, sorafenib group). Overall survival, progression-free survival, objective response rate, and treatment-related adverse events were compared.\n\nResults\n\nThe median overall survival was 9.37 months (95% CI, 7.05–11.68) in the soraOXA group versus 4.8 months (95% CI, 2.98–6.62) in the sorafenib group (HR 0.46 [95% CI, 0.29–0.72]; P < 0.001). The soraOXA group also showed a higher objective response rate (16 [34.8%] vs 1 [1.7%]; P < 0.001) and a longer progression-free survival rate (5.5 months [95% CI, 2.32–8.68] vs 2.4 months [95% CI, 1.65–3.15], HR 0.54 [95% CI, 0.36–0.81], P = 0.003) than the sorafenib group. There was no significant difference in the overall incidence of any grade adverse events, grade 3/4 adverse events, serious adverse events, or incidence of treatment termination due to adverse events between the two groups.\n\nConclusion\n\nCompared with sorafenib alone, sorafenib plus HAIC with oxaliplatin showed favorable treatment outcomes in patients with advanced HCC. The merits of this approach need to be established with a prospective trial.\n\nKeywords\n\nHepatocellular carcinoma\nBarcelona clinic liver cancer stage C\nSorafenib\nHepatic arterial infusion chemotherapy\nOxaliplatin\n==== Body\npmcIntroduction\n\nHepatocellular carcinoma (HCC) is the fourth leading cause of cancer around the world.1 About 50% of patients are diagnosed with Barcelona Clinic Liver Cancer (BCLC) stage C (advanced stage),2 with symptoms and/or macrovascular invasion or extrahepatic spread.3 These patients have an extremely poor prognosis, with a median survival of 4.2–7.9 months with supportive care.4,5 Sorafenib is the current standard treatment for these patients.4,5 However, the outcome of these patients treated with sorafenib remains poor, with a median survival time of 6.5–10.7 months.4,5\n\nCisplatin-based hepatic arterial infusion chemotherapy (HAIC) has been widely used in patients with advanced HCC in Japan.6 This procedure offers a feasible approach to elicit a greater antitumor effect than systemic chemotherapy and can reduce toxicity against other systemic organs, which significantly provides a better response rate (20.8–52%)7,8 than that of systemic chemotherapy (8%)9 and sorafenib monotherapy (2–3.3%).4,5 However, the disease commonly begins to progress again even after HAIC shrinks the tumor. Since sorafenib improved survival rates through disease stabilization and has been shown to exert a synergistic anticancer effect with chemotherapeutic agents in preclinical research studies,10, 11, 12 sorafenib combined with HAIC might benefit patients with advanced HCC more than either of the treatments alone. A phase 2 trial in patients with advanced HCC showed better outcomes with single-dose cisplatin arterial infusion chemotherapy plus sorafenib than with sorafenib monotherapy,13 but a randomized phase 3 trial showed that the combination of sorafenib and HAIC with cisplatin and 5-fluorouracil failed to demonstrate survival superiority over sorafenib.14 In summary, sorafenib plus cisplatin-based HAIC does not provide survival benefits for advanced HCC compared to sorafenib alone.\n\nCompared with cisplatin, oxaliplatin has distinct pharmacokinetic, biochemical, cytotoxic, and immunological properties.15, 16, 17 Our previous phase 2 trial demonstrated the efficacy and safety of combined treatment with sorafenib and HAIC with FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 5-fluorouracil 400 mg/m2 on day 1, and 5-fluorouracil 2400 mg/m2 for 46 hours) in patients with HCC and major portal vein tumor thrombus (PVTT).18 However, some patients cannot tolerate infusion chemotherapy in bed for 2 days, and administration of 5-fluorouracil for a short time is useless as its action on tumor cells is time-dependent,19 and so these patients received arterial infusion of oxaliplatin (OXA) without leucovorin and 5-fluorouracil. In addition, one phase I study showed that HAI-oxaliplatin is a feasible, well tolerated, and demonstrated activity in patients with advanced HCC.20\n\nHerein, we aimed to compare the efficacy of sorafenib plus HAIC with oxaliplatin to that of sorafenib monotherapy in patients with advanced HCC.\n\nMethods\n\nStudy design and participants\n\nEthical approval was obtained from the Ethical Review Committee of Sun Yat-sen University Cancer Center for this retrospective study, and informed consent was obtained from all patients before conducting the treatment. The study was conducted in accordance with the principles of the Declaration of Helsinki. This study was conducted in 104 consecutive patients with advanced HCC who were treated with sorafenib plus HAI-OXA therapy (soraOXA group, n = 46) or sorafenib monotherapy (sorafenib group, n = 58) between April 3, 2017 and July 2, 2018. All recruited patients with hepatitis B virus-related HCC received preemptive antiviral therapy.\n\nThe inclusion criteria for this study were: 18 years or older, at least one complete cycle (3 weeks) of sorafenib plus HAIC or sorafenib alone, biopsy-confirmed HCC, BCLC stage C (advanced-stage), Child-Pugh A class liver function, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1, no previous treatment for HCC, at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1,21 and adequate organ function (white blood cell count ≥3.0 × 10⁹ per L, absolute neutrophil count ≥ 1.5 × 10⁹ per L, platelet count ≥75 × 10⁹ per L, aspartate transaminase and alanine transaminase levels of ≤5 × upper limit of the normal, creatinine clearance rate of ≤1.5 × upper limit of the normal, and left ventricular ejection ≥45%). The exclusion criteria were: hepatic decompensation, including esophageal or gastric variceal bleeding or hepatic encephalopathy, central nervous system metastases, a known history of human immunodeficiency virus (HIV) infection, pregnancy or breastfeeding, a secondary malignancy, patients who received a treatment crossover, and patients lost to follow-up.\n\nSorafenib cohort\n\nAll patients initially received the standard 400 mg dose of sorafenib twice daily. Treatment interruptions and dose reductions (to 400 mg once daily or to 400 mg every other day) were permitted in cases of adverse drug reactions.4 If further dose reductions were required, patients were withdrawn from the study.\n\nSorafenib plus HAIC cohort\n\nPatients in the soraOXA group were treated with 400 mg sorafenib orally twice daily every day, and the HAIC regimen was administered every 3 weeks. The start time of sorafenib and HAIC was within 1 week of each other.\n\nSorafenib was administered as above. For the HAIC, a 3.5 French catheter was inserted into the celiac trunk or superior mesenteric artery for arteriography, and both the gastroduodenal artery and the right gastric artery were embolized with a metallic coil. Then, a 2.7 French microcatheter was super selectively inserted and located in the feeding hepatic artery. The following regimen was administered via the hepatic artery: oxaliplatin 85 mg/m2 for 2 hours. After HAIC was completed, the catheter and sheath were removed. Repetitive catheterization was performed in the next HAIC cycle.\n\nHAIC was delayed until recovery if the neutrophil counts were less than 1200 cells/μL; platelet counts, less than 60 000 platelets/μL; total bilirubin levels, >30 mmol/L; albumin levels <3.0 mg/dL; or serum creatinine levels up to 1.5 times the institutional upper limit of normal. Dose reduction (to 65 mg/m2) was allowed in cases of intolerable (grade 3 or 4) drug-related toxicities.\n\nFollow-up and assessments\n\nSorafenib or sorafenib plus HAIC was continued as long as possible until one of the following criteria for cessation of therapy were met: death, adverse events that required termination of treatment, the need for another anticancer treatment (such as surgery), no benefit from treatment, or withdrawal of consent. When disease progression was observed and doctors considered that patients can benefit from treatment, sorafenib or sorafenib plus HAIC would be continued. Before treatment discontinuation, patient visits were scheduled every 3 weeks to monitor safety and clinical and biological parameters. Additionally, computed tomography scans were performed every 6 weeks.\n\nOverall survival was defined as the time from commencement of treatment to death from any cause, and progression-free survival was defined as the time from commencement of treatment to progression by RECIST criteria or death from any cause. Objective response rate was the proportion of patients with complete response or partial response according to RECIST version 1.1, and adverse events were according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.03.\n\nStatistical analyses\n\nBecause this was a retrospective study, no sample size calculations were performed. The results were compared using Student's t-tests or chi-square tests. Survival outcomes were calculated with the Kaplan-Meier method and compared by log-rank tests. Any factors that were statistically significant with a P value less than 0.10 in the univariate analysis were candidates for entry into a multivariable Cox proportional hazards model. All P values were two-sided, with P values less than 0.05 considered significant. The statistical package used to perform analyses was SAS, version 9.0 (SAS Institute).\n\nResults\n\nPatient characteristics and treatment\n\nBetween April 3, 2017 and July 2, 2018, 135 consecutive patients with advanced HCC were treated using either sorafenib plus HAI-OXA or sorafenib, and 104 patients met the inclusion criteria in this analysis: 46 patients underwent sorafenib plus HAIC and 58 patients underwent sorafenib (Fig. 1). The follow-up ended on April 1, 2019. The baseline characteristics of all patients included in the analysis are described in Table 1. There were no significant differences between groups. Of the 104 patients, 91 (87.5%) were infected with hepatitis B virus, 87 (83.7%) had multiple lesions, and 90 (86.5%) had PVTT that extended into the main portal vein (Vp4) or the first branch portal vein (Vp3).Fig. 1 Patients selection flow. HCC, hepatocellular carcinoma. HAIC, hepatic arterial infusion chemotherapy. OXA, oxaliplatin. SoraOXA group = sorafenib plus hepatic arterial infusion of oxaliplatin. Sorafenib group = Sorafenib monotherapy group.\n\nFig. 1\n\nTable 1 Patient baseline demographics and clinical characteristics.\n\nTable 1Characteristics\tBaseline characteristics analysis\tUnivariable analysis\t\nSoraOXA group (n = 46)\tSorafenib group (n = 58)\tP1 value\tMedian survival time, months\tP2 value\t\nAge, years\t\t\t0.55\t\t0.38\t\n ≤ 50\t27\t30\t\t4.8\t\t\n > 50\t19\t28\t\t7.33\t\t\nSex\t\t\t0.5\t\t0.51\t\n Male\t41\t54\t\t7\t\t\n Female\t5\t4\t\t6.57\t\t\nECOG\t\t\t0.77\t\t0.015\t\n 0\t7\t7\t\t11.17\t\t\n 1\t39\t51\t\t5.53\t\t\nHBsAg\t\t\t0.56\t\t0.91\t\n Negative\t7\t6\t\t5.5\t\t\n Positive\t39\t52\t\t6.83\t\t\nTumor size (cm)\t\t\t0.69\t\t0.13\t\n ≤ 10\t28\t33\t\t6.13\t\t\n > 10\t18\t25\t\t7.23\t\t\nTumor number\t\t\t0.26\t\t0.78\t\n Single\t9\t18\t\t7.13\t\t\n Multiple\t37\t40\t\t6.57\t\t\nPVTT degree\t\t\t0.76\t\t0.007\t\n Vp0-2\t5\t9\t\t8.2\t\t\n Vp3\t23\t29\t\t7.13\t\t\n Vp4\t18\t20\t\t5.13\t\t\nExtrahepatic sites, n (%)\t\t\t0.37\t\t0.026\t\n Absent\t37\t42\t\t7.13\t\t\n Present\t9\t16\t\t4.5\t\t\nAFP, ng/ml\t\t\t0.4\t\t0.57\t\n ≤ 400\t13\t22\t\t7.13\t\t\n > 400\t33\t36\t\t6.17\t\t\nAbbreviations: ECOG PS, Eastern Cooperative Oncology Group Performance Status; HBsAg, surface antigen of the hepatitis B virus; AFP, alpha-fetoprotein; PVTT, portal vein tumor thrombus; Vp4, main portal vein invasion; Vp3, first branch portal vein invasion; Vp2, second branch portal vein invasion; Vp1, third branch portal vein invasion.\n\nSoraOXA group = sorafenib plus hepatic arterial infusion of oxaliplatin. Sorafenib group = Sorafenib monotherapy group.\n\nP1 value was calculated by a two-sided Chi-square test.\n\nP2 value was calculated with two-sided log-rank test.\n\nAfter the termination of treatment, some patients received the following other subsequent therapies: resection (1 patient), PD-1 inhibitor treatment (6 patients), lenvatinib (4 patients), and TACE (2 patients) in the soraOXA group, and D-1 inhibitor treatment (8 patients), lenvatinib (5 patients), systemic chemotherapy (1 patient), and TACE (4 patients) in the sorafenib group.\n\nEfficacy\n\nPatients in the soraOXA group had a median overall survival of 9.37 months (95% confidence interval [CI], 7.05–11.68) compared with 4.8 months (95% CI, 2.98–6.62) in the sorafenib group (hazard ratio [HR] 0.46 [95% CI, 0.29–0.72]; P < 0.001; Fig. 2A). The results of the univariable survival analysis are listed in Table 1, and treatment allocation, ECOG score, PVTT degree, and the presence or absence of extrahepatic sites were found to be statistically significant at P < 0.05 on univariate analysis. In the multivariable analysis, independent risk factors of survival were treatment allocation (HR 0.38 [95% CI, 0.24–0.62], P < 0.001), ECOG score (HR 0.45 [95% CI, 0.22–0.94], P = 0.033), and portal vein invasion grade Vp0-2 vs Vp4 (HR 0.33 [95% CI, 0.16–0.67], P = 0.002).Fig. 2 Kaplan-Meier curves for overall survival (A), and progression-free survival (B). SoraOXA group = sorafenib plus hepatic arterial infusion of oxaliplatin. Sorafenib group = Sorafenib monotherapy group.\n\nFig. 2\n\nPatients in the soraOXA group had a significantly longer median progression-free survival (5.5 months [95% CI, 2.32–8.68]) than those in the sorafenib group (2.4 months [95% CI, 1.65–3.15]; HR 0.54 [95% CI, 0.36–0.81], P = 0.003; Fig. 2B). On the basis of RECIST, the overall response was significantly higher in the soraOXA group (34.8%, 16 of 46 patients) than in the sorafenib group (1.7%, 1 of 58 patients; Table 2; P < 0.001).Table 2 Best tumor responses by RECIST criteria.\n\nTable 2\tSoraOXA group (n = 46)\tSorafenib group (n = 58)\tP value\t\nComplete response\t0\t0\t\t\nPartial response\t16 (34.8%)\t1 (1.7%)\t<0.001\t\nStable disease\t15 (32.6%)\t29 (50%)\t0.11\t\nProgressive disease\t14 (30.4%)\t27 (46.6%)\t0.11\t\nNot evaluable*\t1 (2.2%)\t2 (3.4%)\t1.00\t\nObjective response\t16 (34.8%)\t1 (1.7%)\t<0.001\t\nDisease control rate\t31 (67.4%)\t30 (51.7%)\t0.12\t\nAbbreviations: RECIST, Response Evaluation Criteria in Solid Tumors.\n\nSoraOXA group = sorafenib plus hepatic arterial infusion of oxaliplatin. Sorafenib group = Sorafenib monotherapy group.\n\n*There were 3 patients who could not be evaluated for treatment response because of death, poor performance status, or patients' refusal of computed tomography scanning.\n\nStatistical significance was assessed with the chi-square test.\n\nSafety\n\nTreatment-related adverse events, which occurred in ≥10% of patients, are shown in Table 3. The overall incidence of treatment-related adverse events was similar between the soraOXA group and the sorafenib group (any grade: 40 [86.96%] vs 49 [84.48%], P = 0.79; grade 3/4: 20 [43.48%] vs 27 [46.55%], P = 0.84). Only “any grade sensory neuropathy” was higher in the soraOXA group (P < 0.001). Serious adverse events were reported in 5 (10.87%) of 46 patients in the soraOXA group (2 gastrointestinal bleeding, 2 renal failures, and 1 ascite) and 8 (13.79%) of 58 patients in the sorafenib group (2 gastrointestinal bleeding, 3 ascites, 1 hepatic encephalopathy, and 2 diarrhea) (P = 0.77).Table 3 Treatment-related adverse events*.\n\nTable 3Adverse event\tSoraOXA group (n = 46)\tSorafenib group (n = 58)\tP value\t\nAny grade\tGrades 3–4\tAny grade\tGrades 3–4\tAny grade\tGrades 3–4\t\nOverall incidence\t40\t20\t49\t27\t0.79\t0.84\t\nBlood/bone marrow suppression\t\n Neutropenia\t19\t3\t17\t2\t0.67\t0.65\t\n Thrombocytopenia\t21\t4\t25\t2\t0.84\t0.4\t\n Anemia\t22\t1\t21\t1\t0.32\t0.75\t\nSystemic toxicity\t\n Hypertension\t10\t1\t16\t2\t0.65\t1.00\t\n Edema\t7\t1\t5\t1\t0.36\t1.00\t\n Fatigue\t27\t1\t25\t1\t0.17\t1.00\t\n Weight loss\t14\t0\t19\t1\t0.84\t1.00\t\n Sensory neuropathy\t15\t0\t2\t0\t<0.001\t–\t\nDermatologic events\t\n Hand–foot skin reaction\t18\t4\t24\t7\t0.84\t0.75\t\n Alopecia\t6\t0\t10\t0\t0.6\t–\t\n Rash\t7\t0\t11\t1\t0.8\t1.00\t\nGastrointestinal events\t\n Nausea\t21\t3\t19\t1\t0.23\t0.32\t\n Vomiting\t16\t1\t12\t0\t0.12\t0.44\t\n Diarrhea\t12\t3\t17\t6\t0.83\t0.73\t\nHepatic function\t\n Elevated ALT\t27\t5\t36\t7\t0.84\t1.00\t\n Elevated AST\t30\t5\t33\t8\t0.43\t0.77\t\n Hyperbilirubinemia\t21\t1\t31\t1\t0.55\t1.00\t\nAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.\n\nSoraOXA group = sorafenib plus hepatic arterial infusion of oxaliplatin. Sorafenib group = sorafenib monotherapy group.\n\nP value was calculated by a two-sided chi-square test.\n\n*Listed are adverse events, as defined by the National Cancer Institute Common Terminology Criteria (version 4.03), that occurred in at least 10% of patients in either study group.\n\nPatients in the soraOXA group were treated with a total of 126 cycles of HAIC, and the median number of HAIC treatments administered to each patient was 3 (range, 1 to 6 cycles). In the soraOXA group, a dose reduction of oxaliplatin was performed in 3 (4.3%) patients because of grade 4 bone marrow suppression. There was no difference in the dose reduction of sorafenib (17 of 46 patients vs 20 of 58 patients, P = 0.84) and the interruption of sorafenib (13 of 46 patients vs 19 of 58 patients, P = 0.67) due to adverse events between the two groups. Reasons for treatment discontinuation are shown in Fig. 1, and there was no difference in the rates of permanent discontinuation due to adverse events between the two groups (4 of 46 patients vs 4 of 58 patients, P = 0.73).\n\nDiscussion\n\nThis is the first retrospective study to compare the efficacy and safety of OXA-based HAIC versus sorafenib in patients with advanced HCC. Compared with patients who received sorafenib alone, patients who received sorafenib plus HAIC with oxaliplatin had a significantly longer overall survival (9.37 vs 4.8 months), a markedly longer median progression-free survival (5.5 vs 2.4 months), and a significantly higher radiologic response rate (34.8% vs 1.7% by RECIST criteria). In addition, both sorafenib plus HAIC with oxaliplatin and sorafenib were well tolerated and had manageable side effects.\n\nThe survival benefit demonstrated in this study may be partly due to the synergistic antitumor effect of sorafenib and chemotherapeutic agents. Sorafenib has multiple targets, including Raf-1, Braf, VEGFR-1-3, and PDGFR-β, and the inhibition of Raf-1 by sorafenib can induce apoptosis and help overcome resistance to chemotherapeutic agents.10 Moreover, sorafenib may induce vessel normalization in HCC and increase drug delivery.12 Besides, sorafenib has been shown to interact with platinum transporter proteins.22 Finally, compared with an implanted port catheter system, repetitive catheterization and digital subtraction angiography before starting each session of HAIC is more reliable for concentrating the chemotherapy dose in the targeted area and avoiding anticancer drug exposure in other organs.\n\nIn this trial, overall survival in the soraOXA group was lower than that observed in our phase 2 trial with sorafenib plus FOLFOX-based HAIC (overall survival: 9.37 months [95% CI, 7.05–11.68] vs 13.2 months [95% CI, 5.4–21]),18 but the objective response rate was similar between the two studies (34.8% vs 40% using RECIST criteria). The survival difference may be related to the lack of infusion of 5-fluorouracil in this study, and experimental data showed synergistic activity of the oxaliplatin/5-fluorouracil combination.23,24 The similar response might be explained by the fact that oxaliplatin played a major role in tumor reduction, and two randomized trials about colorectal cancer showed that the objective response rate was more than two times higher in patients who received oxaliplatin plus 5-fluorouracil than in patients who received 5-fluorouracil alone.25,26 Whether sorafenib plus HAIC with FOLFOX is superior to sorafenib plus HAIC with oxaliplatin needs to be assessed in further randomized prospective trials. In addition, the overall survival among participants in the sorafenib group in this study appeared to be less satisfactory than that in previous studies,4,5 because this trial enrolled patients with more advanced tumors; 86.5% (90 of 104 patients) had advanced PVTT (Vp3 or Vp4).\n\nMoreover, the adverse events in the soraOXA group were slightly lower than those observed in our phase 2 study,18 and all sorafenib-related adverse events were consistent with those in previous trials of sorafenib.4,5 Although patients treated with sorafenib plus HAIC had significantly elevated frequencies of any grade sensory neuropathy that is related to oxaliplatin, these adverse events were not unexpected and were manageable by treatment interruption or dose modification. In addition, there was no significant difference in the overall incidence of any grade or grade 3/4 adverse events between groups.\n\nThe present study has some limitations. First, the study included only a small number of patients and was retrospective in nature. A large-scale prospective trial should be performed in the future to verify the efficacy of sorafenib plus oxaliplatin in patients with advanced HCC. Second, this study was performed in an endemic area. The predominant etiology of HCC in China was hepatitis B virus. Therefore, whether the results could be applied to western countries, where the etiology of hepatocellular carcinoma is mainly hepatitis C virus, remains to be elucidated.\n\nIn summary, sorafenib plus HAIC with oxaliplatin showed a favorable efficacy and safety in patients with advanced HCC, resulting in a significantly higher objective response rate, longer progression-free survival, and longer overall survival than those with sorafenib alone. Further prospective studies are needed to clarify the results.\n\nFunding\n\nThis work was supported by 10.13039/501100012166 National Key R&D Program of China (2017YFA0505803), 10.13039/501100001809 National Natural Science Foundation of China (No. 81625017, No.81572385), 10.13039/501100012166 National Science and Technology Major Project of China (2018ZX10302205).\n==== Refs\nReferences\n\n1 Global Burden of Disease Cancer C. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study JAMA Oncol 3 2017 524 548\n2 Cabibbo G. Enea M. Attanasio M. A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma Hepatology 51 2010 1274 1283 20112254\n3 Forner A. Reig M.E. de Lope C.R. Current strategy for staging and treatment: the BCLC update and future prospects Semin Liver Dis 30 2010 61 74 20175034\n4 Llovet J.M. Ricci S. Mazzaferro V. Sorafenib in advanced hepatocellular carcinoma N Engl J Med 359 2008 378 390 18650514\n5 Cheng A.L. Kang Y.K. Chen Z. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial Lancet Oncol 10 2009 25 34 19095497\n6 Kudo M. Matsui O. Izumi N. JSH consensus-based clinical practice guidelines for the management of hepatocellular carcinoma: 2014 update by the liver cancer study group of Japan Liver canc 3 2014 458 468\n7 Ando E. Tanaka M. Yamashita F. Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: analysis of 48 cases Cancer 95 2002 588 595 12209752\n8 Park J.Y. Ahn S.H. Yoon Y.J. Repetitive short-course hepatic arterial infusion chemotherapy with high-dose 5-fluorouracil and cisplatin in patients with advanced hepatocellular carcinoma Cancer 110 2007 129 137 17508408\n9 Qin S. Bai Y. Lim H.Y. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia J Clin Oncol : Off. J. Am. Soc. Clin. Oncol. 31 2013 3501 3508\n10 Ma S.Q. Cao B.R. Zhang H. The lack of Raf-1 kinase feedback regulation enhances antiapoptosis in cancer cells Oncogene 36 2017 2014 2022\n11 Malofeeva E.V. Domanitskaya N. Gudima M. Modulation of the ATPase and transport activities of broad-acting multidrug resistance factor ABCC10 (MRP7) Cancer Res 72 2012 6457 6467 23087055\n12 Lewin M. Fartoux L. Vignaud A. The diffusion-weighted imaging perfusion fraction f is a potential marker of sorafenib treatment in advanced hepatocellular carcinoma: a pilot study Eur Radiol 21 2011 281 290 20683597\n13 Ikeda M. Shimizu S. Sato T. Sorafenib plus hepatic arterial infusion chemotherapy with cisplatin versus sorafenib for advanced hepatocellular carcinoma: randomized phase II trial Ann Oncol 27 2016 2090 2096 27573564\n14 Kudo M. Ueshima K. Yokosuka O. Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial The lancet Gastroenterol. Hepatol 3 2018 424 432 29631810\n15 Bruno P.M. Liu Y. Park G.Y. A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress Nat Med 23 2017 461 471 28263311\n16 Dzodic R. Gomez-Abuin G. Rougier P. Pharmacokinetic advantage of intra-arterial hepatic oxaliplatin administration: comparative results with cisplatin using a rabbit VX2 tumor model Anti Cancer Drugs 15 2004 647 650 15205611\n17 Tesniere A. Schlemmer F. Boige V. Immunogenic death of colon cancer cells treated with oxaliplatin Oncogene 29 2010 482 491 19881547\n18 He M.K. Zou R.H. Li Q.J. Phase II study of sorafenib combined with concurrent hepatic arterial infusion of oxaliplatin, 5-fluorouracil and leucovorin for unresectable hepatocellular carcinoma with major portal vein thrombosis Cardiovasc Interv Radiol 41 2018 734 743\n19 Calabro-Jones P.M. Byfield J.E. Ward J.F. Time-dose relationships for 5-fluorouracil cytotoxicity against human epithelial cancer cells in vitro Cancer Res 42 1982 4413 4420 7127282\n20 Rathore R. Safran H. Soares G. Phase I study of hepatic arterial infusion of oxaliplatin in advanced hepatocellular cancer: a brown university oncology group study Am J Clin Oncol 33 2010 43 46 19687731\n21 Eisenhauer E.A. Therasse P. Bogaerts J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer 45 2009 228 247 19097774\n22 Heim M. Scharifi M. Zisowsky J. The Raf kinase inhibitor BAY 43-9006 reduces cellular uptake of platinum compounds and cytotoxicity in human colorectal carcinoma cell lines Anti Cancer Drugs 16 2005 129 136 15655409\n23 Raymond E. Buquet-Fagot C. Djelloul S. Antitumor activity of oxaliplatin in combination with 5-fluorouracil and the thymidylate synthase inhibitor AG337 in human colon, breast and ovarian cancers Anti Cancer Drugs 8 9 1997 876 885 9402315\n24 Mathe G. Kidani Y. Segiguchi M. Oxalato-platinum or 1-OHP, a third-generation platinum complex: an experimental and clinical appraisal and preliminary comparison with cis-platinum and carboplatinum Biomed Pharmacother 43 1989 237 250 2675999\n25 de Gramont A. Figer A. Seymour M. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer J Clin Oncol 18 2000 2938 2947 10944126\n26 Giacchetti S. Perpoint B. Zidani R. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer J Clin Oncol 18 2000 136 147 10623704\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2590-0293",
"issue": "2(2)",
"journal": "Journal of interventional medicine",
"keywords": "Barcelona clinic liver cancer stage C; Hepatic arterial infusion chemotherapy; Hepatocellular carcinoma; Oxaliplatin; Sorafenib",
"medline_ta": "J Interv Med",
"mesh_terms": null,
"nlm_unique_id": "9918265602006676",
"other_id": null,
"pages": "78-83",
"pmc": null,
"pmid": "34805877",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article",
"references": "19095497;26280007;23087055;20175034;9402315;19687731;19881547;20112254;17508408;29327075;29631810;15205611;27918777;12209752;27841865;18650514;19097774;2675999;23980077;10944126;28263311;10623704;20683597;7127282;15655409;27573564",
"title": "Sorafenib plus hepatic arterial infusion chemotherapy with oxaliplatin versus sorafenib alone for advanced hepatocellular carcinoma.",
"title_normalized": "sorafenib plus hepatic arterial infusion chemotherapy with oxaliplatin versus sorafenib alone for advanced hepatocellular carcinoma"
} | [
{
"companynumb": "CN-BAYER-2020-029846",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": null,
"... |
{
"abstract": "Ultrasound-guided thrombin injection (UGTI) has emerged as the first-line treatment for moderately sized or persistent pseudoaneurysms (PSAs). Although rare, the most feared complication of UGTI is arterial thrombosis or embolism during the off-label injection of thrombin causing acute limb ischemia requiring emergent surgical intervention. Higher thrombin volume, rapidity of injection, and wide or short-neck PSAs are all thought to increase the risk of arterial thrombosis or embolism during this procedure. For patients with unfavorable PSA anatomy who are high-risk surgical candidates due to their medical comorbidities or active critical illness, balloon-assisted thrombin injection (BATI) has been suggested as a means to potentially reduce the risk of thrombosis or distal embolization associated with UGTI. This minimally invasive technique also decreases the risk of groin wound dehiscence or infection associated with open repair, especially in patients who are morbidly obese or have had prior groin surgery. We report a patient with a complex femoral artery PSA after endovascular intervention who was successfully treated with BATI and describe the procedure in detail.",
"affiliations": "Department of Cardiovascular Surgery, Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, TX, USA.;Department of Cardiovascular Surgery, Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, TX, USA.;Department of Cardiovascular Surgery, Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, TX, USA.;Department of Cardiovascular Surgery, Methodist DeBakey Heart & Vascular Center, Houston Methodist Hospital, Houston, TX, USA.",
"authors": "Vowels|Travis J|TJ|;Zubair|M Mujeeb|MM|https://orcid.org/0000-0003-4224-0048;Bismuth|Jean|J|;Le|Linda|L|",
"chemical_list": "D013917:Thrombin",
"country": "United States",
"delete": false,
"doi": "10.1177/1538574420927861",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-5744",
"issue": "54(6)",
"journal": "Vascular and endovascular surgery",
"keywords": "balloon-assisted; iatrogenic; pseudoaneurysm; thrombin injection; ultrasound-guided",
"medline_ta": "Vasc Endovascular Surg",
"mesh_terms": "D017541:Aneurysm, False; D021721:Balloon Occlusion; D005260:Female; D005263:Femoral Artery; D006801:Humans; D007049:Iatrogenic Disease; D007269:Injections, Intra-Arterial; D008875:Middle Aged; D013917:Thrombin; D016896:Treatment Outcome; D018084:Ultrasonography, Interventional; D057772:Vascular System Injuries",
"nlm_unique_id": "101136421",
"other_id": null,
"pages": "532-535",
"pmc": null,
"pmid": "32452286",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Balloon-Assisted Ultrasound-Guided Percutaneous Thrombin Injection of Iatrogenic Femoral Artery Pseudoaneurysms: A Case Report and Description of the Technique.",
"title_normalized": "balloon assisted ultrasound guided percutaneous thrombin injection of iatrogenic femoral artery pseudoaneurysms a case report and description of the technique"
} | [
{
"companynumb": "US-TEVA-2020-US-1815216",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "A 67-year-old man with history of heart failure developed dyspnea. In this report, we describe an increase in his device-detected respiratory rate. Monitoring respiratory rate is recommended for evaluating acute cardiac decompensation, but such an algorithm could also be used to diagnose episodes of pneumonia caused by severe acute respiratory syndrome-coronavirus-2 infection. (Level of Difficulty: Intermediate.).",
"affiliations": "Cardiac Electrophysiology and Pacing Unit, ASST Papa Giovanni XXIII, Bergamo, Italy.;Boston Scientific Italia, Milan, Italy.;Cardiac Electrophysiology and Pacing Unit, ASST Papa Giovanni XXIII, Bergamo, Italy.;Cardiology Unit, ASST Papa Giovanni XXIII, Bergamo, Italy.;Cardiac Electrophysiology and Pacing Unit, ASST Papa Giovanni XXIII, Bergamo, Italy.",
"authors": "Malanchini|Giovanni|G|;Malacrida|Maurizio|M|;Ferrari|Paola|P|;Senni|Michele|M|;De Filippo|Paolo|P|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jaccas.2021.03.012",
"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(21)00303-X\n10.1016/j.jaccas.2021.03.012\nImaging Vignette\nClinical Vignette\nRemote Monitoring of Respiratory Pattern in an ICD Patient With COVID-19 Pneumonia\nMalanchini Giovanni MD gmalanchini@asst-pg23.it\na∗\nMalacrida Maurizio MSc b\nFerrari Paola MD a\nSenni Michele MD c\nDe Filippo Paolo MD a\na Cardiac Electrophysiology and Pacing Unit, ASST Papa Giovanni XXIII, Bergamo, Italy\nb Boston Scientific Italia, Milan, Italy\nc Cardiology Unit, ASST Papa Giovanni XXIII, Bergamo, Italy\n∗ Address for correspondence: Dr. Giovanni Malanchini, Cardiac Electrophysiology and Pacing Unit, ASST Papa Giovanni XXIII, Bergamo, Italy. gmalanchini@asst-pg23.it\n05 5 2021\n07 7 2021\n05 5 2021\n3 7 10071009\n15 1 2021\n16 2 2021\n18 3 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/).\nA 67-year-old man with history of heart failure developed dyspnea. In this report, we describe an increase in his device-detected respiratory rate. Monitoring respiratory rate is recommended for evaluating acute cardiac decompensation, but such an algorithm could also be used to diagnose episodes of pneumonia caused by severe acute respiratory syndrome-coronavirus-2 infection. (Level of Difficulty: Intermediate.)\n\nCentral Illustration\n\nKey Words\n\ncardiology\ncase report\nCOVID-19\nimplantable cardioverter-defibrillator\nremote monitoring\nrespiratory rate trend\nSARS-CoV-2\nAbbreviations and Acronyms\n\nCRT, cardiac resynchronization therapy\nCOVID-19, coronavirus disease-2019\nICD, implantable cardioverter-defibrillator\nPPM, pacemaker\nRR, respiratory rate\nRRT, respiratory rate trend\nSARS-CoV-2, severe acute respiratory syndrome-coronavirus-2\n==== Body\nImplantable devices, including implantable cardioverter-defibrillators (ICDs), cardiac resynchronization therapy (CRT), and pacemakers (PPMs), enable continuous measurement of clinical variables and access to patients' data via remote monitoring systems. It remains unclear whether such technologies could provide useful insights into coronavirus disease-2019 (COVID-19)−related infections because no clinical experience has yet been reported.\n\nWe report the case of a patient who tested positive for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection and who was implanted with an ICD (AUTOGEN X4 cardiac resynchronization therapy defibrillator; Boston Scientific, St. Paul, Minnesota) equipped with respiratory rate trend (RRT), a diagnostic algorithm for continuous respiratory rate (RR) monitoring and followed-up with the LATITUDE (Boston Scientific) remote monitoring system.\n\nA 67-year-old man with a history of hypertension, diabetes, permanent atrial fibrillation, and myocardial infarction developed signs and symptoms of COVID-19 and was admitted to the hospital in March 2020.\n\nHe was treated with acetaminophen, azithromycin, hydroxychloroquine, and oxygen supplementation with a nasal cannula and a Venturi mask. His symptoms began to resolve in the second week of the hospital stay, and he was discharged on April 11.\n\nAs depicted in Figure 1, there was an increase in the device-detected RR from an average of 17 respirations/min recorded on the first day of symptom onset to a peak of 22 respirations/min, recorded 2 to 3 days after admission. RRT continued to show values higher than average during the recovery phase, whereas the patient continued to receive oxygen, and RRT reached its nadir before discharge.Figure 1 Clinical Course of Coronavirus Disease-19 Symptoms and Clinically Relevant Parameters, Together With Device-Detected Respiratory Rate Trend in a Patient With an Implantable Cardioverter Defibrillator\n\nThe x axis represents time. (Top) Respiratory rate variations. (Middle) Daily activity level is plotted. The yellow lines represent days of symptom onset and hospital discharge. (Bottom) Super-imposed red lines refer to daily temperature as extracted from patient’s medical record.\n\nCardiovascular diseases are dynamic entities, but they may have acute manifestations for which it is common to require urgent evaluation and intervention. Because COVID-19 has forced cardiologists to minimize in-person clinic visits and defer interventions, physicians are asked to make new decisions regarding new urgencies in a new setting (1). Device-based continuous monitoring of a patient’s derived parameters could be helpful for diagnostic and prognostic evaluation of clinical conditions after device implantation, thereby potentially improving the remote clinical management of patients with cardiac devices (e.g., ICDs, CRT, or PPMs), especially during the ongoing pandemic.\n\nRecent reports have highlighted the substantial decrease in activity level recorded through continuous monitoring of cardiac devices as an important phenomenon during the COVID-19 pandemic (2). In the past decade, cardiac devices capable of measuring the RRT have been developed. In the MultiSENSE (Multisensor Chronic Evaluation in Ambulatory Heart Failure Patients) study, the novel HeartLogic algorithm for heart failure monitoring (Boston Scientific), which combines data from multiple device-based sensors and includes RRT function, was implemented. Notably, this index proved to be a sensitive and timely predictor of impending heart failure decompensation (3). Although monitoring RR is recommended by international guidelines primarily for evaluating acute decompensation, such an algorithm could also be useful to evaluate episodes of a sudden increase in RR, a potential sign of respiratory illness, such as pneumonia caused by SARS-CoV-2 infection.\n\nThe case provided a first step in elucidating how data derived from continuous and remote monitoring of relevant variables could help an uneventful situation; we reported a potential new application for the detection of possible new COVID-19 infections.\n\nFunding Support and Author Disclosures\n\nM. Malacrida is an employee of Boston Scientific. The other authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. M. Malacrida is Boston Scientific employee. For more information, visit the Author Center.\n==== Refs\nReferences\n\n1 Archer S.L. Sharp W.W. Weir E.K. Differentiating COVID-19 pneumonia from acute respiratory distress syndrome and high altitude pulmonary edema: therapeutic implications Circulation 142 2020 101 104 32369390\n2 Malanchini G. Malacrida M. Ferrari P. Impact of the coronavirus disease-19 outbreak on physical activity of patients with implantable cardioverters J Card Fail 26 2020 898 899 32827643\n3 Boehmer J.P. Hariharan R. Devecchi F.G. A multisensor algorithm predicts heart failure events in patients with implanted devices: results from the MultiSENSE study J Am Coll Cardiol 5 2017 216 225\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2666-0849",
"issue": "3(7)",
"journal": "JACC. Case reports",
"keywords": "COVID-19; COVID-19, coronavirus disease-2019; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator; PPM, pacemaker; RR, respiratory rate; RRT, respiratory rate trend; SARS-CoV-2; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2; cardiology; case report; implantable cardioverter-defibrillator; remote monitoring; respiratory rate trend",
"medline_ta": "JACC Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101757292",
"other_id": null,
"pages": "1007-1009",
"pmc": null,
"pmid": "33972934",
"pubdate": "2021-07-07",
"publication_types": "D016428:Journal Article",
"references": "28254128;32369390;32827643",
"title": "Remote Monitoring of Respiratory Pattern in an ICD Patient With COVID-19 Pneumonia.",
"title_normalized": "remote monitoring of respiratory pattern in an icd patient with covid 19 pneumonia"
} | [
{
"companynumb": "IT-NOVARTISPH-NVSC2022IT054145",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZITHROMYCIN DIHYDRATE"
},
"drugaddition... |
{
"abstract": "Background: Constipation is a common gastrointestinal disorder that in general population is associated with worse health-related quality of life (HRQoL). The epidemiology of constipation has not been reliably determined in conservatively-treated CKD patients. We aimed to determine the prevalence of constipation and constipation-related symptoms in conservatively-treated CKD patients, to find factors associated with their altered prevalence ratio (PR), and to verify the associations between constipation and HRQoL. Methods: In this cross-sectional study, 111 conservatively-treated CKD outpatients fulfilled questionnaires that included questions addressing HRQoL (SF-36v2®), constipation-related symptoms (The Patient Assessment of Constipation-Symptoms questionnaire), the Bristol stool form scale (BSFS), Rome III criteria of functional constipation (FC), and frequency of bowel movement (BM). Results: Depending on the used definition, the prevalence of constipation was 6.6-28.9%. Diuretics and paracetamol were independently associated with increased PR of BSFS-diagnosed constipation (PR 2.86, 95% CI 1.28-6.37, P = 0.01) and FC (PR 2.67, 95% CI 1.07-6.64, P = 0.035), respectively. The most commonly reported symptoms were bloating (50.9%) and straining to pass a BM (42.7%). Abdominal discomfort (37.3%) was independently associated with worse scores in all analyzed HRQoL domains. In multiple regressions, FC and having <7 BM/week, but not BSFS-diagnosed constipation, were associated with lower scores in several HRQoL domains. Conclusions: Constipation and related symptoms are prevalent in CKD patients. FC and decreased frequency of defecation, but not BSFS-diagnosed constipation, are associated with worse assessment of HRQoL in conservatively-treated CKD patients.",
"affiliations": "Department of Pathophysiology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.;Department of Nephrology, Transplantology and Internal Medicine, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.;Department of Nephrology, Transplantology and Internal Medicine, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.;Department of Nephrology, Transplantology and Internal Medicine, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.;Department of Nephrology, Transplantology and Internal Medicine, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.;Department of Pathophysiology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.;Department of Nephrology, Transplantology and Internal Medicine, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.",
"authors": "Ruszkowski|Jakub|J|;Heleniak|Zbigniew|Z|;Król|Ewa|E|;Tarasewicz|Agnieszka|A|;Gałgowska|Joanna|J|;Witkowski|Jacek M|JM|;Dębska-Ślizień|Alicja|A|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.7150/ijms.49648",
"fulltext": "\n==== Front\nInt J Med Sci\nInt J Med Sci\nijms\nInternational Journal of Medical Sciences\n1449-1907 Ivyspring International Publisher Sydney \n\n10.7150/ijms.49648\nijmsv17p2954\nResearch Paper\nConstipation and the Quality of Life in Conservatively Treated Chronic Kidney Disease Patients: A Cross-sectional Study\nRuszkowski Jakub 12✉ Heleniak Zbigniew 2 Król Ewa 2 Tarasewicz Agnieszka 2 Gałgowska Joanna 2 Witkowski Jacek M. 1 Dębska-Ślizień Alicja 2 1 Department of Pathophysiology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland\n2 Department of Nephrology, Transplantology and Internal Medicine, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland\n✉ Corresponding author: Jakub Ruszkowski, MD, Department of Pathophysiology, Medical University of Gdańsk, Dębinki 7, 80-211 Gdańsk, Poland. Tel.: +48 58 349 15 12; E-mail: jakub.ruszkowski@gumed.edu.plCompeting Interests: The authors have declared that no competing interest exists.\n\n\n2020 \n18 10 2020 \n17 18 2954 2963\n18 6 2020 31 8 2020 © The author(s)2020This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.Background: Constipation is a common gastrointestinal disorder that in general population is associated with worse health-related quality of life (HRQoL). The epidemiology of constipation has not been reliably determined in conservatively-treated CKD patients. We aimed to determine the prevalence of constipation and constipation-related symptoms in conservatively-treated CKD patients, to find factors associated with their altered prevalence ratio (PR), and to verify the associations between constipation and HRQoL.\n\nMethods: In this cross-sectional study, 111 conservatively-treated CKD outpatients fulfilled questionnaires that included questions addressing HRQoL (SF-36v2®), constipation-related symptoms (The Patient Assessment of Constipation‐Symptoms questionnaire), the Bristol stool form scale (BSFS), Rome III criteria of functional constipation (FC), and frequency of bowel movement (BM).\n\nResults: Depending on the used definition, the prevalence of constipation was 6.6-28.9%. Diuretics and paracetamol were independently associated with increased PR of BSFS-diagnosed constipation (PR 2.86, 95% CI 1.28-6.37, P = 0.01) and FC (PR 2.67, 95% CI 1.07-6.64, P = 0.035), respectively. The most commonly reported symptoms were bloating (50.9%) and straining to pass a BM (42.7%). Abdominal discomfort (37.3%) was independently associated with worse scores in all analyzed HRQoL domains. In multiple regressions, FC and having <7 BM/week, but not BSFS-diagnosed constipation, were associated with lower scores in several HRQoL domains.\n\nConclusions: Constipation and related symptoms are prevalent in CKD patients. FC and decreased frequency of defecation, but not BSFS-diagnosed constipation, are associated with worse assessment of HRQoL in conservatively-treated CKD patients.\n\nchronic kidney diseaseconstipationflatulenceSF-36v2\n==== Body\nIntroduction\nConstipation is a common gastrointestinal problem. In the general population of Europe, the mean value of the reported constipation prevalence is 17.1%, and its higher value is frequently associated with older age, female sex, less self-reported physical activity, and certain medications 1, 2. In general population, constipation is associated not only with worse health-related quality of life (HRQoL) 3, 4 but also with higher risk of cardiovascular events and all-cause mortality 5-7.\n\nChronic kidney disease (CKD), that is defined as abnormalities of kidney structure or function, present for >3 months, with implications for health 8, is a condition affecting approximately 9.1-13.4% of the global population 9, 10. The severity of CKD is divided into 5 stages (G1-G5) according to the level of glomerular filtration rate (GFR). Recent studies suggest a two-way relationship between constipation and CKD. On the one hand, the presence of constipation is independently associated with a higher risk of developing CKD and end-stage renal disease (ESRD); it is hypothesized that these relationships can be mediated by an altered gut microbiota and/or be a result of common cause such as lack of regular physical activity 11-13. On the other hand, CKD since its moderate stage (i.e. G3b, eGFR < 45 ml/min/1.73 m2) is known to be associated with several upper gastrointestinal symptoms such as loss of appetite and vomiting 14. As the disease progresses, the prevalence of the gastrointestinal (GI) symptoms increases 14, 15. Among all GI symptoms, constipation is the most frequently assessed GI symptom in dialysis patients, and the prevalence of constipation is higher in hemodialysis (HD) patient than in peritoneal dialysis (PD) patients (23.8-71.7% vs 14.2-28.9% of patients, respectively) 16. In dialysis patients, like in a general population, constipation is associated with worse HRQoL 17.\n\nHowever, there is little known on the epidemiology of constipation and related symptoms in patients in the earlier stages of CKD (non-ESRD) 18. The present study aimed to determine the prevalence of constipation and constipation-related symptoms in conservatively-treated CKD patients, to find factors associated with their altered prevalence ratio (PR), and to verify the associations between the occurrence of constipation and HRQoL.\n\nMaterials and Methods\nThis cross-sectional study was carried out within the time frame of June 2018 and December 2019. We recruited a total of 111 outpatients that were visiting Nephrological Outpatient Clinic, a part of the University Clinical Centre in Gdańsk. Ethical permission for the study was obtained from the Bioethical Committee for Scientific Research at the Medical University of Gdańsk (NKBBN/426-56/2018).\n\nThe participants were selected according to the following criteria: diagnosis of CKD, age above 18 years, voluntary participation. Exclusion criteria were receiving currently or in the past dialysis, kidney transplantation, cognitive deficits and visual impairment that unable of answering the questionnaire; having a serious illness in an acute treatment phase. All patients were informed about the nature and purposes of the study. As the research was based on the voluntarily filled anonymous surveys, additional written informed consents were unnecessary and were not collected.\n\nAll included participants were asked to voluntarily complete questionnaires that included a battery of surveys: (1) addressing the HRQoL: the Polish versions of the SF-36v2® Health Survey (SF-36v2); (2) addressing symptoms of constipation: a question about the number of defecation per week, The Patient Assessment of Constipation‐Symptoms (PAC‐SYM) questionnaire 19, simple questions containing Rome III criteria of functional constipation (FC) 20, and a request to select the most common stool consistency on the Bristol stool form scale (BSFS) 21, 22.\n\nThe physician completed a questionnaire that included multiple-choice questions about comorbidities (diabetes, hypertension, heart failure, hypothyroidism, depression, inflammatory bowel disease) and taken medications (iron, calcium, vitamin D, antihistamines, calcium channel blockers, beta-blockers, diuretics, hypnotics, tricyclic antidepressants, nonsteroidal anti-inflammatory drugs, paracetamol, lactulose, other laxatives, probiotics, oral contraceptives). Data on sex, age, body weight, height, estimated glomerular filtration rate (eGFR) based on CKD-EPI formula, and etiology of CKD were collected. The body mass index (BMI) was calculated as the body weight divided by the square of the body height.\n\nTo use the SF-36v2, a non-commercial license agreement was made between JR and OptumInsight Life Sciences, Inc. (license number: QM044526). Validation and scoring of SF-36v2 were performed using desktop scoring software PRO CoRE Version 1.4 provided by Optum. The SF-36v2 questionnaire consists of 36 items that measure eight dimensions of HRQoL: physical functioning (PF); role limitations due to physical health problems (RP); bodily pain (BP); general health perception (GH); vitality (VT); social functioning (SF); role limitations due to emotional problems (RE); and mental health (MH). All dimensions are scored such that higher scores indicate better HRQoL. Firstly, the reliability and validity of subscales were tested (Supplementary material, Table S1). Only the GH subscale was neither reliable (Cronbach's alpha = 0.65) nor valid. This finding is supported by Żołnierczyk-Zreda who found that all subscales of the Polish version of SF-36v2, besides GH (Cronbach's alpha = 0.63), are reliable in general population 23. Based on the poor reliability and validity of GH, it was excluded from further analysis.\n\nTo use the PAC-SYM, a non-commercial license agreement was made between JR and Mapi Research Trust (license number: 10328). The questionnaire contains 12 items assessing the severity of abdominal, rectal, and stool symptoms of constipation 19. Items are scored on 5‐point Likert scale (0 = “symptom absent”, 1 = “mild”, 2 = “moderate”, 3 = “severe”, and 4 = “very severe”). In statistical analysis, due to small number of patients reporting “severe” or “very severe” symptoms, they were counted together with patients reporting “moderate” severity of symptoms.\n\nIn the context of BSFS, constipation was defined as either type 1 (“Separate hard lumps, like nuts (difficult to pass)”) or type 2 (“Sausage-shaped but lumpy”) stool form. For the diagnosis of FC, the presence of at least 2 out of 6 symptoms (straining; lumpy or hard stools; sensation of incomplete evacuation; sensation of anorectal obstruction or blockage during defecation; less than three bowel movements per week; need for manual maneuvers to facilitate defecation) in at least 25% of the defecations, for at least 3 months, with symptom onset at least 6 months before diagnosis, had been met 20.\n\nStatistical analysis\nTesting the normality of the distribution of collected data was performed using the Shapiro-Wilk test. Continuous variables with non-normal distribution were presented using medians and interquartile ranges (IQR). Categorical variables were presented as a percentage share of the obtained data. Patient groups were compared using Mann-Whitney U, Kruskal-Wallis ANOVA, and Pearson's chi-squared (χ2) tests. Statistical testing was done with Statistica, v.13.0 (StatSoft Polska, Inc. 2016) and Python libraries: Pandas 24, Pingouin 25, Statsmodels 26. P values < 0.05 were considered significant. P values for multiple comparisons were adjusted using Hommel method. Figure 2 was designed in Microsoft Excel 2013.\n\nDue to high disproportion in number of patients across stages of CKD, patients were divided into 3 groups according to eGFR terciles: with low eGFR (≤ 32 ml/min/1.73 m²), medium eGFR (33-43 ml/min/1.73 m²), and high eGFR (≥44 ml/min/1.73 m²). Correlations between eGFR terciles and symptoms severities were presented as Goodman-Kruskal gamma coefficient, and their significance was tested with Z-test.\n\nAs several variables were suspected to be associated with constipation, we used Poisson regression models with robust variance (computed with Statsmodels adaptation of R code published by Gallis and Turner 27) to estimate prevalence ratio (PR) simultaneously controlling for multiple variables. Potential predictors of constipation occurrence were age, BMI, sex, eGFR terciles, comorbidities (all besides hypertension as it is not associated with altered gastrointestinal motility in the literature), and taking specific medications. All variables were initially tested in univariate Poisson regression models with robust variance. If P value of model testing the association between taking a drug and constipation was lower than 0.20, this variable was selected for inclusion into a single Poisson regression model with all variables related to demographics and comorbidities. If the interaction between sex and age was statistically significant, it was added to the multiple regression model.\n\nTo determine whether constipation or constipation-related symptoms were independently associated with altered score in any of the HRQoL domain, multivariable ordinary least squares regressions were applied. Each of the models was adjusted to sex, age, BMI, eGFR tercile and comorbidities. Such models were shown if both GI symptom coefficient significantly differs from zero (T-test) and its adding to model significantly improves model (ANOVA F-test). To select final model for each HRQoL domain, among models with all combinations of GI symptoms from the previous step, one was chosen based on Akaike's information criterion that aims to balance goodness‑of‑fit and model complexity.\n\nResults\nWe have screened 150 patients. The main exclusion criteria were as follows: visual impairment that made it impossible to complete the questionnaire; lack of consent without explaining the reason.\n\nDemographics and comorbidities\nDemographics and comorbidities were presented in Table 1. Except for the higher frequency of hypothyroidism in women (26.5% vs men: 8.1%; unadjusted P = 0.009, adjusted P = 0.04), no other differences were found between sexes. Similarly, patients divided into groups based on terciles of eGFR did not differ between each other in manner of comorbidities nor BMI, but patients with medium eGFR were significantly older than those with high eGFR (adjusted P = 0.01; post-hoc P = 0.005).\n\nConstipation and related symptoms\nThe median number of defecation per week was 7 (IQR: 6-7). No differences were found in the frequency of defecation neither between genders nor among eGFR terciles (data not shown). In Figure 1, the distribution of bowel movements (BMs) frequency per week was shown. The majority of patients—43.4%—reported a mean seven BMs a week. Lower frequency of defecation occurred in 35.8% of patients, and 6.6% of patients reported frequency even lower than three BMs a week. In contrast, 20.8% of patients had BM more often than once a day. Interestingly, lower than mean 7 BMs per week was reported by 25.0%, 39.4%, and 43.2% of patients with high, medium, and low eGFR, but the observed difference was insignificant (P = 0.23).\n\nThe most commonly reported symptoms in the PAC-SYM questionnaire were following: bloating (50.9%), straining/squeezing to pass BM (42.7%), too hard stool (39.1%), abdominal discomfort (37.3%), and feeling of incomplete BM (34.5%). If a symptom was reported, it was reported to be mild, moderate, severe and very severe in 56.5%, 35.5%, 6.4% and 1.6% of cases, respectively (see Fig. 2 for absolute numbers). After adjustment for multiple comparisons, patients with high, medium and low eGFR did not significantly differ in the frequency of constipation-related symptoms; however, terciles of eGFR did negatively correlate with severity of four symptoms (Table 2), i.e. patients with lower eGFR more frequently reported higher severity of the symptoms.\n\nFC and constipation diagnosed with BSFS were found in 21 (18.9%) and 28 (28.9% of patients who completed the scale) of patients, respectively. Neither the above-mentioned symptoms nor any kind of constipation were associated with gender (data not shown).\n\nSince constipation is a common side effect of certain drugs, we estimated prevalence ratio (PR) of constipation in patients according to their drug-use patterns, adjusted to demographics, eGFR tercile and comorbidities (see details in Methods). The frequency of drug-taking is summarized in Supplementary material, Table S2. As shown in Table 3, for constipation diagnosed with the BSFS, besides female sex and increasing age, taking diuretics was independently associated with increased PR of constipation (adjusted PR 2.86, 95% CI 1.28-6.37, P = 0.01). In contrast, paracetamol and low eGFR (≤ 32 ml/min/1.73 m2) were associated with increased PR of FC, whereas taking NSAIDs was independently associated with lower PR of FC (Supplementary material, Table S3). No drug was independently associated with having less than once BM a day (Supplementary material, Table S4).\n\nHealth-related quality of life\nSF-36v2 is a tool commonly used to assess the HRQoL that has been validated also in Poland 23. To evaluate associations between HRQoL and GI symptoms, we performed linear regressions that were adjusted for demographic and clinical data (columns 'Adjusted univariate analyses' in Table 4 and Supplementary material, Tables S5-S10). We found that the presence of discomfort in the abdomen was independently associated with worse scores in all HRQoL domains (Table 4 and Supplementary material, Tables S5-S10). Similarly, the presence of pain in the abdomen was associated with worse assessment of all, save RE, HRQoL domains (Table 4 and Supplementary material, Tables S5-S9). Also, painful BMs reporting was significantly associated with lower scores in MH, VT, SF, and RE (Table 4 and Supplementary material, Tables S8-S10). Defecation less frequently than mean once a day was associated with lower scores in PF, RP and MH (Table 4 and Supplementary material, Tables S5-S6). FC was associated with BP and VT (Supplementary material, Tables S7-S8). Interestingly, BSFS-diagnosed constipation was not associated with a lower score in any HRQoL domain.\n\nTo find out how many and which of the symptoms should be considered assessing the HRQoL, we have selected the balanced adjusted multiple regression model for each HRQoL domain (columns 'Selected adjusted multiple regression' in Table 4 and Supplementary material, Tables S5-S10). The following symptoms were in at least two models: pain in the abdomen (PF, RP, BP, SF), discomfort in the abdomen (VT, SF), altered frequency of defecation (PF, RP), having BMs that were too hard (BP, VT), too small (PF, RE) or painful (VT, RE). Such selected models explained 33.7-53.0% of the variability of the HRQoL scores (R2 reported in columns 'Selected adjusted multiple regression' in Table 4 and Supplementary material, Tables S5-S10), whereas models based only on sex, age, BMI, eGFR tercile and comorbidities explained only 13.6-34.6% of the variability.\n\nDiscussion\nOur study aimed to determine the prevalence of constipation-related symptoms in conservatively-treated CKD patients, as well as to verify the relationship between them and HRQoL. Using validated questionnaires, we found that a number of gastrointestinal symptoms are frequently reported by CKD patients, and that presence of symptoms was associated with worse HRQoL.\n\nSince constipation prevalence varies widely due to differences in the used constipation definition 2, 28-30, we used three ways to define constipation: the BSFS, Rome III criteria, and the decreased frequency of BM per week. In the general population of Europe, the mean value of the reported constipation rates is 17.1% 2; that is a lower value than the prevalence of FC and BSFS-based constipation in our study; that is 18.9% and 28.9%, respectively. Recently published comprehensive review article about constipation in CKD revealed that despite strong evidence on higher prevalence of constipation in dialysis patients (23.8-71.7% and 14.2-28.9% of HD and PD patients, respectively 16), information is scarce on the epidemiology of constipation among patients with conservatively-treated patients 18. To our knowledge, up-to-date only two studies that included conservatively-treated CKD patients used Rome III criteria and BSFS to determine the prevalence of constipation 12, 30. In the first, FC and BSFS-diagnosed constipation were recognized in 5% and 19% of 21 non-dialysis ESRD patients, respectively. In the second, FC and BSFS-diagnosed constipation were recognized in 35% and 33% of 43 non-dialysis nondiabetic patients with eGFR <45 mL/min/1.73 m2, respectively. Since the number of included participants was limited, we agree with authors of the above-mentioned review article that there is a need for more data on constipation epidemiology among conservatively-treated CKD patients 18. We not only did determine the prevalence in more than twofold bigger population of patients, but also found factors associated with the altered prevalence of constipations.\n\nIndeed, we found out that paracetamol and diuretics were independently associated with increased PR of constipation diagnosed with Rome III criteria and BSFS, respectively. Even though all these drugs have been associated with constipation in other patients populations 31-33, the mechanisms leading to such side-effects are not clear. Regarding paracetamol, Chang et al. suggested that its pro-constipation properties can be attributed to the anti-serotonergic effects of paracetamol; however, it was not investigated directly yet 32. It is hypothesized that diuretics can cause constipation secondary to dehydration, electrolyte disturbances, or, less probably, directly suppressing gut motility 33, 34. In the presented study, we confirmed associations between the presence of constipation and lower HRQoL. We have demonstrated that FC is independently associated with BP and VT, parts of SF-36v2 physical and mental summary components, respectively. Similarly, Zhang et al. have shown that FC is associated with lower scores in both physical and mental summary components of HRQoL in both HD and PD patients 17. Interestingly, our study has indicated that constipation diagnosed with BSFS is not associated with worse HRQoL in conservatively-treated CKD patients. It is highly interesting as previous studies did not perform such analyses. As the BSFS is a clinical surrogate of whole-gut and colonic transit 35, we hypothesize that the deterioration in HRQoL of constipated CKD patients is not a consequence of delayed gut transit. More probable, given the associations between functional constipation and decreased HRQoL, and following the knowledge about the pathophysiology of functional gastrointestinal disorders, decreased HRQoL might be a manifestation of a disturbance in bidirectional relationship of the gastrointestinal tract and nervous system 36.\n\nEven though we have not seen an association between constipation diagnosed with BSFS and worse HRQoL, assessment of BSFS should not be neglected in CKD patients. Ramos et al. found that so defined constipation was associated with significantly higher serum concentration of p-cresyl sulfate, a microbial-derived uremic toxin 12. Interestingly, the same study failed to show an association between FC and the serum concentration of either p-cresyl sulfate or indoxyl sulfate. Since cardiovascular disease is the leading cause of death in CKD and there are data suggesting that constipation is associated with increased cardiovascular risk 5, 37, further studies are needed to compare clinical associations and cardiovascular mortality between CKD patients with constipation according to BSFS versus Rome criteria.\n\nUsing the PAC-SYM questionnaire, we have shown that the severity of straining to pass BM, as well as painful, incomplete, or too hard BM correlated with the deterioration of kidney function. That is, patients with low eGFR assessed the severity of these symptoms as at least moderate from 1.8 (straining to pass BM) to even 4 (incomplete BM) times more frequently than patients with high eGFR. Moreover, low eGFR was independently associated with a 2.85 times higher prevalence of FC in comparison to high eGFR. The high and low eGFR terciles in our study share high similarity to G1-G3a and G4-G5 CKD stages, respectively. Unfortunately, patients with G3b CKD were also present as a small fractions of upper tercile (8% of individuals in this tercile) and lower tercile (35% of individuals in this tercile), thus direct translation of the results into CKD stages is impossible due to high disproportion in the number of recruited patients across stages of CKD.\n\nKnowing the prevalence of constipation and related symptoms and their deteriorating impact on HRQoL, it is important to find effective methods of lower gastrointestinal symptoms management for CKD patients. Firstly, nonpharmacological treatment should be considered, i.e. increase in physical activity and improvement of diet 38. Indeed, one can recommend a fiber-rich diet because it shortens intestinal transit time (via bulking effect 39) and, additionally, is a part of healthy dietary patterns that are associated with lower mortality in CKD patients 40. However, based on the high prevalence of bloating among CKD patients in our study, as well as that some CKD patients require fluid intake restriction, the recommendation of a diet rich in fiber should be given cautiously. In fact, the high-fiber diet can lead to exacerbation of flatulence (via retardation of intestinal gas propulsion 41)42, and water restriction reduces the pro-motile effect of fiber 43. Unfortunately, there are no clinical trials assessing the efficacy of diet modification on constipation reduction in conservatively-treated CKD patients. Interestingly, the consumption of 40 g of raw almonds daily for four weeks was safe and improved both BSFS-diagnosed constipation and HRQoL in HD patients 44. In view of our findings, similar trials are desirable in the population of conservatively-treated CKD patients.\n\nThe next step of constipation management is the introduction of pharmacotherapy 18. Since there is no data on the safety and efficacy of laxatives in CKD patients, one should take into account that some of them can have limited efficacy in patients restricting fluid intake (stool softeners, i.e. docusate sodium/calcium) and some may exacerbate constipation-related symptoms, e.g. flatulence (lactulose). As the majority of CKD patients in our study reported bloating, anti-foaming agents—simethicone and dimethicone—should be taken into account because they are effective in relieving abdominal distension and flatulence in functional gastrointestinal disorders 45, 46. Moreover, alleviation of abdominal bloating in constipated patients is achievable using new laxative drugs: lubiprostone (a type-2 chloride channel activator), linaclotide (a guanylate cyclase-C receptor agonist), prucalopride (selective 5-HT4 receptor agonist), and elobixibat (an ileal bile acid transporter inhibitor) 47-50.\n\nInterestingly, according to animal studies, a part of drugs used in constipation treatment can possess nephroprotective properties. In adenine-induced CKD rat model, lactulose—a prebiotic disaccharide—was shown to possess nephroprotective properties (i.e. suppressed tubulointerstitial fibrosis) via reduction of microbiota-derived uremic toxin, indoxyl sulfate 51. Since lactulose reduces microbiota-derived uremic toxins, indoxyl sulfate and p-cresol, in humans 52, it can be hypothesized that introduction of such constipation treatment can additionally slow the progression of CKD. Similarly, lubiprostone and linaclotide can possess nephroprotective properties via improving the gut microbiota and intestinal environment as was demonstrated in adenine-induced CKD mouse model 53, 54. However, the nephroprotective properties of these laxatives should be confirmed in clinical trials with conservatively-treated CKD patients. Such studies could also determine whether the treatment of constipation significantly improves HRQoL in this population. In a multicenter, observational study of hemodialysis patients with FC, elobixibat significantly increased the frequency of BM and improved patients' HRQoL 55. Furthermore, based on mechanistic insights into the “gut-kidney-heart” axis, Sumida and Kovesdy have recently hypothesized that the administration of laxatives might be a gut microbiota-targeted therapeutic intervention for reduction cardiovascular risk in patients with CKD 37.\n\nThe relatively small number of surveyed patients, lack of healthy control group, lack of information about proteinuria, direct usage of Rome III criteria in authors' questions instead of validated diagnostic questionnaire to diagnose FC, and a cross-sectional character of the study can limit the importance of obtained results. However, our study possesses also considerable advantages such as comprehensiveness (detailing the prevalence of constipation and constipation-related symptoms, finding factors associated with the altered prevalence of constipation, and analysis of associations between the symptoms and HRQoL domains), inclusion of more than twofold bigger population than in previous similar studies, and use of the method of P values correction limiting the probability of false discovery (a type I error). Our study, as one of the first in the field, should prompt researchers to determine the epidemiology of constipation and related symptoms in conservatively-treated CKD patients, as well as to establish the biochemical, clinical and patient-oriented benefits of their treatment.\n\nSupplementary Material\nSupplementary tables.\n\nClick here for additional data file.\n\n This work was supported by the Medical University of Gdańsk, under grants no. ST 02-0004/07/122, MN 01-0421/08/262, and ST-58.\n\nFigure 1 The histogram of the bowel movements frequency per week\n\nFigure 2 Frequency of symptom reporting and absolute number of patients reporting each severity of gastrointestinal symptoms in PAC-SYM scale\n\nTable 1 Demographic and clinical parameters of the total study population and according to eGFR tercile\n\n\tAll\tHigh eGFR tercile\tMedium eGFR tercile\tLow eGFR tercile\tUnadjusted P value\t\nParticipants, n\t111\t37\t34\t40\t-\t\nMale, n (%)\t62 (55.9)\t21 (56.8)\t12 (35.3)\t29 (72.5)\t0.006\t\nAge, years, median (IQR)\t68 (55.0-74.0)\t64 (44.0-71.0)\t71.0 (68.0-76.0)\t66.0 (53.5-72.5)\t0.005\t\nBMI, kg/m2, median (IQR)\t28.48 (25.63-31.14)\t28.09 (25.18-30.76)\t28.48 (26.23-30.49)\t28.58 (24.49-31.92)\t0.84\t\neGFR, median (IQR)\t38.0 (30.0-48.0)\t57.0 (48.0-67.0)\t38.0 (35.0-42.0)\t26.5 (17.0-31.0)\t<0.001\t\nHypertension, n (%)\t97 (87.4)\t31 (83.8)\t32 (94.1)\t34 (85.0)\t0.36\t\nDiabetes, n (%)\t35 (31.5)\t6 (16.2)\t13 (38.2)\t16 (40.0)\t0.05\t\nHeart failure, n (%)\t22 (19.8)\t4 (10.8)\t8 (23.5)\t10 (25.0)\t0.24\t\nHypothyroidism, n (%)\t18 (16.2)\t6 (16.2)\t7 (20.6)\t5 (12.5)\t0.64\t\nDepression, n (%)\t5 (4.5)\t0\t3 (8.8)\t2 (5.0)\t0.20\t\nAbbreviations: BMI: body mass index; CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate\n\nTable 2 The frequencies of constipation-related symptoms reporting by eGFR-grouped patients and the correlations between symptoms severities and eGFR terciles\n\nSymptom and its severity\tPercentage of patients reporting the symptom\tGamma coefficient\tP value\t\nHigh eGFR group (n = 36)\tMedium eGFR group (n = 34)\tLow eGFR group (n = 40)\tUnadjusted\tAdjusted\t\nPainful BM\tLack\t97.2%\t85.3%\t75.0%\t-0.569\t<0.001\t0.002\t\nMild\t0.0%\t11.8%\t17.5%\t\nAt least moderate\t2.8%\t2.9%\t7.5%\t\nStraining to pass BM\tLack\t83.3%\t82.3%\t77.5%\t-0.427\t<0.001\t<0.001\t\nMild\t11.1%\t11.8%\t12.5%\t\nAt least moderate\t5.6%\t5.9%\t10.0%\t\nIncomplete BM\tLack\t75.0%\t73.5%\t50.0%\t-0.371\t<0.001\t0.006\t\nMild\t19.4%\t17.7%\t27.5%\t\nAt least moderate\t5.6%\t8.8%\t22.5%\t\nToo hard BM\tLack\t77.8%\t52.9%\t52.5%\t-0.323\t0.002\t0.015\t\nMild\t11.1%\t29.4%\t20.0%\t\nAt least moderate\t11.1%\t17.6%\t27.5%\t\nAbbreviations: BM: bowel movement; eGFR: estimated glomerular filtration rate\n\nTable 3 Poisson regression models showing variables significantly and independently associated with prevalence ratio of constipation diagnosed with the Bristol Stool Form Scale\n\nVariable\tUnivariate analyses (each row represents separate model)\tMultiple regression\t\nPR (95% CI)\tP value\tPR (95% CI)\tP value\t\nUse of diuretics\t2.72 (1.21-6.14)\t0.016\t2.86 (1.28-6.37)\t0.010\t\nAge, years\t1.015 (0.99-1.04)\t0.231\t1.053 (1.01-1.10)\t0.012\t\nFemale sex\t1.57 (0.83-2.97)\t0.161\t120.72 (2.54-5728.74)a\t0.015\t\nFemale sex × age interaction\t-\t-\t0.935 (0.89-0.99)\t0.015\t\nBMI, kg/m2\t1.004 (0.94-1.07)\t0.897\t1.02 (0.96-1.09)\t0.528\t\neGFR tercile:\t\t\t\t\t\nHigh\treference\t-\treference\t-\t\nMedium\t1.43 (0.54-3.75)\t0.469\t1.38 (0.58-3.33)\t0.468\t\nLow\t1.30 (0.50-3.42)\t0.592\t1.74 (0.68-4.49)\t0.250\t\nDiabetes\t1.05 (0.53-2.06)\t0.891\t0.81 (0.41-1.61)\t0.546\t\nHeart failure\t1.09 (0.51-2.33)\t0.832\t0.84 (0.38-1.87)\t0.667\t\nHypothyroidism\t1.23 (0.55-2.73)\t0.616\t1.10 (0.50-2.37)\t0.817\t\nDepression\t1.46 (0.47-4.48)\t0.512\t1.10 (0.31-3.89)\t0.879\t\nAbbreviations: BMI: body mass index; CI: confidence interval; eGFR: estimated glomerular filtration rate; PR: prevalence ratio\n\na Due to significant interaction with age, being women at median age of 69 was associated with PR approx. 1.17 compared to men in this age (exp(ln(120.72) + ln(1.053)×69 + ln(0.935)×69) / exp(ln(1.053)×69)).\n\nTable 4 Mental health (MH) score regressions adjusted to sex, age, BMI, eGFR tercile, and comorbidities for constipation and constipation-related symptoms\n\nVariable\tAdjusted univariate analyses\n(row represents separate model)\tSelected adjusted multiple regression\n(AIC 865.9, R2 = 0.352, P < 0.001)\t\nCoefficient\tP value\tAIC\tCoefficient (95% CI)\tP value\t\nFrequency of defecation:\n\t\t\t886.2\t\t\t\nOnce a day\treference\t-\t\treference\t-\t\nLess than once a day\t-15.35\t<0.001\t\t-10.63 (-18.96, -2.31)\t0.013\t\nMore than once a day\t-3.21\t0.507\t\t-0.08 (-9.25, 9.08)\t0.986\t\nDiscomfort in abdomen a\t-17.31\t<0.001\t911.1\t-14.07 (-21.69, -6.45)\t<0.001\t\nDiscomfort in abdomen:\t\t\t912.5\t-\t-\t\nLack\treference\t-\t\t\t\t\nMild\t-15.41\t<0.001\t\t\t\t\nMedium/severe\t-19.50\t<0.001\t\t\t\t\nPain in abdomen a\t-16.18\t<0.001\t917.1\t-\t-\t\nPain in abdomen:\t\t\t919.1\t-\t-\t\nLack\tReference\t-\t\t\t\t\nMild\t-16.03\t<0.001\t\t\t\t\nMedium/severe\t-16.51\t0.009\t\t\t\t\nBloating in abdomen a\t-10.68\t0.005\t925.0\t-\t-\t\nBloating in abdomen:\t\t\t924.1\t-\t-\t\nLack\treference\t-\t\t\t\t\nMild\t-7.35\t0.087\t\t\t\t\nMedium/severe\t-15.90\t0.002\t\t\t\t\nPainful BM a\t-13.97\t0.013\t926.8\t-\t-\t\nBM that was too small a\t-11.36\t0.013\t926.8\t-\t-\t\nBM that was too small:\t\t\t926.9\t-\t-\t\nLack\treference\t-\t\t\t\t\nMild\t-7.03\t0.214\t\t\t\t\nMedium/severe\t-16.86\t0.008\t\t\t\t\nStomach cramps a\t-10.98\t0.014\t926.9\t-\t-\t\nStraining/squeezing a\t-9.94\t0.011\t926.39\t-\t-\t\nStraining/squeezing:\t\t\t926.35\t\t\t\nLack\tReference\t-\t\t\t\t\nMild\t-6.60\t0.149\t\t\t\t\nMedium/severe\t-14.22\t0.005\t\t\t\t\nFeeling false alarm a\t-11.91\t0.015\t927.1\t\t\t\nAbbreviations: AIC: Akaike information criterion; BM: bowel movement.\n\na presence of the symptom, regardless of its severity\n==== Refs\n1 Bharucha AE Wald A Chronic Constipation Mayo Clin Proc 2019 94 2340 2357 31054770 \n2 Peppas G Alexiou VG Mourtzoukou E Epidemiology of constipation in Europe and Oceania: A systematic review BMC Gastroenterology 2008 8 5 18269746 \n3 Tvistholm N Munch L Danielsen AK Constipation is casting a shadow over everyday life - a systematic review on older people's experience of living with constipation Journal of Clinical Nursing 2017 26 902 914 27271918 \n4 Belsey J Greenfield S Candy D Systematic review: Impact of constipation on quality of life in adults and children Alimentary Pharmacology and Therapeutics 2010 31 938 949 20180788 \n5 Sumida K Molnar MZ Potukuchi PK Constipation and risk of death and cardiovascular events Atherosclerosis 2019 281 114 120 30658186 \n6 Salmoirago-Blotcher E Crawford S Jackson E Constipation and risk of cardiovascular disease among postmenopausal women Am J Med 2011 124 714 723 21663887 \n7 Honkura K Tomata Y Sugiyama K Defecation frequency and cardiovascular disease mortality in Japan: The Ohsaki cohort study Atherosclerosis 2016 246 251 256 26812003 \n8 KDIGO Chapter 1: Definition and classification of CKD Kidney Int Suppl 2013 3 19 62 \n9 Hill NR Fatoba ST Oke JL Global prevalence of chronic kidney disease - A systematic review and meta-analysis PLoS ONE 2016 11 e0158765 27383068 \n10 Bikbov B Purcell CA Levey AS Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017 Lancet 2020 395 709 733 32061315 \n11 Sumida K Molnar MZ Potukuchi PK Constipation and Incident CKD J Am Soc Nephrol 2017 28 1248 1258 28122944 \n12 Ramos CI Armani RG Canziani ME Bowel Habits and the Association With Uremic Toxins in Non-Dialysis-Dependent Chronic Kidney Disease Patients J Ren Nutr 2020 30 31 35 30956092 \n13 Guo C Tam T Bo Y Habitual physical activity, renal function and chronic kidney disease: A cohort study of nearly 200 000 adults Br J Sports Med 2020 [Epub ahead of print] \n14 Zhang X Bansal N Go AS Gastrointestinal symptoms, inflammation and hypoalbuminemia in chronic kidney disease patients: a cross-sectional study BMC Nephrol 2015 16 211 26651991 \n15 Senanayake S Gunawardena N Palihawadana P Symptom burden in chronic kidney disease; a population based cross sectional study BMC Nephrol 2017 18 228 28693434 \n16 Zuvela J Trimingham C Le Leu R Gastrointestinal symptoms in patients receiving dialysis: A systematic review Nephrology 2018 23 718 727 29468835 \n17 Zhang J Huang C Li Y Health-related quality of life in dialysis patients with constipation: a cross-sectional study Patient Prefer Adherence 2013 7 589 94 23814466 \n18 Sumida K Yamagata K Kovesdy CP Constipation in Chronic Kidney Disease Kidney Int Reports 2020 5 121 134 \n19 Frank L Kleinman L Farup C Psychometric validation of a constipation symptom assessment questionnaire Scand J Gastroenterol 1999 34 870 877 10522604 \n20 Longstreth GF Thompson WG Chey WD Functional Bowel Disorders Gastroenterology 2006 130 1480 1491 16678561 \n21 O'Donnell LJD Virjee J Heaton KW Detection of pseudodiarrhoea by simple clinical assessment of intestinal transit rate Br Med J 1990 300 439 440 2107897 \n22 Wojtyniak K Szajewska H Dziechciarz P Translation to Polish, cross-cultural adaptation, and validation of the Bristol Stool Form Scale among healthcare professionals and patients Prz Gastroenterol 2018 13 35 39 29657609 \n23 Zołnierczyk-Zreda D [The Polish version of the SF-36v2 questionnaire for the quality of life assessment] Przegl Lek 2010 67 1302 7 21591357 \n24 McKinney W Data Structures for Statistical Computing in Python In: van der Walt S, Millman J, eds. Proceedings of the 9th Python in Science Conference. Austin, TX: SciPy 2010 p:56-61 \n25 Vallat R Pingouin: statistics in Python J Open Source Softw 2018 3 1026 \n26 Seabold S Perktold J Statsmodels: Econometric and Statistical Modeling with Python In: van der Walt S, Millman J, eds. Proceedings of the 9th Python in Science Conference. Austin, TX: SciPy 2010 p:92-96 \n27 Gallis JA Turner EL Relative Measures of Association for Binary Outcomes: Challenges and Recommendations for the Global Health Researcher Ann Glob Heal 2019 85 137 \n28 Werth BL Williams KA Fisher MJ Defining constipation to estimate its prevalence in the community: results from a national survey BMC Gastroenterol 2019 19 75 31113366 \n29 Mugie SM Benninga MA Di Lorenzo C Epidemiology of constipation in children and adults: A systematic review Best Pract Res Clin Gastroenterol 2011 25 3 18 21382575 \n30 Lee A Lambert K Byrne P Prevalence of constipation in patients with advanced kidney disease J Ren Care 2016 42 144 149 27113374 \n31 Turco R Miele E Russo M Early-life factors associated with pediatric functional constipation J Pediatr Gastroenterol Nutr 2014 58 307 312 24145619 \n32 Chang JY Locke GR Schleck CD Risk factors for chronic constipation and a possible role of analgesics Neurogastroenterol Motil 2007 19 905 911 17988275 \n33 Fosnes GS Lydersen S Farup PG Constipation and diarrhoea - common adverse drug reactions? A cross sectional study in the general population BMC Clin Pharmacol 2011 11 2 21332973 \n34 Kaewsaro K Nualplub S Bumrungsri S Furosemide suppresses ileal and colonic contractility via interactions with GABA-A receptor in mice Clin Exp Pharmacol Physiol 2017 44 1155 1165 28744897 \n35 Saad RJ Rao SSC Koch KL Do stool form and frequency correlate with whole-gut and colonic transit results from a multicenter study in constipated individuals and healthy controls Am J Gastroenterol 2010 105 403 411 19888202 \n36 Mukhtar K Nawaz H Abid S Functional gastrointestinal disorders and gut-brain axis: What does the future hold? World Journal of Gastroenterology 2019 25 552 566 30774271 \n37 Sumida K Kovesdy CP The gut-kidney-heart axis in chronic kidney disease Physiol Int 2019 106 195 206 31560235 \n38 Gao R Tao Y Zhou C Exercise therapy in patients with constipation: a systematic review and meta-analysis of randomized controlled trials Scandinavian Journal of Gastroenterology 2019 54 169 177 30843436 \n39 Camerotto C Cupisti A D'Alessandro C Dietary fiber and gut microbiota in renal diets Nutrients 2019 11 2149 \n40 Kelly JT Palmer SC Wai SN Healthy dietary patterns and risk of mortality and ESRD in CKD: A meta-analysis of cohort studies Clin J Am Soc Nephrol 2017 12 272 279 27932391 \n41 Gonlachanvit S Coleski R Owyang C Inhibitory actions of a high fibre diet on intestinal gas transit in healthy volunteers Gut 2004 53 1577 1582 15479674 \n42 Peng AW Juraschek SP Appel LJ Effects of the DASH diet and sodium intake on bloating: Results from the DASH-Sodium trial Am J Gastroenterol 2018 114 1109 1115 \n43 Anti M Pignataro G Armuzzi A Water supplementation enhances the effect of high-fiber diet on stool frequency and laxative consumption in adult patients with functional constipation Hepatogastroenterology 1998 45 727 732 9684123 \n44 Lambert K Bird L Borst AC Safety and Efficacy of Using Nuts to Improve Bowel Health in Hemodialysis Patients J Ren Nutr 2020 [Epub ahead of print] \n45 Bernstein JE Kasich AM A Double-Blind Trial of Simethicone in Functional Disease of the Upper Gastrointestinal Tract J Clin Pharmacol 1974 14 617 623 4612060 \n46 Burta O Iacobescu C Mateescu RB Efficacy and safety of APT036 versus simethicone in the treatment of functional bloating: A multicentre, randomised, double-blind, parallel group, clinical study Transl Gastroenterol Hepatol 2018 3 72 30511026 \n47 Chang L Chey WD Drossman D Effects of baseline abdominal pain and bloating on response to lubiprostone in patients with irritable bowel syndrome with constipation Aliment Pharmacol Ther 2016 44 1114 1122 27669680 \n48 Lacy BE Schey R Shiff SJ Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled Trial PLoS One 2015 10 e0134349 26222318 \n49 Tack J Stanghellini V Dubois D Effect of prucalopride on symptoms of chronic constipation Neurogastroenterol Motil 2014 26 21 27 24106924 \n50 Acosta A Camilleri M Elobixibat and its potential role in chronic idiopathic constipation Therapeutic Advances in Gastroenterology 2014 7 167 175 25057297 \n51 Sueyoshi M Fukunaga M Mei M Effects of lactulose on renal function and gut microbiota in adenine-induced chronic kidney disease rats Clin Exp Nephrol 2019 23 908 30895529 \n52 Ruszkowski J Witkowski JM Lactulose: Patient- and dose-dependent prebiotic properties in humans Anaerobe 2019 59 100 106 31176002 \n53 Mishima E Fukuda S Shima H Alteration of the intestinal environment by lubiprostone is associated with amelioration of adenine-induced CKD J Am Soc Nephrol 2015 26 1787 1794 25525179 \n54 Nanto-Hara F Kanemitsu Y Fukuda S The guanylate cyclase C agonist linaclotide ameliorates the gut-cardio-renal axis in an adenine-induced mouse model of chronic kidney disease Nephrol Dial Transplant 2020 35 250 264 31411705 \n55 Kamei D Kamei Y Nagano M Elobixibat alleviates chronic constipation in hemodialysis patients: A questionnaire-based study BMC Gastroenterol 2020 20 26 32005162\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1449-1907",
"issue": "17(18)",
"journal": "International journal of medical sciences",
"keywords": "SF-36v2; chronic kidney disease; constipation; flatulence",
"medline_ta": "Int J Med Sci",
"mesh_terms": "D000328:Adult; D000368:Aged; D000072700:Conservative Treatment; D003248:Constipation; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D011788:Quality of Life; D051436:Renal Insufficiency, Chronic",
"nlm_unique_id": "101213954",
"other_id": null,
"pages": "2954-2963",
"pmc": null,
"pmid": "33173416",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "32043026;10522604;20180788;30658186;29657609;21332973;4612060;24106924;31411705;21663887;26812003;19888202;27113374;26222318;29468835;31505733;31807416;25057297;28122944;30511026;32001127;27271918;17988275;2107897;30895529;30843436;15479674;27383068;31206400;27669680;27932391;31560235;16678561;32061315;23814466;31113366;28693434;24145619;25525179;26651991;28744897;9684123;21382575;21591357;31054770;30774271;32005162;30956092;18269746;31176002;31969348",
"title": "Constipation and the Quality of Life in Conservatively Treated Chronic Kidney Disease Patients: A Cross-sectional Study.",
"title_normalized": "constipation and the quality of life in conservatively treated chronic kidney disease patients a cross sectional study"
} | [
{
"companynumb": "PL-SHIELD TX (UK) LTD-PL-STX-21-NOR-0002",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditio... |
{
"abstract": "OBJECTIVE\nHereditary hypophosphatemic rickets (HR) is conventionally treated with phosphate and calcitriol. Exploring genotype and phenotypic spectrum of X-linked hypophosphatemic rickets (XLHR), focusing on short-term, long-term, and pubertal impact of conventional treatment was aimed.\n\n\nMETHODS\nSixteen patients from 12 unrelated families with HR were analyzed for phosphate regulating endopeptidase homolog X-linked (PHEX) mutation. Initially Sanger sequencing analysis was performed. If PHEX mutation was not detected, multiplex ligation-dependent probe amplification (MLPA) was performed. If molecular defect was detected, first-degree relatives were analyzed. Thirteen patients (81%) and five first-degree relatives with XLHR were evaluated for genotype-phenotype or gender-phenotype correlation. Clinical characteristics and response to conventional treatment were determined retrospectively.\n\n\nRESULTS\nNine different PHEX mutations were identified; four splice-site, three point mutations, and two single exon deletions. Four were novel mutations. Despite conventional treatment, median adult height was lower than median height on admission (-3.8 and -2.3 SDS, respectively), metabolic and radiographic recovery were not achieved, adherence was low (30%). Although mean adult height was better in compliant patients than noncompliants (-2.6 vs. -3.7 SDS, respectively), they were still short. Correlation between phenotype and genotype or gender could not be shown. Median phosphate decreased significantly throughout puberty (p=0.014). Median pubertal height was lower than prepubertal height (-4.4 vs. -3.6 SDS; respectively), pubertal growth spurt was not observed. Among five patients with a follow-up longer than five years, three had nephrocalcinosis (60%), two had hyperparathyroidism (40%), 4/6 (33%) required correction osteotomy.\n\n\nCONCLUSIONS\nConventional treatment appears to have limited effect on metabolic, clinical and radiographic recovery in XLHR. Metabolic control and growth worsened during puberty. Although, long-term adverse effects are yet to be seen, introduction of burosumab as first-line treatment may be an alternative after infancy.",
"affiliations": "Division of Pediatric Endocrinology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Pediatric Endocrinology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Pediatric Endocrinology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Pediatric Endocrinology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Pediatric Endocrinology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Division of Medical Genetics, Department of Medical Genetics, Hacettepe University Faculty of Medicine, Ankara, Turkey.",
"authors": "Alikasifoglu|Ayfer|A|https://orcid.org/0000-0003-3379-6407;Unsal|Yagmur|Y|https://orcid.org/0000-0002-9113-8683;Gonc|Elmas Nazli|EN|;Ozon|Zeynep Alev|ZA|;Kandemir|Nurgun|N|;Alikasifoglu|Mehmet|M|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1515/jpem-2021-0387",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0334-018X",
"issue": "34(12)",
"journal": "Journal of pediatric endocrinology & metabolism : JPEM",
"keywords": "conventional treatment; genetic variability; growth; hypophosphatemic rickets",
"medline_ta": "J Pediatr Endocrinol Metab",
"mesh_terms": null,
"nlm_unique_id": "9508900",
"other_id": null,
"pages": "1573-1584",
"pmc": null,
"pmid": "34525271",
"pubdate": "2021-12-20",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term effect of conventional phosphate and calcitriol treatment on metabolic recovery and catch-up growth in children with PHEX mutation.",
"title_normalized": "long term effect of conventional phosphate and calcitriol treatment on metabolic recovery and catch up growth in children with phex mutation"
} | [
{
"companynumb": "TR-ROCHE-2921105",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CALCITRIOL"
},
"drugadditional": "3",
"druga... |
{
"abstract": "BACKGROUND\nRestless legs syndrome (RLS) is related to parity, and its symptoms may worsen during pregnancy. Treatment with levodopa or dopamine agonists is the first-line therapy for RLS; however, there are limited data on treatment in pregnancy. We therefore assessed the safety of levodopa, pramipexole, rotigotine, and ropinirole in pregnancy.\n\n\nMETHODS\nProspective documentation of pregnancies exposed to levodopa, pramipexole, rotigotine, and ropinirole between 1998 and 2011 was evaluated as to their outcome (teratogenicity or fetotoxicity) by the Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy.\n\n\nRESULTS\nWe were able to complete 59 pregnancy outcomes exposed to RLS pharmacotherapy. For specific treatments, the numbers of exposed pregnancies/live born children/spontaneous abortions/induced abortions/malformations were as follows: levodopa only: 38/29 (one pair of twins)/3/7/3; pramipexole only: 12/9/3/0/0; rotigotine only: 2/2/0/0/0; ropinirole only: 3/2/0/1/0; levodopa combined with pramipexole: 3/3/0/0/0; levodopa combined with ropinirole: 1/1/0/0/0. No major birth defects were found with any RLS treatment, and three infants exposed to levodopa had minor anomalies.\n\n\nCONCLUSIONS\nIn our small prospective case series, there was no increased risk above baseline for major malformations or other adverse outcomes for levodopa and pramipexole. If necessary, levodopa treatment may be considered as an alternative to cabergoline, for which safety has been well documented in pregnancy.",
"affiliations": "Pharmakovigilanz- und Beratungszentrum für Embryonaltoxikologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.",
"authors": "Dostal|M|M|;Weber-Schoendorfer|C|C|;Sobesky|J|J|;Schaefer|C|C|",
"chemical_list": "D018491:Dopamine Agonists; D007211:Indoles; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C046649:ropinirole; D007980:Levodopa; C047508:rotigotine",
"country": "England",
"delete": false,
"doi": "10.1111/ene.12001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1351-5101",
"issue": "20(9)",
"journal": "European journal of neurology",
"keywords": "fetal outcome; levodopa; pramipexole; pregnancy; restless legs syndrome; ropinirole; rotigotine",
"medline_ta": "Eur J Neurol",
"mesh_terms": "D018491:Dopamine Agonists; D005260:Female; D006801:Humans; D007211:Indoles; D007980:Levodopa; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012148:Restless Legs Syndrome; D013764:Tetrahydronaphthalenes; D013876:Thiophenes",
"nlm_unique_id": "9506311",
"other_id": null,
"pages": "1241-6",
"pmc": null,
"pmid": "23083216",
"pubdate": "2013-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pregnancy outcome following use of levodopa, pramipexole, ropinirole, and rotigotine for restless legs syndrome during pregnancy: a case series.",
"title_normalized": "pregnancy outcome following use of levodopa pramipexole ropinirole and rotigotine for restless legs syndrome during pregnancy a case series"
} | [
{
"companynumb": "DE-GLAXOSMITHKLINE-B0843265A",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FORMOTEROL"
},
"drugadditional": null,
... |
{
"abstract": "We compare the efficacy and safety of intravenous lidocaine with that of hydromorphone for the treatment of acute abdominal pain in the emergency department (ED).\n\n\n\nThis was a randomized, double-blind, clinical trial conducted in 2 EDs in the Bronx, NY. Adults weighing 60 to 120 kg were randomized to receive 120 mg of intravenous lidocaine or 1 mg of intravenous hydromorphone. Thirty minutes after administration of the first dose of the study drug, participants were asked whether they needed a second dose of the investigational medication to which they were randomized. Patients were also stratified according to clinical suspicion of nephrolithiasis. The primary outcome was improvement in pain scores of 0 to 10 between baseline and 90 minutes. An important secondary outcome was need for \"off-protocol\" parenteral analgesics, including opioids and nonsteroidal anti-inflammatory drugs.\n\n\n\nWe enrolled 154 patients, of whom 77 received lidocaine and 77 received hydromorphone. By 90 minutes, patients randomized to lidocaine improved by a mean of 3.8 points on the 0-to-10 scale, whereas those randomized to hydromorphone improved by a mean of 5.0 points (mean difference 1.2; 95% confidence interval 0.3 to 2.2). Need for off-protocol \"rescue\" analgesics occurred for 39 of 77 lidocaine patients (51%) and 20 of 77 hydromorphone patients (26%) (difference 25%; 95% confidence interval 10% to 40%). Adverse events were comparable between groups. Among the subset of 22 patients with nephrolithiasis, lidocaine patients reported a mean improvement of 3.4 points on the pain scale, whereas hydromorphone patients reported a mean improvement of 6.4 points (mean difference 3.0; 95% confidence interval 0.5 to 5.5).\n\n\n\nIntravenous hydromorphone was superior to intravenous lidocaine both for general abdominal pain and a subset of patients with nephrolithiasis. A majority of patients randomly allocated to lidocaine required additional analgesics.",
"affiliations": "Department of Emergency Medicine, Albert Einstein College of Medicine, Montefiore, Bronx, NY; Department of Emergency Medicine, Jacobi Medical Center, Bronx, NY.;Department of Emergency Medicine, Albert Einstein College of Medicine, Montefiore, Bronx, NY. Electronic address: bwfriedmanmd@gmail.com.;Medical College, Albert Einstein College of Medicine, Montefiore, Bronx, NY.;Department of Emergency Medicine, Albert Einstein College of Medicine, Montefiore, Bronx, NY.;Pharmacy Department, Montefiore, Bronx, NY.;Pharmacy Department, Montefiore, Bronx, NY.;Department of Emergency Medicine, Albert Einstein College of Medicine, Montefiore, Bronx, NY; Department of Emergency Medicine, Jacobi Medical Center, Bronx, NY.;Department of Emergency Medicine, Albert Einstein College of Medicine, Montefiore, Bronx, NY.;Department of Emergency Medicine, Albert Einstein College of Medicine, Montefiore, Bronx, NY.;Department of Emergency Medicine, Albert Einstein College of Medicine, Montefiore, Bronx, NY.;Department of Emergency Medicine, Albert Einstein College of Medicine, Montefiore, Bronx, NY.",
"authors": "Chinn|Elliott|E|;Friedman|Benjamin W|BW|;Naeem|Farnia|F|;Irizarry|Eddie|E|;Afrifa|Freda|F|;Zias|Eleftheria|E|;Jones|Michael P|MP|;Pearlman|Scott|S|;Chertoff|Andrew|A|;Wollowitz|Andrew|A|;Gallagher|E John|EJ|",
"chemical_list": "D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D008012:Lidocaine; D004091:Hydromorphone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.annemergmed.2019.01.021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-0644",
"issue": "74(2)",
"journal": "Annals of emergency medicine",
"keywords": null,
"medline_ta": "Ann Emerg Med",
"mesh_terms": "D015746:Abdominal Pain; D059787:Acute Pain; D061605:Administration, Intravenous; D000328:Adult; D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D004091:Hydromorphone; D008012:Lidocaine; D008297:Male; D008875:Middle Aged; D053040:Nephrolithiasis; D009518:New York; D010147:Pain Measurement; D016896:Treatment Outcome",
"nlm_unique_id": "8002646",
"other_id": null,
"pages": "233-240",
"pmc": null,
"pmid": "30819520",
"pubdate": "2019-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "14887342;16301253;1790567;18996618;19507803;19560838;21507527;2221511;22559856;24768290;25147364;26044546;26074387;26116224;26704774;28894783;29395284;29741660;29864216",
"title": "Randomized Trial of Intravenous Lidocaine Versus Hydromorphone for Acute Abdominal Pain in the Emergency Department.",
"title_normalized": "randomized trial of intravenous lidocaine versus hydromorphone for acute abdominal pain in the emergency department"
} | [
{
"companynumb": "IR-ALKEM LABORATORIES LIMITED-IR-ALKEM-2019-02904",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugad... |
{
"abstract": "OBJECTIVE\nTo evaluate if ibuprofen 800mg reduces pain with intrauterine device (IUD) insertion among U.S. women.\n\n\nMETHODS\nWe conducted a randomized, double-blind, placebo-controlled trial of women undergoing IUD insertion approximately 2-6weeks following first-trimester uterine aspiration. Subjects were randomized to receive ibuprofen 800mg or placebo 30-45min prior to IUD insertion. A 100-mm visual analog scale (VAS) was administered to measure pain after speculum insertion (baseline) and immediately following IUD insertion.\n\n\nRESULTS\nA total of 202 women were enrolled, with 101 randomized to each group (ibuprofen or placebo). Sociodemographic characteristics and baseline VAS scores were similar between groups. The median pain score with IUD insertion was 41.5mm in the placebo group and 38.0mm in the ibuprofen group (p=.50). Mean and median pain scores did not differ between placebo and ibuprofen when nulliparous and parous women were analyzed independently. Overall, median pain scores were 17.5mm higher in nulliparous women than parous women (p=.004). Median pain scores did not differ by age, IUD-type, history of dysmenorrhea or time since aspiration.\n\n\nCONCLUSIONS\nAdministration of ibuprofen 800mg prior to IUD insertion does not reduce pain associated with the procedure for U.S. women. Overall, nulliparous women report more pain with IUD insertion than multiparous women.",
"affiliations": "Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USA. Electronic address: bednarek@ohsu.edu.;Department of Obstetrics and Gynecology, University of California, Davis, Sacramento, CA, USA.;National Abortion Federation, Washington, DC, USA.;Department of Gynecology and Obstetrics, Emory University, Atlanta, GA, USA.;Department of Obstetrics and Gynecology, University of New Mexico, Albuquerque, NM, USA.;Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USA.",
"authors": "Bednarek|Paula H|PH|;Creinin|Mitchell D|MD|;Reeves|Matthew F|MF|;Cwiak|Carrie|C|;Espey|Eve|E|;Jensen|Jeffrey T|JT|;|||",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D007052:Ibuprofen",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0010-7824",
"issue": "91(3)",
"journal": "Contraception",
"keywords": "IUD; Ibuprofen; Intrauterine device; Pain",
"medline_ta": "Contraception",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D018712:Analgesics, Non-Narcotic; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007052:Ibuprofen; D007434:Intrauterine Devices; D010146:Pain; D059408:Pain Management; D010147:Pain Measurement; D010298:Parity; D013525:Surgical Instruments; D013997:Time Factors; D055815:Young Adult",
"nlm_unique_id": "0234361",
"other_id": null,
"pages": "193-7",
"pmc": null,
"pmid": "25487172",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Prophylactic ibuprofen does not improve pain with IUD insertion: a randomized trial.",
"title_normalized": "prophylactic ibuprofen does not improve pain with iud insertion a randomized trial"
} | [
{
"companynumb": "US-JNJFOC-20150308210",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nPatients with clinically amyopathic dermatomyositis (CADM) with anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) frequently develop rapidly progressive interstitial pneumonia (RPIP), often with fatal outcomes. Therapeutic plasma exchange (TPE) has been reported as effective against CADM-RPIP refractory to conventional immunosuppressive therapy. However, the detailed mechanisms by which TPE improves disease activity of CADM-RPIP remain unclear.\n\n\nOBJECTIVE\nTo elucidate the clinical and demographic characteristics of patients with anti-MDA5 Ab-positive CADM-RPIP treated with TPE and to analyze changes in laboratory findings before, during, and after TPE.\n\n\nMETHODS\nPatients hospitalized for CADM-RPIP and treated with TPE in 2017 and 2018 were analyzed retrospectively.\n\n\nRESULTS\nThree patients were successfully treated with TPE, with good tolerance. Anti-MDA5 Ab titers decreased significantly over the course of TPE.\n\n\nCONCLUSIONS\nWe emphasize that TPE could represent an effective treatment option for CADM-RPIP refractory to traditional therapy. Removal of anti-MDA5 Ab and other pathogenic factors may facilitate favorable outcomes.",
"affiliations": "Department of Respiratory Medicine, Ohara Healthcare Foundation, Kurashiki Central Hospital, Okayama, Japan.;Department of Respiratory Medicine, Ohara Healthcare Foundation, Kurashiki Central Hospital, Okayama, Japan.;Department of Respiratory Medicine, Ohara Healthcare Foundation, Kurashiki Central Hospital, Okayama, Japan.;Department of Respiratory Medicine, Ohara Healthcare Foundation, Kurashiki Central Hospital, Okayama, Japan.;Department of Endocrinology and Rheumatology, Ohara Healthcare Foundation, Kurashiki Central Hospital, Okayama, Japan.;Department of Endocrinology and Rheumatology, Ohara Healthcare Foundation, Kurashiki Central Hospital, Okayama, Japan.;Department of Respiratory Medicine, Ohara Healthcare Foundation, Kurashiki Central Hospital, Okayama, Japan.",
"authors": "Yamagata|Akira|A|https://orcid.org/0000-0001-6941-7152;Arita|Machiko|M|;Tanaka|Ayaka|A|;Tokioka|Fumiaki|F|;Yoshida|Tomohiro|T|;Nishimura|Keisuke|K|;Ishida|Tadashi|T|",
"chemical_list": "D001323:Autoantibodies; C452815:IFIH1 protein, human; D000072640:Interferon-Induced Helicase, IFIH1; D011112:Polymyxin B",
"country": "United States",
"delete": false,
"doi": "10.1002/jca.21824",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0733-2459",
"issue": "35(5)",
"journal": "Journal of clinical apheresis",
"keywords": "anti-melanoma differentiation-associated gene 5 antibody; apheresis; clinically amyopathic dermatomyositis; rapidly progressive interstitial pneumonia; therapeutic plasma exchange",
"medline_ta": "J Clin Apher",
"mesh_terms": "D001323:Autoantibodies; D003882:Dermatomyositis; D005260:Female; D006464:Hemoperfusion; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D010951:Plasma Exchange; D011112:Polymyxin B; D012189:Retrospective Studies",
"nlm_unique_id": "8216305",
"other_id": null,
"pages": "435-443",
"pmc": null,
"pmid": "32810902",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Therapeutic plasma exchange for clinically amyopathic dermatomyositis (CADM) associated with rapidly progressive interstitial pneumonia.",
"title_normalized": "therapeutic plasma exchange for clinically amyopathic dermatomyositis cadm associated with rapidly progressive interstitial pneumonia"
} | [
{
"companynumb": "JP-FRESENIUS KABI-FK202010751",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALBUMIN HUMAN"
},
"drugadditional": null... |
{
"abstract": "Mycoplasma hominis can be isolated frequently from the genitourinary tract of some healthy individuals. On rare occasions, it acts as a pathogen in immunocompromised patients such as transplant recipients. Here, we describe the case of a 39-year-old man with end-stage kidney disease secondary to diabetic nephropathy who received a simultaneous pancreas-kidney transplant. He developed pancreatitis and arterial thrombosis 2 weeks post-transplant and required a pancreatectomy. His kidney allograft function remained normal. He developed severe left hip pain 2 weeks post-transplant with a trochanteric bursal effusion detected on magnetic resonance imaging. The effusion grew M. hominis. The patient was treated with 100 mg of doxycycline twice daily for 9 months with full resolution of the effusion at 4 months post-treatment. We also review all previously reported M. hominis infections in transplant recipients.",
"affiliations": "Department of Medicine, Royal Adelaide Hospital, Adelaide, SA, Australia.;Department of Microbiology and Infectious Disease, Flinders Medical Centre, Adelaide, SA, Australia.;College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.;College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.",
"authors": "Hulme-Jones|Jarrod P|JP|https://orcid.org/0000-0002-0602-3145;Gordon|David L|DL|;Barbara|Jeffrey A|JA|;Li|Jordan Y|JY|https://orcid.org/0000-0002-5028-6903",
"chemical_list": "D004318:Doxycycline",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13392",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "22(6)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nMycoplasma hominis\n; bursitis; diabetes; immunosuppression; kidney and pancreas transplant",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D002062:Bursitis; D004318:Doxycycline; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D009175:Mycoplasma Infections; D019535:Mycoplasma hominis; D016035:Pancreas Transplantation; D066027:Transplant Recipients",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13392",
"pmc": null,
"pmid": "32603519",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Mycoplasma hominis bursitis in a simultaneous pancreas-kidney transplant recipient: case report and literature review.",
"title_normalized": "mycoplasma hominis bursitis in a simultaneous pancreas kidney transplant recipient case report and literature review"
} | [
{
"companynumb": "AU-ALKEM LABORATORIES LIMITED-AU-ALKEM-2020-04585",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"dru... |
{
"abstract": "Possible human immunodeficiency virus (HIV)-1 clearance has rarely been reported. In this study, we describe a unique case of an HIV-positive, combination antiretroviral therapy (cART)-experienced woman with prior acquired immunodeficiency syndrome (AIDS) who has not experienced viral rebound for over 12 years since discontinuing cART.\nLeukapheresis, colonoscopy, and lymph node excision were performed for detailed examination of virologic (including HIV reservoir) and immunologic features. Comparisons were made with chronically infected patients and healthy controls.\nNo HIV-specific antibodies were detected in serum. Plasma HIV ribonucleic acid (RNA) levels were <0.2 copies/mL, and, except for low-frequency HIV deoxyribonucleic acid (DNA)+ cells in lymph node tissue (1 copy/3 × 106 cells), HIV antigen could not be detected by quantitative virus outgrowth (<0.0025 infectious units/106 CD4+ T cells) or by most measurements of HIV RNA or DNA in blood, lymph node, or gut-associated mononuclear cells. Human immunodeficiency virus-specific T-cell responses were detectable but low. Brain imaging revealed a prior biopsy site and persistent white matter disease since 1996. Human immunodeficiency virus DNA+ cells in the 1996 brain biopsy specimen confirmed her identity and initial HIV diagnosis.\nThis represents the first report of complete seroreversion, prolonged posttreatment virus suppression, a profoundly small HIV reservoir, and persistent HIV-specific T cells in an adult with prior AIDS.",
"affiliations": "Helios Salud, Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina.;Helios Salud, Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina.;Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.;Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.;Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.;Laboratory of Pathology, National Cancer Institute, National Institutes of Health Clinical Center, Bethesda, Maryland, USA.;Center for Infectious Disease Imaging, National Institutes of Health Clinical Center, Bethesda, Maryland, USA.;Dental Clinical Research Core, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.;Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.;Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.;Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.;Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.;Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.;Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.;Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.;Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.;Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.;Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.;Section of Infections of the Nervous System, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.;Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.;Section of Infections of the Nervous System, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.;Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.;Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.",
"authors": "Uruena|Analia|A|;Cassetti|Isabel|I|;Kashyap|Neena|N|;Deleage|Claire|C|;Estes|Jacob D|JD|;Trindade|Christopher|C|;Hammoud|Dima A|DA|;Burbelo|Peter D|PD|;Natarajan|Ven|V|;Dewar|Robin|R|;Imamichi|Hiromi|H|;Ward|Addison J|AJ|;Poole|April|A|;Ober|Alexander|A|;Rehm|Catherine|C|;Jones|Sara|S|;Liang|C Jason|CJ|;Chun|Tae-Wook|TW|;Nath|Avindra|A|;Lane|H Clifford|HC|;Smith|Bryan R|BR|;Connors|Mark|M|;Migueles|Stephen A|SA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofaa613",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2328-8957",
"issue": "8(1)",
"journal": "Open forum infectious diseases",
"keywords": "HIV-1 seroreversion; HIV-specific T cells; functional cure",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofaa613",
"pmc": null,
"pmid": "33511235",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": "22490332;19062316;22826124;30085241;23671416;9757856;14532178;25988888;15238784;16467198;32848246;17157815;18922865;8959245;11413318;27432972;19213682;31217270;15736021;28350553;27430032;29212716;19726501;16447118;19656066;32169158;18945778;26588174;16791025;20549847;19956090;12757923;10611346;31191910;12368910;23516360;24286982;24948364;20962613;16831088;20523897;19494307;8195386;16418398;22666392;29324842;17428922;30836379",
"title": "Prolonged Posttreatment Virologic Control and Complete Seroreversion After Advanced Human Immunodeficiency Virus-1 Infection.",
"title_normalized": "prolonged posttreatment virologic control and complete seroreversion after advanced human immunodeficiency virus 1 infection"
} | [
{
"companynumb": "AR-VIIV HEALTHCARE LIMITED-US2021GSK049557",
"fulfillexpeditecriteria": "1",
"occurcountry": "AR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ABACAVIR"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nAlthough risperidone is increasingly used for behavioral indications in children, the associated adverse events (AEs) are not well defined in this population.\n\n\nOBJECTIVE\nWe determined the incidence of and risk factors for AEs among children treated with risperidone at our institution, an academic medical center with inpatient, outpatient, generalist, and specialist pediatric care.\n\n\nMETHODS\nThe study included children aged ≤ 18 years with ≥ 4 weeks of risperidone exposure. Data were obtained using de-identified electronic health records. AEs were defined as any untoward event attributed to risperidone reported by the patient, parent/guardian, or physician or detected following a laboratory investigation. Associations between AEs and clinical variables were determined using univariate and multivariate analyses.\n\n\nRESULTS\nThe study cohort included 371 individuals (median age 7.8 years [interquartile range 5.9-10.2]; 271 [73.0%] male). The two most common primary diagnoses were attention-deficit/hyperactivity disorder (160 [43.1%]) and autism (102 [27.5%]). The most frequent indications for risperidone were aggression (166 [44.7%]) and behavioral problems (114 [30.7%]). Altogether, 110 (29.6%) individuals had 156 AEs. Weight gain (32 [20.5%]) and extrapyramidal symptoms (23 [14.7%]) were the most common AEs. Aggression, irritability, and self-injurious behavior were positively associated with AEs, and concomitant analgesics and antibiotics were negatively associated. In multivariate analysis, associations remained significant for self-injurious behavior (adjusted odds ratio [aOR] 3.1; 95% confidence interval [CI] 1.7-5.4) and concomitant antibiotics (aOR 0.2; 95% CI 0.1-0.9).\n\n\nCONCLUSIONS\nNearly one in three children treated with risperidone for ≥ 1 month experienced one or more AEs. Particular vigilance is warranted for children with self-injurious behavior.",
"affiliations": "Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.;Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA.;Department of Pediatrics, Vanderbilt University School of Medicine, 8232 DOT, 2200 Children's Way, Nashville, TN, USA.;Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.;Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. sara.van.driest@vumc.org.",
"authors": "Oshikoya|Kazeem A|KA|;Carroll|Robert|R|;Aka|Ida|I|;Roden|Dan M|DM|;Van Driest|Sara L|SL|http://orcid.org/0000-0003-2580-1405",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s40801-019-0151-7",
"fulltext": "\n==== Front\nDrugs Real World OutcomesDrugs Real World OutcomesDrugs - Real World Outcomes2199-11542198-9788Springer International Publishing Cham 15110.1007/s40801-019-0151-7Original Research ArticleAdverse Events Associated with Risperidone Use in Pediatric Patients: A Retrospective Biobank Study Oshikoya Kazeem A. 1Carroll Robert 2Aka Ida 3Roden Dan M. 124http://orcid.org/0000-0003-2580-1405Van Driest Sara L. 615-936-2425sara.van.driest@vumc.org 131 0000 0001 2264 7217grid.152326.1Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN USA 2 0000 0001 2264 7217grid.152326.1Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN USA 3 0000 0001 2264 7217grid.152326.1Department of Pediatrics, Vanderbilt University School of Medicine, 8232 DOT, 2200 Children’s Way, Nashville, TN USA 4 0000 0001 2264 7217grid.152326.1Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN USA 27 3 2019 27 3 2019 6 2019 6 2 59 71 © The Author(s) 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Background\nAlthough risperidone is increasingly used for behavioral indications in children, the associated adverse events (AEs) are not well defined in this population.\n\nObjective\nWe determined the incidence of and risk factors for AEs among children treated with risperidone at our institution, an academic medical center with inpatient, outpatient, generalist, and specialist pediatric care.\n\nMethods\nThe study included children aged ≤ 18 years with ≥ 4 weeks of risperidone exposure. Data were obtained using de-identified electronic health records. AEs were defined as any untoward event attributed to risperidone reported by the patient, parent/guardian, or physician or detected following a laboratory investigation. Associations between AEs and clinical variables were determined using univariate and multivariate analyses.\n\nResults\nThe study cohort included 371 individuals (median age 7.8 years [interquartile range 5.9–10.2]; 271 [73.0%] male). The two most common primary diagnoses were attention-deficit/hyperactivity disorder (160 [43.1%]) and autism (102 [27.5%]). The most frequent indications for risperidone were aggression (166 [44.7%]) and behavioral problems (114 [30.7%]). Altogether, 110 (29.6%) individuals had 156 AEs. Weight gain (32 [20.5%]) and extrapyramidal symptoms (23 [14.7%]) were the most common AEs. Aggression, irritability, and self-injurious behavior were positively associated with AEs, and concomitant analgesics and antibiotics were negatively associated. In multivariate analysis, associations remained significant for self-injurious behavior (adjusted odds ratio [aOR] 3.1; 95% confidence interval [CI] 1.7–5.4) and concomitant antibiotics (aOR 0.2; 95% CI 0.1–0.9).\n\nConclusions\nNearly one in three children treated with risperidone for ≥ 1 month experienced one or more AEs. Particular vigilance is warranted for children with self-injurious behavior.\n\nElectronic supplementary material\nThe online version of this article (10.1007/s40801-019-0151-7) contains supplementary material, which is available to authorized users.\n\nhttp://dx.doi.org/10.13039/100006108National Center for Advancing Translational SciencesUL1 TR000445KL2 TR000446Van Driest Sara L. http://dx.doi.org/10.13039/100000861Burroughs Wellcome Fund1015006Van Driest Sara L. http://dx.doi.org/10.13039/100000862Doris Duke Charitable Foundation2017075Van Driest Sara L. http://dx.doi.org/10.13039/100000057National Institute of General Medical Sciences5T32 GM007569Oshikoya Kazeem A. issue-copyright-statement© The Author(s) 2019\n==== Body\nKey Points\n\nUse of risperidone in children is common, especially among children with developmental and behavioral problems such as autism and attention-deficit/hyperactivity disorder.\t\nNearly one in three pediatric patients treated with risperidone experienced one or more adverse event. Weight gain and extrapyramidal symptoms were the most common adverse events.\t\nThe pre-exposure presence of self-injurious behavior was associated with higher odds of adverse events, whereas concomitant use of antibiotics was associated with lower odds of adverse events.\t\n\n\n\nIntroduction\nDespite relatively narrow US FDA-approved indications in children and adolescents, antipsychotic drugs are important in the treatment of several pediatric conditions, and prescription rates for young people are on the rise [1–4]. Risperidone, a serotonin-dopamine antagonist, is FDA approved for use in children aged 5–16 years to treat irritability associated with autism, in children aged 10–17 years to treat mania and mixed state due to bipolar disorder, and in children aged 13–17 years to treat schizophrenia [3]. Risperidone is also increasingly used “off-label” for conditions including developmental and disruptive disorders, depression, obsessive-compulsive disorder (OCD), post-traumatic stress disorder, personality disorder, attention-deficit/hyperactivity disorder (ADHD), and Tourette syndrome [4, 5].\n\nClinically important adverse events (AEs) attributed to risperidone include weight gain, prolonged QTc, tardive and withdrawal dyskinesia, diabetes mellitus, and hyperlipidemia, all of which have been well-documented in adults [6–8]. The reported incidence of AEs with risperidone, based on limited studies in adults, ranges from 1 in 16 patients to 68 in 100 patients, depending on the population studied and the definition of AEs [9, 10]. According to the American Academy of Child and Adolescent Psychiatry, AEs with atypical antipsychotics in children are similar to those seen in adults [4], but there are concerns that the consequences of risperidone-related AEs may be more serious in children than in adults [6].\n\nThere are very limited data documenting the AE profile of risperidone in young patients. Studies published to date have been of small patient cohorts representing specific subgroups of pediatric patients and have focused on the most common AEs such as weight gain and enuresis [7, 10–16]. Further, the studies were limited to ≤ 8 weeks and were unable to capture the AEs associated with prolonged use of risperidone. There are reports of additional AEs with prolonged use of risperidone, including iron deficiency anemia, pituitary tumors, hyperprolactinemia, low bone mineral density, arterial hypertension, and posterior reversible cerebral edema syndrome [17–20].\n\nDue to developmental changes in the expression of drug targets, transporters, ion channels, receptors, and downstream signal transduction pathways, AE profiles may differ across age groups [21]. Further, children and adolescents may also be at a greater risk for rare AEs than adults. Because fewer children than adults are treated with most atypical antipsychotic medicines, the data available from passive reporting databases such as the FDA Adverse Event Reporting System (FAERS) are limited, and available information on rare AEs of risperidone may be insufficient to guide rational prescribing for children and adolescents.\n\nIn this study, we sought to determine the incidence of and risk factors for AEs among children treated with risperidone at our institution. We used a de-identified electronic health record (EHR)-based data repository to study AEs among 371 children and adolescents exposed to risperidone for at least 4 weeks and, in doing so, also enabled an analysis of risperidone use patterns at this tertiary care children’s hospital.\n\nMethods\nStudy Design\nThe study was performed using the Synthetic Derivative (SD), a de-identified EHR data repository from > 2.8 million individuals from Vanderbilt University Medical Center (VUMC) [22, 23]. VUMC is an academic medical center that provides both primary and subspecialty care for pediatric patients in inpatient and outpatient settings. The study was reviewed by the Vanderbilt Institutional Review Board and determined to be non-human subjects research. Inclusion criteria included inpatient or outpatient treatment with risperidone for ≥ 4 weeks and age ≤ 18 years at first dose of risperidone. Exclusion criteria were treatment with risperidone outside of the VUMC system (e.g., patients seen by a pediatric subspecialist but not the risperidone prescriber), insufficient follow-up, or missing data.\n\nCase Definition and Identification\nThe primary outcome of interest (AEs) was defined as any untoward event reported by the patient or their parent/guardian, observed by a physician, or detected following a laboratory investigation that was documented in the EHR and attributed to risperidone. As a retrospective study, no causality assessment was performed to establish the relationship between the AEs and risperidone. The EHR of each individual in the cohort was manually reviewed to ensure no AEs were omitted, including all records from the time of risperidone initiation through risperidone discontinuation, loss to follow-up, or the current date.\n\nData Extraction\nStudy data were collected and managed using REDCap electronic data capture tools hosted at Vanderbilt University [24]. Data were extracted on the demographic and clinical details of the patient (including sex, race/ethnicity per administrative data in the EHR, psychiatric/behavioral diagnoses, and comorbidities), medications (including dose amount, route, frequency, duration, and indications), and AEs through manual extraction and use of MedEx data [25]. The first mention of risperidone in the case note or medication administration record was defined as the time risperidone was first commenced. In addition, we noted whether the starting dose of risperidone was modified (increased, decreased, or discontinued) during the course of treatment. In cases with AEs, the type, time of onset, total daily dose of risperidone at the time of the AE, action taken by the physician, and any new antipsychotic orders or prescriptions were documented.\n\nStatistical Analysis\nDemographic, clinical, and dosing data were described as frequencies and percentages for categorical variables or median and interquartile range (IQR) for continuous variables, unless otherwise specified. Comparisons of individuals with and without AE were made using Pearson’s Chi-squared, Fisher’s exact test, or the Mann–Whitney U test, as appropriate. Multivariate logistic regression was performed with AEs as the primary outcome and the following covariates: presence of comorbid conditions, age at which risperidone was commenced, risperidone starting dose and frequency of dosing, dose increase of risperidone, three major indications (aggression, irritability, and self-injurious behavior), and concomitant use of analgesics, antibiotics, and orexigenic (appetite stimulating) medicines. Post hoc analyses of risperidone dosing at the time of the AEs of daytime hypersomnia and extrapyramidal symptoms were performed. Data were analyzed using SPSS statistics software, version 21.0 (IBM Corp; Armonk, NY, USA). All p values < 0.05 were considered statistically significant, and all statistical tests were two-tailed.\n\nResults\nStudy Cohort\nOf 520 individuals initially identified in a search for risperidone-exposed young people, 371 (71.3%) met the inclusion criteria (Fig. 1). The subjects were predominantly males (271 [73.0%]), White (308 [83.0%]), and non-Hispanic (356 [96.0%]) (Table 1). The median age when risperidone was commenced was 7.8 (IQR 5.9–10.2) years (Table 1). Figure 2a shows the primary psychiatric or medical diagnoses for the patients; the two most common were ADHD (160 [43.1%]) and autism (102 [27.5%]). The most common indications for risperidone were aggression (166 [44.7%]) and behavioral problems (114 [30.7%]) (Fig. 2b). In all, 137 (36.9%) patients had at least one of the 81 identified comorbidities; seizure disorder (58 [42.3%]) and asthma (34 [24.8%]) were the most common (Fig. 2c). Most of the prescriptions for risperidone were off-label (277 [74.7%]).Fig. 1 Identification of risperidone exposures and adverse events (AEs). All cases were ascertained from electronic health records from Vanderbilt University Medical Center (VUMC)\n\n\nTable 1 Demographics and risperidone exposures in study cohort\n\nCharacteristic\tN = 371\t\nAge at commencement of risperidone, years\t7.8 (5.9–10.2)\t\nSex\t\n Male\t271 (73.0)\t\n Female\t100 (27.0)\t\nRace\t\n White\t308 (83.0)\t\n African–American\t47 (12.7)\t\n Asian/Pacific Islander\t8 (2.2)\t\n Native American\t2 (0.5)\t\n Unknown\t6 (1.6)\t\nEthnicity\t\n Non-Hispanic\t356 (96.0)\t\n Hispanic\t8 (2.2)\t\n Unknown\t7 (1.9)\t\nRisperidone starting dose, mg/day\t0.50 (0.37–1.00)\t\nData are presented as n (%) or median (interquartile range)\n\n\nFig. 2 Clinical conditions and concomitant medications in individuals treated with risperidone. a Psychiatric and non-psychiatric diagnoses in the cohort. The total number of diagnoses (458) was higher than the total number of patients (371), as some patients had multiple diagnoses. b Indications for risperidone. The total number of indications (586) was higher than the total number of patients (371), as some patients had multiple indications for risperidone use. c Comorbid conditions in individuals treated with risperidone; 137 individuals had one or more comorbid conditions. d Classes of medicines used concomitantly with risperidone. The total number of concomitant medications (1251) was higher than the total number of patients with concomitant medications (360), as some patients had multiple concomitant medications. *Chromosomal abnormalities included Angelman syndrome, Prader–Willi syndrome, Russell–Silver syndrome, Klinefelter syndrome, trisomy 12p, trisomy 21, 4q deletion, and 7q22.1 deletion; **other diagnoses with only a single count included borderline personality disorder, mixed bipolar affective disorder (depression, anxiety, and panic attack), psychosis, Apert syndrome, asthma, bacteremia and peritonitis, cardiofaciocutaneous syndrome, cerebral palsy only, cerebral palsy with periventricular leukomalacia, chorea/movement disorder, cystic fibrosis with pancreatic insufficiency, ectrodactyly-ectodermal dysplasia-clefting syndrome, end-stage cardiac disease, focal segmental glomerulosclerosis, glomerulonephritis, Henoch–Schönlein purpura, hypoplastic cerebellum, spastic cerebral palsy, hepatic disease, ischemic stroke, meningitis, nephrotic syndrome, neurodegeneration and seizure disorder, non-ketotic hyperglycemia, non-accidental trauma with subdural hemorrhage, pica, post-viral encephalitis seizure disorder, septic shock and encephalopathy, and viral infection; ***other comorbidities with a single count included abdominal pain, acute respiratory failure, anemia, anxiety, bulimia nervosa, Burkitt’s lymphoma, celiac sprue, cerebral palsy, cholesteatoma, chronic adeno-tonsillitis, chronic bronchiolitis, chronic kidney disease, clostridium difficile disease, Crohn’s disease, diabetes insipidus, elevated liver enzymes, endocrine dysfunction, fatty liver disease, failure to thrive, familial hypercholesterolemia, fructose intolerance, gastritis, glomerulonephritis, Grave’s disease, hemophilia A, Henoch Schonlein purpura, hepatitis, Hunter’s disease, hypoalbuminemia, intestinal lymphoid nodular hyperplasia, immunosuppression, latent tuberculosis, liver cirrhosis, malnutrition, meningitis, neuromyotonia, nocturnal enuresis, pancreatitis, perianal candidiasis, periorbital cellulitis, pulmonary hypertension, recurrent hypoglycemia, ruptured appendicitis, scurvy, sickle cell disease, suicidal ideation, transient hypogammaglobinemia of infancy, and VACTERL syndrome. ^Other drugs included antidiabetics, antidiuretics, antifailure medicine, antifungals, antilipidemic medicine. antisecretory medicine, antispasmodic medicine, antiretroviral medicine, anti-tuberculous medicine, antiviral medicine, clotting promoter, diuretics, dopamine promoter, fish oil, iron supplement, laxatives, synthetic growth hormone, thyroxine, urinary bladder relaxant, vasodilator, and vitamins. NOS not otherwise specified, WAGRO Wilms’ tumor/aniridia/genitourinary anomalies/mental retardation syndrome/obesity\n\n\n\n\nRisperidone and Concomitant Medications\nThe median starting dose of risperidone was 0.50 mg/day (IQR 0.37–1.00), given as a single dose (n = 160 [43.1%]) or two to six divided doses (n = 211 [56.9%]) (Table 2). Risperidone starting dose was later increased, decreased, or discontinued for 178 (48.0%) patients over the period of treatment. Poor response was the reason for dose increase (n = 94), whereas AEs (n = 4) and good response (n = 8) were the reasons for dose decrease. The drug was discontinued due to treatment completion for postoperative delirium (n = 1), AEs (n = 34), or failure to respond to treatment (n = 37).Table 2 Comparison of the demographics and baseline clinical variables of those with and without adverse events\n\nCharacteristic\tAEs present (n = 110)\tAEs absent (n = 261)\tp value\t\nDemographics\t\n Age at risperidone commencement, years\t7.8 (5.9–10.3)\t7.9 (5.9–10.2)\t0.830a\t\n Sex\t\t\t0.097b\t\n Male\t87 (79.8)\t184 (70.0)\t\t\n Female\t23 (20.2)\t77 (30.0)\t\t\n Race\t\t\t\n0.030\nb\n\t\n African-American\t11 (9.6)\t36 (13.7)\t\t\n Asian/Pacific Island\t1 (0.9)\t7 (2.6)\t\t\n Caucasian\t92 (84.5)\t216 (83.0)\t\t\n Native American\t1 (0.9)\t1 (0.4)\t\t\n Unknown\t5 (4.4)\t1 (0.4)\t\t\n Ethnicity\t\t\t0.652b\t\n Non-Hispanic\t104 (94.7)\t252 (96.4)\t\t\n Hispanic\t3 (2.6)\t5 (1.9)\t\t\n Unknown\t3 (2.6)\t4 (1.5)\t\t\nDiagnoses\t\n Presence of comorbid conditions\t\t\t0.638b\t\n Yes\t43 (38.6)\t94 (37.0)\t\t\n No\t67 (61.4)\t167 (63.0)\t\t\n Specific comorbidities\t\t\t\t\n Seizure disorder\t14 (13.2)\t44 (17.4)\t0.351c\t\n Asthma\t7 (6.1)\t27 (10.7)\t0.324c\t\n Specific psychiatric diagnoses\t\t\t\t\n Attention deficit hyperactivity disorder\t47 (43.9)\t113 (42.2)\t0.822c\t\n Autism\t35 (30.7)\t67 (24.8)\t0.256c\t\n Specific indications for risperidone use\t\n Aggression\t59 (52.6)\t107 (40.0)\t\n0.030\nc\n\t\n Behavioral problems\t30 (28.0)\t84 (32.2)\t0.389c\t\n Agitation\t25 (22.8)\t44 (17.8)\t0.191c\t\n Irritability\t33 (28.9)\t52 (19.3)\t\n0.042\nc\n\t\n Self-injurious behaviors\t37 (33.3)\t31 (11.5)\t\n< 0.001\nc\n\t\nRisperidone prescribing\t\n Starting dose of risperidone (mg/day)\t0.50 (0.47–1.00)\t0.50 (0.25–1.00)\t0.975a\t\n Starting dose frequency (doses/day)\t\t\t0.069b\t\n Once\t48 (48.6)\t112 (43.0)\t\t\n Two times\t44 (39.5)\t126 (48.1)\t\t\n Three times\t9 (8.8)\t15 (5.9)\t\t\n Four times\t8 (7.0)\t4 (1.5)\t\t\n Five times\t0 (0.0)\t1 (0.4)\t\t\n Six times\t1 (0.9)\t3 (1.1)\t\t\n One or more dose modification\t\t\t\n< 0.001\nc\n\t\n Yes\t80 (72.8)\t98 (37.8)\t\t\n No\t30 (27.2)\t163 (62.6)\t\t\n Type of dose modification\t\t\t\n< 0.001\nb\n\t\n Increased dose\t33 (30.7)\t61 (24.1)\t\t\n Decreased dose\t5 (4.4)\t7 (2.6)\t\t\n Drug discontinuation\t42 (37.7)\t30 (11.1)\t\t\n No modification\t30 (21.2)\t163 (62.2)\t\t\n On- and off-label use of risperidone\t\t\t0.072b\t\n On-label\t34 (29.8)\t60 (22.2)\t\t\n Off-label\t76 (70.2)\t201 (77.8)\t\t\nConcomitant medications\t\n Number of co-prescribed drugs\t\t\t0.099b\t\n One\t10 (8.8)\t25 (10.7)\t\t\n Two\t24 (21.1)\t45 (16.7)\t\t\n Three\t34 (30.7)\t62 (23.3)\t\t\n Four\t22 (19.3)\t43 (16.7)\t\t\n Five\t9 (8.8)\t27 (10.7)\t\t\n Six and above\t9 (9.6)\t50 (20.0)\t\t\n None\t2 (1.8)\t9 (3.3)\t\t\n Type or class of co-prescribed drug\t\n α2-agonist\t40 (36.8)\t104 (40.0)\t0.561c\t\n Anticonvulsant\t37 (33.3)\t84 (33.0)\t0.809c\t\n Antidepressant\t48 (43.9)\t97 (36.3)\t0.247c\t\n Psychostimulant\t37 (33.3)\t104 (38.5)\t0.293c\t\n Analgesic\t6 (7.0)\t44 (17.8)\t\n0.003\nc\n\t\n Antiulcer\t21 (19.3)\t72 (28.9)\t0.090c\t\n Hypnotic\t33 (28.9)\t62 (24.4)\t0.241c\t\n Antibiotic\t2 (3.5)\t32 (13.2)\t\n0.001\nc\n\t\n Orexigenicd\t13 (11.4)\t41 (15.9)\t0.420c\t\n Antihistamine\t14 (13.2)\t55 (20.7)\t0.079c\t\nData are presented as n (%) or median (interquartile range) unless otherwise indicated\n\nSignificant p values (< 0.05) are in bold\n\nAE adverse event\n\nap value from Mann–Whitney U test\n\nbp value from Pearson Chi-squared test\n\ncp value from Fisher’s exact test\n\ndMirtazapine, amitriptyline, gabapentin, pregabalin, cyproheptadine, olanzapine, quetiapine, dexamethasone, prednisone, and hydrocortisone\n\n\n\nMost individuals (n = 360 [97.0%]) used one or more concomitant medicines with risperidone (Fig. 2d). Antidepressants (n = 145 [40.3%]), α2- agonists (n = 144 [40.0%]), psychostimulants (n = 141 [39.2%]), and anticonvulsants (n = 121 [33.6%]) were the leading classes of concomitant medicines.\n\nAdverse Events to Risperidone\nAltogether, 110 (29.6%) patients had a total of 156 AEs (Fig. 3). Weight gain (n = 32 [20.5%]) and extrapyramidal symptoms (n = 23 [14.7%]) were the most common AEs. The specific AEs experienced by each patient and the actions taken by providers are presented in the table in the Electronic Supplementary Material (ESM).Fig. 3 Adverse events during risperidone therapy in the study cohort. *Extrapyramidal symptoms included akathisia, dystonic movement, tremor, and spastic rigidity; **other adverse events included anxiety, droopy eyes, early menstrual flow, fainting spell, headache, heavy tongue, hot flashes, hyperthermia, multiple bruises, musculoskeletal pain, nervousness, oculogyric crisis, premature adrenarche, restlessness, tachycardia, thirst, worsened behavioral problem, and worsened muscle cramp. DM diabetes mellitus\n\n\n\n\nThe demographics, clinical variables, and dosing regimen of risperidone for subjects with and without AEs were compared in a univariate analysis (Table 2). There were significant associations between the AE status of the subjects and their race (p = 0.030), risperidone use to treat aggression (p = 0.030), irritability (p = 0.042) or self-injurious behavior (p < 0.001), dose modification of risperidone (p < 0.001), type of dose modification (p < 0.001), and concomitant use of analgesics (p = 0.003) or antibiotics (p = 0.001). On-label versus off-label use was not associated with incidence of AE.\n\nCovariates for multivariate analysis were selected based on adequate group size (≥ 30), significance in the univariate analysis (dose increase of risperidone, aggression, irritability, self-injurious behavior, concomitant analgesics, concomitant antibiotics), prior studies of risperidone AEs (age, starting dose, frequency of dosing, presence of comorbid conditions), and potential direct influence on AEs (concomitant orexigenic drugs). In the multivariable analysis including these 11 covariates, self-injurious behaviors and antibiotic therapy were significantly associated with increased AEs (Table 3). The odds of AEs were higher in the presence of self-injurious behavior (adjusted odds ratio [aOR] 3.1; 95% confidence interval [CI] 1.7–5.4) compared with children without this indication for risperidone use, whereas the odds of AEs were lower among those using concomitant antibiotics (aOR 0.20; 95% CI 0.05–0.94) than among children not using antibiotics concomitantly with risperidone.Table 3 Clinical factors associated with adverse events to risperidone\n\nVariable\tOR (95% CI) for AEa\t\nUnadjustedb\tAdjustedc\t\nIndications\t\n Self-injurious behaviors (present vs. absent)\t\n3.76 (2.18–6.49)\n\t\n3.06 (1.72–5.44)\n\t\n Aggression (present vs. absent)\t\n1.67 (1.06–2.61)\n\t1.15 (0.70–1.88)\t\n Irritability (present vs. absent)\t\n1.72 (1.03–2.86)\n\t1.44 (0.82–2.52)\t\nPresence of comorbidity (present vs. absent)\t1.14 (0.72–1.80)\t1.20 (0.73–1.97)\t\nAge at commencing risperidone (each additional year)\t1.02 (0.97–1.06)\t1.02 (0.99–1.07)\t\nRisperidone dosing regimen\t\n Starting dose of risperidone (per additional mg/day)\t1.05 (0.84–1.30)\t1.01 (0.80–1.27)\t\n Starting dosing frequency of risperidone (single vs. multiple dosing)\t1.15 (0.90–1.47)\t1.28 (0.98–1.68)\t\n Risperidone dose increase (present vs. absent)\t1.38 (0.84–2.26)\t1.22 (0.68–2.16)\t\nConcomitant medicines\t\n Analgesics (present vs. absent)\t0.29 (0.12–0.69)\t0.44 (0.16–1.14)\t\n Antibiotics (present vs. absent)\t\n0.13 (0.03–0.56)\n\t\n0.20 (0.05–0.94)\n\t\n Orexigenics (present vs. absent)\t0.72 (0.36–1.40)\t1.01 (0.49–2.06)\t\nSignificant associations are in bold\n\nAE adverse event, CI confidence interval, OR odds ratio\n\naThe model was generated using binary logistic regression\n\nbUnadjusted OR refers to the OR for each variable with no others in the model\n\ncAdjusted OR refers to the OR after all variables were included in the model\n\n\n\n\nExtrapyramidal symptoms and daytime hypersomnia may be related to risperidone dose. Of 20 children with daytime hypersomnia, the starting dose of risperidone had been increased in four (20.0%), resulting in a risperidone dose of 0.75–5 mg/day at the time of the AE (ESM table). The remaining 16 (80.0%) children had daytime hypersomnia while on low starting doses (0.25–1 mg/day) of risperidone (ESM table). The frequency of increased dose among children with daytime hypersomnia did not differ from children with no risperidone AEs (p = 1.0). In children with extrapyramidal symptoms (n = 23), seven (30.4%) occurred on an increased risperidone dose of 2–6 mg/day, and 16 (69.6%) occurred at a low starting dose (0.25–1.5 mg/day) (ESM table). The frequency of increased risperidone dose did not differ among those with extrapyramidal symptoms and those without AEs (p = 0.45).\n\nDiscussion\nRisperidone use in our cohort resulted in substantial number of common and rare AEs. On-label versus off-label use was not significantly associated with AE and, after controlling for the significant clinical variables, only self-injurious behavior and concomitant antibiotics were associated with AEs. The odds of AEs were higher in the presence of self-injurious behavior than in children without this indication for risperidone use, and lower with concomitant antibiotics.\n\nNearly one-third of this study cohort had experienced at least one AE, warranting close monitoring of children and adolescents treated with risperidone. Previous smaller studies involving children and adolescents with prolonged exposure to risperidone have reported higher rates (48–65%) [12, 13, 26], whereas a single study reported a lower rate (28.2%) [27]. Differences in the population studied, the methodology used, the duration of use of risperidone, and sample sizes may underlie the disparate AE rates. Our cohort included children and adolescents with a wide range of psychiatric and non-psychiatric disorders. By contrast, most prior studies of risperidone AEs involved children and adolescents with autism/autism spectrum disorder or disruptive behavior disorders [12, 13, 26, 27]. Our study was retrospective, with AEs detected from EHR documentation, whereas others were prospective, randomized, and double blind or open label, with active monitoring for AEs [12, 13, 26]. While the retrospective nature of our study leads to some limitations, merits of this design are less selection bias than prospective clinical trials and a focus on AEs that were documented by clinicians. Thus, our data may be more representative of “real-world” populations and clinically relevant findings. We also evaluated a larger cohort of 371 individuals, whereas the largest cohort published to date includes ≤172 individuals [13, 26–29].\n\nOur cohort had a wide range of AEs, including common AEs (e.g., weight gain, extrapyramidal symptoms, and daytime hypersomnia) and rare AEs (e.g., premature adrenarche, precocious puberty, and early menstrual flow). Nearly one-quarter of our patients experienced multiple AEs. Consistent with other studies, common and rare AEs have been reported with risperidone among children and adolescents with autism and disruptive behavioral disorders, and weight gain is one of the most common AEs [12, 13, 26–29]. Some prior studies had reported respiratory system disorders as common AEs with risperidone (e.g., upper respiratory tract infection, rhinitis, pharyngitis) [12, 13], which we did not identify in our cohort. Respiratory AEs had previously been assessed as unrelated or of doubtful relationship to risperidone treatment [13] and thus may not have been documented as risperidone AEs in the EHR.\n\nExtrapyramidal symptoms and daytime hypersomnia are common AEs with risperidone therapy and potentially related to risperidone dose. In our cohort, the majority of children with daytime hypersomnia experienced this effect while on a low starting dose of risperidone. An earlier study evaluating the efficacy and safety of low-dose (0.125 mg/day for children weighing 20 to < 45 kg; 0.175 mg/day for children weighing > 45 kg) and high-dose (1.25 mg/day for children weighing 20 to < 45 kg; 1.75 mg/day for children weighing > 45 kg) risperidone or placebo in 96 children and adolescents (aged 5–17 years) with autism reported hypersomnia (somnolence and sedation) following low- and high-dose exposures; however, the AE was more frequent in high-dose than low-dose groups [30]. Similarly, the majority of children in our cohort with extrapyramidal symptoms were on low starting doses of risperidone. Data from multiple fixed-dose (1–16 mg/day and placebo) trials of risperidone in adults with schizophrenia suggested extrapyramidal symptoms are risperidone dose related [31, 32]. Those on placebo or low-dose risperidone (1 mg/day) experienced more extrapyramidal symptoms than those on high doses (2–16 mg/day). Another study had shown that dystonia might occur in susceptible individuals during the first few days of risperidone use, even at low doses [32, 33].\n\nOne patient each experienced rare AEs, including droopy eyes, hyperthermia, early menstrual flow, fainting spell, precocious puberty, heavy tongue, hot flashes, multiple bruises, musculoskeletal pain, nervousness, oculogyric crisis, premature adrenarche, and restlessness. While there are reports of risperidone-induced AEs involving the ocular muscles (blepharospasm and oculogyric crisis) [26, 34], and potentially thermoregulatory disorder (febrile seizure) [29], the other rare AEs are not previously reported, and the mechanism is unknown. Some of these rare AEs may be attributed to comorbid conditions or concomitant medications and may not be truly risperidone-related. Nonetheless, it is important to make note of these rare AEs in the future monitoring of risperidone in children and adolescents.\n\nPoor response was the major reason for increasing the dose of risperidone in our patients; of the 94 patients with dose increase to > 1 mg/day, 42.4% had AEs (Table 2 and ESM table). However, this is not surprising as previous studies had shown that higher doses of risperidone are associated with high rates of extrapyramidal symptoms and hypersomnia in children with various behavioral problems [35]. Further, the starting dose of risperidone was decreased in four patients and discontinued in 37 patients due to AEs (Table 2 and ESM table). Four other atypical antipsychotic agents (aripiprazole, olanzapine, paliperidone, and quetiapine) currently have FDA-approved indications for use in children and adolescents [36]. These other agents were used as alternatives to risperidone in our patients after discontinuation due to AEs. Aripiprazole was the most frequently used substitute for risperidone, and this may be attributed to its relatively lower AEs and good tolerability compared with other newer atypical antipsychotic agents [37]. Aripiprazole has been successfully used to address risperidone-induced mild hypothermia in an 11-year-old with schizophrenia [38].\n\nAlthough the univariate analyses showed that dosing frequency and dose-modification pattern of risperidone were significantly associated with AEs (Table 2), these two factors did not remain significant in the multivariate analysis (Table 3). There is a lack of studies identifying risk factors for risperidone-induced AEs. However, younger age and higher medication dose have been reported as predictors of adverse weight gain in children exposed to risperidone for 8 weeks [39]. Despite weight gain being the most reported AE among our cohort, age at commencement of risperidone and increased dose did not significantly impact the risk for AEs in our cohort. By contrast, use of risperidone to treat self-injurious behavior was associated with a higher risk of AEs compared with children without this behavioral problem. This is a new finding that will be strengthened by validation in an independent dataset. It is noteworthy that children with autism spectrum disorder (ASD) and various forms of chromosomal abnormalities, which constitutes a significant proportion of our patients, are known to have a high prevalence of self-injurious behaviors [40], which might have influenced our observation that self-injurious behaviors are associated with AE risk. It is possible that AEs are reported with higher frequency in this subset, due to more frequent follow-up, higher vigilance for AEs, or more difficulty in discerning drug effects. These individuals may also be receiving additional drugs, contributing to AEs and drug–drug interactions. In addition, risperidone is primarily metabolized by the polymorphic cytochrome P450 2D6 enzyme (CYP2D6) [41]. A study comparing the distribution of CYP2D6*4 and CYP2D6*41 alleles (implicated in the efficacy and adverse effects of risperidone) in patients with ASD and healthy control groups showed higher frequencies of both alleles in patients with ASD [42]. This is a potential confounder that might have contributed to the high odds ratio of AEs among individuals with self-injurious behavior. Our ongoing study of the roles of CYP2D6 polymorphisms in risperidone AEs in children will test this hypothesis. Further, concomitant use of antibiotics was associated with a lower risk of AEs compared with children who did not use antibiotics. One potential mechanism for this observation is increased metabolism of risperidone due to enzymatic induction. An in vitro study demonstrated risperidone metabolism by CYP3A4 and CYP3A5 enzymes [43], which can be induced by antibiotics. Although we did not ascertain whether the antibiotics enhanced the metabolism of risperidone to produce this protective effect and cannot determine causation in this retrospective study, the impact of this minor metabolic pathway and this potential drug–drug interaction merit further investigation.\n\nWe acknowledge several limitations. This was a single-center study, and these findings may not be generalizable to the entire pediatric population. However, we believe our findings are robust based on the larger sample size analyzed compared with previous smaller studies [12, 13, 26–29]. Weight gain and sedation are common adverse effects of some concomitant drugs, such as valproic acid, used by our patients, which could potentially increase the prevalence of risperidone-induced weight gain and hypersomnia reported in this study [44]. Another limitation is that risperidone exposure and the associated AEs were audited retrospectively in the EHR, which may have missing and inaccurate data [45, 46]. For example, an AE ascertained at another hospital may not be captured [47, 48], we may not have complete ascertainment of mild AEs [49], the primary diagnoses and indications for risperidone exposure may not be complete, there may be errors in the documented dosing regimen, and weight and height were not serially assessed at every visit for every individual. Further, patients with early AEs may have been excluded from the study due to the inclusion criteria of ≥ 4 weeks of risperidone therapy. We did not perform causality assessment between the AEs and risperidone to exclude concomitant medications as the likely cause. Generally, AE refers to any problem occurring at the time a medicine is used, whether or not it is identified as a cause of the problem [50]. For this cohort with a high incidence of polypharmacy, other medications or a drug–drug interaction may have been truly responsible for some AEs. Our cohort size was not large enough to explore all possible risk factors (or combinations of risk factors) contributing to risperidone-related AEs. Meta-analysis across many cohorts may enable more granular detail and more precisely guide future prescribing advice.\n\nConclusions\nRisperidone was associated with a significant proportion of one or more AEs among children and adolescents after using the medicine for ≥ 4 weeks. The age at commencement of risperidone, presence of comorbidities, dosing regimen of risperidone, and concomitant use of analgesics or orexigenic medicines did not predict AEs in this study, but there was an increased risk for AEs among patients with self-injurious behavior. Clinicians should be cautious in prescribing risperidone to patients with self-injurious behavior. Further research is needed to identify clinical factors or biomarkers to accurately predict risperidone AEs.\n\nElectronic supplementary material\nBelow is the link to the electronic supplementary material.\nSupplementary material 1 (PDF 153 kb)\n\n \n\n\nFunding\nThis work used a dataset from Vanderbilt University Medical Center’s BioVU, which is supported by the Vanderbilt Institute for Clinical and Translational Research (VICTR) and the National Institutes of Health (NIH) National Center for Advancing Translational Sciences grants UL1 TR000445. This work was also supported by KL2 TR000446 (SLV), Burroughs Wellcome Fund Innovation in Regulatory Science Award 1015006 (SLV), Doris Duke Clinical Scientist Development Award 2017075 (SLV), and NIH/National Institute of General Medical Sciences Clinical Pharmacology Training Program 5T32 GM007569 (KAO).\n\nEthical Approval\nThe study was reviewed by the Vanderbilt Institutional Review Board and determined to be non-human subjects research.\n\nConflict of Interest\nDr. Van Driest has been an invited speaker to Merck. Dr. Oshikoya, Dr. Carroll, Ms. Aka, and Dr. Roden have no conflicts of interest that are directly relevant to the content of this article.\n==== Refs\nReferences\n1. Cabaleiro T Ochoa D López-Rodríguez R Román M Novalbos J Ayuso C Effect of polymorphisms on the pharmacokinetics, pharmacodynamics, and safety of risperidone in healthy volunteers Hum Psychopharmacol. 2014 29 459 469 25042870 \n2. Stahl S Stahl’s essential psychopharmacology: neuroscientific basis and practical applications 2008 3 New York Cambridge University Press \n3. Essick CJ. Examining the effect of FDA approval of risperdal for pediatric use on prescribing trends from 2005–2008. Public Health Theses, 2012. 1082. https://elischolar.library.yale.edu/cgi/viewcontent.cgi?article=1081&context=ysphtdl. Accessed 23 Feb 2019.\n4. American Academy of Child and Adolescent Psychiatry (AACAP) Committee on quality issues. Practice parameter for the use of atypical antipsychotic medications in children and adolescents. https://www.aacap.org/App_Themes/AACAP/docs/practice_parameters/Atypical_Antipsychotic_Medications_Web.pdf. Accessed 5 June 2016.\n5. Correll CU Penzner JB Parikh UH Mughal T Javed T Carbon M Recognizing and monitoring adverse events of second-generation antipsychotics in children and adolescents Child Adolesc Psychiatr Clin N Am. 2006 15 177 206 16321730 \n6. Correll CU Carlson HE Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents J Am Acad Child Adolesc Psychiatry. 2006 45 771 791 16832314 \n7. Safer DJ A comparison of risperidone-induced weight gain across the age span J Clin Psychopharmacol. 2004 24 429 435 15232335 \n8. Findling RL Kusumakar V Daneman D Moshang T Desmedt G Binder C Prolactin levels during long-term risperidone treatment in children and adolescents J Clin Psychiatry. 2003 64 1362 1369 14658952 \n9. Miyaji S Yamamoto K Hoshino S Yamamoto H Sakai Y Miyaoka H Comparison of the risk of adverse events between risperidone and haloperidol in delirium patients Psychiatry Clin Neurosci. 2007 61 275 282 17472596 \n10. Aman MG Arnold LE McDougle CJ Vitiello B Scahill L Davies M Acute and long-term safety and tolerability of risperidone in children with autism J Child Adolesc Psychopharmacol. 2005 15 869 884 16379507 \n11. Gencer O, Emiroglu FN, Miral S, Baykara B, Baykara A, Dirik E. Comparison of long-term efficacy and safety of risperidone and haloperidol in children and adolescents with autistic disorder. An open label maintenance study. Eur Child Adolesc Psychiatry. 2008;17:217–225.\n12. Haas M Karcher K Pandina GJ Treating disruptive behavior disorders with risperidone: a 1-year, open-label safety study in children and adolescents J Child Adolesc Psychopharmacol. 2008 18 337 345 18759643 \n13. Reyes M Buitelaar J Toren P Augustyns I Eerdekens M A randomized, double-blind, placebo-controlled study of risperidone maintenance treatment in children and adolescents with disruptive behavior disorders Am J Psychiatry. 2006 163 402 410 16513860 \n14. Malone RP Maislin G Choudhury MS Gifford C Delaney MA Risperidone treatment in children and adolescents with autism: short- and long-term safety and effectiveness J Am Acad Child Adolesc Psychiatry. 2002 41 140 147 11837403 \n15. McDougle CJ Holmes JP Bronson MR Anderson GM Volkmar FR Price LH Risperidone treatment of children and adolescents with pervasive developmental disorders: a prospective open-label study J Am Acad Child Adolesc Psychiatry. 1997 36 685 693 9136504 \n16. Findling RL McNamara NK Branicky LA Schluchter MD Lemon E Blumer JL A double-blind pilot study of risperidone in the treatment of conduct disorder J Am Acad Child Adolesc Psychiatry. 2000 39 509 516 10761354 \n17. Calarge CA Ziegler EE Iron deficiency in pediatric patients in long-term risperidone treatment J Child Adolesc Psychopharmacol. 2013 23 101 109 23480322 \n18. Szarfman A Tonning JM Levine JG Doraiswamy PM Atypical antipsychotics and pituitary tumors: a pharmacovigilance study Pharmacotherapy. 2006 26 748 758 16716128 \n19. Calarge CA Zimmerman B Xie D Kuperman S Schlechte JA A cross-sectional evaluation of the effect of risperidone and selective serotonin reuptake inhibitors on bone mineral density in boys J Clin Psychiatry. 2010 71 338 347 20331935 \n20. Milani GP Bianchetti MG Mazzoni MB Triulzi F Mauri MC Agostoni C Fossali EF Arterial hypertension and posterior reversible cerebral edema syndrome induced by risperidone Pediatrics. 2014 133 e771 e774 24567018 \n21. Mulla H Understanding developmental pharmacodynamics: importance for drug development and clinical practice Paediatr Drugs. 2010 12 223 233 20593907 \n22. Roden DM Pulley JM Basford MA Bernard GR Clayton ER Balser JR Development of a large-scale de-identified DNA biobank to enable personalized medicine Clin Pharmacol Ther. 2008 84 362 369 18500243 \n23. McGregor TL Van Driest SL Brothers KB Bowton EA Muglia LJ Roden DM Inclusion of pediatric samples in an opt-out biorepository linking DNA to de-identified medical records: pediatric BioVU Clin Pharmacol Ther. 2013 93 204 211 23281421 \n24. Harris PA Taylor R Thielke R Payne J Gonzalez N Conde JG Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support J Biomed Inform. 2009 42 377 381 18929686 \n25. Xu H Stenner SP Doan S Johnson KB Waitman LR Denny JC MedEx: a medication information extraction system for clinical narratives J Am Med Informatics Assoc. 2010 17 19 24 \n26. Kent JM Hough D Singh J Karcher K Padina G An open-label extension study of the safety and efficacy of risperidone in children and adolescents with autistic disorder J Child Adolesc Psychosopharmacol. 2013 23 676 686 \n27. Youngster I Zachor DA Gabis LV Bar-Chaim A Benveniste-Levkovitz P Britzi M CYP2D6 genotyping in paediatric patients with autism treated with risperidone: a preliminary cohort study Dev Med Child Neurol. 2014 56 990 994 24828442 \n28. Aman MG Arnold LE McDougle CJ Vitiello B Scahill L Davies M Acute and long-term safety and tolerability of risperidone in children with autism J Child Adolesc Psychopharmacol 2005 15 869 884 16379507 \n29. Malone RP Maislin G Choudhury MS Gifford C Delaney MA Risperidone treatment in children and adolescents with autism: short- and long-term safety and effectiveness J Am Acad Child Adolesc Psychiatry. 2002 41 140 147 11837403 \n30. Kent JM Kushner S Ning X Karcher K Ness S Aman M Singh J Hough D Risperidone dosing in children and adolescents with autistic disorder: a double-blind, placebo-controlled study J Autism Dev Disord. 2013 43 8 1773 1783 23212807 \n31. Thomson SR Chogtu B Bhattacharjee D Agarwal S Extrapyramidal symptoms probably related to risperidone treatment: a case series Ann Neurosci. 2017 24 3 155 163 28867897 \n32. Risperdal® (risperidone). Highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020272s056,020588s044,021346s033,021444s03lbl.pdf. Accessed 30 Nov 2018.\n33. Chandra NC Sheth SA Mehta RY Dave KR Severe tardive dystonia on low dose short duration exposure to atypical antipsychotics: factors explored Indian J Psychol Med. 2017 39 1 96 98 28250568 \n34. Masliyah T Ad-Dab’bagh Y Low-dose risperidone-induced oculogyric crises in an adolescent male with autism, Tourette’s and developmental delay J Can Acad Child Adolesc Psychiatry. 2011 20 214 216 21804851 \n35. Vanwong N, Srisawasdi P, Ngamsamut N, Nuntamool N, Puangpetch A, Chamkrachangpada B, Hongkaew Y, Limsila P, Kittitharaphan W, Sukasem C. Hyperuricemia in children and adolescents with autism spectrum disorder treated with risperidone: the risk factors for metabolic adverse effects. Front Pharmacol. 2017;7:527. 10.3389/fphar.2016.00527(eCollection 2016).\n36. Saljoughian M Atypical antipsychotics: safety and use in pediatric patients US Pharm. 2015 40 5 52 55 \n37. Harrison JN Cluxton-Keller F Gross D Antipsychotic medication prescribing trends in children and adolescents J Pediatr Health Care. 2012 26 2 139 145 22360933 \n38. Grau K Plener PL Gahr M Denzer C Freudenmann RW Mild hypothermia in a child with low-dose risperidone: a case report Zeitschrift für Kinder- und Jugendpsychiatrie und Psychotherapie 2017 45 335 337 27685194 \n39. Hoekstra PJ Troost PW Lahuis BE Mulder H Mulder EJ Franke B Risperidone-induced weight gain in referred children with autism spectrum disorders is associated with a common polymorphism in the 5-hydroxytryptamine 2C receptor gene J Child Adolesc Psychopharmacol. 2010 20 473 477 21186965 \n40. Oliver C Richards C Practitioner review: self-injurious behaviour in children with developmental delay J Child Psychol Psychiatry. 2015 56 10 1042 1054 25916173 \n41. Mannens G Huang ML Meuldermans W Hendrickx J Woestenborghs R Heykants J Absorption, metabolism, and excretion of risperidone in humans Drug Metab Disp 1993 21 6 1134 1141 \n42. Bauze D. Genetic aspects of autism spectrum disorders. Summary of the Doctoral Thesis for obtaining the degree of a Doctor of Medicine, Speciality—Medical Genetics. Rīga, 2014. https://pdfs.semanticscholar.org/eae0/d6ba0dc08fe731f3b652810a69699739aff2.pdf. Accessed 30 Nov 2018.\n43. Fang J Bourin M Baker GB Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 Naunyn Schmiedebergs Arch Pharmacol. 1999 359 147 151 10048600 \n44. Rocha GP Batista BH Nunes ML Use of psychoactive and antiepileptic drugs: guidelines for pediatricians J Pediatr (Rio J). 2004 80 2 Suppl S45 S55 15154072 \n45. Madden JM Lakoma MD Rusinak D Lu CY Soumerai SB Missing clinical and behavioral health data in a large electronic health record (EHR) system J Am Med Informatics Assoc. 2016 23 1143 1149 \n46. Stiglic G, Kocbek P, Fijacko N, Sheikh A, Pajnkihar M. Challenges associated with missing data in electronic health records: a case study of a risk prediction model for diabetes using data from Slovenian primary care. Health Informatics J. 2017;1460458217733288. 10.1177/1460458217733288(Epub ahead of print)\n47. Wilson RM Runciman WB Gibberd RW Harrison BT Newby L Hamilton JD The quality in Australian health care study Med J Aust. 1995 163 458 471 7476634 \n48. Leape LL, Brennan TA, Laird N, Lawthers AG, Localio AR, Barnes BA, et al. The nature of adverse events in hospitalized patients. Results of the Harvard Medical Practice Study II. N Engl J Med. 1991;324:377–84.\n49. Zegers M de Bruijne MC Wagner C Groenewegen PP Waaijman R van der Wal G Design of a retrospective patient record study on the occurrence of adverse events among patients in Dutch hospitals BMC Health Serv Res. 2007 7 27 17319971 \n50. Bates DW, Cullen DJ, Laird N, Petersen LA, Small SD, Servi D, et al. Incidence of adverse drug events and potential adverse drug events. Implications for prevention. ADE Prevention Study Group. JAMA. 1995;274:29–34.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2198-9788",
"issue": "6(2)",
"journal": "Drugs - real world outcomes",
"keywords": null,
"medline_ta": "Drugs Real World Outcomes",
"mesh_terms": null,
"nlm_unique_id": "101658456",
"other_id": null,
"pages": "59-71",
"pmc": null,
"pmid": "30919267",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": "10048600;10761354;11837403;14658952;15154072;15232335;16321730;16379507;16513860;16716128;16832314;17319971;17472596;18026891;1824793;18500243;18759643;18929686;20064797;20331935;20593907;21186965;21804851;22360933;23212807;23281421;23480322;24350813;24567018;24828442;25042870;25916173;27079506;27685194;28105014;28250568;28867897;29027512;7476634;7507814;7791255;9136504",
"title": "Adverse Events Associated with Risperidone Use in Pediatric Patients: A Retrospective Biobank Study.",
"title_normalized": "adverse events associated with risperidone use in pediatric patients a retrospective biobank study"
} | [
{
"companynumb": "US-TEVA-2019-US-1125371",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "The novel anti-mitotic based tumor treating fields (TTFields) is FDA approved for recurrent glioblastoma. Recently the phase III upfront trial combining the Novo TTF-100A device, called Optune, with temozolomide following concurrent radiation therapy and chemotherapy, demonstrated improvement in survival. Wider use of this novel therapy is expected. The most common adverse event is dermatologic, which dominates compared to the next most frequently observed adverse event of headaches, the incidence of which was even in both arms in the phase III registration trial for recurrent glioblastoma. Our case review outlines the presentation, treatment, and outcome of representative patients using TTFields. In summary, preventative strategies to inform and educate patients and operators can prevent many of these dermatological events. Skin toxicity in the setting of concurrent use of TTFields with other therapies such as bevacizumab is an unknown and will need to be closely followed.",
"affiliations": "Department of Neurology, Northwestern University, Chicago, IL, USA.;Department of Clinical Oncology Pharmacy, University of Kentucky, Lexington, KY, 40536-0093, USA.;Beth Israel Deaconess Medical Center, Boston, MA, USA.;Departments of Medicine, Neurology, and Neurosurgery, University of Kentucky, Lexington, KY, 40536-0093, USA. jlvillano@uky.edu.",
"authors": "Lukas|Rimas V|RV|;Ratermann|Kelley L|KL|;Wong|Eric T|ET|;Villano|John L|JL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s11060-017-2612-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-594X",
"issue": "135(3)",
"journal": "Journal of neuro-oncology",
"keywords": "Brain tumor; CTCAE; Glioblastoma; Infection; Skin; Tumor treating fields",
"medline_ta": "J Neurooncol",
"mesh_terms": "D000328:Adult; D001932:Brain Neoplasms; D003131:Combined Modality Therapy; D004599:Electric Stimulation Therapy; D005260:Female; D005909:Glioblastoma; D006801:Humans; D008297:Male; D008875:Middle Aged; D012871:Skin Diseases",
"nlm_unique_id": "8309335",
"other_id": null,
"pages": "593-599",
"pmc": null,
"pmid": "28849343",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22608262;19133110;23659608;23891283;23299141;24794308;10699472;25213869;7209758;26670971;18596382;21407241;22502948;24564687;15758009",
"title": "Skin toxicities associated with tumor treating fields: case based review.",
"title_normalized": "skin toxicities associated with tumor treating fields case based review"
} | [
{
"companynumb": "US-TEVA-2018-US-844104",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Delafloxacin is an investigational anionic fluoroquinolone in development for oral or intravenous administration for the treatment of infections caused by Gram-positive (including MRSA), Gram-negative, atypical and anaerobic organisms.\nTo establish the non-inferiority of delafloxacin compared with vancomycin plus aztreonam for the treatment of acute bacterial skin and skin structure infections and to compare the safety of the two antimicrobials.\nA Phase 3, multicentre, randomized, double-blind, active-controlled study with 660 patients compared delafloxacin 300 mg or vancomycin 15 mg/kg plus aztreonam 2 g each administered twice daily intravenously for 5-14 days. Non-inferiority was evaluated by objective response (≥20% erythema reduction) at 48-72 h after initiation of study drug, investigator subjective assessment of outcome and microbiological responses. Clinical Trials Registration: NCT01811732. EudraCT number: 2012-001767-71.\nIn the ITT analysis set, the objective response was 78.2% in the delafloxacin arm and 80.9% in the vancomycin/aztreonam arm (mean treatment difference, -2.6%; 95% CI, -8.78% to 3.57%). Investigator-assessed cure was similar between the two groups at follow-up (52.0% versus 50.5%) and late follow-up (70.4% versus 66.6%). Bacterial eradication of MRSA was 100% and 98.5% in the delafloxacin group and the vancomycin/aztreonam group, respectively. Frequency of treatment-emergent adverse events in the delafloxacin and vancomycin/aztreonam groups was similar. Treatment-emergent adverse events leading to study drug discontinuation were higher in the vancomycin/aztreonam group compared with the delafloxacin group (4.3% versus 0.9%).\nDelafloxacin, an anionic fluoroquinolone, was statistically non-inferior to vancomycin/aztreonam at 48-72 h following the start of therapy and was well tolerated as monotherapy in the treatment of acute bacterial skin and skin structure infections.",
"affiliations": "Mercury Street Medical, Butte, MT, USA.;Pauls Stradins Clinical University Hospital, Riga, Latvia.;FCPP Clinical Research Facility, Modesto, CA, USA.;Melinta Therapeutics, Lincolnshire, IL, USA.;Melinta Therapeutics, Lincolnshire, IL, USA.;Melinta Therapeutics, Lincolnshire, IL, USA.;H2O Clinical, Hunt Valley, MD, USA.;Melinta Therapeutics, Lincolnshire, IL, USA.",
"authors": "Pullman|J|J|;Gardovskis|J|J|;Farley|B|B|;Sun|E|E|;Quintas|M|M|;Lawrence|L|L|;Ling|R|R|;Cammarata|S|S|;|||",
"chemical_list": "D000890:Anti-Infective Agents; D024841:Fluoroquinolones; C477891:delafloxacin; D014640:Vancomycin; D001398:Aztreonam",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkx329",
"fulltext": "\n==== Front\nJ Antimicrob ChemotherJ. Antimicrob. ChemotherjacJournal of Antimicrobial Chemotherapy0305-74531460-2091Oxford University Press 2902927810.1093/jac/dkx329dkx329Original ResearchEfficacy and safety of delafloxacin compared with vancomycin plus aztreonam for acute bacterial skin and skin structure infections: a Phase 3, double-blind, randomized study Pullman J 1Gardovskis J 2Farley B 3Sun E 4Quintas M 4Lawrence L 4Ling R 5Cammarata S 4PROCEED Study Group †\n1 Mercury Street Medical, Butte, MT, USA\n2 Pauls Stradins Clinical University Hospital, Riga, Latvia\n3 FCPP Clinical Research Facility, Modesto, CA, USA\n4 Melinta Therapeutics, Lincolnshire, IL, USA\n5 H2O Clinical, Hunt Valley, MD, USA* Corresponding author. Tel: +1-203-624-5606; Fax: +1-203-624-5627; E-mail: scammarata@melinta.com† Members are listed in the Acknowledgements section.\n\n12 2017 05 10 2017 05 10 2017 72 12 3471 3480 15 3 2017 27 6 2017 25 7 2017 07 8 2017 © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.2017This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\nDelafloxacin is an investigational anionic fluoroquinolone in development for oral or intravenous administration for the treatment of infections caused by Gram-positive (including MRSA), Gram-negative, atypical and anaerobic organisms.\n\nObjectives\nTo establish the non-inferiority of delafloxacin compared with vancomycin plus aztreonam for the treatment of acute bacterial skin and skin structure infections and to compare the safety of the two antimicrobials.\n\nPatients and methods\nA Phase 3, multicentre, randomized, double-blind, active-controlled study with 660 patients compared delafloxacin 300 mg or vancomycin 15 mg/kg plus aztreonam 2 g each administered twice daily intravenously for 5–14 days. Non-inferiority was evaluated by objective response (≥20% erythema reduction) at 48–72 h after initiation of study drug, investigator subjective assessment of outcome and microbiological responses. Clinical Trials Registration: NCT01811732. EudraCT number: 2012-001767-71.\n\nResults\nIn the ITT analysis set, the objective response was 78.2% in the delafloxacin arm and 80.9% in the vancomycin/aztreonam arm (mean treatment difference, −2.6%; 95% CI, −8.78% to 3.57%). Investigator-assessed cure was similar between the two groups at follow-up (52.0% versus 50.5%) and late follow-up (70.4% versus 66.6%). Bacterial eradication of MRSA was 100% and 98.5% in the delafloxacin group and the vancomycin/aztreonam group, respectively. Frequency of treatment-emergent adverse events in the delafloxacin and vancomycin/aztreonam groups was similar. Treatment-emergent adverse events leading to study drug discontinuation were higher in the vancomycin/aztreonam group compared with the delafloxacin group (4.3% versus 0.9%).\n\nConclusions\nDelafloxacin, an anionic fluoroquinolone, was statistically non-inferior to vancomycin/aztreonam at 48–72 h following the start of therapy and was well tolerated as monotherapy in the treatment of acute bacterial skin and skin structure infections.\n==== Body\nIntroduction\nAcute bacterial skin and skin structure infections (ABSSSIs) have diverse aetiologies due, in part, to varying epidemiological settings, with many different microbes identified as potential causes.1,2 MRSA and other MDR Gram-positive and Gram-negative bacteria are of particular concern due to significant patient morbidity coupled with high utilization of healthcare resources and costs.3–6 Many antimicrobials are generally effective for ABSSSIs, although their use is limited by resistance7,8 and adverse effects.9 These challenges have stimulated efforts to develop new antimicrobial agents with a favourable safety profile and clinical efficacy with appropriate pathogen coverage aligning with antimicrobial stewardship principles.5\n\nDelafloxacin is an anionic fluoroquinolone for oral or intravenous administration recently approved by the FDA for the treatment of ABSSSI, caused by designated susceptible bacteria including Gram-positive organisms (including MRSA) and Gram-negative organisms. Delafloxacin is chemically distinct from other quinolones in its size, shape and charge profile. These properties result in a highly active agent, particularly against Gram-positive pathogens.10,11 Delafloxacin is more active in vitro than levofloxacin against most Gram-positive pathogens, including levofloxacin non-susceptible isolates, and is 32-fold more active than levofloxacin against MRSA isolates.12 The spectrum of activity13–15 of delafloxacin suggests a potential for use in infections with Gram-positive and Gram-negative pathogens and mixed pathogens.\n\nPrevious Phase 216,17 ABSSSI studies demonstrated that delafloxacin is well tolerated and has favourable clinical efficacy compared with tigecycline,16 linezolid and vancomycin.17 Statistically better outcomes in obese patients with delafloxacin compared with vancomycin in one Phase 2 study led to pre-specified secondary endpoints in obese patients in the study reported here.17\n\nThe primary objective of this study was to evaluate the clinical efficacy and safety of delafloxacin monotherapy compared with vancomycin plus aztreonam for the treatment of ABSSSIs at 48–72 h following treatment initiation in accordance with FDA18 guidelines and at the follow-up (FU) visit (Day 14 ± 1) per EMA19 guidelines.\n\nPatients and methods\nStudy design\nThis Phase 3, multicentre, multinational, stratified, randomized, double-blind trial assessed the efficacy and safety of intravenous delafloxacin compared with vancomycin/aztreonam for the treatment of adults with ABSSSIs. Clinical Trials Registration: NCT01811732. EudraCT number: 2012-001767-71.\n\nEthics\nThis study was conducted in compliance with the principles of ICH E6(R1) and the principles of the World Medical Association Declaration of Helsinki. A written informed consent in compliance with US Title 21 Code of Federal Regulations Part 50, ICH E6(R1) and other applicable regulatory requirements was obtained from each patient or legally authorized representative before entering the study or performing any unusual or non-routine procedure that involved risk to the patient. A list of institutional review boards used for this study is available.\n\nPatients\nEligibility criteria were age ≥18 years and a diagnosis of ABSSSI classified as cellulitis/erysipelas, wound infection, major cutaneous abscess or burn infection with ≥75 cm2 of erythema and ≥2 signs of systemic infection. Exclusion criteria were consistent with current guidance and included receipt of systemic antibiotic therapy in the 14 days before enrolment unless one of the following was documented: the patient received at least 48 h of antibiotic therapy for ABSSSI and clinical progression of ABSSSI was documented; the patient completed a treatment course within 7 days for an infection other than ABSSSI with an antibacterial drug not having activity against bacterial pathogens that cause ABSSSI; and patients who received one dose of a single, potentially effective, short-acting antimicrobial drug for the treatment of the ABSSSI under study in the 14 days before study entry. Prior single dose antibiotic use was limited to no more than 25% of the total randomly assigned patients. Further details regarding the eligibility and exclusion criteria are available in Table S1 (available as Supplementary data at JAC Online).\n\nPatients were enrolled at 34 study centres in seven countries between April 2013 and June 2014 and randomized (1:1) to delafloxacin or vancomycin/aztreonam using an interactive web response system. Vancomycin was chosen as the comparator in accordance with FDA and EMA guidelines.18,19 Randomization was stratified by infection type, ensuring that ≤25% and ≤35% of patients had a major cutaneous abscess or wound infection, respectively.\n\nInterventions\nPatients received intravenous delafloxacin 300 mg or vancomycin 15 mg/kg (actual body weight) plus aztreonam 2 g every 12 h on an inpatient or outpatient basis. Vancomycin levels were monitored on Day 2 (+1) and Day 6 (± 1), with dose adjustments based on a target trough of 15–20 μg/mL.20 Patients received aztreonam for Gram-negative coverage, which was discontinued once baseline cultures did not reveal Gram-negative organisms. Both groups were treated for at least 5 days and no more than 14 days, with the duration of therapy based on the investigators’ assessment of signs and symptoms of ABSSSI.\n\nStudy visits took place at screening, daily during treatment, FU (Day 14 ± 1) and late FU (LFU; Days 21–28). Telephone FU was conducted for all patients 30 days after the last dose of study drug to obtain 28 day all-cause mortality rates, adverse events (AEs) and use of post-treatment medications.\n\nEfficacy assessments\nThe FDA-defined primary efficacy endpoint was the objective response at 48–72 h (± 2) following treatment initiation and defined as ≥20% reduction in erythema of the ABSSSI lesion determined by digital planimetry of the leading edge without evidence of clinical failure. Clinical failure at this timepoint was defined as any of the following: (i) <20% reduction in erythema area determined by digital planimetry; (ii) administration of rescue antibacterial drug therapy or non-study antibacterial drug therapy before the primary efficacy endpoint assessment; (iii) unplanned surgical intervention except for limited bedside debridement and standard wound care before the primary efficacy endpoint assessment; or (iv) death within 74 h after treatment initiation. Patients were classified as clinical failures in the ITT analysis if digital planimetry was not available within the 48–72 h (± 2) window.\n\nThe EMA-defined primary efficacy measure was the investigator assessment of clinical cure (no remaining signs or symptoms) at the FU visit in the ITT population. An additional secondary endpoint was investigator-assessed success (cure or improved and no further antibiotic needed) at the FU visit.\n\nClinical response at FU and LFU was based on investigator assessment of ABSSSI signs and symptoms and categorized as cure (complete resolution of symptoms); improved (near resolution with some remaining symptoms not requiring antibiotic therapy); failure (additional non-study antibiotics or unplanned major surgical intervention required); or indeterminate. Patients lost to FU (or with indeterminate outcomes) and those categorized as improved were considered failures in the primary analysis. Other antibiotic studies in skin infections have defined a successful outcome as resolution or near resolution of signs and symptoms that no longer require antibiotic therapy. This definition aligns with the definition of success in this study.\n\nBecause a previous Phase 2 study showed statistically better outcomes in obese patients, it was pre-specified that data sets would be analysed by patient baseline BMI for patients with baseline BMI <30 kg/m2 and patients with baseline BMI ≥30 kg/m2.17\n\nPatients’ subjective assessment of pain was recorded on a numerical rating scale ranging from 0 (no pain) to 10 (worst imaginable pain) at screening, during treatment, end of treatment (EOT), FU and LFU.\n\nMicrobiological assessments\nMicrobiological response for patients in the microbiological ITT (MITT) and microbiologically evaluable (ME) analysis sets was based on results of the baseline and post-baseline cultures through the FU and LFU visits, susceptibility testing and the clinical response assigned by the investigator. ABSSSI samples were collected before initiation of any rescue therapy and from all clinical failures that had material available for culture. Microbiological response was categorized as documented eradicated (baseline pathogen absent in FU cultures); presumed eradicated (no FU material available for culture with a clinical response of success); documented persisted (baseline pathogen present in FU cultures); or presumed persisted (no FU material available for culture with an investigator-assessed response of failure).\n\nSafety and tolerability assessments\nSafety assessments included all AEs, physical examinations, vital signs, 12-lead ECGs at baseline and if clinically indicated thereafter, and clinical laboratory tests. AEs were summarized by treatment group and overall for the safety analysis set. Treatment-emergent AEs (TEAEs) were those that occurred or worsened in severity after administration of the first dose of the study drug through the telephone FU with patients 30 days after the last dose. The Medical Dictionary for Regulatory Activities Version 16.1 was used to code AEs.\n\nStatistical analysis\nSeparate statistical analysis plans were prospectively developed prior to database lock and unblinding for the FDA and the EMA endpoints. All clinical efficacy outcomes were analysed for the ITT population. The safety analysis set included all enrolled patients who received ≥1 dose of the study drug.\n\nAnalysis of microbiological outcomes was based on the MITT population. There were multiple ME and clinically evaluable (CE) analysis sets based on the timing of assessments [48–72 h (± 2), EOT, FU and LFU].\n\nContinuous variables were described with descriptive statistics such as mean, standard deviation, median, minimum and maximum while counts and percentages were calculated for categorical data. The rate of the primary FDA-defined efficacy endpoint was the sample responder rate defined as [responder/(responder + non-responder)]. The rate of the primary EMA-defined efficacy endpoint was the sample cure rate defined as [cure/(cure + failure)].\n\nA two-sided 95% CI was calculated based on differences between delafloxacin and vancomycin/aztreonam in responder rates at 48–72 h (± 2) after initiation of treatment (FDA-defined endpoint) and investigator-assessed response rates (EMA-defined endpoint) using a non-stratified method proposed by Miettinen and Nurminen.21 Non-inferiority was concluded if the lower limit of this 95% CI was > −10%, with mean differences between treatments expressed as delafloxacin minus vancomycin/aztreonam. The FDA-defined primary efficacy analysis was performed on the ITT analysis set while the EMA-defined primary efficacy analysis included the ITT and CE at FU analysis sets.\n\nThe same analysis method was applied to the comparison of microbiological response rates between treatment groups.\n\nAll analyses and summaries were produced using SAS® software (SAS Institute, Inc., Cary, NC, USA) Version 9.3 (or higher).\n\nResults\nPatient disposition and analysis sets\nSix-hundred and sixty patients were randomized to delafloxacin or vancomycin/aztreonam and comprised the ITT analysis population (Figure 1). Among patients enrolled, 547 (82.9%) completed the study through the LFU visit. The safety analysis set included 650 patients who received study drug. The median duration of treatment with delafloxacin was 5 and 5.5 days for the vancomycin/aztreonam group. The median duration of aztreonam/aztreonam placebo use was 2 days for either group.\n\nFigure 1. CONSORT diagram of patient disposition. ITT analysis set included all patients who were randomly assigned to treatment. CE analysis set included all patients in the ITT population who: (i) received ≥80% of the total expected doses of the assigned study drug or were clinical failures and received ≥4 doses of study drug; (ii) did not receive any concomitant, systemic antibacterial therapy with activity against the identified pathogen; and (iii) had no major protocol deviations. MITT analysis set consisted of all patients in the ITT analysis set that had bacterial pathogens known to cause ABSSSI at baseline. ME analysis set included all patients in the MITT population who met the criteria established for the CE analysis set. SAF, safety; TC, telephone call.\n\nPatient demographic and clinical characteristics\nBaseline characteristics were similar between treatment groups (Table 1). The majority of patients were men (62.9%) and Caucasian (91.1%), with a mean (SD) age of 45.8 (± 14.2) years and a mean (SD) BMI of 28.1 (6.4) kg/m2; 32.4% of patients had BMI ≥30 kg/m2. Less than 20% of patients received antibacterial therapy prior to randomization (15.7% in the delafloxacin group and 21.6% in the vancomycin/aztreonam group).\nTable 1. Patient demographics and baseline characteristics (ITT population)\n\nCharacteristic\tDelafloxacin, N = 331\tVancomycin + aztreonam, N = 329\t\nAge (years), mean ± SD (range)\t46.3 ±13.91 (18–94)\t45.3 ±14.4 (19–90)\t\nAge category (years), n (%)\t\n ≤65\t309 (93.4)\t309 (93.9)\t\n >65\t22 (6.6)\t20 (6.1)\t\n >75\t7 (2.1)\t10 (3.0)\t\nMen, n (%)\t206 (62.2)\t209 (63.5)\t\nRace, n (%)\t\n white\t297 (89.7)\t304 (92.4)\t\n black or African American\t27 (8.2)\t19 (5.8)\t\n American Indian or Alaska native\t5 (1.5)\t2 (0.6)\t\n Asian\t1 (0.3)\t1 (0.3)\t\n native Hawaiian or other Pacific Islander\t1 (0.3)\t2 (0.6)\t\n other\t0\t1 (0.3)\t\nEthnicity, n (%)\t\n Hispanic or Latino\t101 (30.5)\t103 (31.3)\t\nRegion, n (%)\t\n Europe\t63 (19.0)\t55 (16.7)\t\n North America\t268 (81.0)\t274 (83.3)\t\nBMI (kg/m2), mean ± SD\t28.4 ± 6.42\t27.9 ±6.36\t\nBMI ≥30 kg/m2, n (%)\t120 (36.3)\t94 (28.6)\t\nDiabetes, n (%)\t30 (9.1)\t27 (8.2)\t\nPrior antibiotic use, n (%)\t52 (15.7)\t71 (21.6)\t\nBaseline pain score, mean ± SD\t7.9 (2.0)\t7.8 (2.2)\t\nDuration of exposure\t\n n\t324\t326\t\n mean (SD) days\t6.18 (2.81)\t6.15 (2.62)\t\n median days\t5.00\t5.50\t\n min, max days\t0.5, 14.0\t0.5, 14.0\t\n\n\nThe types of ABSSSI were similarly distributed across the two treatment groups (Table 2). Baseline lesion size was similar between the two treatment groups with a median lesion size ∼300 cm2. Of the 660 enrolled patients, 490 (74.2%) had a positive ABSSSI culture. Of patients with positive cultures, Staphylococcus aureus was identified in 65.4% of patients treated with delafloxacin and 66.8% of those in the vancomycin/aztreonam group; MRSA infections were confirmed in 78 (32.1%) and 91 (36.8%) patients in the delafloxacin and vancomycin/aztreonam groups, respectively. Delafloxacin MIC50/90 was 0.008 and 0.25 mg/L (range 0.002–0.5 mg/L) for S. aureus; 0.12 and 0.25 mg/L (range 0.004–0.5 mg/L) for MRSA and 0.008 and 0.12 mg/L (range 0.002–0.5 mg/L) for MSSA. Approximately 40% of S. aureus isolates were levofloxacin non-susceptible (delafloxacin MIC range 0.004–0.5 mg/L); the majority were also MRSA. Of the MITT population, 40 (16.5%) in the delafloxacin and 43 (17.4%) in the vancomycin/aztreonam treatment groups were Gram-negative (Table S2). Overall, 15 patients (2.3%) had bacteraemia.\nTable 2. Summary of ABSSSI characteristics (ITT population)\n\nCharacteristic\tDelafloxacin, N = 331\tVancomycin + aztreonam, N = 329\t\nABSSSI category, n (%)\t\n cellulitis/erysipelas\t128 (38.7)\t128 (38.9)\t\n wound infection\t116 (35.0)\t116 (35.3)\t\n major cutaneous abscess\t84 (25.4)\t83 (25.2)\t\n burn infection\t3 (0.9)\t2 (0.6)\t\nErythema size (cm2; digital), mean ± SD (IQR)\t294.8 ±308.34 (121.5–332.7)\t319.1 ±314.03 (130.2–385.7)\t\nInduration size (cm2; digital), mean ± SD (IQR)\t94.1 ±208.66 (22.3–94.8)\t120.7 ±219.6 (26.2–121.6)\t\nSystemic signs, n (%)\t\n lymph node enlargement\t285 (86.1)\t287 (87.2)\t\n elevated C-reactive protein, >10× ULN\t131 (39.6)\t136 (41.3)\t\n elevated white blood count, ≥10 000 cells/μL\t159 (48.0)\t165 (50.2)\t\n fever, ≥38 °C\t78 (23.6)\t63 (19.1)\t\n lymphangitis\t68 (20.5)\t55 (16.7)\t\nBacteraemia, n (%)\t6 (1.8)\t9 (2.7)\t\nLocal signs, n (%)\t\n erythema/extension of redness\t329 (99.4)\t328 (99.7)\t\n heat/localized warmth\t328 (99.1)\t326 (99.1)\t\n pain/tenderness\t328 (99.1)\t327 (99.4)\t\n swelling/induration\t323 (97.6)\t324 (98.5)\t\n drainage/discharge\t209 (63.1)\t207 (62.9)\t\n fluctuance\t175 (52.9)\t179 (54.4)\t\nPathogens identified at baseline (MITT), n (%)a\t\n S. aureusb\t159 (65.4)\t165 (66.8)\t\n MRSA\t78 (32.1)\t91 (36.8)\t\n MSSA\t82 (33.7)\t74 (30.0)\t\na Patients with baseline pathogens: N = 243 for delafloxacin and N = 247 for vancomycin/aztreonam.\n\nb Patients with both MRSA and MSSA were counted only once. Percentages based on number of patients with baseline pathogens.\n\n\n\nClinical outcomes\nObjective response\nThe percentage of responders at the 48–72 h objective response assessment in the ITT analysis set was similar between the two groups at 78.2% and 80.9% for delafloxacin and vancomycin/aztreonam, respectively, and non-inferiority was declared (Figure 2). Delafloxacin was comparable to vancomycin + aztreonam for the objective response at 48–72 h whether using the CE, ME or MITT analysis sets.\n\nFigure 2. Objective response and investigator-assessed response at FU and LFU by analysis set, MRSA infection at baseline and BMI category. *Primary endpoint. Cure = no remaining signs and symptoms. Improved = some remaining signs and symptoms, but no further antibiotics required. Success = cure + improved. ITT, all patients randomized; MITT, ITT patients with eligible pathogen; CE patients who completed activities as defined in the protocol; ME, CE patients with eligible pathogen. BMI was calculated as body weight (in kg)/h (in m2).\n\nThe mean percentage change from baseline in erythema was similar between the treatment groups at each LFU visit (Figure 3).\n\nFigure 3. Percentage change from baseline in reduction of erythema (digital planimetry) at each visit (ITT population).\n\nInvestigator assessment of response\nInvestigator-assessed cure rates and success rates were similar between study arms at the FU and LFU visits in the ITT population, meeting the non-inferiority criteria, and were comparable between the two treatment groups for the CE, MITT or ME analysis sets. The investigator-assessed response at the FU visit was also analysed by infection type and was found to be comparable between the delafloxacin and the vancomycin/aztreonam treatment groups (Table 3). Among patients with MRSA, the absolute difference in cure and clinical success at FU was 6.3% and 1.5% higher, respectively, for the delafloxacin group compared with the vancomycin/aztreonam group (Figure 2). The cure and success rates were numerically higher in obese patients at FU and LFU and statistically significantly higher cure at LFU for delafloxacin (71.7%) compared with vancomycin/aztreonam (57.4%). See Figure 2.\nTable 3. Investigator-assessed response at FU visit by infection type (ITT analysis set)\n\n\tDelafloxacin, N = 331\tVancomycin + aztreonam, N = 329\tCI\t\nCellulitis\t\n cure\t86/128 (67.2%)\t78/128 (60.9%)\t6.3 (−5.52, 17.87)\t\n success\t107/128 (83.6%)\t108/128 (84.4%)\t−0.8 (−9.94, 8.37)\t\nAbscess\t\n cure\t44/84 (52.4%)\t40/83 (48.2%)\t4.2 (−10.93, 19.12)\t\n success\t70/84 (83.3%)\t70/83 (84.3%)\t−1.0 (−12.46, 10.47)\t\nWound\t\n cure\t39/116 (33.6%)\t48/116 (41.4%)\t−7.8 (−20.02, 4.72)\t\n success\t90/116 (77.6%)\t94/116 (81.0%)\t−3.5 (−13.97, 7.08)\t\nBurn\t\n cure\t3/3 (100%)\t0/2 (0.0%)\t100.0 (2.02, 100.00)\t\n success\t3/3 (100%)\t2/2 (100%)\tnot evaluable\t\nCure = complete resolution of symptoms. Success = cure plus improved and no further antibiotic needed.\n\n\n\nThe median baseline patient-reported pain score was 8.0 for either group. The mean reduction in pain was comparable between treatment groups, with a change from baseline to EOT of −5.4 (3.14) for delafloxacin and −5.1 (3.18) for vancomycin/aztreonam.\n\nMicrobiological efficacy\nIn the ME population at FU, microbiological responses were documented or presumed eradicated in 175 of 179 (97.8%) and 181 of 184 (98.4%) of patients treated with delafloxacin and vancomycin/aztreonam, respectively. Among patients with MRSA isolated at baseline, 100% and 98.5% of responses in the delafloxacin and vancomycin/aztreonam groups, respectively, were documented or presumed eradicated. Additionally, there was 100% documented or presumed eradication for the levofloxacin non-susceptible S. aureus isolates in the delafloxacin group. Per pathogen early objective response at 48–72 h and microbiological response rates at FU against pathogens that cause ABSSSI including Gram-positive pathogens including MRSA and Gram-negative pathogens were similar between delafloxacin and vancomycin/aztreonam patients (see Table 4). No superinfections were identified in either treatment group. New infections were detected in four patients including two in the delafloxacin group and two in the vancomycin/aztreonam group.\nTable 4. Per pathogen microbiological response\n\n\tBy pathogen objective responders at 48–72 h, ME at 48–72 h analysis set\tPer pathogen microbiological response (documented or presumed eradication),a ME at FU analysis set\t\ndelafloxacin, N = 220\tvancomycin + aztreonam, N = 225\tdelafloxacin, N = 179\tvancomycin + aztreonam, N = 184\t\nS. aureus\t123/145 (84.8%)\t134/150 (89.3%)\t115/117 (98.3%)\t119/121 (98.3%)\t\n MRSA\t59/72 (81.9%)\t76/84 (90.5%)\t58/58 (100%)\t65/66 (98.5%)\t\n MSSA\t65/74 (87.8%)\t58/66 (87.9%)\t57/59 (96.6%)\t54/55 (98.2%)\t\nStreptococcus anginosus groupb\t28/30 (93.3%)\t33/37 (89.2%)\t22/22 (100%)\t26/27 (96.3%)\t\nStaphylococcus epidermidis\t16/18 (88.9%)\t13/15 (86.7%)\t13/14 (92.9%)\t14/14 (100%)\t\nKlebsiella pneumoniae\t10/11 (90.9%)\t9/10 (90%)\t9/9 (100%)\t9/9 (100%)\t\nEscherichia coli\t3/5 (60%)\t9/9 (100%)\t4/4 (100%)\t7/7 (100%)\t\nStreptococcus pyogenes\t5/7 (71.4%)\t2/5 (40%)\t5/5 (100%)\t4/4 (100%)\t\nStaphylococcus lugdunensis\t6/7 (85.7%)\t3/3 (100%)\t7/7 (100%)\t1/1 (100%)\t\nStaphylococcus haemolyticus\t5/5 (100%)\t2/2 (100%)\t5/5 (100%)\t2/2 (100%)\t\na Investigator-assessed response in ME at FU analysis set was the same as per pathogen microbiological response.\n\nb S. anginosus group includes S. anginosus, Streptococcus intermedius and Streptococcus constellatus.\n\n\n\nSafety\nAmong the safety analysis set (n = 650), ≥1 TEAE was observed in 154 patients (47.5%) treated with delafloxacin and 193 patients (59.2%) in the vancomycin/aztreonam group (Table 5).\nTable 5. Summary of AEs affecting either treatment group: safety population\n\nSummary of AE, n (%)\tTreatment group\t\ndelafloxacin, N = 324\tvancomycin + aztreonam, N = 326\t\nOverall TEAEs\t154 (47.5)\t193 (59.2)\t\nTEAEs affecting ≥5% of patients\t\n diarrhoea\t27 (8.3)\t10 (3.1)\t\n headache\t10 (3.1)\t25 (7.7)\t\n infection\t28 (8.6)\t25 (7.7)\t\n infusion-site extravasation\t28 (8.6)\t44 (13.5)\t\n nausea\t24 (7.4)\t28 (8.6)\t\nTEAEs by intensity\t\n mild\t90 (27.8)\t126 (38.7)\t\n moderate\t53 (16.4)\t60 (18.4)\t\n severe\t11 (3.4)\t7 (2.1)\t\nTEAEs related to study drug\t\n total related to study drug\t78 (24.1)\t107 (32.8)\t\n possibly\t56 (17.3)\t75 (23.0)\t\n probably\t14 (4.3)\t23 (7.1)\t\n definitely\t8 (2.5)\t9 (2.8)\t\nTEAEs leading to early discontinuation of study drug\t3 (0.9)\t14 (4.3)\t\nRelated TEAEs leading to early discontinuation of study drug\t1 (0.3)\t8 (2.5)\t\nOverall serious AEs\t12 (3.7)\t12 (3.7)\t\nDeaths\t1 (0.3)\t1 (0.3)\t\n\n\nThe majority of TEAEs were considered mild and unrelated to study drug in both groups, with a lower percentage of patients experiencing treatment-related TEAEs in the delafloxacin arm compared with vancomycin/aztreonam. The most common treatment-related AEs in delafloxacin-treated patients were gastrointestinal in nature reported in 12% of patients, primarily nausea and diarrhoea. Extensive analysis of AEs typically seen with fluoroquinolones was conducted. There were no cases of Clostridium difficile diarrhoea and there were no cases of tendinitis or tendon rupture, peripheral neuropathy or myopathy thought to be related to delafloxacin treatment. One delafloxacin-treated patient and two vancomycin/aztreonam-treated patients had a report of hypoglycaemia related to treatment; two delafloxacin patients and one vancomycin/aztreonam patient had reported hyperglycaemia potentially related to treatment. Intensive glucose monitoring for 12 h post-dose in patients who were also undergoing pharmacokinetic testing did not show differences between the two treatment groups (Figure 4). Treatment-related infusion reactions (extravasations, pain, oedema, phlebitis, swelling, etc.) occurred in 3% of patients in each treatment group. Renal failure was reported as potentially related to treatment in three patients on vancomycin/aztreonam compared with one report of renal impairment on delafloxacin. The occurrence of TEAEs resulting in premature study drug discontinuation was lower in the delafloxacin group compared with the vancomycin/aztreonam arm (0.9% and 4.3%, respectively).\n\nFigure 4. Box-plot of glucose concentrations (mmol/L): intense glucose analysis set. Note: the lower fence reflects the actual minimum value or 1.5× IQR below quartile 1, whichever is bigger; the upper fence reflects the actual maximum value or 1.5× IQR above quartile 3, whichever is smaller.\n\nThe rate of serious AEs was equal between the two treatment groups (3.7%), respectively. Of those, none in the delafloxacin treatment group and one in the vancomycin/aztreonam treatment group were considered to be potentially related to treatment. One death occurred in each treatment arm, with neither considered related to the study drug.\n\nThe groups were generally similar regarding changes from baseline in haematology and serum chemistry. Vital sign measurements, physical examination findings and ECGs were unremarkable. There were no increases in hepatic AEs in the delafloxacin treatment group when compared with vancomycin/aztreonam. In all patients regardless of baseline medical history or baseline laboratories, only three patients in the delafloxacin treatment group reported ALT >5× upper limit of normal (ULN) result at any time in the study, compared with five patients in the vancomycin/aztreonam treatment groups. Only two patients in either treatment group had AST >5× ULN any time during the trial (see Table S3). There were no reports of cases meeting the Hy's law definition in any patients during this study. Serum creatinine >2× ULN was seen in three vancomycin-treated patients any time during the trial, compared with no reports in delafloxacin-treated patients.\n\nDiscussion\nThis large, multicentre, double-blind, randomized, Phase 3 trial established that delafloxacin, an anionic fluoroquinolone, was non-inferior to vancomycin/aztreonam for the treatment of ABSSSIs. The non-inferiority of delafloxacin and vancomycin/aztreonam was demonstrated for the objective response at 48–72 h after initiation of treatment (FDA primary endpoint) and the investigator-assessed cure at FU (EMA primary endpoint). Moreover, across the various sensitivity analyses and secondary objectives, the delafloxacin and vancomycin/aztreonam arms were comparable. This study demonstrates that delafloxacin monotherapy is effective across a range of Gram-positive and -negative pathogens, and was comparable to vancomycin in the treatment of MRSA. Treatment with vancomycin requires a second antibiotic (aztreonam in this study) as initial empirical therapy if Gram-negative pathogens are suspected.\n\nThe focus of recent antibiotic development in ABSSSI has been on the coverage of Gram-positive infections, particularly MRSA. However, the risk for inappropriate antimicrobial therapy increases in skin infections when Gram-negative and mixed cultures are present.22,23 Other MDR bacteria are demonstrating similar trends, as seen with the rise in MRSA, and are increasing in prevalence in ABSSSIs. In addition, while Gram-negative pathogens can play an important role in long-standing polymicrobial infections, they are also increasingly found in monomicrobial skin and soft tissue infections (SSTIs).5,6 Gram-negative only cultures have been reported at a rate of 12.8% and mixed cultures in 10.6%–20.5% of patients hospitalized with serious skin infections.24,25\n\nInitial therapy failure rates in skin infections have been shown to range from 16% to 43% depending on type of infection and results in additional days of hospitalization and increased costs.26,27 Combination therapy is used 40% of the time; however, the pathogen is never identified in 61% of cases. When choosing empirical therapy for infections with presumed Gram-negative bacteria, local epidemiology should be taken into account and consideration given to individual patient characteristics such as type of infection including certain SSTIs, comorbidities such as diabetes and compromised vascular profusion and by setting, e.g. residence in a nursing home or recent hospitalization.4,21–28\n\nIn this study, cure was defined by more stringent criteria, which required patients to be completely cured, and not merely improved for a positive investigator response. Other antibiotic studies in skin infections have defined a successful outcome as clinical improvement where no further antibiotic therapy is required. This aligns with the definition of success in this study. Whether using cure or success (cure + improved), delafloxacin was comparable to vancomycin/aztreonam in later clinical response at FU and LFU demonstrating a sustained clinical response.\n\nDelafloxacin was well tolerated with a lower overall discontinuation rate compared with vancomycin/aztreonam. The safety profile reported in this study is consistent with previous clinical studies.16,17 Previous studies have shown that delafloxacin has minimal potential for drug interactions and no evidence of QT interval prolongation or phototoxicity.29–32 Taken together, delafloxacin has similar efficacy and safety compared with vancomycin/aztreonam for the treatment of ABSSSI. Delafloxacin offers the potential for the treatment of infections caused by Gram-positive pathogens including MRSA and Gram-negative pathogens, without the need for combination therapy.\n\nPharmacotherapy of obese patients presents additional challenges to physicians and pharmacists.33 A previous Phase 2 study noted better outcomes with delafloxacin in obese patients than vancomycin at FU and LFU.16 Unlike vancomycin, delafloxacin does not require weight-based dosing or drug monitoring. The results of this study demonstrated that, in obese patients (BMI ≥30 kg/m2), the investigator-assessed outcome at FU and LFU favoured delafloxacin, although it failed to meet statistical significance in all but investigator-assessed cure at LFU. However, the current study was not stratified for obesity at enrolment and a weight limit of 140 kg was instituted due to difficulties in blinding of vancomycin in an obese population.\n\nOther limitations to this study include a low number of burn infections and surgical wounds and the number of Gram-negative pathogens was limited by use of the current ABSSSI definition that favours Gram-positive infections. There were a low number of older adults and non-whites and the rate of diabetes was lower than in the general population.\n\nDelafloxacin was found to have comparable clinical activity to vancomycin in the treatment of patients with ABSSSI by early objective response, later clinical assessments and microbiological response including impact on MRSA. Additionally, delafloxacin was well tolerated. With both intravenous and oral formulations, delafloxacin is appropriate for the treatment of diverse skin infection types due to Gram-positive and -negative bacteria, including patients with MRSA.\n\nSupplementary Material\nSupplementary Tables Click here for additional data file.\n\n Acknowledgements\nAn abstract of the data was presented at IDWeek 2015, San Diego, CA, USA, 2015 (Abstract no. 776).\n\n\nMembers of the PROCEED Study Group\nAnna Barvinska, Lviv, Ukraine; Michal Chowers, Kfar Saba, Israel; Dennis Cortes, Miramar, FL, USA; Sadia Dar, Smryna, TN, USA; Oleksii Datsenko, Kharkiv, Ukraine; Robert Eyzaguirre, Long Beach, CA, USA; Brett Farley, Modesto, CA, USA; Janis Gardovskis, Riga, Latvia; Juan Pablo Horcajada Gallego, Barcelona, Spain; Osamah Hussein, Safed, Israel; Heidi Kabler, Las Vegas, NV, USA; Richard Keech, Anaheim, CA, USA; Lajos Kemény, Szeged, Hungary; Sergii Kosulnykov, Dnipropetroversusk, Ukraine; Oleksandr Kosynskyi, Dnipropetroversusk, Ukraine; Viktors Lovcinovskis, Daugavpils, Latvia; Christopher Lucasti, Somers Point, NJ, USA; Paul Manos, Oceanside, CA, USA; Carlos Munoz, Richmond, TX, USA; Maris Nalivaiko, Liepaja, Latvia; William Nseir, Nazareth, Israel; Steven O'Mara, Montgomery, AL, USA; William O'Riordan, Chula Vista, CA, USA; Scott Overcash, La Mesa, CA, USA; Ivan Puljiz, Zagreb, Croatia; John Pullman, Butte, MT; Galia Rahav, Ramat-Gan, Israel; Juan Diego Ruiz Mesa, Málaga, Spain; Shaukat Shah, Stockton, CA, USA; Vadym Shevchenko, Cherkasy, Ukraine; Warren Shu, Pasadena, CA, USA; Kaspars Snipe, Riga, Latvia; Sergiy Vasylyuk, Ivano-Frankiversusk, Ukraine; Anatoliy Zaichuk, Odesa, Ukraine.\n\n These members enrolled patients in the study.\n\nFunding\nThis work was funded by Melinta Therapeutics. In addition the editorial assistance (see below) was funded by Melinta Therapeutics.\n\nTransparency declarations\nJ. P., B. F. and J. G. received payment for their services in enrolling patients. E. S., M. Q., L. L. and S. C. are employees of Melinta Therapeutics. R. L. was a consultant paid by Melinta Therapeutics.\n\n Editorial assistance with this manuscript was provided by Strategic Healthcare Communications, Hillsborough, NJ, USA.\n\nAuthor contributions\nAll authors participated in the execution and completion of the study and drafting and review of this manuscript. E. S., L. L., S. C. and M. Q. were responsible for development of the protocol. R. L. provided statistical and analytic support. J. P. and J. G. were investigators in the study.\n\nSupplementary data\nTables S1 to S3 are available as Supplementary data at JAC Online.\n==== Refs\nReferences\n1 \nStevens DL , Bisno AL , Chambers HF \n\nPractice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America . Clin Infect Dis 2014 ; 59 : e10 –52 .24973422 \n2 \nStevens DL , Bisno AL , Chambers HF \n\nPractice guidelines for the diagnosis and management of skin and soft-tissue infections . Clin Infect Dis 2005 ; 41 : 1373 –406 .16231249 \n3 \nBarie PS , Wilson SE. \nImpact of evolving epidemiology on treatments for complicated skin and skin structure infections: the surgical perspective . J Am Coll Surg 2015 ; 220 : 105 –16 .25459370 \n4 \nGuillamet CV , Kollef MH. \nHow to stratify patients at risk for resistant bugs in skin and soft tissue infections? \nCurr Opin Infect Dis \n2016 ; 29 : 116 –23 .26779773 \n5 \nBassetti M , Merelli M , Temperoni C \n\nNew antibiotics for bad bugs: where are we? \nAnn Clin Microbiol Antimicrob \n2013 ; 12 : 22. 23984642 \n6 \nItani KM , Merchant S , Lin SJ \n\nOutcomes and management costs in patients hospitalized for skin and skin-structure infections . Am J Infect Control 2011 ; 39 : 42 –9 .20673598 \n7 \nMoellering RC , Ferraro MJ. \nIntroduction: solving the clinical problem of vancomycin resistance . Clin Infect Dis 2012 ; 54 Suppl 3: S201 –2 .22431849 \n8 \nStryjewski ME , Lentnek A , O’Riordan W \n\nA randomized Phase 2 trial of telavancin versus standard therapy in patients with uncomplicated Staphylococcus aureus bacteremia: the ASSURE study . BMC Infect Dis 2014 ; 14 : 289 .24884578 \n9 \nRodvold KA , McConeghy KW. \nMethicillin-resistant Staphylococcus aureus therapy: past, present and future . Clin Infect Dis 2014 ; 58 Suppl 1: S20 –7 .24343828 \n10 \nLemaire S , Tulkens PM , Van Bambeke F. \nContrasting effects of acidic pH on the extracellular and intracellular activities of the anti-Gram-positive fluoroquinolones moxifloxacin and delafloxacin against Staphylococcus aureus . Antimicrob Agents Chemother 2011 ; 55 : 649 –58 .21135179 \n11 \nVan Bambeke F. \nDelafloxacin, a non-zwitterionic fluoroquinolone in Phase III of clinical development: evaluation of its pharmacology, pharmacokinetics, pharmacodynamics and clinical efficacy . Future Microbiol 2015 ; 10 : 1111 –23 .26119479 \n12 \nMcCurdy S , Lawrence L , Quintas M \n\nIn vitro activity of delafloxacin and microbiological response against fluoroquinolone susceptible and non-susceptible S. aureus isolates from two Phase 3 studies of acute bacterial skin and skin structure infections (ABSSSI) . Antimicrob Agents Chemother 2017 ; doi:10.1128/AAC.00772-17.\n13 \nNilius AM , Shen LL , Hensey-Rudloff D \n\nIn vitro antibacterial potency and spectrum of ABT-492, a new fluoroquinolone . Antimicrob Agents Chemother 2003 ; 47 : 3260 –9 .14506039 \n14 \nAlmer LS , Hoffrage JB , Keller EL \n\nIn vitro and bactericidal activities of ABT-492, a novel fluoroquinolone, against gram-positive and gram-negative organisms . Antimicrob Agents Chemother 2004 ; 48 : 2771 –7 .15215148 \n15 \nHarnett SJ , Fraise AP , Andrews JM \n\nComparative study of the in vitro activity of a new fluoroquinolone, ABT-492 . J Antimicrob Chemother 2004 ; 53 : 783 –92 .15056651 \n16 \nO’Riordan W , Mehra P , Manos P \n\nA randomized phase 2 study comparing two doses of delafloxacin with tigecycline in adults with complicated skin and skin-structure infections . Int J Infect Dis 2015 ; 30 : 67 –73 .25448332 \n17 \nKingsley J , Mehra P , Lawrence LE \n\nA randomized, double-blind, Phase 2 study to evaluate subjective and objective outcomes in patients with acute bacterial skin and skin structure infections treated with delafloxacin, linezolid or vancomycin . J Antimicrob Chemother 2016 ; 71 : 821 –9 .26679243 \n18 \nCenter for Drug Evaluation and Research (CDER) . Guidance for Industry\nAcute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment, August 2010. Silver Spring, MD: FDA, US Department of Health and Human Services.\n19 \nEMA . Committee for Medicinal Products for Human Use (CHMP). Guideline on the Evaluation of Medicinal Products Indicated for Treatment of Bacterial Infections Draft. London, 18 February 2010. CPMP/EWP/558/95 rev 2. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/03/WC500079928.pdf.\n20 \nRybak M , Lomaestro B , Rotschafer JC \n\nTherapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists . Am J Health Syst Pharm 2009 ; 66 : 82 –98 .19106348 \n21 \nMiettinen O , Nurminen M. \nComparative analysis of two rates . Stat Med 1985 ; 4 : 213 –26 .4023479 \n22 \nZilberberg MD , Micek ST , Kollef MH \n\nRisk factors for mixed complicated sin and skin structure infections to help tailor appropriate empiric therapy . Surg Infect (Larchmt) 2012 ; 13 : 377 –82 .23216526 \n23 \nLipsky BA , Napolitano LM , Moran GJ \n\nEconomic outcomes of inappropriate initial antibiotic treatment for complicated skin and soft tissue infections: a multicenter prospective observational study . Diagn Microbiol Infect Dis 2014 ; 79 : 266 –72 .24657171 \n24 \nBerger A , Oster G , Edelsberg J \n\nInitial treatment failure in patients with complicated skin and skin structure infections . Surg Infect (Larchmt) 2013 ; 14 : 304 –12 .23590851 \n25 \nHalilovic J , Heintz BH , Brown J. \nRisk factors for clinical failure in patients hospitalized with cellulitis and cutaneous abscess . J Infect 2012 ; 65 : 128 –34 .22445732 \n26 \nRusso A , Concia E , Cristini F \n\nCurrent and future trends in antibiotic therapy of acute bacterial skin and skin-structure infections . Clin Microbiol Infect 2016 ; 22 Suppl 2: S27 –36 .27125562 \n27 \nTamma PD , Cosgrove SE , Maragakis LL. \nCombination therapy for treatment of infections with Gram-negative bacteria . Clin Microbiol Rev 2012 ; 25 : 450 –70 .22763634 \n28 \nDryden MS. \nComplicated skin and soft tissue infection . J Antimicrob Chemother 2010 ; 65 Suppl 3: iii35 –44 .20876627 \n29 \nLitwin JS , Benedict MS , Thorn MD \n\nA thorough QT study to evaluate the effects of therapeutic and supratherapeutic doses of delafloxacin on cardiac repolarization . Antimicrob Agents Chemother 2015 ; 59 : 3469 –73 .25845864 \n30 \nLawrence L , Benedict M , Hart J \n Pharmacokinetics (PK) and safety of single doses of delafloxacin administered intravenously in healthy human subjects. In: Abstracts of the Fifty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, USA, 2011. Abstract A2-045A. American Society for Microbiology, Washington, DC, USA.\n31 \nLawrence L , Benedict M , Litwin J \n A thorough Phase 1 QTc study of delafloxacin compared with placebo and moxifloxacin (MXF). In: Abstracts of the Fifty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, USA, 2012. Abstract A1958. American Society for Microbiology, Washington, DC, USA.\n32 \nFerguson J , Lawrence L , Paulson S \n Assessment of phototoxicity potential of delafloxacin in healthy male and female subjects: a Phase 1 study. In: Abstracts of the Fifty-fifth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, USA, 2015. Abstract F-1198a. American Society for Microbiology, Washington, DC, USA.\n33 \nPai MP , Bearden DT. \nAntimicrobial dosing considerations in obese adult patients . Pharmacotherapy 2007 ; 27 : 1081 –91 .17655508\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0305-7453",
"issue": "72(12)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": null,
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D061605:Administration, Intravenous; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000890:Anti-Infective Agents; D001398:Aztreonam; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions; D024841:Fluoroquinolones; D006801:Humans; D008875:Middle Aged; D017192:Skin Diseases, Bacterial; D016896:Treatment Outcome; D014640:Vancomycin; D055815:Young Adult",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "3471-3480",
"pmc": null,
"pmid": "29029278",
"pubdate": "2017-12-01",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "15056651;26679243;22445732;28630189;14506039;19106348;23984642;26119479;26779773;15215148;23590851;20673598;22763634;25448332;24973422;23216526;16231249;4023479;24343828;25845864;25459370;22431849;21135179;24884578;24657171;27125562;17655508;20876627",
"title": "Efficacy and safety of delafloxacin compared with vancomycin plus aztreonam for acute bacterial skin and skin structure infections: a Phase 3, double-blind, randomized study.",
"title_normalized": "efficacy and safety of delafloxacin compared with vancomycin plus aztreonam for acute bacterial skin and skin structure infections a phase 3 double blind randomized study"
} | [
{
"companynumb": "US-PFIZER INC-2019496726",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZTREONAM"
},
"drugadditional": null,
... |
{
"abstract": "This study aimed to identify pharmacist professional liability patterns and trends associated with 2 of the most common allegations in legal claims: wrong drug dispensing errors and wrong dose dispensing errors.\n\n\n\nThis study used pharmacist professional liability claim data from the Healthcare Providers Service Organization professional liability insurance program, underwritten by CNA. The final 2018 claims dataset consisted of pharmacist professional liability (i.e., malpractice) claims that closed between 2012 and 2016 and incurred a payment of at least $1 from the Healthcare Providers Service Organization program. Using malpractice claim data, the claims were classified by clinical license (pharmacist or pharmacy technician), primary allegation type, and total payment amount. These claims were then analyzed to determine the risk factors that most often led to wrong drug and wrong dose dispensing errors and the factors that led to claims with higher-than-average total payments. Then, the results were compared with the 2013 claims dataset to identify patterns and trends.\n\n\n\nInclusion criteria, applied to 1264 reported adverse incidents and claims, created the 2018 claim dataset consisting of 184 closed claims over the 5 years available for review. The average total payment was $124,407 for closed claims with a payment of at least $1. Wrong drug dispensing errors represented 36.8% of claims in the 2018 dataset, and wrong dose dispensing errors represented 15.3% of claims. Comparisons with the 2013 dataset revealed that the percentage of claims associated with wrong drug dispensing errors decreased from 43.8% in the 2013 dataset to 36.8% in the 2018 dataset. The percentage of wrong dose claims also decreased since the 2013 dataset from 31.5% to 15.3%.\n\n\n\nAlthough technology and automation have contributed to improvements in the area of medication error prevention, wrong drug and wrong dose dispensing errors continue to occur because of system and human factor errors.",
"affiliations": null,
"authors": "Reiner|Georgia|G|;Pierce|Stephanie Lynn|SL|;Flynn|Jennifer|J|",
"chemical_list": "D004364:Pharmaceutical Preparations",
"country": "United States",
"delete": false,
"doi": "10.1016/j.japh.2020.02.027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1086-5802",
"issue": "60(5)",
"journal": "Journal of the American Pharmacists Association : JAPhA",
"keywords": null,
"medline_ta": "J Am Pharm Assoc (2003)",
"mesh_terms": "D006801:Humans; D016365:Liability, Legal; D008318:Malpractice; D008508:Medication Errors; D004364:Pharmaceutical Preparations; D010595:Pharmacists",
"nlm_unique_id": "101176252",
"other_id": null,
"pages": "e50-e56",
"pmc": null,
"pmid": "32217085",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Wrong drug and wrong dose dispensing errors identified in pharmacist professional liability claims.",
"title_normalized": "wrong drug and wrong dose dispensing errors identified in pharmacist professional liability claims"
} | [
{
"companynumb": "US-SPECGX-T202100055",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "MORPHINE SULFATE"
},
"drugadditional": null,
... |
{
"abstract": "This case report describes the progress of an immunosuppressed renal transplant patient who presented with signs and symptoms of community acquired pneumonia. He did not respond to conventional therapy and underwent further investigation. Definitive diagnosis proved challenging. On the basis of multiple investigation results he was treated variously for bacterial, viral and tuberculous infections. At one point it was thought pulmonary malignancy was likely. After excision of a subcutaneous nodule, microscopy and culture confirmed diagnosis of disseminated Nocardia farcinica. This case demonstrates the difficulty in diagnosing this rare infection in immunocompromised patients, the problems posed by concomitant infection and the potential hazards of multiple drug interactions. On initiation of optimum antimicrobial therapy and with safe levels of immunosuppression our patient made full recovery without any loss in graft function.",
"affiliations": "Department of Renal and Transplant, Southmead Hospital, Bristol, UK. thomasjorna@gmail.com",
"authors": "Jorna|Thomas|T|;Taylor|Joanne|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D006801:Humans; D007165:Immunosuppression Therapy; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009617:Nocardia Infections; D011183:Postoperative Complications",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "23505268",
"pubdate": "2013-03-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21824241;22215305;15497524;8055469;22089782",
"title": "Disseminated Nocardia infection in a renal transplant patient: the pitfalls of diagnosis and management.",
"title_normalized": "disseminated nocardia infection in a renal transplant patient the pitfalls of diagnosis and management"
} | [
{
"companynumb": "GB-MYLANLABS-2018M1006928",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Graft-verse-host disease (GVHD) is an uncommon fatal complication following liver transplantation (LTx). In mainland China, only six cases have been reported with a morbidity rate up to 1%-2%. Definitive diagnosis was achieved by molecular techniques (HLA typing or PCR-STR) in only two cases and the remaining cases were diagnosed based on typical clinical features with exclusion of other possible causes. All patients died of septic shock or multiple organ failure even after administration of increased corticosteroids and supportive therapy, and reduced immunosuppressive agents. In our center, two cases of GVHD were found among 128 (1.56%) patients. One case was diagnosed by detecting lymphocyte macrochimerism through DNA-STR. Both of them died even after aggressive treatment. In China, the incidence of GVHD is similar to that reported by foreign centers except for an extremely bad prognosis. Rapid diagnosis is crucial for a better prognosis. In China, only 37.5% of cases are diagnosed by molecular methods. We recommend detecting lymphocyte macrochimerism through DNA-STR to get a rapid diagnosis, and interleukin 2-receptor antibody (basiliximab or daclizumab) therapy seems to be a good choice for the disease.",
"affiliations": "Organ Transplantation Center, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong Province, China.",
"authors": "Guo|Zhi-Yong|ZY|;He|Xiao-Shun|XS|;Wu|Lin-Wei|LW|;Zhu|Xiao-Feng|XF|;Ju|Wei-Qiang|WQ|;Wang|Dong-Ping|DP|;You|Shen|S|;Ma|Yi|Y|;Wang|Guo-Dong|GD|;Huang|Jie-Fu|JF|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.14.974",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "14(6)",
"journal": "World journal of gastroenterology",
"keywords": null,
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D002681:China; D017809:Fatal Outcome; D006086:Graft vs Host Disease; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "974-9",
"pmc": null,
"pmid": "18240363",
"pubdate": "2008-02-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16303012;10719017;10607689;4875305;7692632;12859540;12359826;11959211;16421472;14966423;12544883;15200885",
"title": "Graft-verse-host disease after liver transplantation: a report of two cases and review of literature.",
"title_normalized": "graft verse host disease after liver transplantation a report of two cases and review of literature"
} | [
{
"companynumb": "CN-PFIZER INC-2021334441",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "We report a case of spontaneous intracerebral hemorrhage (sICH) due to delta storage pool disease in a 60-year-old female on a serotonin-norepinephrine reuptake inhibitor (SNRI). Increased susceptibility to SNRI-effects on hemostasis was due to a genetic disposition mediated by a polymorphism of the SLC6A4 gene coding for the human serotonin transporter (SERT). Pathophysiological and clinical implications of these findings are discussed.",
"affiliations": "Department of Neurology 1, Kepler University Hospital, Medical Faculty of the Johannes Kepler University Linz, Linz, Austria.;Department of Neurology 1, Kepler University Hospital, Medical Faculty of the Johannes Kepler University Linz, Linz, Austria.;Institute for Clinical Pathology, Kepler University Hospital, Medical Faculty of the Johannes Kepler University Linz, Linz, Austria.;Department of Neurology 1, Kepler University Hospital, Medical Faculty of the Johannes Kepler University Linz, Linz, Austria.;Department of Neurology 1, Kepler University Hospital, Medical Faculty of the Johannes Kepler University Linz, Linz, Austria.;Institute of Neuroradiology, Kepler University Hospital, Medical Faculty of the Johannes Kepler University Linz, Linz, Austria.;Department of Neurology 1, Kepler University Hospital, Medical Faculty of the Johannes Kepler University Linz, Linz, Austria.",
"authors": "Leibetseder|Annette|A|;Wagner|Judith|J|;Tomasits|Josef|J|;Haring|Hans-Peter|HP|;Hutterer|Markus|M|;Trenkler|Johannes|J|;von Oertzen|Tim J|TJ|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fneur.2019.01257",
"fulltext": "\n==== Front\nFront NeurolFront NeurolFront. Neurol.Frontiers in Neurology1664-2295Frontiers Media S.A. 10.3389/fneur.2019.01257NeurologyCase ReportSpontaneous Intracerebral Hemorrhage Due to Delta Storage Pool Disease in a Patient on a Serotonin-Norepinephrine Reuptake Inhibitor Leibetseder Annette 1†Wagner Judith 1*†Tomasits Josef 2Haring Hans-Peter 1Hutterer Markus 1Trenkler Johannes 3von Oertzen Tim J. 11Department of Neurology 1, Kepler University Hospital, Medical Faculty of the Johannes Kepler University Linz, Linz, Austria2Institute for Clinical Pathology, Kepler University Hospital, Medical Faculty of the Johannes Kepler University Linz, Linz, Austria3Institute of Neuroradiology, Kepler University Hospital, Medical Faculty of the Johannes Kepler University Linz, Linz, AustriaEdited by: Thanh G. Phan, Monash Health, Australia\n\nReviewed by: Igor Sibon, Centre Hospitalier Universitaire (CHU) de Bordeaux, France; Walter Struhal, AKh Linz, Austria\n\n*Correspondence: Judith Wagner juna.wagner@gmx.deThis article was submitted to Stroke, a section of the journal Frontiers in Neurology\n\n†These authors have contributed equally to this work\n\n26 11 2019 2019 10 125731 5 2019 12 11 2019 Copyright © 2019 Leibetseder, Wagner, Tomasits, Haring, Hutterer, Trenkler and von Oertzen.2019Leibetseder, Wagner, Tomasits, Haring, Hutterer, Trenkler and von OertzenThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.We report a case of spontaneous intracerebral hemorrhage (sICH) due to delta storage pool disease in a 60-year-old female on a serotonin-norepinephrine reuptake inhibitor (SNRI). Increased susceptibility to SNRI-effects on hemostasis was due to a genetic disposition mediated by a polymorphism of the SLC6A4 gene coding for the human serotonin transporter (SERT). Pathophysiological and clinical implications of these findings are discussed.\n\nintracerebral hemorrhagestrokeSSRISNRIthrombocytopathydelta storage pool disease\n==== Body\nBackground\nSpontaneous intracerebral hemorrhage (sICH) is most often caused by hypertension, cerebral amyloid angiopathy, vascular malformation, and inherited or acquired coagulopathies (1). Platelets are an essential component of primary hemostasis. Their activation is initiated and maintained by small molecules released from dense granules contained within the platelets (2). Serotonin is among the molecules stored in platelet granules. Upon release, it promotes platelet aggregation via the 5-HT2A receptor. Number or content of dense granules is reduced in delta storage pool disease, a rare and etiologically heterogeneous platelet disorder (3).\n\nUptake of serotonin into the platelet cytosol is mediated via the serotonin transporter (SERT), which is identical to the one found in neurons. SERT is coded by the SLC6A4 gene on chromosome 17 (4, 5). Serotonergic antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRI) are known to reduce platelet serotonin content (6). Use of SSRIs is also associated with an increased risk for sICH as recently shown in a population-based study (7). The extent of the SSRI effect on platelet function is related to an insertion/deletion polymorphism in the promoter region (5-HTTLPR; serotonin-transporter-linked polymorphic region) of the SLC6A4 gene coding for the human SERT. The 5-HTTLPR gene has a short (S) and a long (L) allele, the S variant being associated with decreased transcription. A higher sensitivity to serotonergic antidepressants—and hence a higher risk of hemorrhage—may be seen in the short gene (SS) polymorphism (8).\n\nCase Presentation\nWe present the case of a 66-year old female who was admitted to our hospital due to a first generalized tonic-clonic seizure. The patient did not report any symptoms suggestive of an epileptic aura. She denied any other focal neurological symptoms, nausea or headaches. The remaining neurological examination was unremarkable except for disorientation as to the situation. Initial investigations including cerebral magnetic resonance imaging (MRI; Figure 1A) and cerebrospinal fluid (CSF) analysis were negative. Blood tests showed no signs for infection or metabolic abnormalities.\n\nFigure 1 MRI (A,B) and CT (C) images. MRI imaging on day of admission after a first seizure was unremarkable (A: axial FLAIR). MRI on day 5 showed a spontaneous left hemispheric ICH with a subarachnoid component (SAB) (B: axial FLAIR; white arrow: ICH, asterisk: SAB). One day later the patient deteriorated again and CT imaging showed a right sided sICH and edema of the left hemisphere (C: axial CT; white arrow: ICH, asterisk: SAB).\n\nThe patient had a history of recurrent episodes of major depression and was treated with the SNRI venlafaxine 150 mg per day. She had started venlafaxine 14 years before the current event, taking doses of 100–150 mg per day (an increase to 225 mg had been suggested earlier—this change had apparently not been implemented by the patient). The combined plasma level of venlafaxine and its active metabolite O-desmethyl venlafaxine was elevated (541 ng/ml, range 100–400 ng/ml). Due to ongoing major depression, the venlafaxine dose was increased to 225 mg/day on the day after hospitalization. At the time of admission, the patient took amisulpride, prothipendyl, hydroxyzine, and zolpidem tartrate in addition to venlafaxine, but no other antidepressant. Within the period of 14 years documented in the patient file, she had not been medicated with another SNRI or SSRI. The only other antidepressant medication tried apart from venlafaxine was trazodone (maximal dose 250 mg/day).\n\nFive days after hospitalization, the patient suffered a spontaneous left hemispheric intracranial hemorrhage with a large intraparenchymal and a small subarachnoidal component (Figure 1B). On the subsequent day, a second bleed occurred on the contralateral side (Figure 1C). Conventional angiography displayed local rarefication of cerebral vessels, most likely secondary to the hemorrhage. Vasculitis, reversible vasoconstriction syndrome and vascular malformations were ruled out with this method. Magnetic resonance (MR) imaging and MR angiography did not show any signs of cerebral amyloid angiopathy, cerebral venous thrombosis, brain metastases, or other suspicious lesions. Cerebrospinal fluid diagnostics exhibited no abnormalities.\n\nOn examination of the coagulation system, a disorder of platelet aggregation was diagnosed. Immunofluorescence microscopy revealed a decrease of the granule markers Lamp 1/2 and CD63, compatible with delta storage pool disease. We assumed a drug-induced pathogenesis due to venlafaxine and replaced it with mirtazapine. Two weeks after discontinuing venlafaxine, the platelet function tests yielded normal results. SERT-promoter sequencing in our patient revealed a heterozygote genotype (SL).\n\nDiscussion\nIn conclusion, we diagnosed an acquired form of delta-storage pool deficiency induced by venlafaxine in a patient with a genetic predisposition due to a heterozygote genotype (SL) of the SLC6A4 gene coding for the platelet SERT. Whereas, patients homozygous for the LL genotype have not displayed an increased bleeding time after SSRI treatment, those with a heterozygote (SL) or homozygote (SS) genotype have (8).\n\nA dose-dependent correlation between antidepressant intake and platelet dysfunction has been found for the selective noradrenaline reuptake inhibitor desipramine. Reduction of platelet serotonin content was proportional to the steady state plasma level of the drug (6). These findings increase the likelihood of our patient's hemorrhage being due to the increased venlafaxine dose she had received.\n\nTo our knowledge, there is no other case on delta storage pool disease and sICH reported in adults on SNRI. However, it is difficult to estimate how often patients with sICH while on this medication are actually investigated for platelet storage disease. We suggest investigating for impaired platelet aggregation and/or SLC6A4-genotyping in patients with spontaneous intracranial hemorrhage or other serious bleeding while on serotonergic antidepressants. Considering all risks and benefits, a switch to a non-serotonergic antidepressant may be considered in an SS- or SL-genotype.\n\nPre-therapeutic screening for susceptibility to adverse effects would require SLC6A4 genotyping as platelet function tests are likely to be normal in this context. With an odds ratio for a hemorrhage of about 3 in a patient on SSRI (and potentially even lower for patients on SNRIs), determination of the SERT polymorphism in all patients prior to starting with an SSRI or SNRI will not be cost-effective (9). However, standard screening for thrombocytopathies in patients already on SSRI or SNRI may be advisable (10). Alternatively, immunocytochemical assays might be helpful in detecting abnormal serotonin levels in platelets of patients on serotonergic antidepressants (11).\n\nIntensive care physicians, stroke specialists as well as psychiatrists should be aware of severe bleeding—including sICH—as a potential side-effect in patients on SNRIs.\n\nThe cause of the epileptic seizure in this patient could not be fully elucidated. MRI and MR angiography on the day of admission did not reveal any acute alterations, particularly no signs of reversible vasoconstriction syndrome or cerebral venous thrombosis. Neither did a CSF count, a full blood and serum analysis or a toxicology screen. Seizures provoked by therapeutic doses of venlafaxine have been reported (12). However, our patient had been on the same dose of venlafaxine for many years and never suffered from seizures before. Nor was there any other change of medication before the seizure occurred. Epidemiological studies have shown an increased risk of subsequent cerebrovascular disease—particularly of hemorrhagic stroke—in patients with late-onset seizures (13). The causal mechanism of this correlation has not yet been fully elucidated. In our patient though, the predisposition for hemorrhagic stroke—namely the increase in venlafaxine dose leading to thrombocytic dysfunction—only occurred after hospital admission. Thus, the seizure can hardly be defined as a pre-stroke seizure. Finally, a bidirectional relationship between depression and epilepsy, possibly due to shared pathophysiological mechanisms, has been described (14). Hence, we diagnosed a late-onset seizure in a patient belonging to an epidemiological risk group and with a potentially lowered seizure threshold due to venlafaxine treatment.\n\nEthics Statement\nAll subjects gave written informed consent in accordance with the Declaration of Helsinki. The patient gave written informed consent for genetic analysis. The study was exempt from ethical approval procedures.\n\nAuthor Contributions\nAL, JW, and TO conceived the idea of this work. AL and JW collected the data. AL, JW, TO, JT, H-PH, MH, and JTr helped with data analysis and interpretation, drafting of the article, and critical revision of the article.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nFunding. This work was supported by Johannes Kepler Open Access Publishing Fund.\n==== Refs\nReferences\n1. Cordonnier C Demchuk A Ziai W Anderson CS . Intracerebral haemorrhage: current approaches to acute management . Lancet . (2018 ) 392 :1257 –68 . 10.1016/S0140-6736(18)31878-6 30319113 \n2. Golebiewska EM Poole AW . Platelet secretion: from haemostasis to wound healing and beyond . Blood Rev. (2015 ) 29 :153 –62 . 10.1016/j.blre.2014.10.003 25468720 \n3. Masliah-Planchon J Darnige L Bellucci S . Molecular determinants of platelet delta storage pool deficiencies: an update . Br J Haematol . (2013 ) 160 :5 –11 . 10.1111/bjh.12064 23025459 \n4. Jedlitschky G Greinacher A Kroemer HK . Transporters in human platelets: physiologic function and impact for pharmacotherapy . Blood . (2012 ) 119 :3394 –402 . 10.1182/blood-2011-09-336933 22337717 \n5. Yubero-Lahoz S Robledo P Farré M de laTorre R . Platelet SERT as a peripheral biomarker of serotonergic neurotransmission in the central nervous system . Curr Med Chem . (2013 ) 20 :1382 –96 . 10.2174/0929867311320110003 23409709 \n6. Javors MA Houston JP Tekell JL Brannan SK Frazer A \nReduction of platelet serotonin content in depressed patients treated with either paroxetine or desipramine . Int J Neuropsychopharmacol . (2000 ) 3 :229 –35 . 10.1017/S146114570000198X 11343600 \n7. Renoux C Vahey S Dell'Aniello S Boivin J-F . Association of selective serotonin reuptake inhibitors with the risk for spontaneous intracranial hemorrhage . JAMA Neurol . (2017 ) 74 :173 –80 . 10.1001/jamaneurol.2016.4529 27918771 \n8. Abdelmalik N Ruhé HG Barwari K van den Dool E-J Meijers JCM Middeldorp S . Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism . J Thromb Haemost . (2008 ) 6 :2168 –74 . 10.1111/j.1538-7836.2008.03196.x 18983505 \n9. Paton C Ferrier IN . SSRIs and gastrointestinal bleeding . BMJ . (2005 ) 331 :529 –30 . 10.1136/bmj.331.7516.529 16150746 \n10. Scharf RE . Drugs that affect platelet function . Semin Thromb Hemost . (2012 ) 38 :865 –83 . 10.1055/s-0032-1328881 23111864 \n11. Maurer-Spurej E Dyker K Gahl WA Devine DV . A novel immunocytochemical assay for the detection of serotonin in platelets . Br J Haematol . (2002 ) 116 :604 –11 . 10.1046/j.0007-1048.2001.03302.x 11849219 \n12. Ye C Ninneman M Christian JS Zhang F Musselman D . Seizure induced by a therapeutic dose of venlafaxine ER: a case report . J Psychiatr Pract . (2018 ) 24 :117 –20 . 10.1097/PRA.0000000000000298 29509182 \n13. Zelano J Larsson D Kumlien E Åsberg S . Pre-stroke seizures: a nationwide register-based investigation . Seizure . (2017 ) 49 :25 –9 . 10.1016/j.seizure.2017.05.010 28544888 \n14. Josephson CB Lowerison M Vallerand I Sajobi TT Patten S Jette N . Association of depression and treated depression with epilepsy and seizure outcomes: a multicohort analysis . JAMA Neurol . (2017 ) 74 :533 –9 . 10.1001/jamaneurol.2016.5042 28241168\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2295",
"issue": "10()",
"journal": "Frontiers in neurology",
"keywords": "SNRI; SSRI; delta storage pool disease; intracerebral hemorrhage; stroke; thrombocytopathy",
"medline_ta": "Front Neurol",
"mesh_terms": null,
"nlm_unique_id": "101546899",
"other_id": null,
"pages": "1257",
"pmc": null,
"pmid": "31849820",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "23409709;29509182;25468720;30319113;16150746;28241168;18983505;23025459;11343600;22337717;11849219;27918771;28544888;23111864",
"title": "Spontaneous Intracerebral Hemorrhage Due to Delta Storage Pool Disease in a Patient on a Serotonin-Norepinephrine Reuptake Inhibitor.",
"title_normalized": "spontaneous intracerebral hemorrhage due to delta storage pool disease in a patient on a serotonin norepinephrine reuptake inhibitor"
} | [
{
"companynumb": "AT-BAUSCH-BL-2020-001187",
"fulfillexpeditecriteria": "1",
"occurcountry": "AT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "A 72-year-old woman was admitted to the hospital because of dorsal, lumbar and lower abdomen pain that had started 4 days before. She had a history of age-related macular degeneration (treated with intraocular bevacizumab). Blood tests showed anaemia, thrombocytopaenia, acute kidney injury, elevated liver enzymes and total bilirubin (mainly because of the indirect fraction). Viral serologies and ADAMTS13 activity levels were normal, and stool testing was negative for Escherichia coli-producing Shiga toxins. E. coli was isolated in urine. Atypical haemolytic uremic syndrome triggered by a urinary tract infection or by the vascular endothelial growth factor-inhibitor bevacizumab were the most likely hypothesis. The patient started urgent plasmapheresis and dialysis that lasted for a total of 18 days. There was complete remission and recovery of kidney function allowing for treatment discontinuation, and she was discharged home. After 6 months of follow-up, she shows no signs of relapse.",
"affiliations": "Nephrology, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal.;Internal Medicine, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal.;Internal Medicine, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal.;Nephrology, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal.",
"authors": "Mira|Filipe Santos|FS|http://orcid.org/0000-0002-5682-3116;Nunes|Ana Luísa|AL|;Elvas|Ana Rita|AR|;Oliveira|Nuno|N|",
"chemical_list": "D042461:Vascular Endothelial Growth Factor A",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-230026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(6)",
"journal": "BMJ case reports",
"keywords": "acute renal failure; dialysis; fluid electrolyte and acid-base disturbances; haematology (incl blood transfusion)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D065766:Atypical Hemolytic Uremic Syndrome; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D010956:Plasmapheresis; D006435:Renal Dialysis; D014552:Urinary Tract Infections; D042461:Vascular Endothelial Growth Factor A",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31253663",
"pubdate": "2019-06-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27989322;26456110;25135378;25500702;21295897;27012908;25949282;26501415;30046676;28946961;19712924;27939104;15761122;18337603;29042465",
"title": "Atypical haemolytic uremic syndrome from multiple missenses to a full-blown disease.",
"title_normalized": "atypical haemolytic uremic syndrome from multiple missenses to a full blown disease"
} | [
{
"companynumb": "PT-PFIZER INC-2019305227",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "Extramedullary hematopoiesis (EMH) occurs as a complication of hematologic disorders such as myelofibrosis, sickle cell anemia and thalassemia. The extramedullary tissue usually involves liver, spleen and lymph nodes, less frequently the chest. We present a recent case of a man with myeloproliferative neoplasm who developed pulmonary hemorrhage secondary to EMH in the lung and pulmonary artery. Radiation therapy was considered the best approach, but it didn't work and the patient died a week after radiation therapy was completed. We also review herein the present literature.",
"affiliations": "Division of Hematology/Oncology and Bone Marrow Transplantation, University of Iowa Hospitals and Clinics , Iowa City, IA, USA.;Division of Hematology/Oncology and Bone Marrow Transplantation, University of Iowa Hospitals and Clinics , Iowa City, IA, USA.",
"authors": "Monga|Varun|V|;Silverman|Margarida|M|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4081/hr.2015.5714",
"fulltext": "\n==== Front\nHematol RepHematol RepHRHematology Reports2038-83222038-8330PAGEPress Publications, Pavia, Italy hr-2015-1-571410.4081/hr.2015.5714Case ReportPulmonary Extramedullary Hematopoiesis Involving the Pulmonary Artery Monga Varun Silverman Margarida Division of Hematology/Oncology and Bone Marrow Transplantation, University of Iowa Hospitals and Clinics, Iowa City, IA, USAUniversity of Iowa Hospitals and Clinics, C-32 GH, Iowa City, IA 52242, USA. +1.319.356.2075 - +1.319.353.8383. varun-monga@uiowa.eduContributions: the authors contributed equally.\n\nConflict of interest: the authors declare no potential conflict of interest.\n\n24 3 2015 24 2 2015 7 1 571401 11 2014 09 2 2015 ©Copyright V. Monga and M. Silverman2015Licensee PAGEPress, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Extramedullary hematopoiesis (EMH) occurs as a complication of hematologic disorders such as myelofibrosis, sickle cell anemia and thalassemia. The extramedullary tissue usually involves liver, spleen and lymph nodes, less frequently the chest. We present a recent case of a man with myeloproliferative neoplasm who developed pulmonary hemorrhage secondary to EMH in the lung and pulmonary artery. Radiation therapy was considered the best approach, but it didn’t work and the patient died a week after radiation therapy was completed. We also review herein the present literature.\n\nKey words\npulmonaryextramedullaryhematopoiesismyeloproliferative neoplasms\n==== Body\nIntroduction\nExtramedullary hematopoiesis (EMH) occurs as a complication of hematologic disorders such as myelofibrosis, sickle cell anemia, and thalassemia. The extramedullary tissue usually involves the liver, spleen and lymph nodes. Although it has been described as occurring at almost any organ/site in the body, it has been infrequently reported in the chest. When described in chest, it has been generally detected as paravertebral masses seen on chest x-ray.1-6 It is important to make this diagnosis as EMH can be associated with intrathoracic cord compression, and rarely fatal hemothorax.5 It is amenable to therapy with both hydroxyurea and radiation.\n\nCase Report\nA 53-year-old Caucasian man presented with a year history of myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) and marrow fibrosis (negative JAK-2 V617F point mutation). He was seen with epistaxis and hemoptysis of two days duration. He had been on ruxolitinib for six months with improvement in appetite and decreased pain secondary to an enlarged spleen. He was being considered for allogeneic stem cell transplantation. Physical examination was significant for a fever of 101.3°F, fine crackles at the right base and an enlarged spleen. Laboratory analyses showed a white blood cell count of 27,500/mm3, hemoglobin level of 7.8 g/dL, hematocrit of 27% and platelet count of 22,000/mm3. Peripheral blood smear review showed markedly increased monocytes many of which appeared atypical. Computed tomographic (CT) scan of the chest with contrast showed a right pulmonary artery filling defect which extended into the right middle lobe (Figure 1A). Enlarged subcarinal, aortopulmonary lymph nodes, splenomegaly and a right liver mass were also seen. Given his longterm smoking history, there was concern that a second malignancy might be present. A recent biopsy of the liver mass had EMH. The differential diagnoses of the right middle lobe and pulmonary artery mass included thromboembolic disease, primary lung malignancy, sarcoma, pneumonia or EMH. An endobronchial ultrasound guided aspiration of the subcarinal lymph node and right pulmonary artery mass showed findings consistent with EMH (Figure 1B). A bone marrow biopsy was performed which showed hypercellular bone marrow (>90%) with decreased megakaryocytes, erythroid dyspoiesis and left shifted granulopoiesis with 5% blasts, a peripheral monocytosis, and moderate marrow fibrosis consistent with chronic myelomonocytic leukemia-2. He received 14 Gy of the planned 20 Gy external beam radiation therapy in 7 fractions using AP/PA approach with 10× energy to the right lung mass as outpatient. Ruxolitinib was stopped due to thrombocytopenia (platelet count of 48,000/mm3, PT –15 sec and INR – 1.5). A week later he presented with a hematoma of his right thigh, severe anemia (hemoglobin 5.5 gm/dL), elevated white blood cell count (89,700/mm3) with predominant monocytosis. He was started on hydroxyurea and received a single dose of decitabine for presumed acute leukemia. The patient suddenly became hypoxemic. Chest x-ray showed right sided pleural effusion. A diagnostic thoracentesis revealed bloody pleural fluid. Cytology of the pleural fluid showed hematopoietic cells similar to the ones noted in the pulmonary artery aspirate specimen. At that time his platelets were 76,000/mm3. The patient was deemed to be inoperable given the multiple comorbidities and he died a day later. Autopsy was not performed.\n\nDiscussion\nExtramedullary hematopoiesis is a compensatory hematopoietic tissue expansion usually involving the reticulo-endothelial system. EMH and myeloid metaplasia have been interchangeably used in the past and refer to the similar pathological process.7 Whether EMH represents differentiation of embryonic stem cells residing within the vessel wall or implantation of hematopoietic tissue escaping from the bone marrow remains uncertain.\n\nPulmonary EMH (PEMH) has been rarely reported. The majority of the pulmonary EMH masses are asymptomatic. However patients sometimes present with hemoptysis,8 acute or progressive dyspnea or chest pain. Patients can sometimes present with life threatening complications such as massive pleural effusion, hemothorax,9 chylothorax,10 or spinal cord compression (posterior mediastinal EMH).11 Differentiation between thromboembolic disease and extramedullary hematopoiesis in such cases can be very critical as the treatments strategies are different for each. Several other non-infectious pulmonary complications of MDS/MPN have been described in the literature.12 Hematopoietic tissue is known to be sensitive to low doses of radiation therapy. The role of radiation therapy in treating patients with EMH causing spinal cord compression has been well established.11,13 Radiation therapy to the lung has been successfully used to treat EMH involving the lung parenchyma.9,14,15 The median suggested dose of radiation is 1.25 Gy. Combined modality treatment with radiation and surgery perhaps would be a better approach reserving surgery for only emergent management. Table 1 outlines the published cases of pulmonary EMH, the respective interventions utilized and the corresponding treatment outcomes.4,5,8-10,14-20\n\nIn our patient several factors could have contributed to the pulmonary hemorrhage including the underlying hematological condition leading to thrombocytopenia and coagulopathy. The transbronchial biopsy procedure could have caused the hemothorax as these hematopoietic masses are very likely to bleed upon intervention. However the 14 day time lag between the procedure and bleeding makes it less likely. Radiation therapy to the hematopoietic mass tissue in the lung could have potentially leaded to necrosis of the tissue thereby causing hemothorax. Review of the other pulmonary EMH case studies suggests that radiation therapy to the lung has led to the best outcomes.\n\nConclusions\nIn summary, we present a patient with myeloproliferative neoplasm who developed pulmonary hemorrhage secondary to EMH in the lung and pulmonary artery. Although rare, presentation of hemoptysis in a patient with underlying myeloproliferative neoplasm should prompt clinicians to consider EMH involving the pulmonary artery in the differential diagnoses. Early recognition of the diagnosis remains important. Radiation therapy to the lung mass (or the whole lung if pulmonary hypertension is diagnosed) can be considered as the best approach if patient is hemodynamically stable recognizing that it may not always work.\n\nFigure 1. A) Coronal view of post contrast computed tomography imaging of the chest with arrow pointing towards the filling defect within the right pulmonary artery. B) High power view of Hematoxylin and Eosin stain of the endobronchial ultrasound guided aspirate of the right pulmonary artery thrombus showing extramedullary hematopoiesis with immature myeloid cells (box arrow) and focally increased areas of blasts (line arrow).\n\nTable 1. Reported cases of patients with underlying myeloproliferative disease presenting with pulmonary involvement by extramedullary hematopoiesis, respective interventions and their outcomes. Diagnosis of pulmonary extramedullary hematopoiesis made ante mortem.\n\nCase\tUnderlying disease\tPresentation\tTreatment for EMH\tOutcome\t\nPinato et al.4\tMyelodysplasia\tProgressive dyspnea\tNone\tUnknown\t\nChute et al.5\tSickle cell trait/β-thalassemia\tHypoxia\tThoracostomy\tDied from hemothorax\t\nOzbudak et al.8\tMyelofibrosis\tDyspnea and hemoptysis\tPrednisone, hydroxyurea, busulfan\tMinimal improvement; died of MI after 2 mths\t\nKupferschmid et al.9\tMyelofibrosis\tDyspnea\tThoracotomy + radiation 1.4 Gy in 10 fractions\tDied of pneumonia\t\nGhosh et al.10\tNone\tProgressive dyspnea\tThoracostomy with talc pleurodesis + radiation 2 Gy in 4 fractions\tComplete resolution\t\nKoch et al.14\t2 cases: agnogenic myeloid metaplasia\tDyspnea, orthopnea, edema weight gain\t1 Gy in 1 fraction of radiation; 1.5 Gy in 10 fractions\tComplete resolution\t\nWeinschenker et al.15\tMyelofibrosis\tDyspnea\tWhole lung radiation 200 Gy/4 fractions\tComplete resolution\t\nRumi et al.16\tMyelofibrosis\tProgressive dyspnea\tHydroxyurea\tComplete resolution after 3 mths\t\nUeno et al.17\tMyelofibrosis\tFever and fatigue\tSteroids started day 90\tDied 10 days later\t\nYusen et al.18\tMyelofibrosis\tDyspnea, cough, fevers and night sweats\t2 days interferon and supportive care\tDied due to respiratory failure\t\nAsakura et al.19\tMyelofibrosis; agnogenic myeloid metaplasia\tDyspnea; dyspnea and fatigue\tSteroids and diuretics; unknown\tDied 6 mths later; died 13 mths later\t\nGlew et al.20\tMyelofibrosis\tFevers\tNone\tDied 5 months later\t\nEMH, extramedullary hematopoiesis.\n==== Refs\nReferences\n1. Mandal PK Dolai TK \nIntrathoracic extramedullary hematopoiesis in E-beta thalassemia . Indian J Pathol Microbiol 2014 ;57 :497 -8 .25118758 \n2. Da Costa JL Loh YS Hanam E. Extramedullary hemopoiesis with multiple tumor-simulating mediastinal masses in hemoglobin E-thalassemia disease . Chest 1974 ;65 :210 -2 .4810684 \n3. Zhou B Yan S Zheng S. Intrathoracic extramedullary hematopoiesis mimicking intrathoracic tumors: a case report . Oncol Lett 2014 ;7 :1984 -6 .24932275 \n4. Pinato DJ Tan W Gately A. An unexpected cause of pulmonary cannonball lesion . J Thorac Oncol 2014 ;9 :259 .24419425 \n5. Chute DJ Fowler DR \nFatal hemothorax due to rupture of an intrathoracic extramedullary hematopoietic nodule . Am J Forensic Med Pathol 2004 ;25 :74 -7 .15075694 \n6. Santini M Fiorelli A Vicidomini G \nIntrathoracic extramedullary haematopoiesis manifested as a neoplastic lesion within anterior mediastinum . Ann Thorac Surg 2009 ;88 :2001 -4 .19932276 \n7. Tefferi A \nMyelofibrosis with myeloid metaplasia . N Engl J Med 2000 ;342 :1255 -65 .10781623 \n8. Ozbudak IH Shilo K Hale S \nAlveolar airspace and pulmonary artery involvement by extramedullary hematopoiesis: a unique manifestation of myelofibrosis . Arch Pathol Lab Med 2008 ;132 :99 -103 .18181682 \n9. Kupferschmid JP Shahian DM Villanueva AG \nMassive hemothorax associated with intrathoracic extramedullary hematopo iesis involving the pleura . Chest 1993 ;103 :974 -5 .8449115 \n10. Ghosh AK Pawade J Standen GR \nPrimary extramedullary hematopoiesis manifesting as massive bilateral chylothorax . Ann Thorac Surg 2005 ;80 :1515 -7 .16181908 \n11. Scott IC Poynton CH \nPolycythaemia rubra vera and myelofibrosis with spinal cord compression . J Clin Pathol 2008 ;61 :681 -3 .18441161 \n12. Lamour C Bergeron A. Non-infectious pulmonary complications of myelodysplastic syndromes and chronic myeloproliferative disorders . Rev Mal Respir 2011 ;28 :e18 -27 .21742229 \n13. Papavasiliou C Gouliamos A Deligiorgi E \nMasses of myeloadipose tissue: radiological and clinical considerations . Int J Radiat Oncol Biol Phys 1990 ;19 :985 -93 .2211267 \n14. Koch CA Li CY Mesa RA \nNonhepatosplenic extramedullary hematopoiesis: associated diseases, pathology, clinical course, and treatment . Mayo Clin Proc 2003 ;78 :1223 -33 .14531481 \n15. Weinschenker P Kutner JM Salvajoli JV \nWhole-pulmonary low-dose radiation therapy in agnogenic myeloid metaplasia with diffuse lung involvement . Am J Hematol 2002 ;69 :277 -80 .11921022 \n16. Rumi E Passamonti F Boveri E \nDyspnea secondary to pulmonary hematopoiesis as presenting symptom of myelofibrosis with myeloid metaplasia . Am J Hematol 2006 ;81 :124 -7 .16432861 \n17. Ueno H Yoneda R Ogawa W \nBilateral interstitial pneumonic shadows caused by perivascular fibrosis and extramedullary megakaryopoiesis of the lung in a case of advanced agnogenic myeloid metaplasia and myelofibrosis . Acta Haematol 2000 ;104 :212 -6 .11279314 \n18. Yusen RD Kollef MH \nAcute respiratory failure due to extramedullary hematopoiesis . Chest 1995 ;108 :1170 -2 .7555137 \n19. Asakura S Colby TV \nAgnogenic myeloid metaplasia with extramedullary hematopoiesis and fibrosis in the lung. Report of two cases . Chest 1994 ;105 :1866 -8 .8205891 \n20. Glew RH Haese WH McIntyre PA \nMyeloid metaplasia with myelofibrosis. The clinical spectrum of extramedullary hematopoiesis and tumor formation . Johns Hopkins Med J 1973 ;132 :253 -70 .4700515\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2038-8322",
"issue": "7(1)",
"journal": "Hematology reports",
"keywords": "extramedullary; hematopoiesis; myeloproliferative neoplasms; pulmonary",
"medline_ta": "Hematol Rep",
"mesh_terms": null,
"nlm_unique_id": "101556723",
"other_id": null,
"pages": "5714",
"pmc": null,
"pmid": "25852851",
"pubdate": "2015-02-24",
"publication_types": "D002363:Case Reports",
"references": "2211267;18441161;14531481;15075694;16432861;24932275;11921022;16181908;11279314;21742229;7555137;19932276;18181682;10781623;25118758;4700515;24419425;8205891;4810684;8449115",
"title": "Pulmonary extramedullary hematopoiesis involving the pulmonary artery.",
"title_normalized": "pulmonary extramedullary hematopoiesis involving the pulmonary artery"
} | [
{
"companynumb": "US-INCYTE CORPORATION-2016IN005367",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RUXOLITINIB"
},
"drugadditional": "1... |
{
"abstract": "The treatment of active antibody-mediated rejection (ABMR) is still a matter of debate, the place of rituximab remaining controversial. The French multicenter double-blind RITUX-ERAH study included 38 patients with ABMR in the first year of renal transplantation. All patients received plasma exchanges, intravenous immunoglobulins, and corticosteroids and were randomly assigned rituximab or placebo infusion at day 5. Additional rituximab infusions were allowed. In the intention-to-treat analysis, 12-month graft survival and renal function were not different between the rituximab and placebo groups. Long-term data are needed to conclude. Evaluation of the 7-year outcomes of the RITUX-ERAH study patients according to the rituximab or placebo treatment received. Eleven patients received placebo and 27 at least one infusion of rituximab. Seven years after ABMR, death-censored kidney allograft survival and renal function were not different between the groups. The evolution of anti-HLA sensitization was similar. There was no statistically significant difference in the incidence of infectious or neoplastic complications, but to be noted, seven cancers developed in six patients treated with rituximab (mean period of 44 months post-ABMR). In this cohort, there was no benefit 7 years after ABMR of rituximab in addition to plasma exchanges, intravenous immunoglobulins, and steroids.",
"affiliations": "Department of Nephrology, Hypertension, Dialysis and Kidney Transplantation, University hospital of Tours, Tours, France.;Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes and Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.;Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes and Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.;Department of Nephrology and Kidney Transplantation, University hospital of Lyon Edouard Herriot, Lyon, France.;Department of Nephrology and Kidney Transplantation, University hospital of Besançon, Besançon, France.;Nephrology-Transplantation Department, University Hospital, Strasbourg, France.;Centre Universitaire des Maladies Rénales, CHU de Caen, Caen, France.;Department of Nephrology and Kidney Transplantation, University hospital of Grenoble, Grenoble, France.;Department of Nephrology and Kidney Transplantation, Assistance Publique - Hôpitaux de Paris, Pitié Salpêtrière Hospital, Paris, France.;Department of Nephrology and Kidney Transplantation, University hospital of Reims, Reims, France.;Department of Nephrology and Kidney Transplantation, Assistance Publique - Hôpitaux de Paris, Necker Hospital, Paris, France.;Department of Nephrology and Kidney Transplantation, University hospital of Rouen, Rouen, France.;Service de Néphrologie et Transplantation, Pôle Cancérologie-Immunité-Transplantation-Infectiologie et Unité INSERM 955, CHU Henri Mondor et Université Paris-Est, Creteil, France.;Department of Hemodialysis, CHT Noumea, Noumea, France.;Service de Néphrologie, CHU Lille and Inserm U995, Lille, France.;Department of Nephrology and Kidney Transplantation, University Hospital of Toulouse, Toulouse, France.;Department of Nephrology, Transplantation, Dialysis and Apheresis, Bordeaux University Hospital, Bordeaux, France.;Department of Nephrology and Kidney Transplantation, University Hospital of Dijon, Dijon, France.;Department of Nephrology and Kidney Transplantation, University Hospital of Montpellier, Montpellier, France.;Department of Nephrology and Kidney Transplantation, E. Herriot Hospital, Université Lyon I, Lyon, France.;Department of Nephrology and Kidney Transplantation, University Hospital of Marseille, Marseille, France.;Department of Nephrology and Kidney Transplantation, University Hospital of Angers, Angers, France.;Department of Nephrology and Kidney Transplantation, University Hospital of Amiens, Amiens, France.;Department of Nephrology, Hypertension, Dialysis and Kidney Transplantation, University hospital of Tours, Tours, France.;Department of Nephrology, Hypertension, Dialysis and Kidney Transplantation, University hospital of Tours, Tours, France.;Department of Nephrology, Hypertension, Dialysis and Kidney Transplantation, University hospital of Tours, Tours, France.",
"authors": "Bailly|Elodie|E|0000-0001-6740-3961;Ville|Simon|S|0000-0003-0618-6187;Blancho|Gilles|G|;Morelon|Emmanuel|E|;Bamoulid|Jamal|J|;Caillard|Sophie|S|;Chatelet|Valérie|V|0000-0002-3107-9087;Malvezzi|Paolo|P|0000-0002-8549-5561;Tourret|Jérôme|J|;Vuiblet|Vincent|V|;Anglicheau|Dany|D|;Bertrand|Dominique|D|;Grimbert|Philippe|P|0000-0002-8235-2864;Haidar|Fadi|F|;Hazzan|Marc|M|;Kamar|Nassim|N|0000-0003-1930-8964;Merville|Pierre|P|;Mousson|Christiane|C|;Pernin|Vincent|V|;Pouteil-Noble|Claire|C|;Purgus|Raj|R|;Sayegh|Johnny|J|;Westeel|Pierre-François|PF|;Sautenet|Bénédicte|B|;Gatault|Philippe|P|0000-0003-1664-2879;Büchler|Matthias|M|",
"chemical_list": "D000906:Antibodies; D007166:Immunosuppressive Agents; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1111/tri.13613",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-0874",
"issue": "33(7)",
"journal": "Transplant international : official journal of the European Society for Organ Transplantation",
"keywords": "antibody-mediated rejection; graft function; graft survival; randomized trial; rituximab",
"medline_ta": "Transpl Int",
"mesh_terms": "D000906:Antibodies; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D000069283:Rituximab",
"nlm_unique_id": "8908516",
"other_id": null,
"pages": "786-795",
"pmc": null,
"pmid": "32279367",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "An extension of the RITUX-ERAH study, multicenter randomized clinical trial comparing rituximab to placebo in acute antibody-mediated rejection after renal transplantation.",
"title_normalized": "an extension of the ritux erah study multicenter randomized clinical trial comparing rituximab to placebo in acute antibody mediated rejection after renal transplantation"
} | [
{
"companynumb": "FR-CELLTRION INC.-2020FR024007",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "The phenotype of primary immunodeficiency disorders (PID), and especially common variable immunodeficiency (CVID), may be dominated by symptoms of autoimmune disorders. Furthermore, autoimmunity may be the first manifestation of PID, frequently preceding infections and the diagnosis of hypogammaglobulinemia, which occurs later on. In this case, distinguishing PID from hypogammaglobulinemia secondary to anti-inflammatory treatment of autoimmunity may become challenging. The aim of this study was to evaluate the diagnostic accuracy of peripheral blood lymphocyte phenotyping in resolving the diagnostic dilemma between primary and secondary hypogammaglobulinemia. Comparison of B and T cell subsets from patients with PID and patients with rheumatic disease, who developed hypogammaglobulinemia as a consequence of anti-inflammatory regimes, revealed significant differences in proportion of naïve B cells, class-switched memory B cells and CD21low B cells among B cells as well as in CD4+ memory T cells and CD4+ T follicular cells among CD4+ T cells. Identified differences in B cell and T cell subsets, and especially in the proportion of class-switched memory B cells and CD4+ T follicular cells, display a considerable diagnostic efficacy in distinguishing PID from secondary hypogammaglobulinemia due to anti-inflammatory regimens for rheumatic disease.",
"affiliations": "Department of Rheumatology and Immunology, Hannover Medical School, 30625 Hannover, Germany.;Department of Rheumatology and Immunology, Hannover Medical School, 30625 Hannover, Germany.;Department of Rheumatology and Immunology, Hannover Medical School, 30625 Hannover, Germany.;Department of Rheumatology and Immunology, Hannover Medical School, 30625 Hannover, Germany.;Department of Rheumatology and Immunology, Hannover Medical School, 30625 Hannover, Germany.;Department of Rheumatology and Immunology, Hannover Medical School, 30625 Hannover, Germany.",
"authors": "Jablonka|Alexandra|A|;Etemadi|Haress|H|;Adriawan|Ignatius Ryan|IR|;Ernst|Diana|D|;Jacobs|Roland|R|;Buyny|Sabine|S|;Witte|Torsten|T|;Schmidt|Reinhold Ernst|RE|;Atschekzei|Faranaz|F|;Sogkas|Georgios|G|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/jcm9041049",
"fulltext": "\n==== Front\nJ Clin Med\nJ Clin Med\njcm\nJournal of Clinical Medicine\n2077-0383 MDPI \n\n10.3390/jcm9041049\njcm-09-01049\nArticle\nPeripheral Blood Lymphocyte Phenotype Differentiates Secondary Antibody Deficiency in Rheumatic Disease from Primary Antibody Deficiency\nhttps://orcid.org/0000-0001-7129-100XJablonka Alexandra † Etemadi Haress † Adriawan Ignatius Ryan Ernst Diana https://orcid.org/0000-0003-2942-7924Jacobs Roland Buyny Sabine Witte Torsten Schmidt Reinhold Ernst Atschekzei Faranaz *† https://orcid.org/0000-0003-0855-2945Sogkas Georgios *† Department of Rheumatology and Immunology, Hannover Medical School, 30625 Hannover, Germany; Jablonka.Alexandra@mh-hannover.de (A.J.); Etemadi.Haress@mh-hannover.de (H.E.); Adriawan.Ignatius@mh-hannover.de (I.R.A.); Ernst.Diana@mh-hannover.de (D.E.); Jacobs.Roland@mh-hannover.de (R.J.); Buyny.Sabine@mh-hannover.de (S.B.); Witte.Torsten@mh-hannover.de (T.W.); Reinhold.Ernst.Schmidt@mh-hannover.de (R.E.S.)\n* Correspondence: Atschekzei.faranaz@mh-hannover.de (F.A.); sogkas.georgios@mh-hannover.de (G.S.); Tel.: +49-(0)-511-532-3871 (F.A.); +49-(0)-511-532-3799 (G.S.)† These authors contributed equally.\n\n\n07 4 2020 \n4 2020 \n9 4 104905 3 2020 06 4 2020 © 2020 by the authors.2020Licensee 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/).The phenotype of primary immunodeficiency disorders (PID), and especially common variable immunodeficiency (CVID), may be dominated by symptoms of autoimmune disorders. Furthermore, autoimmunity may be the first manifestation of PID, frequently preceding infections and the diagnosis of hypogammaglobulinemia, which occurs later on. In this case, distinguishing PID from hypogammaglobulinemia secondary to anti-inflammatory treatment of autoimmunity may become challenging. The aim of this study was to evaluate the diagnostic accuracy of peripheral blood lymphocyte phenotyping in resolving the diagnostic dilemma between primary and secondary hypogammaglobulinemia. Comparison of B and T cell subsets from patients with PID and patients with rheumatic disease, who developed hypogammaglobulinemia as a consequence of anti-inflammatory regimes, revealed significant differences in proportion of naïve B cells, class-switched memory B cells and CD21low B cells among B cells as well as in CD4+ memory T cells and CD4+ T follicular cells among CD4+ T cells. Identified differences in B cell and T cell subsets, and especially in the proportion of class-switched memory B cells and CD4+ T follicular cells, display a considerable diagnostic efficacy in distinguishing PID from secondary hypogammaglobulinemia due to anti-inflammatory regimens for rheumatic disease.\n\nhypogammaglobulinemiasecondary hypogammaglobulinemiaprimary immunodeficiencycommon variable immunodeficiencymethotrexateDMARDsystemic lupus erythematosusrheumatoid arthritisCD4+ T follicular cellsclass-switched memory B cells\n==== Body\n1. Introduction\nHypogammaglobulinemia as a consequence of hematological malignancies, systemic disorders causing excessive loss or catabolism of immunoglobulins, viral infections or drugs, such as antiepileptic agents and anti-inflammatory medications, is defined as secondary hypogammaglobulinemia [1,2]. Its exclusion is required for the diagnosis of primary immunodeficiency disorders (PID) [3]. Common variable immunodeficiency (CVID) is the most common form of symptomatic PID [4,5]. Besides bacterial infections due to primary antibody failure, CVID may manifest with autoimmunity, granulomatous and/or lymphoproliferative disease [6]. Autoimmunity in CVID includes rheumatic disease, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS) [7,8,9]. These conditions necessitate anti-inflammatory treatment, which could lead to hypogammaglobulinemia even in the absence of a PID.\n\nSecondary hypogammaglobulinemia is distinguished from primary hypogammaglobulinemia on the basis of a patient’s medical history [2,3]. In other words, the diagnosis of a PID is clear in case the diagnosis of hypogammaglobulinemia precedes immunosuppressive treatment of autoimmune or lymphoproliferative conditions. However, autoimmunity or lymphoproliferative disease and introduction of immunosuppressive treatment could precede the diagnosis of hypogammaglobulinemia [8,9,10,11,12]. The relatively recent discovery of monogenic disorders manifesting as CVID and subsequent studies of cohorts of patients with common monogenic defects revealed that hypogammaglobulinemia in primary immunodeficiency may have a later onset than autoimmunity or lymphoproliferative disease, which can phenotypically prevail [13,14,15,16]. In that case, distinction between primary and secondary hypogammaglobulinemia may become a diagnostic challenge.\n\nAfter activating antigen recognition, progressive differentiation of T cells can be traced by characterizing CD45RA, CD27 and CD28 expression [17]. Upon activation, CD45RA switches to CD45RO, while CD28 and CD27 expression are lost sequentially in the course of T cell differentiation. In the case of CD8+ T cell differentiation, CD27−CD28− cells (late effector cells) display an effector-like phenotype, whereas CD27+CD28− cells (early effector cells) appear to have a recent replicative history and partial effector function [18]. Co-expression of CD31 and CD45RA defines recent thymic emigrants, associating with the presence of T cell receptor excision circles (TRECs) [19]. Follicular T cells are antigen-experienced CD4+ T cells, expressing CXCR5. These cells regulate antigen-specific activation of B cells in the context of a germinal center reaction but are also identified in peripheral blood [20]. After initial differentiation of B cells in the bone marrow, including the successful expression of a B cell receptor, transitional B cells emigrate from the bone marrow [21]. Expression of high levels of IgM and CD38 are used to characterize these cells. Naïve B cells are differentiated from memory ones on the basis of expression of CD27 and IgD [22]. CD21low B-cells are an innate-like memory B cell subset, found to be increased in autoimmune diseases such as SLE and RA as well as in CVID patients with autoimmune manifestations [23,24,25]. Peripheral blood lymphocyte phenotyping has been traditionally employed to evaluate immunodeficiency within PID and define disease subgroups [25]. According to the current diagnostic criteria of CVID, characterization of particular B and T cell subsets is required for the diagnosis of CVID and its differentiation from combined immunodeficiency (CID) [3].\n\nIn a previous study, secondary antibody deficiency as a consequence of glucocorticoid therapy with or without methotrexate has been associated with reduced naïve and transitional B cells as well as with reduced CD4 memory T cells [26]. Class-switched memory cells, which are found to be reduced in the majority of CVID patients, remained on the other hand unaffected [26,27]. Additional changes in peripheral lymphocyte subset counts, such as an increased numbers of transitional and CD21low B cells as well as elevated circulating CD4+ T follicular helper cells have been described in CVID [23,28,29]. So far, it remains unclear whether CVID-associated changes in peripheral lymphocyte counts could aid diagnostic distinction between primary and secondary hypogammaglobulinemia. Hence, we conducted a case-control study to examine the differences in peripheral B- and T- subpopulations between patients with secondary hypogammaglobulinemia due to immunosuppressive treatment of rheumatic disease and patients with CVID. Considering the identified differences, we propose criteria for the distinction of primary from secondary hypogammaglobulinemia and evaluate their diagnostic accuracy.\n\n2. Experimental Section\nThis single-center study included all rheumatic disease patients with secondary hypogammaglobulinemia visiting our Rheumatology outpatient clinic between December 2018 and April 2019. Visits of patients were scheduled approximately every 3 to 6 months and serum immunoglobulin (Ig) levels were measured at every visit. Secondary hypogammaglobulinemia has been defined as persistently reduced IgG (< 7 g/L) at time of the study and in follow-up visits during at least the year before the study, developing as a consequence of anti-inflammatory regimens including prednisolone, diverse disease-modifying anti-rheumatic drugs (DMARD) and biological therapies [30]. The systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K) and the disease activity score 28-c reactive protein score (DAS28-CRP) were calculated for SLE and RA patients, respectively, as described by others [31,32].\n\nPatients with secondary hypogammaglobulinemia were compared with PID patients having an appointment in the Clinical Immunology outpatient clinic of Hannover Medical University at the same time. PID has been diagnosed in the absence of evidence for secondary hypogammaglobulinemia, including a history of previous steroid treatment and classified according to the current ESID diagnostic criteria [3]. Results of phenotypic analysis of lymphocytes from patients with secondary hypogammaglobulinemia were compared with data from patients with PID. Patients’ demographic data and Ig values are shown in Table 1. Table 2 shows the rheumatic diseases of patients with secondary hypogammaglobulinemia, their current treatment, the treatment at the time point of diagnosis of hypogammaglobulinemia as well as all previous anti-inflammatory treatments.\n\nPhenotypic analysis of lymphocytes has been performed as described previously [33]. Briefly, peripheral blood mononuclear cells (PBMC) were obtained from heparinized blood samples of consenting patients by centrifugation over a Ficoll-Hypaque gradient. Phenotypic analyses were performed as multicolor immunofluorescence of PBMC, utilizing directly labeled monoclonal antibodies. 1 × 105 to 2 × 106 cells/well were incubated with murine monoclonal antibodies against the appropriate antigens at an optimal dilution for 20 min at 4° C. Nonspecific binding was eliminated by mixing the samples with a 1:5 solution of a commercial human IgG (Octagam; Octapharma, Lingolsheim, Germany). Samples were washed three times in phosphate buffered saline (PBS) supplemented with 0.5% bovine serum albumin (BSA) and at least 104 cells per appropriate gate were analyzed using a FACSCanto II flow cytometer with Cell Quest software (Becton Dickinson, Franklin Lakes, USA). Offline data analysis was performed by using FCS Express software V6 (Denovo Software, Pasadena, USA). Gating strategy to measure B cell and T cell subsets is shown in Figure S1 and Figure S2, respectively.\n\nThe following antibodies (all obtained from Biolegend, San Diego, USA, if not otherwise stated) were used for this study: CD3 PerCP (BD Pharmingen, Franklin Lakes, USA), CD3 PE, CD3 APC, CD4 FITC (Beckman Coulter, Brea, USA), CD4 PerCP, CD8 PE, CD8 PECy7, CD16 FITC, CD19 BV510, CD21 PE, CD24 FITC, CD27 FITC, CD28 BV421, CD31 FITC, CD38 PECy7, CD45R0 BV421, CD45RA BV510, CXCR5 PE, IgD PE, IgM Alexa Fluor 647. Each flow cytometric analysis was controlled with appropriate isotype-matched antibodies.\n\nDifferences between patients with primary and secondary hypogammaglobulinemia were evaluated with the Mann–Whitney test. Comparison of more than two groups was performed with the Kruskal–Wallis test. Correlation was evaluated with Spearman’s rho (r) analysis. For statistical calculation and diagrams we used GraphPad prism 5.00 (GraphPad, La Jolla, USA). Diagnostic value of studied lymphocyte subsets was evaluated with the “pROC” statistical package on R (v.3.6.0) [34].\n\nThis study was conducted in accordance with the Declaration of Helsinki and was approved from the Ethic committee of the Hannover Medical School (approval number: 8875 (21.03.14)). All patients signed an informed consent form.\n\n3. Results\nThirty-eight patients with persistent secondary hypogammaglobulinemia as a consequence of anti-inflammatory treatment of their rheumatic disease have been identified and compared with 38 patients with PID, visiting our outpatient clinics at same time. Most of them (n = 32) had CVID, four had IgG deficiency falling under unclassified antibody deficiency and two had CID with reduced IgG and IgA levels. Secondary hypogammaglobulinemia appears to have a later onset than PID, as its diagnosis was made at a later age than PID ((53.42 y (interquartile range, IQR: 47.5–61.25) Vs. 38.5 y (IQR: 24.75–53.75)) (Table 1). On average, secondary hypogammaglobulinemia was diagnosed 7.3 y (IQR: 1–10.75) after the first diagnosis of rheumatic disease. Patients with secondary hypogammaglobulinemia had considerably higher levels of all measured Ig classes at diagnosis of hypogammaglobulinemia. There were 8/38 patients with secondary hypogammaglobulinemia and who had low IgA in addition to low IgG and 3/38 had low IgM. In contrast to the PID patients, who nearly all (37/38) were receiving immunoglobulin replacement treatment, only a minority of rheumatic patients with hypogammaglobulinemia required immunoglobulin replacement, which comes in accordance with the significantly higher IgG values in the case of secondary hypogammaglobulinemia. The majority of studied patients with secondary hypogammaglobulinemia had received more than one anti-inflammatory drug in addition to prednisolone, including DMARDs and biologics in combination with prednisolone (Table 2). Most rheumatic patients (34/38) were diagnosed with hypogammaglobulinemia while treated with anti-inflammatory regimens based on conventional DMARDs. There were 4/32 patients receiving oral prednisolone monotherapy and 13/38 developed hypogammaglobulinemia as a consequence of the first and only DMARD, which in most cases (11/13) was methotrexate. Most rheumatic patients displayed no significant disease activity at time measurement of peripheral lymphocyte subsets. SLE patients had a mean SLEDAI-2K score of 1.8 (IQR: 0.75–2.5). Except for two, all SLE patients had low-disease activity (SLEDAI-2K ≤ 2) considering the serologic parameters C3, C4 and anti–double-stranded DNA antibodies. The same holds true for the majority of studied patients with RA (9/11), who were in remission (DAS28-CRP ≤ 2.6, mean DAS28-CRP: 2.1, IQR: 1.6–2.6). Furthermore, nearly all studied patients (36/38) were receiving at time of testing no or a low-dosed prednisolone (≤5 mg/d, patient 11 was receiving 10 mg/d prednisolone and was on tapering and patient 13 had a maintenance dose of 7.5 mg/d).\n\nComparison of T cell counts in patients with PID and secondary hypogammaglobulinemia revealed a significantly higher percentage of memory CD4+ T cells and CD4+ T follicular cells in cases of primary hypogammaglobulinemia than in those with secondary (Figure 1). No substantial differences were observed for the rest of evaluated T cell subsets. This difference in proportion of memory CD4+ T cells and CD4+ T follicular cells among CD4+ T cells corresponded to increased absolute cell counts in the PID group as compared to secondary hypogammaglobulinemia (Figure S3). With respect to the B cell subsets, we found an increased proportion of naïve, transitional, plasma and CD21low B cells in peripheral lymphocytes from PID patients as compared to patients with secondary hypogammaglobulinemia (Figure 2). In contrast, the proportions of memory/marginal zone B cells and cl. sw. memory B cells were significantly reduced in cases of PID. With the exception of memory/marginal B cells, absolute counts for B cell subsets corresponded with changes in their proportions among B cells (Figure S3). Significantly lower levels of all studied immunoglobulin classes in patients with primary hypogammaglobulinemia than those with secondary could be the consequence of differences in the composition of peripheral lymphocyte subsets. To test this, we evaluated if immunoglobulin levels associate with the proportions of lymphocytes subsets. This revealed significant association of IgG or IgA values with the percentages of cl. sw. memory B cells in both patients with primary and secondary hypogammaglobulinemia (Table S1), suggesting that lower immunoglobulin values may be the consequence of alterations within the B cell compartment. However, both in case of PID and secondary hypogammaglobulinemia patients, T cell subset proportions did not associate with immunoglobulin levels (Table S1). Six among the PID patients were receiving anti-inflammatory drugs at the time of evaluation of their lymphocyte subset counts (Table S2). All six of them displayed reduced percentages of class-switched memory B cell counts and the majority had increased CD4+ T follicular cells, similar to the majority of PID patients, who were receiving no anti-inflammatory drugs. This suggests that changes in lymphocyte subsets in PID are rather related to disease-intrinsic mechanisms and are not the consequence of anti-inflammatory drugs, though the limited number of PID patients as well as the diversity of anti-inflammatory drugs does not allow firm conclusions concerning the way anti-inflammatory medications influence the lymphocyte phenotype.\n\nMost studied patients with secondary hypogammaglobulinemia were diagnosed with either RA (11/38) or SLE (10/38). Despite the limited number of patients, separate analysis of lymphocyte subsets in patients with RA and secondary hypogammaglobulinemia revealed significantly reduced proportions of memory CD4+ and CD4+ follicular T cells and an increased percentage of class-switched memory B cells as compared with the PID patients (Figure 3). In case of SLE changes in memory, CD4+ and CD4+ follicular T cells did not reach significance, likely due to the small number of tested patients. However, within the B cells, SLE patients had significantly higher proportions of memory/marginal zone B cells and class-switched B and lower naïve B cells, compared to PID patients (Figure 3). As mentioned previously, the secondary hypogammaglobulinemia group included 11 patients, who each developed hypogammaglobulinemia as a consequence of methotrexate in combination with prednisolone. All those patients achieved remission, allowing prednisolone tapering to 0–5 mg/day. Aiming at identifying a likely drug-specific effect on peripheral T and B cell counts, we performed separate analysis of the relatively sizeable group of patients on methotrexate, which revealed similar differences to the ones described previously. In particular, increased proportions of CD4+ T follicular cells, memory CD4+ T cells as well as class-switched memory B cells and reduced naïve B cells were found in the methotrexate-treated patients as compared to the PID group (Figure S4). Differences for transitional and CD21low B cells did not reach significance, likely due to the limited number of methotrexate treated patients.\n\nOverall, lymphocyte phenotyping in patients with primary and secondary hypogammaglobulinemia identified a differential B and T cell subset distribution (Figure 4A). To evaluate the diagnostic accuracy of peripheral T and B cell subsets in discriminating primary from secondary hypogammaglobulinemia, values for each of the significantly changed parameters (i.e., the proportions of memory CD4+ T cells, CD4+ T follicular cells, naïve B cells, memory/marginal zone B cells, class-switched memory B cells, transitional B cells, IgM+/- plasma cells and CD21low B cells) were ranked, fitted into logistic regression and plotted into receiver operating characteristic (ROC) curves (Figure S5). Optimal threshold values for distinguishing PID from secondary hypogammaglobulinemia for each parameter and the corresponding area under the curve (AUC) values for each of the aforementioned parameters was calculated (Figure S5). The proportions of memory CD4+ T cells and CD4+ T follicular cells, as well as those of naïve B cells, class-switched memory B cells and CD21low B cells, displayed adequate but still low sensitivity and specificity for the discrimination of primary from secondary hypogammaglobulinemia. Especially, the specificity values matching calculated threshold values were unsatisfactory, and were therefore adapted, to yield specificity higher than 85% (Table 3). Adapted threshold values and the respective proposed diagnostic criteria as well as their fulfilment by all studied patients with hypogammaglobulinemia are presented in Figure 4 (B and C). This adaptation of threshold values and the consequent increased specificity comes at the expense of a further reduction in sensitivity. Table 3 shows the diagnostic efficacy of the proposed diagnostic criteria in distinguishing primary from secondary hypogammaglobulinemia. The relatively poor performance of every single proposed criterion which can, however, be offset by an alternative consideration of both of the two better performing diagnostic parameters, which were the proportion of CD4+ T follicular cells and class-switched memory B cells. Alternative consideration of these two lymphocyte subsets displayed the best diagnostic efficacy among all other possible criteria combinations and could discriminate primary from secondary hypogammaglobulinemia with a specificity of 94.74% (c.i.: 88.25–99.36) and a sensitivity of 76.32% (59.76–88.56) (Table 3).\n\n4. Discussion\nA common side effect of anti-inflammatory regimens including corticosteroids, DMARD and biologics is hypogammaglobulinemia, which sometimes associates with clinically evident immunodeficiency [1,2]. In the present study approximately 20% of patients with secondary hypogammaglobulinemia displayed recurrent infections and were treated with immunoglobulin replacement. This—according to the literature—high proportion of patients on immunoglobulin replacement most likely reflects the fact that this study was conducted in a tertiary care center, where such patients are often referred to [30]. Furthermore, consistent with previous studies, suggesting the safety of most biologics with respect to the risk of infections [35,36,37], all studied rheumatic patients were diagnosed with hypogammaglobulinemia while treated with anti-inflammatory regimens containing conventional DMARDs.\n\nPID and especially CVID may manifest as autoimmune diseases [6,7,8,9], which necessitates anti-inflammatory treatment with drugs that can result in hypogammaglobulinemia, independently of an underlying PID [2]. Measurement of immunoglobulin levels before starting an anti-inflammatory treatment, likely to cause hypogammaglobulinemia is therefore extremely important, as it may identify a preexisting hypogammaglobulinemia. The latter would be a per se primary hypogammaglobulinemia, falling under PID. Unfortunately, serum immunoglobulin levels before starting anti-inflammatory regiment are rarely tested by treating physicians, which may make the discrimination between primary and secondary hypogammaglobulinemia challenging. Furthermore, primary immunodeficiency and especially in CVID can be progressive and hypogammaglobulinemia may be absent in patients whose first manifestation is autoimmunity [38]. Our data suggest that hypogammaglobulinemia secondary to anti-inflammatory drugs differs from PID. In contrast to studied PID patients, the great majority of whom had combined IgG and IgA or IgM deficiency, the majority of patients with secondary hypogammaglobulinemia had an isolated IgG deficiency, which comes in accordance with a previous study on hypogammaglobulinemia in patients with giant cell arteritis or polymyalgia rheumatic [26]. However, approximately one fourth of studied patients with secondary hypogammaglobulinemia displayed a concomitant reduction of IgA and/or IgM, suggesting that isolated IgG deficiency cannot be a stringent criterion for discriminating primary from secondary hypogammaglobulinemia. Characterization of lymphocyte subsets among PID patients revealed abnormalities both within the B and the T cells. In case of B cells, in accordance with previous reports, we identify changes, such as the expansion of CD21low B cells and the reduction of switched memory B cells that have been described in CVID [25]. With respect to the T cells, our data reveal expanded peripheral CD4+ T follicular helper cells, as described in other reports [29,39].\n\nFor rheumatic disease, on the other hand, a broad heterogeneity within B and T cell subsets has been described [40]. Furthermore, changes in lymphocyte subsets in rheumatic disease reflect not only disease-specific immune dysregulation but also the effect of anti-inflammatory regimens, which may be different for different drugs. Several studies are aimed at addressing the effect of single-drug regimens on peripheral lymphocyte subsets. However, discriminating the effect of single DMARD or biologics is difficult, as most patients had received glucocorticoids and/or other anti-inflammatory drugs. Glucocorticoids have been shown to affect lymphocyte trafficking and survival [41]. The selective decrease in transitional and naïve B cells in patients under glucocorticoid has been suggested to stem from increased apoptosis of human bone marrow progenitors [42]. Methotrexate can induce a reduction of transitional B cells, as well [43]. Within the T cells, methotrexate has been shown to induce an expansion of CD4+ T follicular helper cells. Several studies have evaluated the effect of biologics on peripheral lymphocyte subsets. For example, BAFF blockade in SLE affects non-memory B cells, inducing a reduction in transitional and naïve B cells [44]. Etanercept treatment specifically induced a reduction in IgM+ memory B cells in a cohort of patients with juvenile idiopathic arthritis (JIA) [43]. Besides B cell depletion, rituximab induced a depletion of CD4+ T cells in patients with RA, which was associated with clinical response [45]. Studies on peripheral lymphocyte subsets in rheumatic diseases such as rheumatoid arthritis, Sjögren’s syndrome, SLE and spondylarthritis have identified changes both within the T and B cells and in some cases associated those changes with disease activity or with phenotypic variations [46,47,48,49,50,51]. Overall, B and T cell subset abnormalities within rheumatic diseases, their association with disease activity or particular disease subgroups and/or anti-inflammatory drugs remain to be better elucidated in larger longitudinal cohorts including in the treatment of naïve patients.\n\nHere, despite the heterogeneity of the secondary hypogammaglobulinemia group, including different rheumatic diseases and anti-inflammatory regimens, a comparison of lymphocyte subsets between patients with secondary hypogammaglobulinemia and those with PID revealed significant differences. Highly significant were the differences in the proportion of class-switched memory B and CD4+ T follicular T cells, which were matched to abnormally low class-switched memory and abnormally high CD4+ T follicular T cell percentages, suggesting the prominent disease-intrinsic effect on peripheral lymphocyte counts in PID. Separate analysis of patients with RA or SLE confirmed differences within T or B cell subsets, despite the limited number of studied patients. With respect to distinguishing primary from secondary hypogammaglobulinemia, considering changes in single cell subsets was of limited diagnostic efficacy. The proportion of class-switched memory cells and CD4+ T follicular cells displayed the best performance in terms of specificity, which however comes at the expense of low sensitivity. The latter could be considerably improved by collective consideration of class-switched memory and CD4+ T follicular cells.\n\nIn summary, peripheral lymphocyte subset counts and especially measurement of CD4+ T follicular helper cells and class-switched memory B cell counts could aid differentiation of primary from secondary hypogammaglobulinemia. Confirmation of our findings in additional cohorts of patients with hypogammaglobulinemia is needed to establish the diagnostic value of lymphocyte phenotyping in resolving the diagnostic dilemma between primary and secondary hypogammaglobulinemia. Studies addressing the effects of underlying rheumatic diseases and anti-inflammatory drugs on peripheral lymphocyte subsets could lead to the identification of disease- or drug-specific changes, which may further improve the diagnostic efficacy of T and B cell subset counts in differentiating PID from secondary hypogammaglobulinemia.\n\nAcknowledgments\nWe thank all nurses and physicians of the outpatient clinics of the department of Clinical Immunology and Rheumatology of the Hannover Medical School for collecting blood samples and informing the patients about the study. \n\nSupplementary Materials\nThe following are available online at https://www.mdpi.com/2077-0383/9/4/1049/s1, Figure S1: Strategy to measure B cell subsets. After doublet exclusion (not shown) and gating on lymphocytes based on SSC and FSC, we selected CD19+ B cells with subsequent gating based on IgD, IgM, CD27 and CD38 expression, as indicated; Figure S2: Strategy to measure T cell subsets. After doublet exclusion (not shown) and gating on lymphocytes based on SSC and FSC, we selected CD3+ T cells with subsequent gating based on TCR2, CD4, CD8, CD27, CD28, CXCR5, CD45RA and CD45RO expression; Figure S3: Comparison of absolute T cell (A) and B cell subset counts (B) in patients with primary (1, n = 38) and secondary hypogammaglobulinemia (2, n = 38 for T cell subsets and n = 37 for B cell subsets, as a patient’s (pat.nr. 37) B cells could not be differentiated due to their low number; * p < 0.05; ** p < 0.01; *** p < 0.001); Figure S4: Comparison of B and T cell subsets in patients with primary (1, n = 38) and secondary hypogammaglobulinemia due to methotrexate (MTX, n = 11; * p < 0.05; ** p < 0.01; *** p < 0.001); Figure S5: Receiver operating characteristic (ROC) curves and the corresponding area under the curve (AUC) values for the indicated B or T subset counts; Table S1: Association of lymphocyte subset percentage counts with immunoglobulin values in patients with primary (1) and secondary (2) hypogammaglobulinemia; Table S2: lymphocyte subset counts of patients with PID on anti-inflammatory regiments.\n\nClick here for additional data file.\n\n Author Contributions\nConceptualization, G.S. and F.A.; methodology, G.S. and F.A.; ROC analysis, I.R.A.; data collection and validation, A.J. and H.E.; analysis of flow cytometric data, D.E., S.B. and R.J.; statistical analysis, A.J., H.E., I.R.A. and G.S.; writing—original draft preparation, G.S. and F.A.; writing—review and editing, all authors; visualization, G.S. and I.R.A.; supervision, G.S., F.A. and R.E.S.; project administration, G.S. and F.A.; funding acquisition, T.W., R.E.S., G.S. and F.A. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nG.S. and A.J. received funding from the Young Academy Clinician/Scientist program of Hannover Medical School, Germany. I.A. was supported by the German Academic Exchange Service (DAAD), the Hannover Biomedical Research School (HBRS) and the Center for Infection Biology (ZIB). All authors and this project are supported by the German Center for Infection Research (DZIF TTU 07.801), the cluster of excellence RESIST (EXC 2155) and the Rosemarie-Germscheid foundation.\n\nConflicts of Interest\nThe authors declare no conflict of interest. \n\nFigure 1 Comparison of T cell subsets in patients with primary (1, n = 38) and secondary (2, n = 38) hypogammaglobulinemia. Normal range values lie within the doted lines (*** p < 0.001).\n\nFigure 2 Comparison of B cell subsets in patients with primary (1, n = 38) and secondary (2, n = 37) hypogammaglobulinemia. Normal range values lie within the doted lines (* p < 0.05; *** p < 0.001).\n\nFigure 3 Comparison of T and B cell subsets in patients with primary (1) and secondary hypogammaglobulinemia with RA (n = 11 and n = 10 in case of B cell subsets, as a patient’s (pat. nr. 37) B cells could not be differentiated due to their very low count) and SLE (n = 10). (A) Normal range values lie within the doted lines (* p < 0.05; *** p < 0.001).\n\nFigure 4 Diagnostic criteria for distinguishing primary from secondary hypogammaglobulinemia based in the differential B and T cell subset distribution in patients with primary immunodeficiency disorders (PID) as compared to patients with rheumatic disease and secondary hypogammaglobulinemia. (A) Heat map showing percentages of B and T cell subsets in all studied patients and highlighting their differential distribution. (B) Schematic representation of fulfilled diagnostic criteria (marked with blue) discriminating PID from secondary hypogammaglobulinemia. (C) Proposed diagnostic criteria for distinguishing primary from secondary hypogammaglobulinemia and cross tables showing all studied patients fulfilling or not fulfilling each time indicated criterion.\n\njcm-09-01049-t001_Table 1Table 1 Characteristics of studied patients with primary and secondary hypogammaglobulinemia.\n\n\n\tPrimary Hypogammaglobulinemia (1)\tSecondary Hypogammaglobulinemia (2)\tp - Value\t\nNumber (n)\t38\t38\t\n\t\nMale Gender (n (%))\t13 (34.21)\t10 (26.32)\tns\t\nCurrent Age (Mean (IQR))\t51.82 y (37.5–60)\t57.66 y (52–66.25)\tns\t\nAge at Diagnosis of Hypogammaglobulinemia (Mean (IQR))\t38.5 y (24.75–53.75)\t53.42 y (47.5–61.25)\t*** (<0.0001)\t\nPatients Treated with Immunoglobulin Replacement (n (%))\t37 (97.37)\t7 (18.42)\t*** (<0.0001)\t\nIgG (Mean (IQR))\t2.74 g/L (0.71–4.6)\t5.63 g/L (4.99–6.22)\t*** (<0.0001)\t\nIgA (Mean (IQR))\t0.45 g/L (0.04–0.48)\t1.45 g/L (0.77–1.97)\t*** (<0.0001)\t\nIgM (Mean (IQR))\t0.69 g/L (0.18–0.96)\t0.83 g/L (0.52–1.05)\t*** (0.0003)\t\nAbsolute Lymphocyte Count (Mean (IQR))\t1653 (1019–2080)\t1469 (1011–1838)\tns\t\nLymphocyte Percentage (Mean (IQR))\t22.82 (16.75–28.25)\t20.92 (13–27)\tns\t\nIQR, interquartile range; ns, non-significant; y, years.\n\njcm-09-01049-t002_Table 2Table 2 Secondary hypogammaglobulinemia patients’ rheumatic disease, current and previous treatments. Prednisolone treatment is noted in case it is the only treatment.\n\nPat. Nr.\tRheumatic Disease\tCurrent Therapy\tTherapy at Diagnosis of Hypogammaglobulinemia\tPrevious Therapies\t\n1\tperSpA\tMTX\tMTX\t\n\t\n2\tRA\tMTX\tMTX\t\n\t\n3\taxSpA\tadalimumab\tMTX\tMTX, SSZ\t\n4\tAOSD\tprednisolone\tprednisolone\t\n\t\n5\tSSc\tMTX\tMTX\t\n\t\n6\tperSpA\tMTX + etanercept\tMTX + SSZ\tMTX, SSZ, LFN\t\n7\tSLE\tMMF\tCYC\tCYC, HCQ\t\n8\tSLE\tMTX\tMTX\tHCQ\t\n9\tSLE\tMMF\tMMF\t\n\t\n10\tRA\tMTX\tMTX\tHCQ, SSZ\t\n11\tSLE\tCYC\tCYC\tAZA, MMF, HCQ\t\n12\tSLE\tCYC\tCYC\tAZA, MMF, HCQ\t\n13\tRA\tTCZ\tMTX + RTX\tMTX, LFN, SSZ, gold, adalimumab, infliximab\t\n14\tRA\tMTX\tMTX\t\n\t\n15\tGCA\tMTX\tMTX\t\n\t\n16\tRA\tMTX + etanercept\tMTX\tMTX, HCQ\t\n17\tSLE\tLFN + HCQ\tMTX + HCQ\tAZA, MTX, HCQ\t\n18\taxSpA\tMTX + infliximab\tMTX + infliximab\tadalimumab\t\n19\tSS\tprednisolone\tprednisolone\t\n\t\n20\tRA\tMTX\tMTX\t\n\t\n21\tSS\tMMF\tMMF\tCYC, AZA\t\n22\tPG\tprednisolone\tprednisolone\t\n\t\n23\tAOSD\tprednisolone\tprednisolone\t\n\t\n24\tSS\tMTX\tMTX\t\n\t\n25\tSLE\tMMF + HCQ\tMMF\tMMF\t\n26\tGCA\tMTX\tMTX\t\n\t\n27\tSS\tMTX\tMTX\t\n\t\n28\tSLE\tAZA + HCQ\tAZA + HCQ\tMTX\t\n29\tRA\tMTX\tMTX\t\n\t\n30\tRA\tMTX\tMTX\t\n\t\n31\tRA\tTCZ\tSSZ + MTX\tMTX, SSZ, LFN, adalimumab, abatacept\t\n32\tperSpA\tadalimumab\tSSZ + MTX\tSSZ, MTX, HCQ\t\n33\tSLE\tAZA\tAZA\tHCQ\t\n34\tSS\tAZA + HCQ\tAZA + HCQ\t\n\t\n35\tSS\tAZA\tAZA\t\n\t\n36\tSLE\tMMF\tMMF\tHCQ\t\n37\tRA\tMTX + RTX\tMTX + RTX\tLFN, MTX, HCQ, SSZ\t\n38\tRA\tMTX + adalimumab\tMTX + RTX\tTCZ, etanercept, abatacept, SSZ, LFN, HCQ, MTX\t\nAOSD, adult-onset Still’s disease; axSpA, axial spondyloarthritis; AZA, azathioprine; CYC, cyclophosphamide; GCA, giant cell arteritis; HCQ, hydroxychloroquine; LFN, leflunomide; MMF, mycophenolate mofetil; MTX, methotrexate; pat. nr., patient number; perSpA, peripheral spondyloarthritis; PG, pyoderma gangrenosum; RA, rheumatoid arthritis; RTX, rituximab; SLE, systemic lupus erythematosus; SS, Sjögren’s syndrome; SSc, systemic sclerosis; SSZ, sulfasalazine.\n\njcm-09-01049-t003_Table 3Table 3 Diagnostic efficacy of peripheral lymphocyte subset counts for differentiation of primary from secondary hypogammaglobulinemia.\n\nProposed\nDiagnostic Criterion\tI. Naive B Cells\n>80 (%B Cells)\tII. cl. sw. Memory B Cells <2.2 (%B Cells)\tIII. CD21low CD38low B Cells\n>10 (%B Cells)\tIV. Memory CD4+ T Cells >70 (%CD4+ T Cells)\tV. CD4+ T Follicular Cells >20 (%CD4+ T Cells)\tVI. At Least One of Criteria II. or V\t\nSensitivity (%)\t52.63\t63.16\t31.58\t39.47\t47.37\t76.32\t\n95% c.i.\t35.82–69.02\t45.99–78.19\t17.5–48.65\t24.04–56.61\t30.98–64.18\t59.76–88.56\t\nSpecificity (%)\t86.49\t94.59\t94.59\t92.11\t100\t94.74\t\n95% c.i.\t71.23–95.46\t81.81–99.34\t81.81–99.34\t78.62–98.34\t90.75–100.0\t88.25–99.36\t\nPPV\t80\t92.31\t85.71\t83.33\t100\t93.55\t\n95% c.i.\t59.3–93.17\t74.87–99.05\t57.19–98.22\t58.58–96.42\t81.47–100.0\t78.58–99.21\t\nNPV\t64\t71.43\t57.38\t60.34\t65.52\t80\t\n95% c.i.\t49.19–77.08\t56.74–83.42\t44.06–69.96\t46.64–72.95\t51.88–77.51\t65.4–90.42\t\np - value\t0.0005\t<0.0001\t0.0062\t0.0024\t<0.0001\t<0.0001\t\nc.i., confidence interval; PPV, positive predictive value; NPV, negative predictive value.\n==== Refs\nReferences\n1. Jolles S. Chapel H. Litzman J. When to initiate immunoglobulin replacement therapy (IGRT) in antibody deficiency: A practical approach Clin. Exp. Immunol. 2017 188 333 341 10.1111/cei.12915 28000208 \n2. Patel S.Y. Carbone J. Jolles S. The Expanding Field of Secondary Antibody Deficiency: Causes, Diagnosis, and Management Front. Immunol. 2019 10 33 10.3389/fimmu.2019.00033 30800120 \n3. Seidel M.G. Kindle G. Gathmann B. Quinti I. Buckland M. van Montfrans J. Scheible R. Rusch S. Gasteiger L.M. Grimbacher B. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity J. Allergy Clin. Immunol. Pract. 2019 7 1763 1770 10.1016/j.jaip.2019.02.004 30776527 \n4. Ameratunga R. Woon S.T. Perspective: Evolving Concepts in the Diagnosis and Understanding of Common Variable Immunodeficiency Disorders (CVID) Clin. Rev. Allergy Immunol. 2019 10.1007/s12016-019-08765-6 31720921 \n5. El-Helou S.M. Biegner A.K. Bode S. Ehl S.R. Heeg M. Maccari M.E. Ritterbusch H. Speckmann C. Rusch S. Scheible R. The German National Registry of Primary Immunodeficiencies (2012-2017) Front. Immunol. 2019 10 1272 10.3389/fimmu.2019.01272 31379802 \n6. Chapel H. Lucas M. Lee M. Bjorkander J. Webster D. Grimbacher B. Fieschi C. Thon V. Abedi M.R. Hammarstrom L. Common variable immunodeficiency disorders: Division into distinct clinical phenotypes Blood 2008 112 277 286 10.1182/blood-2007-11-124545 18319398 \n7. Fernández-Castro M. Mellor-Pita S. Citores M.J. Muñoz P. Tutor-Ureta P. Silva L. Vargas J.A. Yebra-Bango M. Andreu J.L. Common variable immunodeficiency in systemic lupus erythematosus Semin. Arthritis Rheum. 2007 36 238 245 10.1016/j.semarthrit.2006.09.005 17276173 \n8. Blazina Š. Markelj G. Jeverica A.K. Toplak N. Bratanič N. Jazbec J. Kopač P. Debeljak M. Ihan A. Avčin T. Autoimmune and Inflammatory Manifestations in 247 Patients with Primary Immunodeficiency-a Report from the Slovenian National Registry J. Clin. Immunol. 2016 36 764 773 10.1007/s10875-016-0330-1 27582173 \n9. Gutierrez M.J. Sullivan K.E. Fuleihan R. USIDNET Consortium Clifton O Bingham 3rd Phenotypic characterization of patients with rheumatologic manifestations of common variable immunodeficiency Semin. Arthritis Rheum. 2018 48 318 326 10.1016/j.semarthrit.2018.02.013 29599028 \n10. Hanitsch L.G. Wittke K. Stittrich A.B. Volk H.D. Scheibenbogen C. Interstitial Lung Disease Frequently Precedes CVID Diagnosis J. Clin. Immunol. 2019 39 849 851 10.1007/s10875-019-00708-2 31637570 \n11. Sogkas G. Fedchenko M. Dhingra A. Jablonka A. Schmidt R.E. Atschekzei F. Primary immunodeficiency disorder caused by phosphoinositide 3-kinase δ deficiency J. Allergy Clin. Immunol. 2018 142 1650 1653 10.1016/j.jaci.2018.06.039 30040974 \n12. Schröder C. Sogkas G. Fliegauf M. Dörk T. Liu D. Hanitsch L.G. Steiner S. Scheibenbogen C. Jacobs R. Grimbacher B. Late-Onset Antibody Deficiency Due to Monoallelic Alterations in NFKB1 Front. Immunol. 2019 10 2618 10.3389/fimmu.2019.02618 31803180 \n13. Schwab C. Gabrysch A. Olbrich P. Patiño V. Warnatz K. Wolff D. Hoshino A. Kobayashi M. Imai K. Takagi M. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects J. Allergy Clin. Immunol. 2018 142 1932 1946 10.1016/j.jaci.2018.02.055 29729943 \n14. Fliegauf M. Bryant V.L. Frede N. Slade C. Woon S.T. Lehnert K. Winzer S. Bulashevska A. Scerri T. Leung E. Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency Am. J. Hum. Genet. 2015 97 389 403 10.1016/j.ajhg.2015.07.008 26279205 \n15. Lawless D. Geier C.B. Farmer J.R. Lango Allen H. Thwaites D. Atschekzei F. Brown M. Buchbinder D. Burns S.O. Butte M.J. Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency J. Allergy Clin. Immunol. 2018 141 2303 2306 10.1016/j.jaci.2018.02.007 29477728 \n16. Fabre A. Marchal S. Barlogis V. Mari B. Barbry P. Rohrlich P.S. Forbes L.R. Vogel T.P. Giovannini-Chami L. Clinical Aspects of STAT3 Gain-of-Function Germline Mutations: A Systematic Review J. Allergy Clin. Immunol. Pract. 2019 7 1958 1969 10.1016/j.jaip.2019.02.018 30825606 \n17. Bateman E.A. Ayers L. Sadler R. Lucas M. Roberts C. Woods A. Packwood K. Burden J. Harrison D. Kaenzig N. T cell phenotypes in patients with common variable immunodeficiency disorders: Associations with clinical phenotypes in comparison with other groups with recurrent infections Clin. Exp. Immunol. 2012 170 202 211 10.1111/j.1365-2249.2012.04643.x 23039891 \n18. Romero P. Zippelius A. Kurth I. Pittet M.J. Touvrey C. Iancu E.M. Corthesy P. Devevre E. Speiser D.E. Rufer N. Four functionally distinct populations of human effector-memory CD8+ T lymphocytes J. Immunol. 2007 178 4112 4119 10.4049/jimmunol.178.7.4112 17371966 \n19. Junge S. Kloeckener-Gruissem B. Zufferey R. Keisker A. Salgo B. Fauchere J.C. Scherer F. Shalaby T. Grotzer M. Siler U. Correlation between recent thymic emigrants and CD31+ (PECAM-1) CD4+ T cells in normal individuals during aging and in lymphopenic children Eur. J. Immunol. 2007 37 3270 3280 10.1002/eji.200636976 17935071 \n20. Fazilleau N. Mark L. McHeyzer-Williams L.J. McHeyzer-Williams M.G. Follicular helper T cells: Lineage and location Immunity 2009 30 324 335 10.1016/j.immuni.2009.03.003 19303387 \n21. Martin V.G. Wu Y.B. Townsend C.L. Lu G.H. O’Hare J.S. Mozeika A. Coolen A.C. Kipling D. Fraternali F. Dunn-Walters D.K. Transitional B Cells in Early Human B Cell Development—Time to Revisit the Paradigm? Front. Immunol. 2016 7 546 10.3389/fimmu.2016.00546 27994589 \n22. Wu Y.C. Kipling D. Dunn-Walters D.K. The relationship between CD27 negative and positive B cell populations in human peripheral blood Front. Immunol. 2011 2 81 10.3389/fimmu.2011.00081 22566870 \n23. Rakhmanov M. Keller B. Gutenberger S. Foerster C. Hoenig M. Driessen G. van der Burg M. van Dongen J.J. Wiech E. Visentini M. Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells Proc. Natl. Acad. Sci. USA 2009 106 13451 13456 10.1073/pnas.0901984106 19666505 \n24. Warnatz K. Wehr C. Dräger R. Schmidt S. Eibel H. Schlesier M. Peter H.H. Expansion of CD19(hi)CD21(lo/neg) B cells in common variable immunodeficiency (CVID) patients with autoimmune cytopenia Immunobiology 2002 206 502 513 10.1078/0171-2985-00198 12607725 \n25. Wehr C. Kivioja T. Schmitt C. Ferry B. Witte T. Eren E. Vlkova M. Hernandez M. Detkova D. Bos P.R. The EUROclass trial: Defining subgroups in common variable immunodeficiency Blood 2008 111 77 85 10.1182/blood-2007-06-091744 17898316 \n26. Wirsum C. Glaser C. Gutenberger S. Keller B. Unger S. Voll R.E. Vach W. Ness T. Warnatz K. Secondary Antibody Deficiency in Glucocorticoid Therapy Clearly Differs from Primary Antibody Deficiency J. Clin. Immunol. 2016 36 406 412 10.1007/s10875-016-0264-7 26980224 \n27. Warnatz K. Denz A. Dräger R. Braun M. Groth C. Wolff-Vorbeck G. Eibel H. Schlesier M. Peter H.H. Severe deficiency of switched memory B cells (CD27(+)IgM(-)IgD(-)) in subgroups of patients with common variable immunodeficiency: A new approach to classify a heterogeneous disease Blood 2002 99 1544 1551 10.1182/blood.V99.5.1544 11861266 \n28. Vlková M. Fronková E. Kanderová V. Janda A. Ruzicková S. Litzman J. Sedivá A. Kalina T. Characterization of lymphocyte subsets in patients with common variable immunodeficiency reveals subsets of naive human B cells marked by CD24 expression J. Immunol. 2010 185 6431 6438 10.4049/jimmunol.0903876 21041728 \n29. Coraglia A. Galassi N. Fernández Romero D.S. Juri M.C. Felippo M. Malbrán A. de Bracco M.M. Common Variable Immunodeficiency and Circulating TFH J. Immunol. Res. 2016 2016 4951587 10.1155/2016/4951587 27069935 \n30. Compagno N. Malipiero G. Cinetto F. Agostini C. Immunoglobulin replacement therapy in secondary hypogammaglobulinemia Front. Immunol. 2014 5 626 10.3389/fimmu.2014.00626 25538710 \n31. Tselios K. Gladman D.D. Touma Z. Su J. Anderson N. Urowitz M.B. Clinical Remission and Low Disease Activity Outcomes Over 10 Years in Systemic Lupus Erythematosus Arthritis Care Res. 2019 71 822 828 10.1002/acr.23720 30055090 \n32. Sheehy C. Evans V. Hasthorpe H. Mukhtyar C. Revising DAS28 scores for remission in rheumatoid arthritis Clin. Rheumatol. 2014 33 269 272 10.1007/s10067-013-2468-z 24384827 \n33. Sogkas G. Adriawan I.R. Ringshausen F.C. Baumann U. Schröder C. Klemann C. von Hardenberg S. Schmidt G. Bernd A. Jablonka A. A novel NFKBIA variant substituting serine 36 of IκBα causes immunodeficiency with warts, bronchiectasis and juvenile rheumatoid arthritis in the absence of ectodermal dysplasia Clin. Immunol. 2020 210 108269 10.1016/j.clim.2019.108269 31683054 \n34. Robin X. Turck N. Hainard A. Tiberti N. Lisacek F. Sanchez J.C. Müller M. pROC: An open-source package for R and S+ to analyze and compare ROC curves BMC Bioinform. 2011 12 77 10.1186/1471-2105-12-77 \n35. Sepriano A. Kerschbaumer A. Smolen J.S. van der Heijde D. Dougados M. van Vollenhoven R. McInnes I.B. Bijlsma J.W. Burmester G.R. de Wit M. Safety of synthetic and biological DMARDs: A systematic literature review informing the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis Ann. Rheum. Dis. 2020 10.1136/annrheumdis-2019-216653 \n36. Grøn K.L. Glintborg B. Nørgaard M. Mehnert F. Østergaard M. Dreyer L. Krogh N.S. Hetland M.L. Overall infection risk in rheumatoid arthritis during treatment with abatacept, rituximab and tocilizumab; an observational cohort study Rheumatology 2019 10.1093/rheumatology/kez530 \n37. Cobo-Ibáñez T. Descalzo M.Á. Loza-Santamaría E. Carmona L. Muñoz-Fernández S. Serious infections in patients with rheumatoid arthritis and other immune-mediated connective tissue diseases exposed to anti-TNF or rituximab: Data from the Spanish registry BIOBADASER 2.0 Rheumatol. Int. 2014 34 953 961 10.1007/s00296-014-2945-y 24414744 \n38. Ameratunga R. Ahn Y. Steele R. Woon S.T. The Natural History of Untreated Primary Hypogammaglobulinemia in Adults: Implications for the Diagnosis and Treatment of Common Variable Immunodeficiency Disorders (CVID) Front. Immunol. 2019 10 1541 10.3389/fimmu.2019.01541 31379811 \n39. Turpin D. Furudoi A. Parrens M. Blanco P. Viallard J.F. Duluc D. Increase of follicular helper T cells skewed toward a Th1 profile in CVID patients with non-infectious clinical complications Clin. Immunol. 2018 197 130 138 10.1016/j.clim.2018.09.006 30219667 \n40. Tanaka Y. Kubo S. Miyagawa I. Iwata S. Nakayamada S. Lymphocyte phenotype and its application to precision medicine in systemic autoimmune diseases Semin. Arthritis Rheum. 2019 48 1146 1150 10.1016/j.semarthrit.2019.04.007 31079846 \n41. Coutinho A.E. Chapman K.E. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights Mol. Cell. Endocrinol. 2011 335 2 13 10.1016/j.mce.2010.04.005 20398732 \n42. Lill-Elghanian D. Schwartz K. King L. Fraker P. Glucocorticoid-induced apoptosis in early B cells from human bone marrow Exp. Biol. Med. 2002 227 763 770 10.1177/153537020222700907 12324655 \n43. Glaesener S. Quách T.D. Onken N. Weller-Heinemann F. Dressler F. Huppertz H.I. Thon A. Meyer-Bahlburg A. Distinct effects of methotrexate and etanercept on the B cell compartment in patients with juvenile idiopathic arthritis Arthritis Rheumatol. 2014 66 2590 2600 10.1002/art.38736 24909567 \n44. Ahmed S. Anolik J.H. B-cell biology and related therapies in systemic lupus erythematosus Rheum. Dis. Clin. N. Am. 2010 36 109 130 10.1016/j.rdc.2009.12.002 20202594 \n45. Mélet J. Mulleman D. Goupille P. Ribourtout B. Watier H. Thibault G. Rituximab-induced T cell depletion in patients with rheumatoid arthritis: Association with clinical response Arthritis Rheum. 2013 65 2783 2790 10.1002/art.38107 23918413 \n46. Brokstad K.A. Fredriksen M. Zhou F. Bergum B. Brun J.G. Cox R.J. Skarstein K. T follicular-like helper cells in the peripheral blood of patients with primary Sjögren’s syndrome Scand. J. Immunol. 2018 e12679 10.1111/sji.12679 29882349 \n47. Long S. Ma L. Wang D. Shang X. High frequency of circulating follicular helper T cells is correlated with B cell subtypes in patients with ankylosing spondylitis Exp. Ther. Med. 2018 15 4578 4586 10.3892/etm.2018.5991 29731839 \n48. Ishioka-Takei E. Yoshimoto K. Suzuki K. Nishikawa A. Yasuoka H. Yamaoka K. Takeuchi T. Increased proportion of a CD38high IgD+ B cell subset in peripheral blood is associated with clinical and immunological features in patients with primary Sjögren’s syndrome Clin. Immunol. 2018 187 85 91 10.1016/j.clim.2017.10.008 29061446 \n49. Szabó K. Papp G. Szántó A. Tarr T. Zeher M. A comprehensive investigation on the distribution of circulating follicular T helper cells and B cell subsets in primary Sjögren’s syndrome and systemic lupus erythematosus Clin. Exp. Immunol. 2016 183 76 89 10.1111/cei.12703 26358223 \n50. Thorarinsdottir K. Camponeschi A. Jonsson C. Granhagen Önnheim K. Nilsson J. Forslind K. Visentini M. Jacobsson L. Mårtensson I.L. Gjertsson I. CD21-/low B cells associate with joint damage in rheumatoid arthritis patients Scand. J. Immunol. 2019 90 e12792 10.1111/sji.12792 31141193 \n51. Shimizu T. Nagafuchi Y. Harada H. Tsuchida Y. Tsuchiya H. Hanata N. Tateishi S. Kanda H. Sumitomo S. Shoda H. Decreased peripheral blood memory B cells are associated with the presence of interstitial lung disease in rheumatoid arthritis: A case-control study Mod. Rheumatol. 2020 5 1 6 10.1080/14397595.2020.1719596 32023138\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2077-0383",
"issue": "9(4)",
"journal": "Journal of clinical medicine",
"keywords": "CD4+ T follicular cells; DMARD; class-switched memory B cells; common variable immunodeficiency; hypogammaglobulinemia; methotrexate; primary immunodeficiency; rheumatoid arthritis; secondary hypogammaglobulinemia; systemic lupus erythematosus",
"medline_ta": "J Clin Med",
"mesh_terms": null,
"nlm_unique_id": "101606588",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32272789",
"pubdate": "2020-04-07",
"publication_types": "D016428:Journal Article",
"references": "25538710;20202594;30219667;26980224;29731839;20398732;32033941;27994589;29882349;30825606;28000208;22566870;29729943;27069935;31720921;32023138;17276173;26279205;26358223;31141193;31379802;17898316;29477728;30055090;17935071;12324655;23918413;18319398;19303387;24909567;31637570;31764977;31683054;23039891;29061446;24384827;24414744;30040974;12607725;30776527;19666505;21414208;30800120;17371966;21041728;29599028;31803180;27582173;11861266;31079846;31379811",
"title": "Peripheral Blood Lymphocyte Phenotype Differentiates Secondary Antibody Deficiency in Rheumatic Disease from Primary Antibody Deficiency.",
"title_normalized": "peripheral blood lymphocyte phenotype differentiates secondary antibody deficiency in rheumatic disease from primary antibody deficiency"
} | [
{
"companynumb": "DE-AMGEN-DEUSP2020093752",
"fulfillexpeditecriteria": "2",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ADALIMUMAB"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nDose-dense doxorubicin and cyclophosphamide (ddAC) followed by dose-dense paclitaxel (ddP) (ddAC-P) has improved disease-free survival of patients with breast cancer. The aim of this study was to evaluate the safety and relative dose intensity (RDI) of ddAC-P administered together with pegfilgrastim.\n\n\nMETHODS\nBetween May 2015 and Aug 2017, 44 patients were retrospectively reviewed; they were administered 4 cycles of ddAC, followed by 4 cycles of ddP. Pegfilgrastim (3.6 mg) was administered in every cycle.\n\n\nRESULTS\nThe mean RDIs for ddAC-P, ddAC, and ddP were 95.0%, 94.5%, and 93.3%, respectively. The prevalence of high RDIs (≥85%) for ddAC-P, ddAC, and ddP was 90.9%, 84.1%, and 88.6%, respectively. Seven of the 10 patients with low RDIs experienced grade 1 or 2 fever.\n\n\nCONCLUSIONS\nDdAC-P administered together with pegfilgrastim (3.6 mg) appears to be feasible and maintains RDI in most of Japanese patients with breast cancer. Rapid evaluation and proper management of fever may prevent low RDI.",
"affiliations": "Department of Medical Oncology, Hyogo Cancer Center, Akashi, Japan.;Department of Medical Oncology, Hyogo Cancer Center, Akashi, Japan.;Department of Medical Oncology, Hyogo Cancer Center, Akashi, Japan.;Department of Pharmacy, Hyogo Cancer Center, Akashi, Japan.;Department of Pharmacy, Hyogo Cancer Center, Akashi, Japan.;Department of Breast Surgery, Hyogo Cancer Center, Akashi, Japan.;Department of Breast Surgery, Hyogo Cancer Center, Akashi, Japan.;Department of Breast Surgery, Hyogo Cancer Center, Akashi, Japan.;Department of Breast Surgery, Hyogo Cancer Center, Akashi, Japan.;Department of Breast Surgery, Hyogo Cancer Center, Akashi, Japan.;Department of Breast Surgery, Hyogo Cancer Center, Akashi, Japan.;Department of Medical Oncology, Hyogo Cancer Center, Akashi, Japan kojmatsu2@hyogo-cc.jp.",
"authors": "Nishimura|Meiko|M|;Onoe|Takuma|T|;Sakai|Hideki|H|;Arase|Minori|M|;Watanabe|Sayuri|S|;Soyama|Misao|M|;Hashimoto|Kazuki|K|;Miki|Mayuko|M|;Tane|Kaori|K|;Hirokaga|Koichi|K|;Takao|Shintaro|S|;Matsumoto|Koji|K|",
"chemical_list": "C455861:pegfilgrastim; D011092:Polyethylene Glycols; D004317:Doxorubicin; D003520:Cyclophosphamide; D017239:Paclitaxel; D000069585:Filgrastim",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.13607",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "39(8)",
"journal": "Anticancer research",
"keywords": "Dose-dense doxorubicin and cyclophosphamide; breast cancer; dose-dense paclitaxel; pegfilgrastim; perioperative chemotherapy",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D001943:Breast Neoplasms; D003520:Cyclophosphamide; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D005260:Female; D000069585:Filgrastim; D006801:Humans; D008875:Middle Aged; D017239:Paclitaxel; D011092:Polyethylene Glycols",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "4379-4383",
"pmc": null,
"pmid": "31366533",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Safety and Relative Dose Intensity of Dose-dense Doxorubicin and Cyclophosphamide Followed by Dose-dense Paclitaxel.",
"title_normalized": "safety and relative dose intensity of dose dense doxorubicin and cyclophosphamide followed by dose dense paclitaxel"
} | [
{
"companynumb": "JP-JNJFOC-20190830398",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "BACKGROUND\nThe association of preoperative systemic and intraperitoneal chemotherapy has been described in Eastern patients with very good outcomes in treatment responders. The aim of this paper is to describe the initial results of this multidisciplinary regimen in gastric cancer patients with very advanced peritoneal metastases.\n\n\nMETHODS\nWe present here the first four cases who received the treatment protocol. They had a baseline PCI between 19 and 33. Two patients had received systemic chemotherapy prior to this regimen. Three of them had significant response and were taken to cytoreductive surgery, while one patient who had 12 cycles of chemotherapy previously showed signs of disease progression and subsequently died. There was no significant postoperative morbidity, and three patients remain alive, two of them with no signs of recurrence.\n\n\nCONCLUSIONS\nSystemic and intraperitoneal chemotherapy led to a marked response in peritoneal disease extent in our initial experience and allowed three of four patients with very advanced disease to be treated with cytoreductive surgery.",
"affiliations": "Department of Abdominal Surgery, A. C. Camargo Cancer Center, Rua Antonio Prudente, 211, Liberdade, Sao Paulo, CEP 01501-900, Brazil.;Department of Abdominal Surgery, A. C. Camargo Cancer Center, Rua Antonio Prudente, 211, Liberdade, Sao Paulo, CEP 01501-900, Brazil. dr.wilsoncosta@gmail.com.;Department of Abdominal Surgery, A. C. Camargo Cancer Center, Rua Antonio Prudente, 211, Liberdade, Sao Paulo, CEP 01501-900, Brazil.;Department of Abdominal Surgery, A. C. Camargo Cancer Center, Rua Antonio Prudente, 211, Liberdade, Sao Paulo, CEP 01501-900, Brazil.;Department of Abdominal Surgery, A. C. Camargo Cancer Center, Rua Antonio Prudente, 211, Liberdade, Sao Paulo, CEP 01501-900, Brazil.;Department of Abdominal Surgery, A. C. Camargo Cancer Center, Rua Antonio Prudente, 211, Liberdade, Sao Paulo, CEP 01501-900, Brazil.;Department of Abdominal Surgery, A. C. Camargo Cancer Center, Rua Antonio Prudente, 211, Liberdade, Sao Paulo, CEP 01501-900, Brazil.;Department of Abdominal Surgery, A. C. Camargo Cancer Center, Rua Antonio Prudente, 211, Liberdade, Sao Paulo, CEP 01501-900, Brazil.;Departament of Medical Oncology, A. C. Camargo Cancer Center, Sao Paulo, Brazil.;Department of Pathology, A. C. Camargo Cancer Center, São Paulo, Brazil.;Department of Abdominal Surgery, A. C. Camargo Cancer Center, Rua Antonio Prudente, 211, Liberdade, Sao Paulo, CEP 01501-900, Brazil.",
"authors": "Fava|Bianca Escorel Costa|BEC|;da Costa|Wilson Luiz|WL|;Medeiros|Maria Luiza L|MLL|;Sonagli|Marina|M|;de Castro Ribeiro|Héber Salvador|HS|;Diniz|Alessandro L|AL|;Godoy|André L|AL|;de Farias|Igor C|IC|;de Jesus|Victor Hugo Fonseca|VHF|;Begnami|Maria Dirlei F S|MDFS|;Coimbra|Felipe J F|FJF|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12957-018-1363-0",
"fulltext": "\n==== Front\nWorld J Surg OncolWorld J Surg OncolWorld Journal of Surgical Oncology1477-7819BioMed Central London 136310.1186/s12957-018-1363-0Case ReportNeoadjuvant intraperitoneal chemotherapy followed by radical surgery and HIPEC in patients with very advanced gastric cancer and peritoneal metastases: report of an initial experience in a western single center Fava Bianca Escorel Costa biancafava40@gmail.com 1da Costa Wilson Luiz Jr+ 55 (11) 2189-5000dr.wilsoncosta@gmail.comdrfelipecoimbra@gmail.com 1Medeiros Maria Luiza L. lumedeiros88@yahoo.com.br 1Sonagli Marina marinasonagli@gmail.com 1de Castro Ribeiro Héber Salvador hsalvadorcr@gmail.com 1Diniz Alessandro L. dr.aldiniz@gmail.com 1Godoy André L. andreluisgodoy@yahoo.com.br 1de Farias Igor C. dr.igorfarias@gmail.com 1de Jesus Victor Hugo Fonseca victorhugoba@gmail.com 2Begnami Maria Dirlei F. S. mariadirlei@gmail.com 3Coimbra Felipe J. F. drfelipecoimbra@gmail.com.br 11 0000 0004 0437 1183grid.413320.7Department of Abdominal Surgery, A. C. Camargo Cancer Center, Rua Antonio Prudente, 211, Liberdade, Sao Paulo, CEP 01501-900 Brazil 2 0000 0004 0437 1183grid.413320.7Departament of Medical Oncology, A. C. Camargo Cancer Center, Sao Paulo, Brazil 3 0000 0004 0437 1183grid.413320.7Department of Pathology, A. C. Camargo Cancer Center, São Paulo, Brazil 22 3 2018 22 3 2018 2018 16 624 10 2017 9 3 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe association of preoperative systemic and intraperitoneal chemotherapy has been described in Eastern patients with very good outcomes in treatment responders. The aim of this paper is to describe the initial results of this multidisciplinary regimen in gastric cancer patients with very advanced peritoneal metastases.\n\nCase presentation\nWe present here the first four cases who received the treatment protocol. They had a baseline PCI between 19 and 33. Two patients had received systemic chemotherapy prior to this regimen. Three of them had significant response and were taken to cytoreductive surgery, while one patient who had 12 cycles of chemotherapy previously showed signs of disease progression and subsequently died. There was no significant postoperative morbidity, and three patients remain alive, two of them with no signs of recurrence.\n\nConclusion\nSystemic and intraperitoneal chemotherapy led to a marked response in peritoneal disease extent in our initial experience and allowed three of four patients with very advanced disease to be treated with cytoreductive surgery.\n\nissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nPatients with advanced gastric cancer present with peritoneal metastases in about 30% of cases [1] and up to 50% of those treated with curative intent will develop relapse in the peritoneum. Standard treatment for these individuals is systemic chemotherapy, but median survival in this scenario is poor, around 3 to 6 months in most studies [2], reaching a little over 1 year in a recent Eastern trial [3].\n\nCytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) for gastric cancer patients with peritoneal metastases has been associated with improved survival in a selected group of patients both in an Eastern [2] and in a large French multicenter series [4]. The results from both studies have emphasized the importance of patient selection, as the ones with the best results were treated with preoperative systemic chemotherapy, had limited peritoneal dissemination, measured by a low peritoneal cancer index (PCI), and were treated with a complete cytoreduction [4].\n\nThe association of neoadjuvant intraperitoneal and systemic chemotherapy has been investigated recently and seems to be a very important tool for patient selection. In a large Eastern series, individuals who had negative cytology after this preoperative regimen and were treated with CRS + HIPEC had improved survival compared to those with positive cytology [5]. The addition of laparoscopic HIPEC (L-HIPEC) and more effective systemic chemotherapy to this multidisciplinary treatment, labeled as bidirectional intraperitoneal and systemic chemotherapy (BISIC), has led to more significant response rates and improved survival in this set of patients [1].\n\nThe aim of this study was to report the first four consecutive cases of gastric cancer patients who presented with advanced disease and disseminated peritoneal metastases and were treated with L-HIPEC and BISIC, followed by CRS + HIPEC.\n\nMethods\nThis is a retrospective, single-center case series based on routinely collected data extracted from patients’ electronic charts. This paper was written in accordance with CARE guideline for case reports [6].\n\nThe inclusion criteria were diagnosis of synchronous metastatic gastric cancer with peritoneal dissemination as the sole site of metastatic disease and treatment with BISIC (as described below) between October 2015 and August 2017 (Table 1).Table 1 Clinical characteristics of the four patients treated for gastric adenocarcinoma metastatic to the peritoneum with BISIC\n\nAge\tSex\tHistology\tBaseline PCI\tPCI at re-staging\tPCI at CRS\tSurvival\tStatus\t\n29\tM\tMixed-type adenocarcinoma\t20\t15\t17 (no CRS performed)\t16\tDEAD\t\n34\tF\tSignet-ring cell adenocarcinoma\t33\t25\t2\t27+\tAWOD\t\n55\tF\tSignet-ring cell adenocarcinoma\t25\t17\t12\t15+\tAWD\t\n57\tM\tSignet-ring cell adenocarcinoma\tNot available\t19\t13\t13+\tAWOD\t\nAWOD alive without disease, AWD alive with disease\n\n\n\nTreatment was adapted according to Yonemura’s original protocol (2006), which he later modified, adding more effective systemic chemotherapy and with a different dosage of the intraperitoneal drugs [1, 7]. As S-1 is not currently available in Brazil, Capecitabine was used instead of S-1. Briefly, during the first laparoscopy, before any treatment, extensive intraperitoneal lavage (EIPL) [8] and L-HIPEC (Cisplatin 30 mg/m2 + Docetaxel 30 mg/m2, for 1 h at 42 oC) were performed. At the end of the procedure, a peritoneal port-a-cath (DistricAth®, Districlass Médical, France) was placed with its tip directed toward the cul-de-sac. After a 15-day period of rest, patients initiated normothermic chemotherapy. On day 1, Cisplatin 30 mg/m2 and Docetaxel 30 mg/m2 were infused into the peritoneal cavity for 2 h after adequate pre-medication. On day 8, Cisplatin 30 mg/m2 and Docetaxel 30 mg/m2 were given intravenously in separate bags according to standard infusion protocols. Capecitabine 850 mg/m2 PO twice a day was administered from day 1 to day 14. Cycles were repeated every 21 days.\n\nTreatment strategy consisted on repeating BISIC cycles three times, followed by CT scans, endoscopy, and a new laparoscopy. According to the surgical findings, another three cycles of BISIC was performed, or patient was taken to CRS, which included gastrectomy + D2-lymphadenectomy, resection of peritoneal lesions, and HIPEC.\n\nDuring treatment, patients were followed for toxicity at least once per cycle, and response evaluation with endoscopy and CT scans were performed every three cycles. After cytoreductive surgery, CT scans were repeated every 2–3 months.\n\nAll patients signed informed consent after extensive discussion with patients and relatives regarding potential benefits and risks of the treatment. Toxicity was graded according to Common Toxicity Criteria (CTC) 4.0.\n\nCase presentation\nCase 1\nA 34-year-old female patient was admitted in September 2015 at our service. She complained of epigastric pain and reported a 13-kg weight loss. Her weight at this time was 39 kg. An upper endoscopy revealed a large gastric tumor that extended from the posterior wall of the greater curvature in the fundus to the gastric antrum. Biopsy confirmed the diagnosis of a poorly differentiated adenocarcinoma. Thoracic and abdominal CT scans were then performed and showed gastric wall thickening in the fundus, mild ascites, enlarged perigastric lymph nodes, and peritoneal nodules. CEA and CA 19-9 levels were 6.4 ng/mL and 555.4 U/mL, respectively.\n\nA staging laparoscopy demonstrated multiple peritoneal nodules in the right and left diaphragm, greater and lesser omentum, pelvis, and parieto-colic gutters. PCI count was 33. Ascites was considered to be moderate, and its cytology was positive for the presence of free cancer cells. Biopsy of two nodules confirmed the diagnosis of adenocarcinoma. After informed consent was obtained, the patient started the protocol described in the “Methods” section.\n\nRe-staging CT scans demonstrated a decrease in gastric wall thickening, ascites, and in the number of peritoneal nodules. A new laparoscopy showed a decrease in the number of peritoneal nodules, but the PCI count remained high (20). Cytology of the peritoneal wash, however, was negative, as were the biopsy of one nodule in the right diaphragmatic peritoneum. After multidisciplinary discussion, we opted to treat the patients with three more BISIC cycles.\n\nAfter six cycles, the patient had regained her weight (50 kg), and her CT scans showed a significant reduction both in gastric wall thickening and peritoneal nodules (Fig. 1). Her CA 19-9 was 13.1 U/mL, and her CEA level was below detection level. During treatment with BISIC, patient developed mild toxicities, including G1 nausea, vomiting, fatigue, alopecia, decreased appetite and diarrhea, and G2 constipation and infection (upper respiratory tract infection). Among hematological toxicities, only grade 2 anemia was observed. There were no dose reductions or treatment delays due to toxicity. No serious adverse event was reported.Fig. 1 Abdominal CT showing gastric wall before (a) and after (b) the BISIC regimen. A significant response with regression of gastric wall thickening can be observed\n\n\n\nThe patient was then taken to surgery in June 2016. A new staging laparoscopy identified no peritoneal lesions (Fig. 2). We proceeded to a laparotomy, and a total gastrectomy with D2-lymphadenectomy was performed. Peritoneal areas in the right and left diaphragm, in the pelvis, and in the small bowel mesenterium were resected. EIPL was performed after resection, followed by HIPEC with Docetaxel 30 mg/m2 and Cisplatin 30 mg/m2 for 1 h. She had an uneventful recovery and was discharged on the tenth postoperative day.Fig. 2 Peritoneal surface before and after systemic and intraperitoneal chemotherapy. a Case 1, before treatment; b case 1, after L-HIPEC and six cycles of BISIC regimen; c case 2, before treatment; d case 2, after L-HIPEC and six cycles of BISIC\n\n\n\nThe peritoneal wash cytology was negative and the pathology report showed only acellular mucin and rare epithelial cells with nuclear atypia in the gastric body and antrum’s mucosa and submucosa. The tumor bed measure was 10 × 4.5 cm. No lymphatic, perineural, or vascular invasion was identified. All margins were negative, and there were no metastases in the 38 dissected lymph nodes. Peritoneal wash cytology was negative, and all peritoneal areas that were resected had no signs of viable disease. Pathological staging was ypT1b ypN0 ypM0 (pathologic TNM I). Response to chemotherapy in the examined tissue was characterized as 5% of viable tumor cells and 95% of fibrosis.\n\nAfter surgery patient was submitted to five additional cycles of capecitabine 750 mg/m2 PO twice a day from day 1 to day 14 every 21 days. At last follow-up (January 2018), she was asymptomatic and exams showed no evidence of disease.\n\nCase 2\nA 55-year-old female presented in September 2016 with a long history of dyspeptic symptoms and an upper endoscopy that showed a Borrmann type IV lesion in the gastric body with a biopsy of signet-ring cell adenocarcinoma.\n\nStaging was performed first with thoracic and abdominal CT scans, which showed diffuse gastric wall thickening and signs of peritoneal metastases. A staging laparoscopy revealed multiple peritoneal metastases, with a PCI count of 25.\n\nAfter three cycles of treatment, re-staging endoscopy demonstrated a significant response to treatment, as no ulcerated lesions remained, only a fibrotic and substenotic area in the body-antrum transition (Fig. 3). Furthermore, CT showed a regression in the thickening area. A new laparoscopy was performed in February 2017, which revealed the presence of remaining peritoneal metastases, and a total PCI of 17. The recommendation as in the previous case was to maintain the BISIC regimen and re-evaluate after three more cycles.Fig. 3 Endoscopic aspect of gastric lesion in case 2 a at diagnosis, b after three cycles of BISIC, and c after six cycles of BISIC demonstrating significant response to treatment\n\n\n\nAfter the sixth cycle, re-staging with endoscopy and CT identified the same signs of response to chemotherapy. During treatment, the patient presented somewhat more toxicity in comparison to the previous patient. G1 vomiting, peripheral neuropathy, alopecia, and decreased appetite were noticed. Moreover, G2 nauseas, fatigue, abdominal pain (due to chemical peritonitis), infection (upper respiratory tract infection), and myalgia were verified. Dose reductions of the intraperitoneal component of BISIC (due to chemical peritonitis) and dose delays were deemed necessary. Severe toxicities were not observed.\n\nA new laparoscopy was performed in June 2017 and showed less spread of peritoneal nodules, with a PCI count of 12. Cytoreductive surgery was then performed, with a total gastrectomy, D2-lymphadenectomy, resection of the diaphragmatic peritoneum, and nodules in the small bowel mesentery. Three of these nodules were sent to frozen section biopsy, with no signs of viable disease in any of them. HIPEC followed, with Cisplatin 30 mg/m2 and Docetaxel 30 mg/m2, perfused for 1 h.\n\nThis patient also had an uneventful recovery and was discharged from the hospital on the eleventh postoperative day. The pathology report described a signet-ring cell adenocarcinoma in the stomach distal body, with serosa infiltration and 4 metastatic lymph nodes, a total of 23 dissected. Regarding the peritoneal nodules, viable disease was detected in the round ligament and in one small bowel implant. (ypT3 ypN2 ypM1—pathologic TNM IV). She received four cycles of adjuvant chemotherapy (FOLFOX), from a planned total of six cycles. She developed peritoneal recurrence 3 months later and is now under treatment with a second-line chemotherapy regimen.\n\nCase 3\nThe next two cases encompass subjects with a different treatment background. The first was a 29-year-old male, admitted in December 2015, with a history of epigastric pain and a 6-kg weight loss. He had an upper endoscopy that showed a Bormann IV lesion in the gastric body and a biopsy of mixed-type adenocarcinoma. Diffuse peritoneal metastases were identified on abdominal CT and on a PET-CT.\n\nA staging laparoscopy confirmed multiple peritoneal metastases, with a PCI count of 20. The patient received systemic chemotherapy, with 12 cycles of modified DCF (Docetaxel, Cysplatin, and 5-Flouracil). After multidisciplinary discussion, a new laparoscopy was performed and PCI was 15. L-HIPEC was then administered with Cisplatin 30 mg/m2 and Docetaxel 30 mg/m2, followed by three cycles of BISIC. The following staging procedure showed a PCI count of 17. Due to this finding of disease progression, surgery was not performed and the patient was started on second line of chemotherapy, with Paclitaxel and Ramucirumab. He had disease progression in the second cycle and died due to complications related to the tumor in April 2017.\n\nCase 4\nCase 4 refers to a 55-year-old male, who had a different treatment background as well. He was admitted at our service in October 2016 with a 6-month history of epigastric pain and a 15-kg weight loss. His upper endoscopy revealed an infiltrative lesion in the upper body of the stomach, which resembled linitis plastica. Biopsy revealed a signet-ring cell adenocarcinoma. He had a previous abdominal CT with findings of diffuse peritoneal metastases and had been treated with eight cycles of FLOT (5-Fluoracil, Leucovorin, Oxaliplatin, and Docetaxel) at a cancer service in his hometown.\n\nHe underwent a staging laparoscopy in December 2016, which confirmed the peritoneal metastases with a PCI count of 19. L-HIPEC was performed as described in the previous two cases and the intraperitoneal port-a-cath positioned. After two cycles of BISIC, also administered as previously described, a new laparoscopy was performed in April 2017 and a PCI count of 13 was identified. A midline incision followed and a total gastrectomy with D2-lymphadenectomy was performed, along with the resection of the subdiaphragmatic and pelvic peritoneum, in which there were some fibrotic areas that could have residual disease. HIPEC was also administered as in the other two patients. Pathology showed a residual mixed-type adenocarcinoma invading the gastric submucosa, 17 lymph node metastases out of 22 dissected nodes and 30% of viable tumor cells in the stomach. All peritoneal areas showed no residual disease. (pT1b pN3b pM0––pathologic TNM IIB). His recovery had no significant events, and he was discharged on the twelfth postoperative day. He underwent six cycles of chemotherapy (FOLFOX) in his home town and now is on follow-up, with no signs of recurrence.\n\nDiscussion\nWe report in this series the first four cases of gastric cancer patients with very advanced peritoneal disease who were treated with a multimodality regimen that included systemic and intraperitoneal chemotherapy in a recently nominated regimen known as BISIC [1], followed by cytoreductive surgery and HIPEC, in a single Western cancer center. The most important findings in these cases were the lack of postoperative morbidity and the significant response in peritoneal dissemination associated with treatment, which turned patients who would be candidates for palliative chemotherapy only into candidates for a more radical therapy and a chance for improved survival.\n\nThree of the four patients reached a significant response that allowed them to be treated with a complete cytoreductive surgery and also received HIPEC with Docetaxel and Cisplatin for 60 min. The association of CRS and HIPEC has been proven superior to CRS alone in a Chinese randomized trial with 68 patients, in which the multimodality group had a median survival of 11 months compared to 6.5 months in the surgery only group. These poor numbers in both groups may be related to patient selection, as 42% of individuals in this study did not have a complete CRS with no residual macroscopic disease (CC-0) [9]. This trial confirmed the findings of a large French multicenter study that subjects who are candidates for this multimodality regimen should receive preoperative chemotherapy, should have low disease burden, expressed in PCI count, and should receive a CC-0 CRS as a mandatory step of their treatment [4].\n\nCanbay et al. first described the use of neoadjuvant intraperitoneal chemotherapy combined with systemic chemotherapy in a large single-center series in Japan, with 194 patients. Out of these individuals, 152 (78%) were classified as responders, a classification that at the time included patients whose cytology became negative after the administration of two cycles of intraperitoneal Cisplatin and Docetaxel and six cycles of S-1. These responders were then taken to CRS and HIPEC, and the median survival of those who received CC-0 surgery was 18 months [5], which was an improvement compared to the results of chemotherapy alone, even in Eastern studies [10].\n\nThis regimen was later modified by the same group, and the concept of a laparoscopic hyperthermic intraperitoneal chemotherapy perfusion (L-HIPEC) was introduced. Its main advantage would be a minimally invasive procedure with direct vision, which would allow for a more valid assessment of the peritoneal disease extent in the peritoneal cavity. Also, a more effective systemic chemotherapy regimen was adopted, with the use of Cisplatin and Docetaxel intravenously associated with the intraperitoneal regimen (BISIC). This treatment has been described in detail in the literature [1, 11]. The most important benefit of this association seems to be a higher response rate in peritoneal disease extent. In a study of this regimen in 105 patients, the association of L-HIPEC and BISIC led to a significant change in PCI, as 44% of patients had baseline PCI under 12, compared to 67% after treatment. Also, 66% of all subjects experienced a decrease or complete disappearance in peritoneal metastases in the re-staging laparoscopy [12]. We identified this response in three of our patients, with decreases of 100, 52, and 31%, with numbers that were obtained in open surgery and that could have been undervalued in the staging laparoscopies. The less significant response and the disease progression findings were identified in the two patients who had systemic chemotherapy prior to L-HIPEC and BISIC. Although sample size was too small to draw any conclusions, it is possible that the performance of this prior treatment could have helped induce drug resistance.\n\nAnother aspect that should be highlighted is the very low morbidity associated with the procedure. In the study above, no patient developed grade IV and V toxicity and only four had grade III events after L-HIPEC and BISIC. Our cases had similar results, with no grade III, IV, or V events after chemotherapy and no postoperative complication. We certainly do not expect zero morbidity in future cases, but that resembles our previous results with adjuvant HIPEC, in which no patient developed organ insufficiency and there was no mortality [13]. Very similar results have been recently reported in an American cancer center series, with 11% morbidity and no mortality associated with the L-HIPEC [14]. That reinforces the notion that the morbidity and mortality associated with CRS and HIPEC is highly influenced by surgery extent.\n\nThis is a very small case series, and interpreting its results is somewhat limited. However, this multimodality treatment has been performed extensively in a Japanese institution and its results have shown a very acceptable toxicity and promising response rates, with long-term survival in selected patients [1]. We report here our group preliminary experience, with favorable results in subjects with very advanced gastric cancer and diffuse peritoneal metastases. A higher number of cases should confirm the validity of these results and provide more meaningful analyses.\n\nConclusions\nIn conclusion, the association of L-HIPEC and BISIC has led to a good response in peritoneal disease extent in our initial experience and allowed radical procedures to be performed in individuals who were otherwise candidates for palliative chemotherapy.\n\nNot applicable.\n\nFunding\nThis study had no sources of funding.\n\nAvailability of data and materials\nThe dataset used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nBECF, WLCJ, and MLLM studied the treatment background and wrote the manuscript. MS and HSC helped with data collection from the patients. MDFSB reviewed the pathology reports, and VHFJ provided detailed analysis of treatment protocol and outcome analysis. ALD, ALG, and FJFC reviewed the manuscript and made suggestions which were added to the last manuscript version. MS, HSC and ICF helped with data collection from the patients. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThis study has been approved by the Ethics Committee of A. C. Camargo Cancer Center.\n\nConsent for publication\nWritten informed consent for publication was obtained from all the patients who were included in the study.\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. Yonemura Y Canbay E Li Y Coccolini F Glehen O Sugarbaker PH A comprehensive treatment for peritoneal metastases from gastric cancer with curative intent Eur J Surg Oncol 2016 42 8 1123 1131 10.1016/j.ejso.2016.03.016 27160355 \n2. Yonemura Y Kawamura T Bandou E Takahashi S Sawa T Matsuki N Treatment of peritoneal dissemination from gastric cancer by peritonectomy and chemohyperthermic peritoneal perfusion Br J Surg 2005 92 3 370 375 10.1002/bjs.4695 15739249 \n3. Yamada Y Higuchi K Nishikawa K Gotoh M Fuse N Sugimoto N Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naive patients with advanced gastric cancer Ann Oncol 2015 26 1 141 148 10.1093/annonc/mdu472 25316259 \n4. Glehen O Gilly FN Arvieux C Cotte E Boutitie F Mansvelt B 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 17 9 2370 2377 10.1245/s10434-010-1039-7 20336386 \n5. Canbay E Mizumoto A Ichinose M Ishibashi H Sako S Hirano M Outcome data of patients with peritoneal carcinomatosis from gastric origin treated by a strategy of bidirectional chemotherapy prior to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in a single specialized center in Japan Ann Surg Oncol 2014 21 4 1147 52. 5 10.1245/s10434-013-3443-2 24356799 \n6. Gagnier JJ Kienle G Altman DG Moher D Sox H Riley D The CARE guidelines: consensus-based clinical case report guideline development J Clin Epidemiol 2014 67 1 46 51 10.1016/j.jclinepi.2013.08.003 24035173 \n7. Yonemura Y Canbay E Endou Y Ishibashi H Mizumoto A Li Y Comprehensive treatment for the peritoneal metastasis from gastric cancer World J Surg Proced 2015 5 187 197 10.5412/wjsp.v5.i2.187 \n8. Kuramoto M Shimada S Ikeshima S Matsuo A Yagi Y Matsuda M Extensive intraoperative peritoneal lavage as a standard prophylactic strategy for peritoneal recurrence in patients with gastric carcinoma Ann Surg 2009 250 2 242 246 10.1097/SLA.0b013e3181b0c80e 19638909 \n9. Yang XJ Huang CQ Suo T Mei LJ Yang GL Cheng FL Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: final results of a phase III randomized clinical trial Ann Surg Oncol 2011 18 6 1575 1581 10.1245/s10434-011-1631-5 21431408 \n10. Kadowaki S Komori A Narita Y Nitta S Yamaguchi K Kondo C Long-term outcomes and prognostic factors of patients with advanced gastric cancer treated with S-1 plus cisplatin combination chemotherapy as a first-line treatment Int J Clin Oncol 2014 19 4 656 661 10.1007/s10147-013-0610-1 23999902 \n11. Canbay E Yonemura Y Peritoneal surface malignancies: a curative approach 2015 Cham Springer 109 \n12. Yonemura Y Ishibashi H Hirano M Mizumoto A Takeshita K Noguchi K Effects of neoadjuvant laparoscopic hyperthermic intraperitoneal chemotherapy and neoadjuvant intraperitoneal/systemic chemotherapy on peritoneal metastases from gastric cancer Ann Surg Oncol 2017 24 2 478 485 10.1245/s10434-016-5487-6 27506661 \n13. Costa WL Jr Coimbra FJ Ribeiro HS Diniz AL de Godoy AL Begnami M Safety and preliminary results of perioperative chemotherapy and hyperthermic intraperitoneal chemotherapy (HIPEC) for high-risk gastric cancer patients World J Surg Oncol 2012 10 195 10.1186/1477-7819-10-195 22992263 \n14. Badgwell B Blum M Das P Estrella J Wang X Ho L Phase II trial of laparoscopic hyperthermic intraperitoneal chemoperfusion for peritoneal carcinomatosis or positive peritoneal cytology in patients with gastric adenocarcinoma Ann Surg Oncol 2017 24 3338 44 10.1245/s10434-017-6047-4 28799004\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1477-7819",
"issue": "16(1)",
"journal": "World journal of surgical oncology",
"keywords": null,
"medline_ta": "World J Surg Oncol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D010478:Chemotherapy, Cancer, Regional Perfusion; D003131:Combined Modality Therapy; D065426:Cytoreduction Surgical Procedures; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local; D010534:Peritoneal Neoplasms; D011379:Prognosis; D012189:Retrospective Studies; D013274:Stomach Neoplasms; D015996:Survival Rate",
"nlm_unique_id": "101170544",
"other_id": null,
"pages": "62",
"pmc": null,
"pmid": "29566715",
"pubdate": "2018-03-22",
"publication_types": "D002363:Case Reports; D016430:Clinical Trial; D016428:Journal Article",
"references": "25316259;24356799;24035173;21431408;27506661;20336386;22992263;23999902;28799004;15739249;19638909;27160355",
"title": "Neoadjuvant intraperitoneal chemotherapy followed by radical surgery and HIPEC in patients with very advanced gastric cancer and peritoneal metastases: report of an initial experience in a western single center.",
"title_normalized": "neoadjuvant intraperitoneal chemotherapy followed by radical surgery and hipec in patients with very advanced gastric cancer and peritoneal metastases report of an initial experience in a western single center"
} | [
{
"companynumb": "BR-DRREDDYS-USA/BRA/18/0104376",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Behçet disease (BD) is a multisystem disease associated with a poor prognosis in cases of gastrointestinal, neurological, or vascular involvement. We conducted a multicenter, prospective, open-label, single-arm phase 3 study to determine the efficacy, safety, and pharmacokinetics of infliximab (IFX) in BD patients with these serious complications who had displayed poor response or intolerance to conventional therapy.IFX at 5 mg/kg was administered to 18 patients (11 intestinal BD, 3 neurological BD [NBD], and 4 vascular BD [VBD]) at weeks 0, 2, and 6 and every 8 weeks thereafter until week 46. In patients who showed inadequate responses to IFX after week 30, the dose was increased to 10 mg/kg. We then calculated the percentage of complete responders according to the predefined criteria depending on the symptoms and results of examinations (ileocolonoscopy, brain magnetic resonance imaging, computed tomography angiography, positron emission tomography, cerebrospinal fluid, or serum inflammatory markers), exploring the percentage of complete responders at week 30 (primary endpoint).The percentage of complete responders was 61% (11/18) at both weeks 14 and 30 and remained the same until week 54. Intestinal BD patients showed improvement in clinical symptoms along with decrease in C-reactive protein (CRP) levels after week 2. Consistently, scarring or healing of the principal ulcers was found in more than 80% of these patients after week 14. NBD patients showed improvement in clinical symptoms, imaging findings, and cerebrospinal fluid examinations. VBD patients showed improvement in clinical symptoms after week 2 with reductions in CRP levels and erythrocyte sedimentation rate. Imaging findings showed reversal of inflammatory changes in 3 of the 4 VBD patients. Irrespective of the type of BD, all patients achieved improvement in quality of life, leading to the dose reduction or withdrawal of steroids. IFX dose was increased to 10 mg/kg in 3 intestinal BD patients, resulting in the improvement of clinical symptoms, CRP levels, and visual analogue scale score. Safety and pharmacokinetics profiles were comparable to those in patients with rheumatoid arthritis or Crohn disease. These findings support IFX as a new therapeutic option for patients with intestinal BD, NBD, or VBD.",
"affiliations": "Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Sagamihara Department of Internal Medicine, Teikyo University School of Medicine, Tokyo Department of Diagnostic Radiology and Nuclear Medicine, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo Mitsubishi Tanabe Pharma Corporation, Osaka Yokohama City University, Yokohama, Japan.",
"authors": "Hibi|Toshifumi|T|;Hirohata|Shunsei|S|;Kikuchi|Hirotoshi|H|;Tateishi|Ukihide|U|;Sato|Noriko|N|;Ozaki|Kunihiko|K|;Kondo|Kazuoki|K|;Ishigatsubo|Yoshiaki|Y|",
"chemical_list": "D015415:Biomarkers; D005765:Gastrointestinal Agents; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000003863",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2731096910.1097/MD.0000000000003863038636900Research ArticleClinical Trial/Experimental StudyInfliximab therapy for intestinal, neurological, and vascular involvement in Behcet disease: Efficacy, safety, and pharmacokinetics in a multicenter, prospective, open-label, single-arm phase 3 study Hibi Toshifumi MD, PhDa∗Hirohata Shunsei MD, PhDbKikuchi Hirotoshi MD, PhDcTateishi Ukihide MD, PhDdSato Noriko BSceOzaki Kunihiko MSceKondo Kazuoki MD, PhDeIshigatsubo Yoshiaki MD, PhDfRosenthal. Ken a Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyob Department of Rheumatology and Infectious Diseases, Kitasato University School of Medicine, Sagamiharac Department of Internal Medicine, Teikyo University School of Medicine, Tokyod Department of Diagnostic Radiology and Nuclear Medicine, Tokyo Medical and Dental University Graduate School of Medicine, Tokyoe Mitsubishi Tanabe Pharma Corporation, Osakaf Yokohama City University, Yokohama, Japan.∗ Correspondence: Toshifumi Hibi, Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, 5-9-1 Shirokane, Minato-ku, Tokyo, Japan (e-mail: thibi@insti.kitasato-u.ac.jp).6 2016 17 6 2016 95 24 e38631 3 2016 27 4 2016 2 5 2016 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.2016This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nBehçet disease (BD) is a multisystem disease associated with a poor prognosis in cases of gastrointestinal, neurological, or vascular involvement. We conducted a multicenter, prospective, open-label, single-arm phase 3 study to determine the efficacy, safety, and pharmacokinetics of infliximab (IFX) in BD patients with these serious complications who had displayed poor response or intolerance to conventional therapy.\n\nIFX at 5 mg/kg was administered to 18 patients (11 intestinal BD, 3 neurological BD [NBD], and 4 vascular BD [VBD]) at weeks 0, 2, and 6 and every 8 weeks thereafter until week 46. In patients who showed inadequate responses to IFX after week 30, the dose was increased to 10 mg/kg. We then calculated the percentage of complete responders according to the predefined criteria depending on the symptoms and results of examinations (ileocolonoscopy, brain magnetic resonance imaging, computed tomography angiography, positron emission tomography, cerebrospinal fluid, or serum inflammatory markers), exploring the percentage of complete responders at week 30 (primary endpoint).\n\nThe percentage of complete responders was 61% (11/18) at both weeks 14 and 30 and remained the same until week 54. Intestinal BD patients showed improvement in clinical symptoms along with decrease in C-reactive protein (CRP) levels after week 2. Consistently, scarring or healing of the principal ulcers was found in more than 80% of these patients after week 14. NBD patients showed improvement in clinical symptoms, imaging findings, and cerebrospinal fluid examinations. VBD patients showed improvement in clinical symptoms after week 2 with reductions in CRP levels and erythrocyte sedimentation rate. Imaging findings showed reversal of inflammatory changes in 3 of the 4 VBD patients. Irrespective of the type of BD, all patients achieved improvement in quality of life, leading to the dose reduction or withdrawal of steroids. IFX dose was increased to 10 mg/kg in 3 intestinal BD patients, resulting in the improvement of clinical symptoms, CRP levels, and visual analogue scale score. Safety and pharmacokinetics profiles were comparable to those in patients with rheumatoid arthritis or Crohn disease. These findings support IFX as a new therapeutic option for patients with intestinal BD, NBD, or VBD.\n\nKeywords\ninfliximabintestinal Behçet diseaseneurological Behçet diseasevascular Behçet diseaseOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nBehçet disease (BD) is a multisystem disease characterized by 4 major symptoms (recurrent oral aphthous ulcers, skin lesions, eye lesions, and genital ulcers) and 5 minor symptoms (arthritis without deformity or ankylosis, epididymitis, gastrointestinal lesions represented by ileocecal ulceration, moderate or severe central nervous system lesions, and vascular lesions).[1] Involvement of the intestinal tract (intestinal BD), the nervous system (neurological BD [NBD]), and the vascular system (vascular BD [VBD]) is rare, although such cases tend to have a poor prognosis.[2,3]\n\nIntestinal BD, NBD, and VBD are generally treated using strong immunosuppressive agents such as steroids and immunomodulators. However, these medications are ineffective in some BD patients, who experience repeated relapses, sequelae, and eventually death.[1,4] Further, steroid treatment also poses problems of steroid dependency and adverse drug reactions associated with long-term use. The development of new therapeutic strategies for BD is therefore imperative.\n\nTumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) are major inflammatory cytokines involved in the pathogenesis of BD.[5] TNF-α production is elevated in the intestinal tissues of intestinal BD patients[6] and in peripheral blood cells of VBD patients,[7] while IL-6 concentrations are elevated in the cerebrospinal fluid (CSF) of NBD patients.[8]\n\nIn 2007, infliximab (IFX), an anti-TNF-α monoclonal antibody, was approved in Japan for the treatment of BD-associated refractory retinitis/uveitis, on the basis of the results of a clinical study.[9] Available data on the efficacy of IFX in intestinal BD, NBD, and VBD have been obtained mainly from case studies and retrospective cohort clinical studies,[10–17] and only rarely from prospective clinical studies. Here, therefore, we conducted a multicenter, prospective, open-label, single-arm phase 3 study to evaluate the efficacy, safety, and pharmacokinetics of IFX in BD patients with the serious complications mentioned above. To our knowledge, this is the first prospective multicenter clinical trial of this agent in BD patients with serious complications.\n\n2 Methods\nThis phase 3 clinical study (ClinicalTrials.gov, NCT01532570) was conducted under a prospective, open-label, single-arm clinical design at 21 medical institutions in Japan between January 2012 and May 2014.[18] The protocol was approved by the institutional review board at each medical institution. All patients gave written informed consent. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Mitsubishi Tanabe Pharma Corporation sponsored this clinical trial and was responsible for the collection of data.\n\n2.1 Patients\nThe study subjects were patients who had been diagnosed as complete or incomplete type of BD with intestinal BD, NBD, or VBD as per the criteria defined by the Ministry of Health, Labour and Welfare (partially revised in 2010) for Japan, and who had insufficient response or intolerance to conventional therapy. Patients were restricted to those aged 16 to 75 years. With regard to type-specific eligibility criteria, intestinal BD patients had to have intestinal BD-associated symptoms (abdominal pain, diarrhea, melena, etc.) and endoscopic evidence of active ulcers in the intestine. NBD was classified as either acute NBD (ANB) or chronic progressive NBD (CPNB) in accordance with the diagnostic criteria for NBD. ANB patients had to have acute or subacute headache, pyrexia, or focal neurological symptoms and a cell count of ≥6.2 cells/mm3 in the CSF or had to have developed acute or subacute symptoms at least twice during the year preceding enrollment, with a cell count of ≥6.2 cells/mm3 in the CSF at the onset of symptoms. CPNB patients had to have neuropsychiatric symptoms (dementia-like symptoms, psychiatric symptoms, truncal ataxia, dysarthria, etc.) and a CSF IL-6 concentration of ≥17.0 pg/mL at enrollment and at the most recent measurement within the year preceding enrollment, or a CSF IL-6 concentration of ≥17.0 pg/mL at enrollment and evidence of brainstem atrophy on brain magnetic resonance imaging (MRI). VBD patients had to have active vasculitis lesions (deep vein thrombosis, aortic lesions, etc.) and abnormalities in inflammatory markers such as serum C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR) at enrollment.\n\nExclusion criteria were as follows: intestinal manifestations that were not differentiated from acute appendicitis, infectious enteritis, Crohn disease (CD), intestinal tuberculosis, or drug-induced enterocolitis; history of resection of intestinal lesions; neurological manifestations that were not differentiated from infection/allergic meningitis/encephalitis/myelitis, systemic lupus erythematosus, brain/spinal cord tumor, vascular disorders, syphilis, multiple sclerosis, psychiatric disease, or sarcoidosis; vascular manifestations that were not differentiated from Takayasu arteritis, Buerger disease, or arteriosclerotic aneurysm; history of treatment with IFX or other biological drugs for intestinal BD, NBD, or VBD; history of treatment with IFX within 1 year before enrollment for diseases other than intestinal BD, NBD, or VBD or discontinuation of previous IFX treatment due to adverse events; history of a surgical procedure within 4 weeks before enrollment; history or complications of a serious infection requiring hospitalization, opportunistic infection, or tuberculosis within 6 months before enrollment; active hepatitis B or C, or hepatitis B virus carrier status; history of human immunodeficiency virus infection; and a history of congestive heart failure, demyelinating diseases or lymphoproliferative disease, or malignant tumor within 5 years before enrollment.\n\n2.2 Study design\nIFX at a dose of 5 mg/kg was intravenously infused to patients at weeks 0, 2, and 6, and every 8 weeks thereafter until week 46. If a patient showed a response to IFX by week 30 but thereafter lost the response and the physician deemed that dose escalation was necessary, a dose of 10 mg/kg was administered every 8 weeks until week 46.\n\nConcomitant use of biological drugs, except for IFX, cyclosporin, tacrolimus, and alkylating agents, was prohibited from enrollment to week 54. Changes to the dose of other anti-BD drugs, including azathioprine, 6-mercaptopurine, methotrexate, and aminosalicylic acid, and starting new treatment with or adding these drugs to the regimen, were prohibited from enrollment to evaluation at week 30. However, withdrawal or dose reduction of oral steroids was permitted in line with improvements in symptoms after week 0.\n\n2.3 Assessments\nAssessments were made in consideration of the specific characteristics of intestinal BD, NBD, and VBD. We assessed clinical symptoms, findings in ileocolonoscopic, brain MRI, computed tomography (CT) angiography, positron emission tomography (PET) studies, CSF (cell count and IL-6 concentration) analysis results, and inflammatory marker (CRP or ESR) levels. We also calculated the percentage of complete responders, defined as those who met the BD type-specific criteria described in Table 1. The primary endpoint was the percentage of complete responders at week 30. Secondary endpoints were the percentages of complete responders at weeks 14 and 54, patient visual analogue scale (VAS) score, Short Form-36 (SF-36) score with regard to physical health, and oral steroid dosage. In addition, we evaluated the major and the other symptoms of BD and assessed the pharmacokinetics and safety of IFX.\n\nTable 1 Definition of complete responders and assessment criteria.\n\nFor intestinal BD patients, the clinical symptoms were scored at weeks 0, 2, and 6, and every 4 weeks thereafter. Ileocolonoscopy was performed at weeks 0, 14, 30, and 54, and scores were determined in terms of changes in the length of the major axis of the principal intestinal ulcer from that at week 0. Additionally, serum CRP levels were measured at weeks 0, 2, and 6, and every 4 weeks thereafter. For NBD patients, the severity of clinical symptoms was scored at weeks 2 and 6 and every 4 weeks thereafter in terms of changes from the data recorded at week 0. Brain MRI was performed at weeks 0, 14, 30, and 54, and the high-intensity areas in ANB patients and the brainstem area in CPNB patients were scored by comparison to the area measurements made at week 0. Cell count (ANB only) and IL-6 concentrations in the CSF were measured at weeks 0, 14, 30, and 54. Further, for ANB patients, the incidence of acute or subacute attacks occurring between weeks 0 and 30 and between weeks 30 and 54 was determined. For VBD patients, we scored the changes in the degree of swelling, pain, or other VBD-associated clinical symptoms at weeks 2 and 6 and every 4 weeks thereafter in terms of the status at week 0. Changes in CT or PET/CT findings were scored at weeks 14, 30, and 54 by comparison with those at week 0. In addition, the levels of serum CRP and ESR were measured at weeks 0, 2, and 6, and every 4 weeks thereafter, and the incidence of venous thrombosis between weeks 0 and 30 and between weeks 30 and 54 was calculated. Details of the scores are provided in Table 1.\n\nImages obtained from NBD and VBD patients were centrally assessed by 2 BD specialists from the image assessment committee who were blinded to patient symptoms and time of imaging. IFX concentration was measured using an enzyme-linked immunosorbent assay[19] (Mitsubishi Tanabe Pharma Corporation, Osaka, Japan).\n\n2.4 Statistical analyses\nThe full analysis set was used for efficacy analysis. Patient characteristics and efficacy at each time point and at the final point of treatment at 5 mg/kg were assessed in terms of the percentage, frequency, or descriptive statistics. Missing data in the primary endpoint were compensated for using the last observation carried forward method. Safety was assessed on an intention-to-treat basis, and the incidence and percentages of adverse events and adverse drug reactions were calculated.\n\n3 Results\n3.1 Patient disposition\nAfter enrollment, IFX at 5 mg/kg was administered to 18 BD patients (11 intestinal BD, 3 NBD [2 ANB and 1 CPNB], and 4 VBD) (Fig. 1). Before week 30, 1 ANB patient withdrew consent and discontinued treatment with IFX. Subsequently, 14 BD patients (8 intestinal BD, 2 NBD, and 4 VBD) received a dose of 5 mg/kg IFX until week 54. The dose was increased to 10 mg/kg after week 30 in 3 intestinal BD patients, 1 of whom then discontinued treatment due to exacerbation of symptoms.\n\nFigure 1 Patient disposition and flow chart of the study. ANB = acute neurological Behçet disease, BD = Behçet disease, CPNB = chronic progressive neurological Behçet disease, IC = informed consent, IFX = infliximab, NBD = neurological Behçet disease, VBD = vascular Behçet disease.\n\nPatient characteristics are shown in Table 2. Skin lesions were the most common major symptom (15/18 [83%]). Among the 11 intestinal BD patients, the ileum (9 patients; 82%) was the most common lesion site, followed by the cecum and ascending colon (3 patients each; 27%), transverse colon and descending colon (1 patient each; 9%), and others (2 patients; 18%). No patients had lesions in the rectum. Of the 4 VBD patients, 3 (75%) had venous lesions (deep vein thrombosis of the lower extremity, 1; others, 2), and 1 (25%) had arterial lesions (arterial occlusion).\n\nTable 2 Baseline characteristics of patients.\n\n3.2 Efficacy\nEleven (61%) of the 18 BD patients showed a complete response at an early stage (week 14). This ratio of complete responses was maintained at week 30, the primary endpoint (61%, 11/18) (Table 3), and then increased to 69% (11/16) at week 54 and 67% (12/18) at the final point of 5 mg/kg therapy. Efficacy of IFX was maintained for up to 1 year. By BD type, the percentage of complete responders at week 30 was 55% (6/11) among intestinal BD patients, 33% (1/3) among NBD patients, and 100% (4/4) among VBD patients.\n\nTable 3 Proportion of complete responders.\n\n3.3 Intestinal BD\nClinical symptoms at week 0 were very mild in 3 patients with intestinal BD, mild in 5, and moderately severe in 3. The percentage of patients showing an improvement in clinical symptoms compared to that at week 0 was 64% (7/11) at week 2 and gradually increased to 73% (8/11) at week 14 and 91% (10/11) at week 30 (Fig. 2A). In addition, the percentage of patients showing an improvement in clinical symptoms was 80% (8/10) at week 54 and 82% (9/11) at the final point of 5 mg/kg therapy. The percentage of patients with no clinical symptoms was 36% (4/11) at week 2, which gradually increased to 64% (7/11) at week 30 and 80% (8/10) at week 54. The percentage of intestinal BD patients with no clinical symptoms at the final point of 5 mg/kg therapy was 73% (8/11).\n\nFigure 2 Efficacy of infliximab on intestinal Behçet disease. (A) Percentage with improved or cured clinical symptoms, (B) changes in size of major ulcers for each patient, and (C) changes in serum C-reactive protein (CRP) levels for each patient.\n\nHealing or scarring of the principal intestinal ulcer was recorded at week 14 in 9 (82%) patients, and most patients showed no recurrence until week 54 (Fig. 2B). The percentage of patients with healing or scarring of the principal ulcer was 82% (9/11) at week 30, 89% (8/9) at week 54, and 82% (9/11) at the final point of 5 mg/kg therapy.\n\nMedian serum CRP level was 0.20 mg/dL (interquartile range: 0.00–1.00 mg/dL) at week 0. This then decreased or remained low from week 2 up to week 54 in most intestinal BD patients (Fig. 2C), as follows: 0.00 mg/dL (0.00–0.00 mg/dL) at week 2, 0.15 mg/dL (0.00–0.80 mg/dL) at week 14, 0.10 mg/dL (0.00–2.20 mg/dL) at week 30, 0.10 mg/dL (0.00–0.20 mg/dL) at week 54, and 0.10 mg/dL (0.00–0.20 mg/dL) at the final point of 5 mg/kg therapy.\n\nIFX dose was increased to 10 mg/kg after week 30 in 3 patients with intestinal BD due to loss of response. Among these, the dose was increased in 1 patient at week 46 due to recurrence of abdominal pain, which caused some difficulties in daily activities. After dose escalation, the clinical symptoms and VAS score of the patient improved. In the 2nd patient, IFX dose was increased at week 38 due to abdominal pain, fever, diarrhea, and melena with high serum CRP level. However, although serum CRP levels, VAS score, and clinical symptoms improved after dose escalation, the disease could not be controlled and worsened at week 54. In the 3rd patient, IFX dose was increased at week 30 due to recurrence of abdominal pain and an increase in the size of the principal ulcer. Although the stomach pain, serum CRP level, and VAS score improved after dose escalation, the disease worsened after 2 doses of 10 mg/kg, and the patient was withdrawn from the study.\n\n3.4 NBD\nOne ANB patient (patient 1) had acute symptoms (fever and headache) and elevated cell count and IL-6 concentration in the CSF at week 0 (37 cells/μL and 145 pg/mL, respectively) (Fig. 3A). At week 2, the acute symptoms disappeared, and the cell count and IL-6 concentration decreased to 7 cells/μL and 1.8 pg/mL, respectively. Aside from a mild headache at week 22, no acute symptoms occurred at other measurement time points, and CSF analysis did not show any evidence of inflammation until week 54 (at week 54: cell count, ≤1 cell/μL; IL-6 concentration, 1.5 pg/mL). FLAIR MRI at week 0 showed high signal intensity in the posterior part of the right lenticular nucleus to the posterior limb of the internal capsule, while FLAIR MRI images showed a small area of high-intensity in the genu of the right internal capsule to the globus pallidus; however, these areas shrank in size by weeks 2, 14, and 30, and the high-intensity area in the right internal capsule was further reduced at week 54. Although 2 episodes of attack (acute symptoms) were reported during the 12 months before the start of administration (1st episode: diplopia and aphagia; 2nd episode: vertigo, nausea, fever, headache, and diplopia), only a single mild attack (mild headache) occurred after the start of IFX treatment. MRI did not depict any new areas of high signal intensity during the study period.\n\nFigure 3 Efficacy of infliximab on neurological Behçet disease. (A) CSF cell count, CSF IL-6 concentration, and FLAIR MRI images in patient 1 (ANB); (B) CSF cell count, CSF IL-6 concentration, and FLAIR MRI images in patient 2 (ANB); and (C) CSF IL-6 concentration and T1-weighted MRI images in patient 3 (CPNB). ANB = acute neurological Behçet disease, CPNB = chronic progressive neurological Behçet disease, CSF = cerebrospinal fluid, IL-6 = interleukin-6, MRI = magnetic resonance imaging.\n\nThe other ANB patient (patient 2) reported headache as a chronic symptom but did not have any acute symptoms or abnormalities on CSF analysis (cell count 3 cells/μL and IL-6 concentration of 2.5 pg/mL) at week 0 (Fig. 3B). Although the patient experienced headache and dull headache as chronic symptoms until week 22, no acute symptoms occurred after the start of IFX treatment. However, this patient withdrew consent and discontinued the study at week 22. CSF cell count was 2 cells/μL both at week 14 and withdrawal. CSF IL-6 concentration was 23.0 pg/mL at week 14 and 6.5 pg/mL at withdrawal. The high-intensity areas in the right forehead and parietal lobe seen on FLAIR MRI of the head at week 0 were reduced at both week 14 and at withdrawal. Although this patient experienced 2 episodes of attack (acute symptoms) in the year preceding the start of IFX treatment (1st episode: headache; 2nd episode: headache and malaise), the attacks did not occur after the start of treatment, although the evaluation period was relatively short.\n\nOne CPNB patient (patient 3) showed slightly slow reactions with a relatively high CSF IL-6 concentration of 64.5 pg/mL at week 0 (Fig. 3C). Despite an increase to 430.0 pg/mL at week 2, no changes in clinical symptoms compared to week 0 were noted. At week 6, all clinical symptoms had resolved, and no symptoms (0 points) appeared until week 54. CSF IL-6 concentration declined to 35.1 pg/mL at week 14 and further decreased to 5.4 pg/mL at week 30, but slightly increased at week 54 (32.1 pg/mL). At week 0, T1-weighted MRI of the head did not reveal any abnormalities. The areas of the midbrain and pons were 87.1 and 597.9 mm2, respectively, at week 0 and remained nearly unchanged until week 54 (93.7 and 589.5 mm2, respectively).\n\n3.5 VBD\nAt week 2, clinical symptoms were improved (1 point) or absent (0 points) in 3 of the 4 VBD patients (Fig. 4A). Aggravation of clinical symptoms did not occur in any of the VBD patients, and improvement was maintained between weeks 38 and 54. Imaging findings at week 14 showed improvement in inflammation (0 points) in 3 of the 4 patients, which continued until week 54. In the remaining VBD patient, imaging findings depicted no aggravation until week 54. PET/CT images of the patient with thrombophlebitis of the lower legs who showed improvement are shown in Fig. 4B. At week 0, inflammation was observed around the veins of the lower legs (slightly more severe in the right lower leg). These inflammatory changes ameliorated at week 14 and showed further improvement at weeks 30 and 54. At this last evaluation, both lower limbs showed no marked difference in severity. With respect to the patient with arterial occlusion in the right armpit, the right radial artery was not palpable and the right extremity was numb at week 0. The arterial occlusion slightly improved at week 14 and further improved at weeks 30 and 54.\n\nFigure 4 Efficacy of infliximab on vascular Behçet disease. (A) Change in clinical symptoms, (B) PET/CT images of thrombophlebitis of the lower legs in a representative patient, (C) changes in serum CRP level for each patient, and (D) changes in serum ESR for each patient. CRP = C-reactive protein, CT = computed tomography, ESR = erythrocyte sedimentation rate, PET = positron emission tomography.\n\nChanges in the serum CRP level and ESR in VBD patients are shown in Fig. 4C and D. The median serum CRP level was 0.90 mg/dL at week 0, which decreased to 0.25 mg/dL at week 2. Levels stayed low at weeks 14, 30, and 54, with median values of 0.15, 0.10, and 0.15 mg/dL, respectively. Median serum ESR was 31.0 mm/hour at week 0, declining to 11.0, 8.5, 4.5, and 6.5 mm/hour at weeks 2, 14, 30, and 54, respectively. Neither clinical symptoms nor imaging findings showed evidence of the development of new lesions throughout the investigational period. No newly occurring venous thrombosis was noted in any of the 4 VBD patients during the study period.\n\n3.6 Improvement of quality of life (QOL) in patients with gastrointestinal lesions, central nervous system lesions, and vascular lesions\nAmong BD patients, VAS score (mean ± standard deviation) improved over time, from 49.8 ± 24.2 mm at week 0 to 34.2 ± 28.3 mm, 27.5 ± 22.9 mm, 24.6 ± 25.5 mm, and 17.0 ± 21.8 mm at weeks 2, 14, 30, and 54, respectively (Fig. 5A). The SF-36 score (mean ± standard deviation) was 35.9 ± 15.6 at week 0, and then improved to 44.9 ± 15.9, 44.4 ± 16.0, and 48.6 ± 10.6 at weeks 14, 30, and 54, respectively (Fig. 5B). VAS and SF-36 scores improved across all types of BD.\n\nFigure 5 Effects of infliximab on quality of life in patients with intestinal, neurological, and vascular Behçet disease. (A) Patient VAS score, (B) SF-36 score (physical health summary score). Data are shown as the means ± standard deviation. SF-36 = Short Form-36, VAS = visual analogue scale.\n\n3.7 Steroid dose reduction and withdrawal\nOf the 14 BD patients treated with oral steroids at week 0, doses were reduced in 6 at week 14 and in these 6 as well as in an additional 1 at week 30 (n = 7 total; Table 4). Two of these 7 patients were eventually free from treatment with steroids, both with intestinal BD. These 7 BD patients remained on reduced steroid doses until week 54 or were free from steroid use by then. By week 54, steroid doses were reduced in another 2 patients, and one of these 2 patients eventually withdrew from steroid use. Steroid dose was reduced across all types of BD. Six of the 9 patients with reduced steroid doses showed complete responses, and 2 of these 6 were free from steroid treatment successfully. No patients required initiation of oral steroid treatment or an increase in dosage during the study period.\n\nTable 4 Incidence of dose reduction and withdrawal of steroids.\n\n3.8 Effects on major symptoms of BD\nMore than 60% of BD patients who had oral aphtha (n = 18), skin symptoms (n = 18), or genital ulcers (n = 18) at week 0 had improved by week 2 (Fig. 6A). The percentage showing improvement after week 6 ranged from 73% to 91% for oral aphtha, 73% to 100% for skin symptoms, and 83% to 100% for genital ulcer and the percentage with no symptoms (0 points) increased after week 2, suggesting that the efficacy of IFX was maintained. One patient had eye symptoms at week 0 that resolved by week 2 and did not recur during the course of the study.\n\nFigure 6 Efficacy of infliximab on major symptoms of Behçet disease (BD) and global assessment of overall disease activities by physicians and patients. (A) Major symptoms of BD (oral aphtha, skin symptoms, and pudendal ulcer), (B) assessment of overall disease activities of BD (assessed by physicians or patients).\n\n3.9 Effects on all symptoms of BD (assessed by physicians or patients)\nAt week 2, the percentages of patients showing slight improvement (1 point) or improvement (0 points) in all symptoms of BD as assessed by physicians and patients were 61% (11/18) and 61% (11/18), respectively (Fig. 6B). Percentages of patients showing slight improvement or improvement as assessed by the physicians and patients were 94% (17/18) and 83% (15/18) at week 14, 100% (17/17) and 76% (13/17) at week 30, and 94% (15/16) and 88% (14/16) at week 54, respectively. These percentages clearly remained high, irrespective of whether reporting was by physicians or patients. Percentages of patients showing improvement as assessed by physicians were 33% (6/18) at week 2, 61% (11/18) at week 14, 71% (12/17) at week 30, and 75% (12/16) at week 54; the corresponding percentages as assessed by patients were 17% (3/18), 50% (9/18), 47% (8/17), and 50% (8/16).\n\n3.10 Pharmacokinetics\nNo marked differences in serum IFX concentration were noted by BD type among patients treated with a dose of 5 mg/kg. Trough serum IFX concentrations were stably maintained for each BD type after week 14 (Fig. 7). In the 3 intestinal BD patients whose doses were increased to 10 mg/kg after week 30 due to loss of response, trough serum IFX concentrations rose after the dose escalation (7.78–18.74, 0.96–6.01, and 4.39–9.77 μg/mL).\n\nFigure 7 Changes in serum infliximab concentration. Data of patients with intestinal and vascular BD are shown as the median. ANB = acute neurological Behçet disease, BD = Behcet disease, CPNB = chronic progressive neurological Behçet disease, IFX = infliximab, VBD = vascular BD.\n\n3.11 Safety\nThe incidence of adverse events across all patients was 94% (17/18), with the following type breakdown: 91% (10/11) in intestinal BD patients, 100% (3/3) in NBD patients, and 100% (4/4) in VBD patients, showing no marked difference among BD types (Table 5). Infections occurred in 11 patients. Regarding the infections reported in more than 10% of patients, we observed upper respiratory tract infection (5/18), nasopharyngitis (4/18), gastroenteritis (2/18), and infectious enteritis (2/18). With regard to serious adverse events, worsening of the underlying disease and cataracts were observed in 1 intestinal BD patient. A causal relationship between these serious adverse events and IFX was ruled out because the 1st patient had similar worsening of the underlying disease with small bowel perforation even before enrollment, and the cataract in the 2nd patient was considered to be a result from a long-term use of oral steroids. In the 3 intestinal BD patients who were administered an increased dose of 10 mg/kg, the only adverse event that occurred after the dose escalation was the worsening of the underlying disease, as mentioned above.\n\nTable 5 Safety profile.\n\n4 Discussion\nIn those patients with intestinal BD, NBD, and VBD who had displayed a poor response or intolerance to conventional therapy, efficacy of IFX was observed soon after starting treatment and was maintained until week 54 of treatment. No major differences in the safety or pharmacokinetics of IFX were noted between our study population versus patients receiving treatment with IFX in rheumatoid arthritis (RA) or CD.\n\nIFX has been reported to exert its effects in BD via a number of mechanisms, including neutralization of TNF-α and subsequent suppression of γδT cell expansion, activation, and cytotoxic activity[20] and a decrease in the levels of CSF IL-6 through cytotoxic effects on monocytes/macrophages.[15] Further, IFX has been found to be effective in treating intestinal BD,[10–12,17] NBD,[13–15,17] and VBD.[16,17] However, most of these reports were case studies and retrospective cohort clinical studies, and little data are available from prospective clinical studies.\n\nWe obtained novel data on IFX through comprehensive assessment of clinical symptoms, morphological characteristics, and levels of inflammatory markers in intestinal BD, NBD, and VBD patients. Approximately 60% of our population treated with IFX showed a complete response at week 14, and efficacy was maintained until the end of the study at week 54. The percentage of complete responders at week 30 (primary endpoint) was 61%. Similar to the French retrospective study,[17] the findings from our prospective study suggest that IFX is indeed effective for BD patients with these serious complications.\n\nIn intestinal BD patients, the clinical symptoms and endoscopic findings improved soon after starting treatment, as evidenced by reductions in serum CRP levels, and this efficacy was maintained until week 54. Our present findings for IFX were comparable to previous findings from studies using other TNF inhibitors, such as adalimumab[21] or etanercept,[22] in terms of efficacy against intestinal BD. Healing or scarring of the principal ulcer was achieved in more than 80% of such patients in the present study, suggesting that IFX has potent mucosal healing effects. Mucosal healing in intestinal BD patients has been reported to predict the long-term prognosis, in terms of the risk of clinical relapse and surgery.[23] Therefore, IFX is expected to maintain low disease activity in the long term, which subsequently may reduce the need for surgery.\n\nIn CPNB patients, IFX has been reported to reduce CSF IL-6 concentrations and thereby inhibit the progression of CPNB.[15] In the present study as well, IFX lowered CSF IL-6 concentrations and resolved clinical symptoms in a CPNB patient without the occurrence of brainstem atrophy. In ANB patients, IFX lowered the cell count and IL-6 concentrations in the CSF and inhibited the onset of attacks. Onset of attacks in NBD patients may lead to the onset or progression of cerebellar disorder-associated gait disorders, dysarthria, and dysuria and then to cognitive impairment, neurological disorders, and personality changes.[24] Although our study involved a relatively small number of NBD patients, our findings suggest that IFX inhibits the onset of attacks and improves or inhibits NBD-associated progressive pathological conditions. Therefore, IFX may improve the overall prognosis in NBD patients.\n\nIn VBD patients, analysis of clinical symptoms, imaging findings, and inflammatory markers demonstrated the efficacy of IFX soon after starting treatment, with effectiveness maintained until week 54. PET/CT findings showed that IFX administration improved thrombophlebitis and arterial occlusion by decreasing the severity of inflammation. Neither the aggravation of VBD nor inflammation was newly seen in any patient receiving IFX treatment during the present study, suggesting that the antiinflammatory effects of IFX inhibit the progression of VBD.\n\nQOL is relatively poor among BD patients.[25] However, in the present study, IFX improved the VAS and SF-36 scores, irrespective of the type of BD. This effect suggests that, by resolving BD symptoms, IFX improves the QOL of BD patients. In the present study, IFX treatment also allowed a reduction in dose or withdrawal of steroid treatment in all BD types, while also improving BD-associated symptoms. IFX improved not only the major symptoms, including recurrent oral aphthous ulcers, skin lesions, eye lesions, and genital ulcers, but also all the other symptoms of BD, from treatment initiation up to week 54. One patient with eye symptoms at baseline did not develop any eye symptoms or ocular attacks throughout the course of the study. In addition, IFX has been reported to suppress the frequency of ocular attacks in patients with BD with refractory uveoretinis.[9] We therefore believe that IFX treatment is effective against all symptoms of BD.\n\nThe efficacy of IFX in treating RA and CD has been reported to depend on its serum concentration, and dose escalation up to 10 mg/kg is possible.[26–31] In the present study, 3 intestinal BD patients who met the dose escalation criteria were administered IFX at 10 mg/kg. After dose escalation, clinical symptoms, serum CRP level, and VAS score continuously or temporarily improved, accompanied by an increase in serum IFX concentration. In spite of the paucity of a number of BD patients, our observations suggest that a dose of 10 mg/kg is useful in those who lose response at 5 mg/kg, as is the case with RA and CD.\n\nNo marked differences in safety were noted among patients by BD type. The safety of IFX administration in the present study was comparable to that determined previously in studies with other diseases, including RA,[26,27] CD,[28–31] and BD with refractory uveoretinitis.[9]\n\nInterpretation of our study is limited by the small population and a lack of any controls. BD is a rare disease in Japan, particularly intestinal BD, NBD, and VBD. After consulting with the Pharmaceuticals and Medical Devices Agency of Japan, the sample size was set to be at least 3 patients per disease type, with a total of 15 patients, in consideration of the number of these patients available and the registration criteria for this study. Our study population was therefore quite small. In addition, we were unable to include a control group for ethical reasons as well as a lack of appropriate control agents and the small number of subjects. We therefore consider it necessary to collect additional data using other methods, such as postmarketing surveillance.\n\nIn conclusion, IFX is effective and well tolerated in the treatment of intestinal BD, NBD, and VBD patients with poor response or intolerance to conventional therapy. We believe that the antiinflammatory effect of IFX at the sites of intestinal, neurological, and vascular lesions may help improve morphological changes (ileocecal ulcerations, high-intensity lesions on brain, brainstem atrophy, thrombophlebitis, etc.), clinical symptoms, and QOL and also help reduce steroid dose. IFX may therefore represent a promising new therapeutic option for use in BD patients with these serious conditions.\n\nAcknowledgements\nThe authors thank the patients, study personnel, and the following investigators who took part in this study: Tatsuya Atsumi, Hokkaido University Graduate School of Medicine; Toshifumi Ashida and Atsuo Maemoto, Sapporo Higashi Tokushukai Hospital; Tomonori Ishii, Tohoku University School of Medicine; Yasuo Suzuki, Department of Internal Medicine, Toho University Sakura Medical Center; Hajime Kono, Teikyo University School of Medicine; Nagamu Inoue, Keio University School of Medicine; Tetsuji Sawada, Tokyo Medical University; Mitsumasa Kishimoto, St. Luke's International Hospital; Keishi Fujio, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo; Hideo Yoshida, Anjo Kosei Hospital; Kenji Watanabe and Hirokazu Yamagami, Osaka City University Graduate School of Medicine; Shiro Nakamura, Department of IBD, Hyogo College of Medicine; Hiroaki Dobashi, Department of Internal Medicine, Faculty of Medicine, Kagawa University; Toshiyuki Matsui, Fukuoka University Chikushi Hospital.\n\nAbbreviations: ANB = acute neurological Behçet disease, BD = Behçet disease, CD = Crohn disease, CPNB = chronic progressive neurological Behçet disease, CRP = C-reactive protein, CSF = cerebrospinal fluid, CT = computed tomography, ESR = erythrocyte sedimentation rate, IFX = infliximab, IL-6 = interleukin-6, MRI = magnetic resonance imaging, NBD = neurological Behçet disease, PET = positron emission tomography, QOL = quality of life, RA = rheumatoid arthritis, SF-36 = Short Form-36, TNF-α = tumor necrosis factor-α, VAS = visual analogue scale, VBD = vascular Behçet disease.\n\nFunding: This study was funded by Mitsubishi Tanabe Pharma Corporation.\n\nToshifumi Hibi, Hirotoshi Kikuchi, and Yoshiaki Ishigatsubo have received consultant and lecture fees from Mitsubishi Tanabe Pharma. Shunsei Hirohata has received research support as well as consultant and lecture fees from Mitsubishi Tanabe Pharma. Ukihide Tateishi has received consultant fees from Mitsubishi Tanabe Pharma. Noriko Sato, Kunihiko Ozaki, and Kazuoki Kondo are employees of Mitsubishi Tanabe Pharma.\n==== Refs\nReferences\n[1] Saadoun D Wechsler B \nBehçet's disease . Orphanet J Rare Dis \n2012 ;7 :20 .22497990 \n[2] Suzuki Kurokawa M Suzuki N \nBehcet's disease . Clin Exp Med \n2004 ;3 :10 –20 .15598081 \n[3] Ideguchi H Suda A Takeno M \nBehçet disease: evolution of clinical manifestations . Medicine \n2011 ;90 :125 –32 .21358436 \n[4] Hisamatsu T Naganuma M Matsuoka K \nDiagnosis and management of intestinal Behçet's disease . Clin J Gastroenterol \n2014 ;7 :205 –12 .24883128 \n[5] Pineton de Chambrun M Wechsler B Geri G \nNew insights into the pathogenesis of Behçet's disease . Autoimmun Rev \n2012 ;11 :687 –98 .22197900 \n[6] Imamura Y Kurokawa MS Yoshikawa H \nInvolvement of Th1 cells and heat shock protein 60 in the pathogenesis of intestinal Behçet's disease . Clin Exp Immunol \n2005 ;139 :371 –8 .15654837 \n[7] Yüksel Ş Eren E Hatemi G \nNovel NLRP3/cryopyrin mutations and pro-inflammatory cytokine profiles in Behçet's syndrome patients . Int Immunol \n2014 ;26 :71 –81 .24135410 \n[8] Hirohata S Kikuchi H \nChanges in biomarkers focused on differences in disease course or treatment in patients with neuro-Behçet's disease . Intern Med \n2012 ;51 :3359 –65 .23257520 \n[9] Ohno S Nakamura S Hori S \nEfficacy, safety, and pharmacokinetics of multiple administration of infliximab in Behçet's disease with refractory uveoretinitis . J Rheumatol \n2004 ;31 :1362 –8 .15229958 \n[10] Travis SP Czajkowski M McGovern DP \nTreatment of intestinal Behçet's syndrome with chimeric tumour necrosis factor alpha antibody . Gut \n2001 ;49 :725 –8 .11600479 \n[11] Naganuma M Sakuraba A Hisamatsu T \nEfficacy of infliximab for induction and maintenance of remission in intestinal Behçet's disease . Inflamm Bowel Dis \n2008 ;14 :1259 –64 .18393375 \n[12] Kinoshita H Kunisaki R Yamamoto H \nEfficacy of infliximab in patients with intestinal Behçet's disease refractory to conventional medication . Intern Med \n2013 ;52 :1855 –62 .23994973 \n[13] Ribi C Sztajzel R Delavelle J \nEfficacy of TNF α blockade in cyclophosphamide resistant neuro-Behçet disease . J Neurol Neurosurg Psychiatry \n2005 ;76 :1733 –5 .16291906 \n[14] Fujikawa K Aratake K Kawakami A \nSuccessful treatment of refractory neuro- Behçet disease with infliximab: a case report to show its efficacy by magnetic resonance imaging, transcranial magnetic stimulation and cytokine profile . Ann Rheum Dis \n2007 ;66 :136 –7 .17178762 \n[15] Kikuchi H Aramaki K Hirohata S \nEffect of infliximab in progressive neuro-Behçet's syndrome . J Neurol Sci \n2008 ;272 :99 –105 .18550081 \n[16] Adler S Baumgartner I Villiger PM \nBehçet's disease: successful treatment with infliximab in 7 patients with severe vascular manifestations. A retrospective analysis . Arthritis Care Res \n2012 ;64 :607 –11 .\n[17] Vallet H Riviere S Sanna A \nEfficacy of anti-TNF alpha in severe and/or refractory Behçet's disease: multicenter study of 124 patients . J Autoimmun \n2015 ;62 :67 –74 .26162757 \n[18] Investigator's brochure: infliximab ; 2015 \nAvailable at: http://www.pmda.go.jp/drugs/2015/P20150824001/index.html. (in Japanese) \n[Accessed February 15, 2016].\n[19] Maini RN Breedveld FC Kalden JR \nTherapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis . Arthritis Rheum \n1998 ;41 :1552 –63 .9751087 \n[20] Accardo-Palumbo A Giardina AR Ciccia F \nPhenotype and functional changes of Vγ9/Vδ2 T lymphocytes in Behçet's disease and the effect of infliximab on Vgamma9/Vdelta2 T cell expansion, activation and cytotoxicity . Arthritis Res Ther \n2010 ;12 :R109 .20525258 \n[21] Tanida S Inoue N Kobayashi K \nAdalimumab for the treatment of Japanese patients with intestinal Behçet's disease . Clin Gastroenterol Hepatol \n2015 ;13 :940 –8 .25245624 \n[22] Ma D Zhang CJ Wang RP \nEtanercept in the treatment of intestinal Behcet's disease . Cell Biochem Biophys \n2014 ;69 :735 –9 .24622940 \n[23] Yim SM Kim DH Lee HJ \nMucosal healing predicts the long-term prognosis of intestinal Behçet's disease . Dig Dis Sci \n2014 ;59 :2529 –35 .24838499 \n[24] Hirohata S Kikuchi H Sawada T \nClinical characteristics of neuro-Behcet's disease in Japan: a multicenter retrospective analysis . Mod Rheumatol \n2012 ;22 :405 –13 .21935641 \n[25] Bodur H Borman P Ozdemir Y \nQuality of life and life satisfaction in patients with Behçet's disease: relationship with disease activity . Clin Rheumatol \n2006 ;25 :329 –33 .16267609 \n[26] Rahman MU Strusberg I Geusens P \nDouble-blinded infliximab dose escalation in patients with rheumatoid arthritis . Ann Rheum Dis \n2007 ;66 :1233 –8 .17392352 \n[27] Takeuchi T Miyasaka N Inoue K \nImpact of trough serum level on radiographic and clinical response to infliximab plus methotrexate in patients with rheumatoid arthritis: results from the RISING study . Mod Rheumatol \n2009 ;19 :478 –87 .19626391 \n[28] Suzuki Y Matsui T Ito H \nCirculating interleukin 6 and albumin, and infliximab levels are good predictors of recovering efficacy after dose escalation infliximab therapy in patients with loss of response to treatment for Crohn's disease: a prospective clinical trial . Inflamm Bowel Dis \n2015 ;21 :2114 –22 .26218144 \n[29] St Clair EW Wagner CL Fasanmade AA \nThe relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial . Arthritis Rheum \n2002 ;46 :1451 –9 .12115174 \n[30] Hanauer SB Feagan BG Lichtenstein GR \nMaintenance infliximab for Crohn's disease: the ACCENT I randomised trial . Lancet \n2002 ;359 :1541 –9 .12047962 \n[31] Hibi T Sakuraba A Watanabe M \nRetrieval of serum infliximab level by shortening the maintenance infusion interval is correlated with clinical efficacy in Crohn's disease . Inflamm Bowel Dis \n2012 ;18 :1480 –7 .21987418\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "95(24)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D001528:Behcet Syndrome; D015415:Biomarkers; D001799:Blood Sedimentation; D001808:Blood Vessels; D005260:Female; D005500:Follow-Up Studies; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D007422:Intestines; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009420:Nervous System; D011446:Prospective Studies; D012074:Remission Induction; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e3863",
"pmc": null,
"pmid": "27310969",
"pubdate": "2016-06",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "21358436;16267609;12115174;16291906;22162223;12047962;18550081;24622940;23257520;15229958;9751087;26218144;21987418;25245624;22497990;18393375;24838499;22197900;23994973;17392352;21935641;20525258;26162757;15654837;24883128;11600479;17178762;15598081;24135410;19626391",
"title": "Infliximab therapy for intestinal, neurological, and vascular involvement in Behcet disease: Efficacy, safety, and pharmacokinetics in a multicenter, prospective, open-label, single-arm phase 3 study.",
"title_normalized": "infliximab therapy for intestinal neurological and vascular involvement in behcet disease efficacy safety and pharmacokinetics in a multicenter prospective open label single arm phase 3 study"
} | [
{
"companynumb": "JP-JNJFOC-20160622283",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "1",
"... |
{
"abstract": "BACKGROUND\nThis Phase IV, open-label, multicentre, randomized study (MEnTOR) compared two low-dose recombinant human follicle-stimulating hormone (r-hFSH) protocols for ovulation induction.\n\n\nMETHODS\nThis study was conducted in six Middle Eastern countries between March 2009 and March 2011. Eligible women (18-37 years), with World Health Organization Group II anovulatory infertility, were randomized to receive r-hFSH (starting daily dose: 75 IU) as a chronic low-dose (CLD) (37.5 IU dose increase on Day 14) or low-dose (LD) (37.5 IU dose increase on Day 7) protocol if no follicles were ≥ 10 mm. The maximum r-hFSH daily dose permitted was 225 IU/day. The total length of ovarian stimulation could not exceed 35 days, unless ultrasound assessment suggested imminent follicular growth and maturation. Patients underwent only one treatment cycle. Primary endpoint: incidence of mono-follicular development. Secondary endpoints included: stimulation duration and rates of bi-follicular development; human chorionic gonadotrophin administration rate; clinical pregnancy; and cycle cancellation (owing to inadequate response). Adverse events (AEs) were recorded. The primary efficacy analysis was performed using data from all patients who received at least one dose of correct study medication, had at least one efficacy assessment, and no protocol violations at treatment start (CLD group, n=122; LD group, n=125).\n\n\nRESULTS\nMono-follicular development rates (primary endpoint) were similar in both groups (CLD: 56.6% [69/122] versus LD: 55.2% [69/125], p=0.93; primary efficacy analysis population). Similarly, there were no significant differences between groups in bi-follicular development, clinical pregnancy or cycle cancellation (inadequate response) rates. In patients who received human chorionic gonadotrophin injections, the mean duration of stimulation was 13.7 days in the CLD group and 12.9 days in the LD group. Clinical pregnancy rates for those patients who received an hCG injection were similar in both groups (CLD: 20.2% [19/94] versus LD: 19.8% [18/91], p=0.94; primary efficacy analysis population). Most AEs were mild in severity. Only one case of ovarian hyperstimulation syndrome was reported (mild; CLD group).\n\n\nCONCLUSIONS\nEfficacy and safety outcomes were similar for the two protocols.",
"affiliations": "Department of Medical Affairs, Merck Serono Middle East FZ - LLC, Dubai, UAE. khaled.esmat@genzyme.com.",
"authors": "Serour|Gamal I|GI|;Aboulghar|Mohamed|M|;Al Bahar|Awatef|A|;Hugues|Jean-Noel|JN|;Esmat|Khaled|K|",
"chemical_list": "D005300:Fertility Agents, Female; D043373:Follicle Stimulating Hormone, Human; D011994:Recombinant Proteins; C571801:follitropin alfa",
"country": "England",
"delete": false,
"doi": "10.1186/1477-7827-12-52",
"fulltext": "\n==== Front\nReprod Biol EndocrinolReprod. Biol. EndocrinolReproductive Biology and Endocrinology : RB&E1477-7827BioMed Central 1477-7827-12-522494215510.1186/1477-7827-12-52ResearchPhase IV, open-label, randomized study of low-dose recombinant human follicle-stimulating hormone protocols for ovulation induction Serour Gamal I 1giserour1@link.netAboulghar Mohamed 2ghar@link.netAl Bahar Awatef 3ajalbahar@dha.gov.aeHugues Jean-Noel 4jean-noel.hugues@jvr.aphp.frEsmat Khaled 56khaled.esmat@genzyme.com1 Department of Obstetrics and Gynaecology and International Islamic Center for Population Studies and Research, Al Azhar University, Cairo, Egypt2 Egyptian IVF Center, Maadi, Cairo, Egypt and Department of Obstetrics and Gynecology, Cairo University, Cairo, Egypt3 Dubai Gynecology and Fertility Center, Dubai, UAE4 Department of Obstetrics and Gynaecology, Center for Reproductive Medicine, Jean Verdier Hospital, University Paris XIII, Paris, France5 Department of Medical Affairs, Merck Serono Middle East FZ – LLC, Dubai, UAE6 Current address: Department of Medical Affairs, Genzyme Intercontinental Region, Dubai, UAE2014 18 6 2014 12 52 52 1 11 2013 11 6 2014 Copyright © 2014 Serour et al.; licensee BioMed Central Ltd.2014Serour et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly 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\nThis Phase IV, open-label, multicentre, randomized study (MEnTOR) compared two low-dose recombinant human follicle-stimulating hormone (r-hFSH) protocols for ovulation induction.\n\nMethods\nThis study was conducted in six Middle Eastern countries between March 2009 and March 2011. Eligible women (18–37 years), with World Health Organization Group II anovulatory infertility, were randomized to receive r-hFSH (starting daily dose: 75 IU) as a chronic low-dose (CLD) (37.5 IU dose increase on Day 14) or low-dose (LD) (37.5 IU dose increase on Day 7) protocol if no follicles were ≥10 mm. The maximum r-hFSH daily dose permitted was 225 IU/day. The total length of ovarian stimulation could not exceed 35 days, unless ultrasound assessment suggested imminent follicular growth and maturation. Patients underwent only one treatment cycle. Primary endpoint: incidence of mono-follicular development. Secondary endpoints included: stimulation duration and rates of bi-follicular development; human chorionic gonadotrophin administration rate; clinical pregnancy; and cycle cancellation (owing to inadequate response). Adverse events (AEs) were recorded. The primary efficacy analysis was performed using data from all patients who received at least one dose of correct study medication, had at least one efficacy assessment, and no protocol violations at treatment start (CLD group, n = 122; LD group, n = 125).\n\nResults\nMono-follicular development rates (primary endpoint) were similar in both groups (CLD: 56.6% [69/122] versus LD: 55.2% [69/125], p = 0.93; primary efficacy analysis population). Similarly, there were no significant differences between groups in bi-follicular development, clinical pregnancy or cycle cancellation (inadequate response) rates. In patients who received human chorionic gonadotrophin injections, the mean duration of stimulation was 13.7 days in the CLD group and 12.9 days in the LD group. Clinical pregnancy rates for those patients who received an hCG injection were similar in both groups (CLD: 20.2% [19/94] versus LD: 19.8% [18/91], p = 0.94; primary efficacy analysis population). Most AEs were mild in severity. Only one case of ovarian hyperstimulation syndrome was reported (mild; CLD group).\n\nConclusions\nEfficacy and safety outcomes were similar for the two protocols.\n\nTrial registration\nClinicaltrials.gov NCT01081626.\n\nAnovulatory infertilityRecombinant human follicle-stimulating hormoneLow-dose protocolOvulation induction\n==== Body\nBackground\nOvulatory disorders account for approximately 30% of all cases of infertility [1]. World Health Organization (WHO) Group II anovulatory infertility is the most common form of ovulatory dysfunction and is characterized by asynchronous gonadotrophin production with follicle-stimulating hormone (FSH) and oestradiol (E2) levels within the normal range. A large proportion of women with WHO Group II anovulatory infertility have polycystic ovary syndrome [2].\n\nFirst-line therapy for WHO Group II anovulatory infertility is usually clomiphene citrate (CC) [3,4]. However, a substantial proportion (approximately 40%) of women with WHO Group II anovulatory infertility fail to conceive following CC therapy [5]. Such patients may benefit from gonadotrophin therapy to stimulate follicle development and induce ovulation [1,4,6-9]. Ovulation induction (OI), however, may be associated with the serious complications of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy [9-11].\n\nThe amount of exogenous FSH required to induce follicular development (the so-called FSH threshold) is highly variable among individuals [12-16]. This is particularly important for women with WHO Group II anovulatory infertility and polycystic ovarian morphology [5], as the ovaries are extremely sensitive to gonadotrophin stimulation [8].\n\nChronic low-dose (CLD) step-up FSH protocols have been developed so that the lowest effective dose of FSH can be used to achieve the objective of mono-follicular development [5,16,17]. The classic CLD regimen involves a low daily starting dose (usually 75 IU) for 14 days and, if necessary, the FSH dose is increased in small increments (37.5 IU), at intervals of no fewer than 7 days, until follicular development is initiated [8]. Combined data from 11 studies indicate that such CLD protocols result in a high mono-ovulation rate (69% of cycles) and low multiple pregnancy and OHSS rates (5.7% and 0.14% of cycles, respectively) [8].\n\nA modified protocol has also been developed and utilized by some clinicians in an attempt to shorten treatment schedules and reduce costs. In this so-called low-dose (LD) protocol, the starting dose of FSH (75 IU) is maintained for only 7 days before small incremental dose increases are permitted [8]. However, evaluation of such LD protocols comprises only one small single-centre study (n = 50), which found that although the duration of FSH stimulation was shorter, the risk of multi-follicular development was greater than with CLD protocols [8].\n\nTechnological advances allow recombinant human (r-h) FSH (follitropin alfa; GONAL-f®; Merck Serono S.A.– Switzerland, a subsidiary of Merck KGaA, Darmstadt, Germany) to be filled by mass (FbM) rather than by conventional bioassay [18]. This results in high batch-to-batch consistency and allows precise dosing of r-hFSH (follitropin alfa), which is likely to be particularly beneficial when using OI protocols with small dose increments. Indeed, it is possible that the use of r-hFSH (follitropin alfa) FbM may reduce the individual variability in ovarian response [19]. In turn, this may result in measurable differences in outcomes between LD and CLD protocols.\n\nThis article reports the findings of the first randomized, multicentre study to compare the efficacy and safety of CLD versus LD protocols for OI using r-hFSH (follitropin alfa FbM). The primary objective of this post-marketing study was to investigate the optimization of r-hFSH treatment in patients with chronic anovulation.\n\nMethods\nStudy design\nThis randomized, multicentre, open-label, Phase IV study (Middle East Trial for Ovulation induction Responders [MEnTOR]; NCT01081626) was conducted between March 2009 and March 2011 in six Middle Eastern countries (Egypt, Iran, Kuwait, Lebanon, Saudi Arabia and United Arab Emirates). Ten sites were originally involved, with three additional sites later added because of slow recruitment.\n\nThe study was performed in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice and all applicable regulatory requirements - see Additional file 1. Independent ethics committee approval was obtained at each study centre. Written informed consent was obtained from all patients prior to study start.\n\nStudy population\nWomen aged 18–37 years with WHO Group II anovulatory infertility (defined as a menstrual cycle duration >35 days or regular cycles with luteal-phase progesterone [P4] levels <10 nmol/mL) and who wished to conceive were eligible for inclusion in the study. Other key inclusion criteria were: body mass index (BMI) >20 to ≤32 kg/m2; spontaneous or CC-induced menses, or a positive progestin-induced withdrawal bleed within the previous year; normal uterine cavity and ≥1 patent fallopian tube; early follicular-phase FSH and prolactin levels within the normal range; total antral follicle count ≥10 (follicles of ≥2 to <11 mm in diameter in both ovaries); and a male partner with sperm considered normal based on local standards.\n\nPatients who had received CC or gonadotrophins within 1 month of screening were excluded from participation. Other key exclusion criteria were: ovarian enlargement or ovarian cyst (unrelated to polycystic ovary syndrome); uterine fibroids; gynaecological bleeding of unknown aetiology; history of ≥3 miscarriages, extra-uterine pregnancy or severe OHSS (classified according to Royal College of Obstetricians and Gynaecologists criteria) [20]; clinically relevant systemic condition (e.g. insulin-dependent diabetes); and medical conditions that in the investigator’s opinion could prevent an effective response to treatment (e.g. primary ovarian failure, malformations of the reproductive organs incompatible with pregnancy) or affect the absorption, distribution, metabolism or excretion of the study drug.\n\nTreatments and interventions\nThe study comprised a screening visit (between Days 7 and 28 of the cycle, before the patient was assigned to treatment) followed by pre-stimulation, stimulation and post-stimulation periods. Patients underwent only one treatment cycle.\n\nFSH, E2, luteinizing hormone and prolactin levels and antral follicle count (determined by transvaginal ultrasound [TVUS]) were measured at the screening visit.\n\nFollowing a negative pregnancy test, patients were randomized (1:1) to receive daily r-hFSH (follitropin alfa FbM) administered subcutaneously according to either a CLD or an LD protocol. Treatment allocation was determined by a computer-generated randomization list and balanced in a 1:1 ratio within each site. Investigators received randomization codes in individual sealed and numbered envelopes. At randomization, the investigator opened the envelope with the next available number to reveal the allocated treatment protocol, which was disclosed to both patients and investigators. Following randomization, study visits occurred weekly up to Day 35 (end of stimulation).\n\nr-hFSH (follitropin alfa) was supplied in a pre-filled pen for injection (the GONAL-f® Revised Formulation Female pen; EMD Serono, Inc., Rockland, MA, USA [a subsidiary of Merck KGaA, Darmstadt, Germany]) in three dose presentations (300, 450 or 900 IU). Administration of r-hFSH was initiated by physicians but (depending on the study centre) subsequent doses could be self-injected by patients; details of self-administered injections were recorded by the patient on a diary card.In the CLD protocol, r-hFSH was initiated at a daily dose of 75 IU with an increase of 37.5 IU on Day 14 if no follicles ≥10 mm were observed. In the LD protocol, r-hFSH was initiated at a daily dose of 75 IU with an increase of 37.5 IU on Day 7 if no follicles ≥10 mm were observed (Figure 1). In both protocols, subsequent dose increases were possible using 37.5 IU increments at 7-day intervals depending on ovarian response. The maximum permitted daily dose of r-hFSH was 225 IU. The total duration of ovarian stimulation could not exceed 35 days, unless ultrasound assessment suggested imminent follicular growth and maturation.\n\nFigure 1 Treatment protocols. aWhen the leading follicle reached ≥17 mm and no more than two follicles had reached >14 mm, a single dose of hCG was injected to trigger ovulation. bDuration of ovarian stimulation could not exceed 35 days, unless ultrasound assessment suggested imminent follicular growth and maturation. The maximum permitted daily dose of r-hFSH was 225 IU. Ovarian response was monitored by TVUS every 7 days until a follicle of ≥10 mm was observed, and then scheduled according to local practice. hCG = human chorionic gonadotrophin; IU, international units; r-hFSH = recombinant human follicle-stimulating hormone; TVUS, trans-vaginal ultrasound.\n\nThe ovarian response was monitored closely by TVUS every 7 days until a follicle of at least 10 mm in diameter was observed, and thereafter according to local practice. When at least one follicle reached 10–12 mm in diameter, the r-hFSH dose was maintained until the leading follicle reached ≥17 mm and no more than two follicles had reached >14 mm. A single dose of human chorionic gonadotrophin (hCG) was then injected to trigger ovulation. Either r-hCG 250 μg (Ovidrel®; EMD Serono, Inc.) administered subcutaneously or urine-derived hCG 5000 IU administered intramuscularly could be used. Intercourse was recommended on the day of, and the day after, hCG administration; intrauterine insemination could be performed using cryopreserved semen if the partner was unavailable. Patients considered to have an under-response (failure of at least one follicle to reach 10–12 mm in diameter) or an over-response (more than three follicles of >14 mm in diameter and/or E2 levels >900 pg/mL) after 35 days of r-hFSH stimulation were withdrawn from the study.\n\nSerum P4 levels were measured 5–7 days and/or 8–10 days after hCG administration. Ovulation was assumed if mid-luteal P4 levels were ≥9.4 ng/mL (30 nmol/L) and/or pregnancy was achieved. A serum beta hCG pregnancy test was performed 15–20 days after hCG administration (if menstruation did not occur). Clinical pregnancy was confirmed by the presence of at least one foetal sac on TVUS 35–42 days after hCG administration.\n\nOutcomes\nEfficacy outcomes\nThe primary efficacy endpoint was the incidence of mono-follicular development, defined as the development of only one follicle ≥17 mm in diameter (and ≤2 other intermediate [>14 mm] follicles) on or before Day 35 of stimulation.\n\nSecondary endpoints were the incidence of bi-follicular development (defined as the proportion of patients developing two follicles ≥17 mm in diameter and ≤1 other intermediate [>14 mm] follicle); incidence of multi-follicular development (more than three follicles >14 mm in diameter); hCG administration rate; clinical pregnancy rate; rate of cycle cancellation (defined as the proportion of patients with cycle cancellation owing to an inadequate response to stimulation [i.e. failure of at least one follicle to reach ≥17 mm in diameter]); duration of r-hFSH stimulation before hCG administration; and total r-hFSH dose required.\n\nThe incidence of bi-follicular development was added after the protocol was finalized to better evaluate the two treatment protocols.\n\nSafety outcomes\nSafety endpoints included the incidence and severity of adverse events (AEs; including OHSS) and local tolerability of r-hFSH administration. AEs were recorded until at least 15–20 days after hCG administration (or 20–30 days after the last dose of r-hFSH if the patient was withdrawn prior to hCG administration). AEs that occurred >30 days after the last dose of r-hFSH were not recorded. The severity of AEs and their relationship to the study drug was determined by the investigator. Serious AEs and medically relevant ongoing/unknown-outcome AEs were followed-up until resolution or stabilization.\n\nMultiple pregancy (confirmed by the presence of more than one foetal sac on TVUS 35–42 days after hCG administration) was also recorded as a safety endpoint. Rates of multiple pregancy and miscarriage are only presented for patients who received hCG injections.\n\nStatistical methods\nThe null hypothesis was that there was no difference in the proportion of patients achieving mono-follicular growth in each treatment group.\n\nDetermination of the target sample size was based on a single analysis of the primary endpoint using the Chi-square test and applying a two-sided 5% alpha level of significance. A mono-follicular development rate of 69% was reported in a previous study using a step-up urine-derived hFSH protocol with a starting dose of 75 IU [8]. A sample size of 134 evaluable patients per treatment group would be required to achieve 80% power to detect a 15% difference in the rate of mono-follicular development between groups, assuming a true rate of 70% in the LD protocol group. Enrolment of 150 women per treatment group was planned to allow for withdrawals and non-evaluable data.\n\nThe primary efficacy analysis was performed using data from all patients who received at least one dose of the correct study medication, had at least one efficacy assessment, and no protocol violations at the start of treatment. Secondary supportive analyses were performed using the per-protocol (PP) population (patients from the primary efficacy analysis population who received all doses of study medication, excluding patients with protocol deviations during the course of treatment). The safety population included all patients who received at least one dose of study medication and had one follow-up visit.\n\nThe primary and secondary efficacy endpoints were analysed using the Chi-square test, with the difference between treatment groups analysed using a 95% confidence interval, and a p-value was provided. Analysis of variance was used to evaluate the duration of stimulation and the dose of r-hFSH required.\n\nResults\nPatient population\nOf the 320 patients who were screened, 310 were randomized and received at least one dose of study treatment: 155 patients in each treatment group (Figure 2). Thirteen patients were withdrawn prematurely from the study due to pregnancy before stimulation (n = 2), financial reason (n = 1), patient decision (n = 1) or lost to follow up (n = 9). A further 50 patients were excluded from evaluations: 45 due to protocol violations (age-related [n = 9], BMI-related [n = 30], high FSH [n = 1], high prolactin [n = 5]) and 5 who were randomized to the wrong treatment. The primary efficacy analysis population comprised 247 patients: 122 patients in the CLD group and 125 in the LD group. Patients’ demographic and baseline characteristics were similar in the two groups (primary efficacy analysis population; Table 1).A total of 189 patients were included in the PP population (95 and 94 patients in the CLD and LD groups, respectively; Figure 2).\n\nFigure 2 Patient disposition. Patients were considered to have had an under-response if there was failure to develop at least one follicle of 10–12 mm in diameter after 35 days of r-hFSH stimulation. Patients were considered to have had an over-response if they developed more than three follicles of >14 mm in diameter and/or their E2 levels were >900 pg/mL after 35 days of r-hFSH stimulation. AFC = antral follicle count; BMI = body mass index; CLD = chronic low-dose; E2 = oestradiol; hCG = human chorionic gonadotrophin; LD = low-dose; PP = per-protocol; PRL = prolactin; r-hFSH = recombinant human follicle-stimulating hormone.\n\nTable 1 Patients’ demographic and baseline fertility characteristics overall and by treatment group (primary efficacy analysis population)\n\nVariable\tCLD group\tLD group\tTotal\t\n(\nn\n = 122)\t(\nn\n = 125)\t(\nN\n = 247)\t\nAge, years\na\n\tn\t122\t124\t246\t\n \tMean (SD)\t27.5 (4.42)\t27.9 (4.33)\t27.7 (4.37)\t\nBMI, kg/m\n2\n\na\n\tn\t119\t124\t243\t\nMean (SD)\t26.4 (2.95)\t26.0 (3.14)\t26.2 (3.05)\t\nRace\nb\n\tn\t122\t124\t246\t\nArab\tn (%)\t68 (55.7)\t69 (55.6)\t137 (55.7)\t\nAsian\tn (%)\t19 (15.6)\t16 (12.9)\t35 (14.2)\t\nBlack\tn (%)\t1 (0.8)\t4 (3.2)\t5 (2.0)\t\nCaucasian\tn (%)\t33 (27.1)\t34 (27.4)\t67 (27.2)\t\nOther\tn (%)\t1 (0.8)\t1 (0.8)\t2 (0.8)\t\nInfertility type\nb\n\tn\t122\t125\t247\t\nPrimary\tn (%)\t92 (75.4)\t96 (76.8)\t188 (76.1)\t\nSecondary\tn (%)\t30 (24.6)\t29 (23.2)\t59 (23.9)\t\nDuration of infertility, years\na\n\tn\t122\t125\t247\t\n \tMean (SD)\t3.8 (2.57)\t4.2 (2.48)\t4.0 (2.53)\t\nCause of infertility\nb\n\tn\t123c\t127c\t250c\t\nOvulatory dysfunction\tn (%)\t120 (97.6)\t121 (95.3)\t241 (96.4)\t\nTubal factor\tn (%)\t0 (0.0)\t1 (0.8)\t1 (0.4)\t\nOther\tn (%)\t3 (2.4)\t5 (3.9)\t8 (3.2)\t\nPrevious infertility treatment\nb\n\tn\t122\t125\t247\t\nYes\tn (%)\t90 (73.8)\t103 (82.4)\t193 (78.1)\t\nNo\tn (%)\t32 (26.2)\t22 (17.6)\t54 (21.9)\t\nPrevious pregnancies\nb\n\tn\t122\t125\t247\t\nNone\tn (%)\t92 (75.4)\t94 (75.2)\t186 (75.3)\t\nAt least one\tn (%)\t30 (24.6)\t31 (24.8)\t61 (24.7)\t\naNot significant; t-test.\n\nbNot significant; Chi-square test.\n\ncMultiple causes of infertility in three patients (CLD group, n = 1; LD group, n = 2).\n\nBMI = body mass index; CLD = chronic low-dose; LD = low-dose; SD = standard deviation.\n\nEfficacy\nSimilar rates of mono-follicular development (primary endpoint) were achieved in the CLD and LD groups in the primary efficacy analysis population: 56.6% (69/122) and 55.2% (69/125), respectively (p = 0.93; Table 2). This was also the case in the PP population: 64.2% (61/95) and 62.8% (59/94), respectively (p = 0.96; Table 3).\n\nTable 2 Primary and secondary efficacy endpoint results in the primary efficacy analysis population\n\nEfficacy endpoint\tCLD group\tLD group\tp\t\n(\nn\n = 122)\t(\nn\n = 125)\t\nMono-follicular development\na\n\t69 (56.6)\t69 (55.2)\t0.93\t\nBi-follicular development\na\n\t17 (13.9)\t22 (17.6)\t0.54\t\nMulti-follicular development\na\n\t17 (13.9)\t15 (12.0)\t0.79\t\nCycle cancellation rate\nb\n\t19 (15.6)\t19 (15.2)\t0.94\t\nhCG injection rate\t94 (77.1)\t91 (72.8)\t0.53\t\nClinical pregnancy rate\nc\n\t19 (20.2)\t18 (19.8)\t0.94\t\nData are n (%).\n\naNumber of patients with follicles ≥17 mm in diameter by Day 35 of stimulation.\n\nbDue to inadequate response.\n\ncPregnancy rate calculated per patients who received hCG injections (CLD group, n = 94; LD group, n = 91).\n\np values show the difference between treatment groups, using the Chi-square test.\n\nCLD = chronic low-dose; hCG = human chorionic gonadotrophin; LD = low-dose.\n\nTable 3 Primary and secondary efficacy endpoint results in the per-protocol population\n\nEfficacy endpoint\tCLD group\tLD group\tp\t\n(\nn\n = 95)\t(\nn\n = 94)\t\nMono-follicular development\na\n\t61 (64.2)\t59 (62.8)\t0.96\t\nBi-follicular development\na\n\t16 (16.8)\t19 (20.2)\t0.68\t\nMulti-follicular development\na\n\t11 (11.6)\t10 (10.6)\t0.84\t\nCycle cancellation rate\nb\n\t7 (7.4)\t6 (6.4)\t0.79\t\nhCG injection rate\t84 (88.4)\t82 (87.2)\t0.98\t\nClinical pregnancy rate\nc\n\t17 (20.2)\t17 (20.7)\t0.37\t\nData are n (%).\n\naNumber of patients with follicles ≥17 mm in diameter by Day 35 of stimulation.\n\nbDue to inadequate response.\n\ncPregnancy rate calculated per patients who received hCG injections (CLD group, n = 84; LD group, n = 82).\n\np values show the difference between treatment groups, using the Chi-square test.\n\nCLD = chronic low-dose; hCG = human chorionic gonadotrophin; LD = low-dose.\n\nNo significant differences between treatment groups were found in the secondary efficacy endpoints. Rates of bi-follicular development, multi-follicular development, and hCG administration in the primary efficacy and PP populations are presented in Table 2 and 3. Clinical pregnancy rates for those patients who received an hCG injection were 20.2% (19/94) and 19.8% (18/91) in the CLD and LD groups, respectively (p = 0.94; primary efficacy analysis population; Table 2). The rate of cycle cancellation owing to inadequate response was 15.6% (19/122) of patients in the CLD group and 15.2% (19/125) of patients in the LD group (p = 0.94, primary efficacy analysis population).\n\nIn those patients who received an hCG injection, the mean duration of r-hFSH stimulation required for OI, while not statistically significant, was slightly longer in the CLD than in the LD group (13.7 versus 12.9 days, respectively; primary efficacy analysis population; Table 4). In addition, the mean daily and total doses of r-hFSH required were slightly lower in the CLD group versus the LD group, although only mean daily dose showed a statistically significant difference between groups (Table 4 and 5).\n\nTable 4 Duration of recombinant human follicle-stimulating hormone (r-hFSH) stimulation and total and daily r-hFSH doses required - primary efficacy analysis population (patients who received hCG injections)\n\n \tCLD group\tLD group\tTotal\tp\t\n(n = 94)\t(\nn\n = 91)\t(\nN\n = 185)\t\nDuration of stimulation, days\t13.7 +/− 6.33\t12.9 +/− 5.58\t13.3 +/− 5.97\t0.36\t\nDaily dose, IU\t78.7 +/− 8.90\t85.0 +/− 15.35\t81.8 +/− 12.86\t<0.001\t\nTotal dose, IU\t1119.4 +/− 690.04\t1155.5 +/− 730.45\t1137.2 +/− 708.50\t0.73\t\nData are mean +/− standard deviation.\n\np values show the difference between treatment groups using analysis of variance.\n\nValues in bold are significant.\n\nCLD = chronic low-dose; hCG = human chorionic gonadotrophin; LD = low-dose.\n\nTable 5 Duration of recombinant human follicle-stimulating hormone (r-hFSH) stimulation and total and daily r-hFSH doses required - Per-protocol population (patients who received hCG injections)\n\n \tCLD group\tLD group\tTotal\tp\t\n(\nn\n = 84)\t(\nn\n = 82)\t(\nN\n = 166)\t\nDuration of stimulation, days\t13.4 +/− 6.04\t13.0 +/− 5.81\t13.2 +/− 5.91\t0.66\t\nDaily dose, IU\t78.5 +/− 8.95\t85.5 +/− 15.88\t81.9 +/− 13.28\t<0.001\t\nTotal dose, IU\t1092.9 +/− 665.19\t1183.1 +/− 762.52\t1137.4 +/− 714.18\t0.42\t\nData are mean +/− standard deviation.\n\np values show the difference between treatment groups using analysis of variance.\n\nValues in bold are significant.\n\nCLD = chronic low-dose; hCG = human chorionic gonadotrophin; LD = low-dose.\n\nSafety\nOf the 135 patients included in the safety population, 30/70 (43%) in the CLD group and 31/65 (48%) in the LD group experienced at least one AE, excluding injection-site reactions. In total, 121 AEs were reported (53 in the CLD group; 68 in the LD group). The majority of AEs were mild in severity (106/121; 87.6%), with only 11 (9.1%) moderate and two (1.7%) severe AEs reported (the severity of two AEs was not recorded). There was only one report of OHSS (CLD group), which was mild in severity and resolved without sequelae. However, the patient was withdrawn from the study as discontinuation was mandatory following the development of OHSS.\n\nOnly one AE resulted in treatment discontinuation and two resulted in modification of treatment. One serious AE was reported: an ectopic pregnancy (moderate in severity) occurred in a patient in the LD group and was considered to be unrelated to the study drug. The patient was hospitalized and successfully managed with medical treatment (methotrexate). The ectopic pregnancy resolved without sequelae.\n\nNo significant difference was found between multiple pregnancy rates in the CLD and LD groups for patients who received hCG: 3.2% (3/94) versus 1.1% (1/91), respectively (p = 0.34), in the primary efficacy analysis population and 2.4% (2/84) versus 1.2% (1/82), respectively (p = 0.58), in the PP population. All multiple pregnancies reported were twins. No significant difference was found between miscarriage rates (for patients who received hCG) in the CLD and LD groups: 4.3% (4/94) versus 6.6% (6/91), respectively (p = 0.48), for the primary efficacy analysis population and 4.8% (4/84) versus 6.1% (5/82), respectively (p = 0.70), for the PP population.\n\nInjection-site tolerability\nTreatment diaries were provided by 150 patients (CLD group: n = 73; LD group: n = 77). Of these, 42 patients (28%) reported ≥1 r-hFSH injection-site reaction (CLD group: n = 19; 26.0%; LD group: n = 23; 29.9%). The r-hFSH injection-site reactions reported were pain (CLD group: n = 9; LD group: n = 20), redness (CLD group: n = 2; LD group: n = 5), bruising (CLD group: n = 6; LD group: n = 2), swelling (CLD group: n = 4; LD group: n = 1) and irritation (CLD group: n = 2; LD group: n = 3).\n\nDiscussion\nTo the authors’ knowledge, the MEnTOR study is the first large, randomized, multicentre trial to compare the efficacy and safety of a CLD versus LD step-up OI treatment protocol using follitropin alfa FbM (r-hFSH). Previously reported data from a small, single-centre study suggested that the LD protocol may substantially reduce the FSH dose requirement and mean treatment duration versus the CLD protocol while maintaining similar pregnancy rates [8]. However, the LD protocol may be associated with a higher multiple pregnancy rate than the CLD protocol [8]. The high batch-to-batch consistency and precise dosing of follitropin alfa FbM was expected to allow any differences in outcomes of the two treatment protocols to be revealed, by reducing individual variability in ovarian response [19]. However, follitropin alfa FbM has been reported to reduce the rate of OI cycle cancellation owing to poor response (p < 0.02) and increase the proportion of cycles not requiring a dose increase (p < 0.001), compared with the follitropin alfa filled-by-bioassay formulation [21]. Indeed, it is possible that the reduced requirement for adjustment of the starting dose when using follitropin alfa FbM [21] could explain the similarity in outcomes of the CLD and LD protocols demonstrated in the current study.\n\nIn the current study, the CLD and LD protocols demonstrated similar efficacy, with no differences found in the primary and secondary efficacy outcomes. In addition, the two protocols were similar in terms of safety outcomes. Of particular importance, similar rates of multiple pregnancy (among patients who received hCG) were reported with the CLD and LD protocols (3.2% versus 1.1%, respectively). It should be noted that the LD protocol was associated with a slightly higher mean daily and total r-hFSH dose requirement, but a shorter duration of stimulation versus the CLD protocol.\n\nRates of clinical (20.2%) and multiple pregnancy (3.2%) for patients who received hCG in the CLD group are in line with a previous compilation of data from 11 CLD protocol studies (21–45% and 0–14%, respectively) [8]. Mono-follicular and bi-follicular development rates reported here in the CLD group are also similar to those reported in two recent publications of similar CLD protocols (54–55% and 17–25%, respectively) [9,16]. Minimal data on the outcomes of LD treatment protocols are available. The multiple pregnancy rate of the LD protocol in the current study was lower than that reported previously [8]; however, direct comparison of data between studies is limited because of differences in the methodology used to calculate rates.\n\nThe strengths of the current study include the large randomized population (N = 310) recruited from six Middle Eastern countries, and the use of follitropin alfa FbM (rather than a formulation of urine-derived hFSH or r-hFSH calibrated using the Steelman and Pohley bioassay). Follitropin alfa FbM is assayed using a physicochemical analytical method, which ensures a precise content per vial and high batch-to-batch consistency [18].\n\nIdentification of factors predictive of response prior to stimulation could also improve the efficacy and safety of OI treatment protocols [16,22]. Such information would allow FSH thresholds for successful ovulation to be better estimated and individualized starting doses defined [16,22]. In an analysis of data from two prospective, randomized, Phase III, multicentre studies, low BMI, low antral follicle count and high normal baseline FSH level were associated with successful OI using a CLD r-hFSH protocol [16]. Previous studies have also identified BMI as a major determinant of successful ovulation, along with cycle history, baseline FSH level, insulin-like growth factor I concentrations and previous history of response to CC [14,23]. Obesity and insulin resistance have been associated with adverse outcomes [14,23].\n\nA potential limitation of the current study is the use of a standard starting dose of r-hFSH regardless of the individual’s BMI (range 20–32 kg/m2). It is possible that failure to tailor the initial dose of r-hFSH could have contributed to the lack of difference in outcomes shown between the two protocols.\n\nConclusions\nThis study provides valuable information on the efficacy and safety of LD and CLD protocols used for OI in women with WHO Group II anovulatory infertility in the Middle East. The r-hFSH LD and CLD protocols resulted in similar efficacy and safety outcomes; although the CLD protocol may be more suitable in patients at risk of multifollicular development.\n\nAbbreviations\nAE: Adverse event; BMI: Body mass index; CC: Clomiphene citrate; CLD: Chronic low dose; E2: Oestradiol; FbM: Filled by mass; FSH: Follicle-stimulating hormone; hCG: Human chorionic gonadotrophin; LD: Low dose; MEnTOR: Middle East Trial for Ovulation induction Responders; OHSS: Ovarian hyperstimulation syndrome; OI: Ovulation induction; P4: Progesterone; PP: Per protocol; r-hCG: Recombinant human chorionic gonadotrophin; r-hFSH: Recombinant human follicle-stimulating hormone; TVUS: Transvaginal ultrasound; WHO: World Health Organization.\n\nCompeting interests\nGamal I Serour has received a grant from Al Azhar University. Jean-Noel Hugues has participated in previous international studies on products manufactured by Merck Serono. Khaled Esmat was an employee of Merck Serono Middle East FZ – LLC, Dubai, UAE (an affiliate of Merck KGaA, Darmstadt, Germany) at the time of the study. Mohamed Aboulghar and Awatef Al Bahar declare that they have no competing interests.\n\nAuthors’ contributions\nAll authors provided substantial contributions to conception and design, acquisition of data, analysis and interpretation of data, and revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.\n\nSupplementary Material\nAdditional file 1\nCONSORT 2010 checklist of information to include when reporting a randomised trial*.\n\nClick here for file\n\n Acknowledgements\nThis study was funded by Merck Serono Middle East FZ – LLC (an affiliate of Merck KGaA, Darmstadt, Germany). The investigators of the MEnTOR Study Group were: Mohamed Aboulghar, Mohamed El Awad, Joseph Azoury, Awatef Al Bahar, Walid Ghouthmi, Antoine Hannun, Nahed Hammadieh, Hassan A. Jabbar, Abdul Fattah Mahmoud Marzouk, Ashraf Moeini, Seyed Mehdi Ahmadi Oloonabadi, David Robertson and Gamal I Serour. The authors thank the MEnTOR Study Group and also Eman Ahmed, Yahia El Faysl, Wael A Ismail Madkour, Noha Sabry and Hena Zaheer and for their valuable contributions to the study. The authors are also grateful to ClinArt FZ LLC for conducting the study and analysing the data. Lastly, the authors thank Hannah Wills, Laura McDonagh and Catherine Kidd of Caudex Medical, Oxford, UK (supported by Merck Serono Middle East FZ – LLC [an affiliate of Merck KGaA, Darmstadt, Germany]) for their assistance in the preparation of this manuscript.\n==== Refs\nHamilton-Fairley D Taylor A Anovulation Br Med J 2003 327 546 549 10.1136/bmj.327.7414.546 12958117 \nBroekmans FJ Knauff EA Valkenburg O Laven JS Eijkemans MJ Fauser BC PCOS according to the Rotterdam consensus criteria: change in prevalence among WHO-II anovulation and association with metabolic factors Br J Obstet Gynaecol 2006 113 1210 1217 10.1111/j.1471-0528.2006.01008.x \nEijkemans MJ Polinder S Mulders AG Laven JS Habbema JD Fauser BC Individualized cost-effective conventional ovulation induction treatment in normogonadotrophic anovulatory infertility (WHO group 2) Hum Reprod 2005 20 2830 2837 10.1093/humrep/dei164 16006473 \nvan Santbrink EJ Fauser BC Ovulation induction in normogonadotropic anovulation (PCOS) Best Pract Res Clin Endocrinol Metab 2006 20 261 270 10.1016/j.beem.2006.03.002 16772156 \nESHRE Capri Workshop Group Mono-ovulatory cycles: a key goal in profertility programmes Hum Reprod Update 2003 9 263 274 10.1093/humupd/dmg020 12859047 \nHugues JN Cedrin-Durnerin I Avril C Bulwa S Herve F Uzan M Sequential step-up and step-down dose regimen: an alternative method for ovulation induction with follicle-stimulating hormone in polycystic ovarian syndrome Hum Reprod 1996 11 2581 2584 10.1093/oxfordjournals.humrep.a019173 9021354 \nHedon B Hugues JN Emperaire JC Chabaud JJ Barbereau D Boujenah A Howles CM Truong F A comparative prospective study of a chronic low dose versus a conventional ovulation stimulation regimen using recombinant human follicle stimulating hormone in anovulatory infertile women Hum Reprod 1998 13 2688 2692 10.1093/humrep/13.10.2688 9804214 \nHomburg R Howles CM Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, results, reflections and refinements Hum Reprod Update 1999 5 493 499 10.1093/humupd/5.5.493 10582786 \nHugues JN Cedrin-Durnerin I Howles CM Amram M Angelini A Balen A Barbereau D Birkhauser M Boujenah A De LV The use of a decremental dose regimen in patients treated with a chronic low-dose step-up protocol for WHO Group II anovulation: a prospective randomized multicentre study Hum Reprod 2006 21 2817 2822 10.1093/humrep/del265 16877376 \nESHRE Capri Workshop Group Multiple gestation pregnancy Hum Reprod 2000 15 1856 1864 10.1093/humrep/15.8.1856 10920117 \nNastri CO Ferriani RA Rocha IA Martins WP Ovarian hyperstimulation syndrome: pathophysiology and prevention J Assist Reprod Genet 2010 27 121 128 10.1007/s10815-010-9387-6 20140640 \nBrown JB Pituitary control of ovarian function–concepts derived from gonadotrophin therapy Aust N Z J Obstet Gynaecol 1978 18 46 54 278588 \nSchoemaker J van Weissenbruch MM Scheele F van der Meer M The FSH threshold concept in clinical ovulation induction Baillière’s Clin Obstet Gynaecol 1993 7 297 308 10.1016/S0950-3552(05)80132-4 8358892 \nImani B Eijkemans MJ Faessen GH Bouchard P Giudice LC Fauser BC Prediction of the individual follicle-stimulating hormone threshold for gonadotropin induction of ovulation in normogonadotropic anovulatory infertility: an approach to increase safety and efficiency Fertil Steril 2002 77 83 90 11779595 \nNyboe Andersen A Balen A Platteau P Devroey P Helmgaard L Arce JC Predicting the FSH threshold dose in women with WHO Group II anovulatory infertility failing to ovulate or conceive on clomiphene citrate Hum Reprod 2008 23 1424 1430 10.1093/humrep/den089 18372254 \nHowles CM Alam V Tredway D Homburg R Warne DW Factors related to successful ovulation induction in patients with WHO group II anovulatory infertility Reprod Biomed Online 2010 20 182 190 10.1016/j.rbmo.2009.11.017 20113956 \nBruna-Catalan I Menabrito M Ovulation induction with minimal dose of follitropin alfa: a case series study Reprod Biol Endocrinol 2011 9 142 10.1186/1477-7827-9-142 22024419 \nBassett RM Driebergen R Continued improvements in the quality and consistency of follitropin alfa, recombinant human FSH Reprod Biomed Online 2005 10 169 177 10.1016/S1472-6483(10)60937-6 15823219 \nHugues JN Barlow DH Rosenwaks Z Cedrin-Durnerin I Robson S Pidoux L Loumaye E Improvement in consistency of response to ovarian stimulation with recombinant human follicle stimulating hormone resulting from a new method for calibrating the therapeutic preparation Reprod Biomed Online 2003 6 185 190 10.1016/S1472-6483(10)61709-9 12675998 \nThe management of ovarian hyperstimulation syndrome. RCOG Guideline Number 5 http://www.rcog.org.uk/files/rcog-corp/GTG5_230611.pdf \nYeko T Pasqualini SR Alam V Tredway D Cumulative ovulation and pregnancy rates according to recombinant human follicle stimulating hormone (r-hFSH) dosing: comparison of a new formulation of follitropin alfa in vials versus the standard formulation of follitropin alfa in ampules Fertil Steril 2004 82 S119 \nFauser BC Diedrich K Devroey P Predictors of ovarian response: progress towards individualized treatment in ovulation induction and ovarian stimulation Hum Reprod Update 2008 14 1 14 18006561 \nMulders AG Laven JS Eijkemans MJ Hughes EG Fauser BC Patient predictors for outcome of gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: a meta-analysis Hum Reprod Update 2003 9 429 449 10.1093/humupd/dmg035 14640376\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1477-7827",
"issue": "12()",
"journal": "Reproductive biology and endocrinology : RB&E",
"keywords": null,
"medline_ta": "Reprod Biol Endocrinol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000858:Anovulation; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D005300:Fertility Agents, Female; D043373:Follicle Stimulating Hormone, Human; D006801:Humans; D007247:Infertility, Female; D059012:Lost to Follow-Up; D008877:Middle East; D006080:Ovarian Follicle; D016471:Ovarian Hyperstimulation Syndrome; D010062:Ovulation Induction; D010352:Patient Dropouts; D011247:Pregnancy; D018873:Pregnancy Rate; D011994:Recombinant Proteins; D014463:Ultrasonography; D055815:Young Adult",
"nlm_unique_id": "101153627",
"other_id": null,
"pages": "52",
"pmc": null,
"pmid": "24942155",
"pubdate": "2014-06-18",
"publication_types": "D017429:Clinical Trial, Phase IV; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "10920117;9804214;18372254;12859047;9021354;18006561;12958117;278588;11779595;22024419;16772156;20140640;8358892;10582786;14640376;16006473;15823219;12675998;16972863;20113956;16877376",
"title": "Phase IV, open-label, randomized study of low-dose recombinant human follicle-stimulating hormone protocols for ovulation induction.",
"title_normalized": "phase iv open label randomized study of low dose recombinant human follicle stimulating hormone protocols for ovulation induction"
} | [
{
"companynumb": "EG-EMD SERONO-8019988",
"fulfillexpeditecriteria": "1",
"occurcountry": "EG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FOLLITROPIN"
},
"drugadditional": null,
... |
{
"abstract": "Combined poisoning with calcium channel blockers (CCBs) and beta-blockers is usually associated with severe hypotension and heart failure. Due to the block of the beta receptors, treatment with adrenergic agonists, even at high doses, can be insufficient, and beta-independent inotropes, such as glucagon, may be required. Phosphodiesterase III (PDEIII) inhibitors represent a possible alternative to glucagon in these cases as they have an inotropic effect which is not mediated by a beta receptor.",
"affiliations": "Department of Anesthesiology and Intensive Care, Catholica University School of Medicine, Rome, Italy.",
"authors": "Sandroni|C|C|;Cavallaro|F|F|;Addario|C|C|;Ferro|G|G|;Gallizzi|F|F|;Antonelli|M|M|",
"chemical_list": "D000322:Adrenergic Agonists; D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D001262:Atenolol; D017335:Enoximone; D014700:Verapamil; D004298:Dopamine; D004837:Epinephrine",
"country": "England",
"delete": false,
"doi": "10.1111/j.0001-3072.2004.00398.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5172",
"issue": "48(6)",
"journal": "Acta anaesthesiologica Scandinavica",
"keywords": null,
"medline_ta": "Acta Anaesthesiol Scand",
"mesh_terms": "D000322:Adrenergic Agonists; D000889:Anti-Arrhythmia Agents; D001262:Atenolol; D001794:Blood Pressure; D002302:Cardiac Output; D002316:Cardiotonic Agents; D004298:Dopamine; D062787:Drug Overdose; D017335:Enoximone; D004837:Epinephrine; D006339:Heart Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D014700:Verapamil",
"nlm_unique_id": "0370270",
"other_id": null,
"pages": "790-2",
"pmc": null,
"pmid": "15196115",
"pubdate": "2004-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment with enoximone for severe poisoning with atenolol and verapamil: a case report.",
"title_normalized": "successful treatment with enoximone for severe poisoning with atenolol and verapamil a case report"
} | [
{
"companynumb": "IT-MYLANLABS-2017M1048215",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VERAPAMIL HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "We present a case of early coma, metabolic acidosis and methemoglobinemia after substantial acetaminophen toxicity in the absence of hepatic failure. A 77-year-old female presented to the emergency department with a decreased level of consciousness. She was found unresponsive by a family member in her bed, and was reported to be acting normally when she was last seen eight hours earlier. Laboratory results on arrival were: pH 7.19, sodium 139 mmol/L, chloride 106 mmol/L, potassium 3.3 mmol/L, CO2 8 mmol/L, and an anion gap of 25. Both venous lactate (10.2 mmol/L) and methemoglobin (9.4 %) were elevated. The patient's acetaminophen concentration was markedly elevated at 7138 µmol/L (1078 µg/ml). Hepatic enzymes and coagulation tests were normal [alanine transaminase (ALT) 8 U/L, international normalized ratio (INR) 1.0]. Intravenous N-acetylcysteine (NAC) was initiated at a dose of 150 mg/kg over 15 minutes, followed by 50 mg/kg over the next four hours, followed by 100 mg/kg over the next 16 hours. Twenty-four hours after admission, the anion gap metabolic acidosis had resolved, and the methemoglobin was 2.1%. Aminotransferases peaked at 44 U/L and INR peaked at 1.9. A urine 5-oxoproline assay performed five days after admission was negative, suggesting no evidence of a 5-oxoprolinase deficiency. We describe the pathophysiology and discuss the literature on acetaminophen-induced coma and metabolic acidosis in the absence of hepatic injury; and propose mechanisms for associated methemoglobinemia.",
"affiliations": null,
"authors": "Kanji|Hussein D|HD|;Mithani|Shazma|S|;Boucher|Paul|P|;Dias|Valerian C|VC|;Yarema|Mark C|MC|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen",
"country": "Australia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2561-8741",
"issue": "20(3)",
"journal": "Journal of population therapeutics and clinical pharmacology = Journal de la therapeutique des populations et de la pharmacologie clinique",
"keywords": null,
"medline_ta": "J Popul Ther Clin Pharmacol",
"mesh_terms": "D000082:Acetaminophen; D000138:Acidosis; D000368:Aged; D018712:Analgesics, Non-Narcotic; D003128:Coma; D005260:Female; D006801:Humans; D008708:Methemoglobinemia",
"nlm_unique_id": "101530023",
"other_id": null,
"pages": "e207-11",
"pmc": null,
"pmid": "24077426",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Coma, metabolic acidosis, and methemoglobinemia in a patient with acetaminophen toxicity.",
"title_normalized": "coma metabolic acidosis and methemoglobinemia in a patient with acetaminophen toxicity"
} | [
{
"companynumb": "CA-VISTAPHARM, INC.-VER201711-001115",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
},
"drugadditional... |
{
"abstract": "Randomized trials demonstrated the superiority of chemoimmunotherapy over chemotherapy in the frontline treatment of CLL. Based on favorable experience with the addition of mitoxantrone (M) to fludarabine (F) plus cyclophosphamide (C), we designed a pilot study testing the combination of FCM plus rituximab (R). Thirty patients with previously untreated, symptomatic CLL, <70 years, and beta-2-microglobulin <twice upper limit of normal were evaluated. Treatment consisted of F 25mg/m(2)/day on days 2-4, C 250 mg/m(2)/day on days 2-4, M 6 mg/m(2) on day 2, and R 375 mg/m(2) on day 1. For cycles 2-6, FCM started day 1 together with R 500 mg/m(2). Pegfilgrastim was administered with each cycle. Cycles were repeated every 4-6 weeks. Complete remission (CR) was achieved in 83% of 30 patients, nodular partial response in 10%, and partial response in 3%. The overall response rate was 96%. Sixteen of 24 CR patients (67%) achieved a flow cytometry response with <1% marrow CD5/CD19-positive cells and 13 of 21 CR patients (62%) were MRD-negative by molecular evaluation for clonal IgV(H). With a median follow up of 38.5 months, the median time to treatment failure (TTF) has not been reached. A comparison with a historical group of FCR-treated patients showed no significant differences with respect to response and toxicities. FCM-R is highly active in patients < 70 years with favorable beta-2-microglobulin levels and previously untreated CLL. Outcome does not differ from FCR-treated patients.",
"affiliations": "Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. sfader@mdanderson.org",
"authors": "Faderl|Stefan|S|;Wierda|William|W|;O'Brien|Susan|S|;Ferrajoli|Alessandra|A|;Lerner|Susan|S|;Keating|Michael J|MJ|",
"chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D001613:beta 2-Microglobulin; D000069283:Rituximab; D003520:Cyclophosphamide; D008942:Mitoxantrone; D014740:Vidarabine; C024352:fludarabine",
"country": "England",
"delete": false,
"doi": "10.1016/j.leukres.2009.07.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-2126",
"issue": "34(3)",
"journal": "Leukemia research",
"keywords": null,
"medline_ta": "Leuk Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D002469:Cell Separation; D003520:Cyclophosphamide; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone; D010865:Pilot Projects; D012074:Remission Induction; D000069283:Rituximab; D016896:Treatment Outcome; D014740:Vidarabine; D001613:beta 2-Microglobulin",
"nlm_unique_id": "7706787",
"other_id": null,
"pages": "284-8",
"pmc": null,
"pmid": "19646755",
"pubdate": "2010-03",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "12472576;18172266;8652811;18358929;15767647;15767648;8558211;10515887;15284112",
"title": "Fludarabine, cyclophosphamide, mitoxantrone plus rituximab (FCM-R) in frontline CLL <70 Years.",
"title_normalized": "fludarabine cyclophosphamide mitoxantrone plus rituximab fcm r in frontline cll 70 years"
} | [
{
"companynumb": "US-AMGEN-USASP2021179686",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGFILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "Statins have a variety of myotoxic effects and can trigger the development of inflammatory myopathies or myasthenia gravis (MG) mediated by immunomodulatory properties. Autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) have been identified in patients with statin-associated myopathy. The purpose of the present study is to develop an enzyme-linked immunosorbent assay (ELISA) of anti-HMGCR antibodies and to elucidate the clinical significance of anti-HMGCR antibodies in Japanese patients with inflammatory myopathies or MG. We enrolled 75 patients with inflammatory myopathies, who were all negative for anti-signal recognition particle and anti-aminoacyl transfer RNA synthetase antibodies. They were referred to Keio University and National Center of Neurology and Psychiatry between October 2010 and September 2012. We also studied 251 patients with MG who were followed at the MG Clinic at Keio University Hospital. Anti-HMGCR antibodies were detected by ELISA. We investigated demographic, clinical, radiological, and histological findings associated with anti-HMGCR antibodies. We established the anti-HMGCR ELISA with the recombinant protein. Protein immunoprecipitation detected autoantigens corresponding to HMGCR. Immunohistochemistry using muscle biopsy specimens revealed regenerating muscle fibers clearly stained by polyclonal anti-HMGCR antibodies and patients' serum. Anti-HMGCR autoantibodies were specifically detected in 8 patients with necrotizing myopathy. The seropositivity rate in the necrotizing myopathy patients was significantly higher than those in the patients with other histological diagnoses of inflammatory myopathies (31% vs 2%, P = 0.001). Statins were administered in only 3 of the 8 anti-HMGCR-positive patients. Myopathy associated with anti-HMGCR antibodies showed mild limb weakness and favorable response to immunotherapy. All 8 patients exhibited increased signal intensities on short T1 inversion recovery of muscle MRI. Of the 251 patients with MG, 23 were administered statins at the onset of MG. One late-onset MG patient experienced MG worsening after 4-wk treatment with atorvastatin. However, anti-HMGCR antibodies were not detected in the 251 MG patients except for one early-onset MG patient with no history of statin therapy. Anti-HMGCR antibodies are a relevant clinical marker of necrotizing myopathy with or without statin exposure, but they are not associated with the onset or deterioration of MG.",
"affiliations": "From the Department of Neurology, Keio University School of Medicine (YW, SS, NS); Department of Neuromuscular Research, National Institute of Neuroscience, and Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo (HN, IN); Department of Neurology, Wakayama Medical University, Wakayama (K-YM); Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Graduate School of Biomedical and Health Sciences, Hiroshima (TK); Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui (MI); Department of Neurology, Mie University Graduate School of Medicine, Tsu (MA); Department of Neurology, University of Toyama, Toyama (HK); Department of Neurology, Graduate School of Medicine, Chiba University, Chiba (SM); and Department of Neurology, Asahikawa Red Cross Hospital, Asahikawa, Japan (SK).",
"authors": "Watanabe|Yurika|Y|;Suzuki|Shigeaki|S|;Nishimura|Hiroaki|H|;Murata|Ken-Ya|KY|;Kurashige|Takashi|T|;Ikawa|Masamichi|M|;Asahi|Masaru|M|;Konishi|Hirofumi|H|;Mitsuma|Satsuki|S|;Kawabata|Satoshi|S|;Suzuki|Norihiro|N|;Nishino|Ichizo|I|",
"chemical_list": "D001323:Autoantibodies; D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006903:Hydroxymethylglutaryl CoA Reductases",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000000416",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2563417110.1097/MD.0000000000000416004165300ArticleObservational StudyStatins and Myotoxic Effects Associated With Anti-3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Autoantibodies An Observational Study in JapanWatanabe Yurika Suzuki Shigeaki MD, PhDNishimura Hiroaki MDMurata Ken-ya MD, PhDKurashige Takashi MD, PhDIkawa Masamichi MD, PhDAsahi Masaru MDKonishi Hirofumi MDMitsuma Satsuki MDKawabata Satoshi MDSuzuki Norihiro MD, PhDNishino Ichizo MD, PhDRajasekharan. Chandrasekharan From the Department of Neurology, Keio University School of Medicine (YW, SS, NS); Department of Neuromuscular Research, National Institute of Neuroscience, and Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo (HN, IN); Department of Neurology, Wakayama Medical University, Wakayama (K-YM); Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Graduate School of Biomedical and Health Sciences, Hiroshima (TK); Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui (MI); Department of Neurology, Mie University Graduate School of Medicine, Tsu (MA); Department of Neurology, University of Toyama, Toyama (HK); Department of Neurology, Graduate School of Medicine, Chiba University, Chiba (SM); and Department of Neurology, Asahikawa Red Cross Hospital, Asahikawa, Japan (SK).Correspondence: Dr. Shigeaki Suzuki, Department of Neurology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160–8582, Japan (e-mail: sgsuzuki@z3.keio.jp).1 2015 30 1 2015 94 4 e41620 10 2014 3 12 2014 7 12 2014 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.2015This is an open access article distributed under the Creative Commons Attribution-NonCommercial License, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be used commercially. http://creativecommons.org/licenses/by-nc/4.0Abstract\nStatins have a variety of myotoxic effects and can trigger the development of inflammatory myopathies or myasthenia gravis (MG) mediated by immunomodulatory properties. Autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) have been identified in patients with statin-associated myopathy. The purpose of the present study is to develop an enzyme-linked immunosorbent assay (ELISA) of anti-HMGCR antibodies and to elucidate the clinical significance of anti-HMGCR antibodies in Japanese patients with inflammatory myopathies or MG.\n\nWe enrolled 75 patients with inflammatory myopathies, who were all negative for anti-signal recognition particle and anti-aminoacyl transfer RNA synthetase antibodies. They were referred to Keio University and National Center of Neurology and Psychiatry between October 2010 and September 2012. We also studied 251 patients with MG who were followed at the MG Clinic at Keio University Hospital. Anti-HMGCR antibodies were detected by ELISA. We investigated demographic, clinical, radiological, and histological findings associated with anti-HMGCR antibodies.\n\nWe established the anti-HMGCR ELISA with the recombinant protein. Protein immunoprecipitation detected autoantigens corresponding to HMGCR. Immunohistochemistry using muscle biopsy specimens revealed regenerating muscle fibers clearly stained by polyclonal anti-HMGCR antibodies and patients’ serum. Anti-HMGCR autoantibodies were specifically detected in 8 patients with necrotizing myopathy. The seropositivity rate in the necrotizing myopathy patients was significantly higher than those in the patients with other histological diagnoses of inflammatory myopathies (31% vs 2%, P = 0.001). Statins were administered in only 3 of the 8 anti-HMGCR-positive patients. Myopathy associated with anti-HMGCR antibodies showed mild limb weakness and favorable response to immunotherapy. All 8 patients exhibited increased signal intensities on short T1 inversion recovery of muscle MRI. Of the 251 patients with MG, 23 were administered statins at the onset of MG. One late-onset MG patient experienced MG worsening after 4-wk treatment with atorvastatin. However, anti-HMGCR antibodies were not detected in the 251 MG patients except for one early-onset MG patient with no history of statin therapy.\n\nAnti-HMGCR antibodies are a relevant clinical marker of necrotizing myopathy with or without statin exposure, but they are not associated with the onset or deterioration of MG.\n\nOPEN-ACCESSTRUE\n==== Body\nSupport was received in the form of a grant from the Japanese Ministry of Education, Science, Sports and Culture (no. 26461298); a Health and Labor Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labor and Welfare of Japan; Intramural Research Grants (Nos. 23–5 and 23–4) for Neurological and Psychiatric Disorders of NCNP; Grants for Research on Intractable Diseases and Comprehensive Research on Disability Health and Welfare from the Ministry of Health, Labor and Welfare of Japan; a Grant-in-Aid for Scientific Research (B) from MEXT (No. 24390227), and a Grant-in-Aid for Challenging Exploratory Research (24659437).\n\nINTRODUCTION\nStatins lower cholesterol levels by specifically inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), a key enzyme in the cholesterol biosynthesis pathway. Statins are associated with ≥1 myotoxic effects including myalgia, elevation of creatine kinase and transaminases, and weakness. Muscle problems occurred in 10% to 25% of patients treated with statins in clinical practice and in approximately 13% of participants of published clinical trials.1 Statins have immunomodulatory properties, and they may unmask or worsen certain neuromuscular disorders including myasthenia gravis (MG), myotonic dystrophy, McArdle disease, and mitochondrial myopathy.2 The most severe problem is the development of inflammatory myopathy requiring immunosuppressive therapy; this is now known to be mediated by anti-HMGCR antibodies.3,4\n\nAnti-HMGCR antibodies were first found as 200- and 100-kDa proteins using protein immunoprecipitation.5 In 2011, the 100-kDa autoantigen was identified as HMGCR by Mammen et al.4 Anti-HMGCR antibodies were detectable using different methods, including enzyme-linked immunosorbent assay (ELISA), addressable laser beam assay, and chemiluminscent immunoassay.4,6–8 These assays showed qualitative agreement and level of anti-HMGCR antibodies showed significant correlation.8 Clinical features associated with anti-HMGCR antibodies detected by these methods in United States and Europe; however, there were no detection methods in Japan.\n\nMG is the most common autoimmune neuromuscular disorder mediated by autoantibodies to acetylcholine receptor (AChR) or muscle-specific tyrosine kinase.9 MG can be exacerbated by a variety of medications, which increase weakness by interrupting neuromuscular junction transmission. Some drugs potentially induce a new onset of MG. In 2002, Parmer et al10 first reported the case of a 67-year-old woman who suffered from the aggregation of generalized MG 12 weeks after being treated with atorvastatin. Special attention has been paid to the association between MG and statins. Some investigators suggested that MG occurs after therapy with statins, and others suggested that statins worsen previously diagnosed MG.10–15 The myotoxic effects of statins on MG symptoms were speculated to be immune-mediated, but the pathogenesis has not been investigated.\n\nThe purpose of the present study was to develop an ELISA of anti-HMGCR antibodies and to elucidate the clinical significance of anti-HMGCR antibodies in Japanese patients with inflammatory myopathies and MG.\n\nMETHODS\nPatients\nWe examined 75 adult patients with inflammatory myopathies, who were referred to Keio University or National Center of Neurology and Psychiatry between October 2010 and September 2012. We included patients with the definite diagnosis of idiopathic inflammatory myopathies by a comprehensive histological examination.16 In addition, the patients were all negative for anti-signal recognition particle (SRP) and anti-aminoacyl transfer RNA synthetase antibodies using RNA immunoprecipitation assay. The 75 patients’ mean age at the examination was 61 ± 15 years (range 20–82), and the sex breakdown (M:F) was 30:45.\n\nHistological diagnoses were based on the established criteria.17,18 Briefly, sporadic inclusion body myositis was diagnosed by the identification of rimmed vacuoles with non-necrotic fibers invaded by mononuclear cells or increased major histocompatibility complex (MHC) class I expression. Polymyositis was diagnosed based on exclusively endomysial inflammation cell infiltrate surrounding or invading non-necrotic muscle fibers, accompanied by ubiquitous MHC class I expression. Dermatomyositis was diagnosed by clinical criteria including a rash typical of dermatomyositis and the identification of perifascicular atrophy. Necrotizing myopathy was diagnosed based on the observation of necrotic fibers with diffuse distribution without or with minimal inflammatory cell infiltration.\n\nWe also studied 251 patients with MG, who were followed at the MG Clinic at Keio University Hospital. The diagnosis of MG was based on clinical, electrophysiologic, and immunologic criteria.9 The clinical classification and quantitative MG score were graded based on the recommendation issued by the Task Force of the Medical Advisory Board of the Myasthenia Gravis Foundation of America.19 Disease subtypes were divided into early-onset, late-onset, and thymoma-associated MG. As disease controls and normal controls, we used serum samples from 25 patients with Duchenne muscular dystrophy and 30 healthy volunteers.\n\nClinical information was retrospectively obtained for all patients by reviewing their clinical charts. All clinical samples and information were collected after the patients and controls gave their written informed consent as approved by the Institutional Review Boards of both the National Center of Neurology and Psychiatry and Keio University. All analyses were performed using statistical analysis software (IBM/SPSS version 20).\n\nAnti-HMGCR ELISA\nOur anti-HMGCR ELISA was developed based on the original method with some modifications.4 First, 96-well polyvinyl plates (Smilon multiwell plate H type; Sumitomo Bakelite) were coated with C-terminal recombinant HMGCR protein (Sigma, St. Louis, MO) at 0.1 μg/mL diluted in phosphate buffered. The remaining blocking sites were blocked with 3% bovine serum albumin. The wells were incubated with serum samples diluted at 1:400 and subsequently with peroxidase-conjugated anti-human IgG (Jackson Immuno Research, Westgrove, PA) diluted 1:100000. The antibody binding was visualized by incubation with tetramethylbenzidine (1 mg/mL) in phosphate-citrate buffer. The reaction was stopped by 1 mol/L sulfuric acid. The optical density at 450 nm (OD450) was read with an automatic plate reader (Biorad, Hercules, CA). Samples were tested in duplicate. The antibody index was calculated from the OD450 of the samples divided by the OD450 of the referential serum (patient 1 in Table 1). The cut-off value was set as the mean + 5SD of 30 healthy control sera.20\n\nTABLE 1 Characteristics of the 8 Patients With anti-HMGCR Antibodies\n\nProtein Immunoprecipitation Assay\nAutoantigens were analyzed by protein immunoprecipitation assay using 35S-labeled RD cellular extracts.21 RD cells (5 × 106 per sample) were cultured in methionine-free DMEM (Sigma) containing 3% heat-inactivated fetal bovine serum in the presence of 20 μCi/mL 35S-methionine for 14 h. The 35S-labeled cells were suspended in an ice-cold buffer containing 500 mmol/L NaCl, 0.1% Nonidet P-40, 10 mmol/L Tris-HCl, and a cocktail of protease inhibitors (Complete; Roche, Indianapolis, IN), and sonicated intermittently on ice for a total of 90 s. The supernatant (containing 35S-labeled soluble proteins originating from the nuclei, cytoplasm, and cellular membrane) was recovered by centrifugation (13,000g for 15 min) and used as the antigen source. Two milligrams of protein A-Sepharose CL-4B (Pharmacia Biotech, Little Chalfont) was incubated with 10 μL of a human serum sample. The immunoglobulins that were bound to protein A-Sepharose beads were then incubated with the 35S-labeled cellular extracts for 2 h. The immunoprecipitated material was resolved by electrophoresis on SDS-7.5% polyacrylamide gels, which were subsequently treated with 0.5 mol/L sodium salicylate to enhance the radioactivity, and evaluated by autoradiography using a BAS-5000 system (Fuji Film, Tokyo).\n\nImmunohistochemistry\nSix micrometer sections of frozen muscle tissue from biopsies were prepared. The sections were incubated with monoclonal mouse anti-neural cell adhesion molecule (NCAM) antibodies (Leica, Wetzlar) diluted 1:25, polyclonal rabbit anti-HMGCR antibodies (Sigma) diluted 1:125 and serum samples diluted 1:40. After incubation with the primary antibodies for 16 h, the sections were incubated for 2 h with a fluorescein isothiocyanate-conjugated anti-mouse, anti-rabbit or anti-human IgG antibody (Jackson Immuno-Research), and the sections were examined with a fluorescence microscope (Eclipse E-800, Nikon, Tokyo).\n\nRESULTS\nAnti-HMGCR ELISA\nSince the cut-off value was set as the mean + 5 × SD of 30 healthy control sera, the cut-off of anti-HMGCR index was 0.48. Positivity for the anti-HMGCR antibody was observed in 8 of 26 the patients with necrotizing myopathy (Figure 1). However, only one of the 24 patients with sporadic inclusion body myositis had a slight elevation of anti-HMGCR index. There was no positivity of anti-HMGCR antibodies in the 25 patients with polymyositis or dermatomyositis, or in the 25 patients with Duchenne muscular dystrophy. The seropositivity rate in the 26 necrotizing myopathy patients was significantly higher compared with those of the 49 patients with other inflammatory myopathies (31% vs 2%, P = 0.001).\n\nFIGURE 1 Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) ELISA. Antibodies reactive with recombinant HMGCR protein by ELISA in sera from inflammatory myopathy patients, Duchenne muscular dystrophy patients, and healthy controls. The cut-off level for positivity is indicated by the broken line (anti-HMGCR index: 0.48).\n\nProtein Immunoprecipitation Assay\nWe analyzed autoantigens immunoprecipitated by anti-HMGCR-positive sera using the protein immunoprecipitation assay. Representative results obtained from 6 patients with anti-HMGCR antibodies detected by anti-HMGCR ELISA are shown in Figure 2A. Anti-HMGCR-positive sera immunoprecipitated the doublet autoantigens located around 50 kDa (lanes 1–6). However, no immunoprecipitates were found in sera without anti-HMGCR antibodies (lanes 7 and 8). Moreover, we added an excess of the recombinant HMGCR protein (50 ng) to the patient 1’ serum at the incubation with protein A-Sepharose. The 50-kDa doublet autoantigens were clearly absorbed (lane 2 in Figure 2B).\n\nFIGURE 2 Confirmation of the HMGCR immunoreactivity. (A) Autoradiograms of immunoprecipitated 35S-labeled RD extracts from serum samples are shown. Immunoprecipitated materials were analyzed on SDS-7.5% polyacrylamide gels. The positions of the molecular weight standards are at the left. Arrows indicate the 50-kDa doublet precipitates detected in the serum sample containing anti-HMGCR antibodies (lanes 1–6). (B) Arrows indicate the 50-kDa doublet precipitates detected in the patient 1 sera (lane 1), but not in a healthy control (lane 3). The autoantigens were absorbed in the presence of recombinant HMGCR protein (lane 2). The panel has been cropped between lanes 2 and 3 to exclude immunoprecipitations that are irrelevant to the current study. (C) Muscle sections were obtained from patient 3 (left panels) and control (right panels). Sections were stained with hematoxylin-eosin (HE), polyclonal anti-neural cell adhesion molecules (NCAM) antibody, polyclonal anti-HMGCR antibody, and anti-HMGCR-positive sera. Scale bar = 50 μm.\n\nWe determine the sensitivity and specificity of the ELISA using this cutoff relative to the protein immunoprecipitation.4,5 Among 75 patients with inflammatory myopathies, 8 sera immunoprecipitated HMGCR protein and all of them were positive by anti-HMGCR ELISA. Conversely, among 9 sera positivity by anti-HMGCR ELISA, 8 were positive by protein immunoprecipitation. Therefore, the sensitivity and specificity of the anti-HMGCR ELISA are 100% and 98.5%, respectively.”\n\nImmunohistochemistry\nWe next performed immunohistochemistry using the muscle tissues obtained from patient 3 (Figure 2C). Regenerated muscle fibers were clearly detected by anti-NCAM antibody. In addition, HMGCR was expressed in the regenerated fibers. Anti-HMGCR-positive sera produced similar staining on the regenerated muscle fibers. Thus, the immunoreactivity was clearly co-localized with staining by the polyclonal anti-HMGCR antibody and patient's sera (left panels, Fig. 2C). In contrast, the anti-HMGCR antibody and patient's sera did not show any staining on the muscle fibers of control muscle.\n\nClinical Features of Patients with Anti-HMGCR Antibodies\nThe clinical features of eight patients (five men and three women) with anti-HMGCR-positive necrotizing myopathy are summarized in Table 1. Their mean age was 66 years, ranging from 49 to 79 years. All but patient 7 deteriorated within two months with a markedly increase level of creatine kinase. The clinical course suggested the initial diagnosis of rhabdomyolysis. Atrovastatins were administered in 3 patients who were over 70 years’ old. The diseases did not recover after the cessation of the statin treatment. Neurological examinations showed symmetrical and proximal limb weakness. Arms and legs were equally affected. The severe limb weakness with the grade ≤2/5 assessed by manual muscle strength (Medical Research Council scale grade) was not observed. No patients had dysphagia. Electromyography also indicated myopathic motor unit potentials (MUPs) in all patients.\n\nWith regard to the histology, all patients showed necrotic and regenerating muscle fibers without inflammatory cell infiltration. Endomysial fibrosis was minimal. MHC class I and class II expression were detected in 50% and 25% of the 8 anti-HMGCR-positive patients, respectively. The 2-year follow-up was available in 7 patients. All patients required immunotherapy and responded well. The recovery of muscle weakness was observed several weeks after the therapy. Since the creatine kinase persisted in higher levels, intravenous immunoglobulin therapy was added in 4 patients. None of the 7 patients experienced disease relapse. Neurological outcome evaluated using the modified Rankin scale showed that 5 of the 7 patients were able to return to their normal daily lives.\n\nMuscle magnetic resonance images (MRIs) were useful for evaluating the distribution of inflammation. Short T1 inversion recovery images in particular showed high signal intensities in all 8 patients. Focal or diffuse abnormal signals were seen in trunk and limb muscles (Figure 3). In contrast to the neurological examination, asymmetry was found on muscle MRI.\n\nFIGURE 3 Muscle MRI of patients with anti-HMGCR antibodies. (A–C) Patient 2. Increased short T1 inversion recovery (STIR) signal abnormalities involving deltoid, infraspinatus muscles (A), biceps brachii and triceps brachii (B), and forearm muscles (C). (D–F) Patient 3. Images of thighs on T1 images (D), T2 images (E), and STIR images (F). High intensity in biceps femoris and semitendinousus muscles on STIR images. (G, H) Patient 4. Increased T2/STIR signal abnormalities in posterior calves. (I) Patient 6. Increased STIR signal in trapezius muscle. (J–L) Patient 7. STIR images of pelvis (J) and enhancement in vastus lateralis and obturator internus muscles (K). Increased signal with enhancement of triceps brachii on STIR images (L).\n\nStatin Exposure and Anti-HMGCR Antibodies in MG Patients\nThe profiles of 251 patients with MG are indicated in Table 2. Of the 251 patients with MG, 23 (9%) including the 5 early-onset, 10 late-onset, and 8 thymoma-associated MG received statins at the disease onset. Statin brands were atorvastatin in 9 patients, pravastatin in 4, fluvastatin in 4, simvastatin in 3, pivastatin in 2, and rosuvastatin in 1 patient. In contrast, only 1 late-onset MG patient experienced MG worsening after statin exposure (Figure 4). Briefly, this 68-year-old woman had a diagnosis of ocular myasthenia at the age of 62 years. Her diplopia and ptosis were well controlled by pyridostigmine and achieved 18-month remission. However, she developed diplopia and ptosis after a 4-week treatment with atorvastatin at the age of 66 years. Her quantitative MG score was increased to 8 with an elevation titer of anti-AChR antibody. Since pyridostigmine was not fully effective, she required prednisolone at a daily dose of 10 mg.\n\nTABLE 2 Profiles of 251 Patients with Myasthenia Gravis\n\nFIGURE 4 Clinical course of a 68-year-old woman with MG worsening after statin treatment. Anti-AChR = anti-acetylcholine receptor antibody, QMG = quantitative myasthenia gravis.\n\nWe examined the presence of anti-HMGCR antibodies by conducting our ELISA, using 251 serum samples from the patients with MG. Only 1 (0.4%) early-onset female patient was found to be seropositive for anti-HMGCR antibodies (anti-HMGCR index: 0.6). She had mild generalized MG (MG Foundation of America class 2A) with no history of statin treatment. She achieved pharmacological remission after treatment with prednisolone and extended thymectomy. In contrast, anti-HMGCR antibodies were not found in the 23 MG patients who had received statins at disease onset. Moreover, the patient with statin-associated MG exacerbation was also negative for anti-HMGCR antibodies at both the onset and the worsening of MG.\n\nDISCUSSION\nWe established an anti-HMGCR ELISA and showed the following clinical relevance of its use:anti-HMGCR autoantibodies were specifically detected in necrotizing myopathy,\n\nmyopathy associated with anti-HMGCR antibodies was characterized by mild limb weakness and favorable response to immunotherapy with or without statin exposure;\n\nof 251 MG patients, 1 woman (0.4%) with no history of statin therapy had anti-HMGCR antibody.\n\n\n\nThe molecular weight of HMGCR is 97-kDa. Original reports indicated that a 100-kDa autoantigen in protein immunoprecipitation was successfully identified as HMGCR.4,5 In contrast, our studies showed the doublet autoantigens at around 50-kDa. It is likely that we detected 2 different cleaved forms of the HMGCR molecule. The discrepancy between the previous and present studies may be due to differences in the experimental protocols such as the culture cell lines used as the antigen source. Moreover, the HMGCR expression was upregulated predominantly in the regenerated muscle fibers of anti-HGMCR-positive patients.4 Our findings demonstrated that the HMGCR expression in the muscle fibers was clearly co-localized with patients’ serum. Taken together, the reactivity of our anti-HMGCR ELISA was successfully supported by other, different methods.\n\nThe most important pathogenesis of necrotizing myopathy is believed to be autoantibody-mediated. It is necessary to identify autoantibodies in sera of patients with necrotizing myopathy, since there is little or no evidence suggesting autoimmune mechanisms in muscle histology. Anti-SRP antibodies were found in 34 (53%) of 64 patients with necrotizing myopathy.16 In the present study, we demonstrated that 31% of the 26 anti-SRP-negative necrotizing myopathy patients had anti-HMGCR antibodies. Our results showed that only 3 (38%) of the 8 anti-HMGCR-positive patients had undergone statin exposure. This prevalence was consistent with that in a European cohort (44%).7 Taken these findings together, we emphasize that anti-HMGCR antibodies can be regarded as the second serological marker of necrotizing myopathy as well as a marker of statin-induced myopathy.\n\nImportantly, there were clear differences in the clinical characteristics associated with autoantibodies to SRP and HMGCR in our investugation.22 The neurological manifestations of the anti-HMGCR-positive patients were mild limb weakness with good response to immunotherapy. Older patients tended to have anti-HMGCR antibodies.3 In contrast, anti-SRP myopathy was characterized by severe limbs weakness and atrophy as well as bulbar and trunk muscle involvement. Younger patients showed severe clinical deficits.22\n\nPrevious reports revealed the clinical features of 15 patients with statin-associated MG.10–15 The ages were ranged as 41 to 71 years (average 58 years) and the sex ratio was 11:4 (M:F). Newly-onset MG was observed in 8 patients and worsening of MG in 7 patients. The patients experienced MG symptoms after 1 to 16 weeks after the statin exposure (average, 4 weeks and within 2 weeks in 8 patients). Ocular MG was observed in 3 patients and generalized MG in 12 patients. The antibodies status was AChR-positive in 10 patients, muscle-specific tyrosine kinase-positive in 4, and seronegative in 1 patient. Discontinuance of statins and initiation of pyridostigmine were effective, but immunotherapy was necessary in 8 patients.\n\nIn our case series, it is likely that statins were less involved in the new onset of MG in 23 patients because myasthenic symptoms did not develop within several weeks after the start of the statin therapy. However, 1 patient's MG worsened after 4 weeks of statin use, after an 18-month MG remission. Her symptoms were limited to ocular myasthenia, but prednisolone was necessary to control her disease.\n\nOh et al13 reported that MG worsening occurred in 6 (11%) of their 54 MG patients with statin treatment. However, the actual incidence of statin-associated MG exacerbation seems to be lower. In clinical practice, we also feel that statins should be used in patients with MG for the same indications as in individuals without MG.23 Statins should be withdrawn if exacerbation of MG occurs, or if the anti-AChR antibody concentration increases markedly.\n\nA limitation of the present study is that anti-HMGCR antibodies were evaluated in only 1 statin-associated MG patient, although the cases of 251 MG patients were examined. However, we think that anti-HMGCR antibodies do not affect the function of neuromuscular transmission. We regard seropositivity with a low titer of anti-HMGCR antibodies in 1 MG patient as a non-specific phenomenon. In a previous report, although organ-specific autoantibodies targeted to thyroid, gastric parietal cells, adrenal cortex, and islet cells were found in up to 30% of 283 MG patients, they had no clinical or pathogenic relevance.24\n\nOur anti-HMGCR ELISA showed an extremely low frequency (0.4%) of seropositivity in MG patients. In this regard, a community-based study also showed that statin users without myopathy were all negative for anti-HMGCR antibodies.25 Based on its high specificity of antibody detection, we contend that the anti-HMGCR ELISA is a useful tool for the diagnosis of necrotizing myopathy, discriminating from other various muscle problems linked to statin exposure.\n\nIn conclusion, anti-HMGCR antibodies are a relevant clinical marker of necrotizing myopathy with or without statin-exposure, but they are not associated with the onset or deterioration of MG.\n\nAcknowledgments\nNone.\n\nAbbreviations: ELISA = enzyme-linked immunosorbent assay, HMGCR = 3-hydroxyl-3-methylglutatyl-coenzyme A reductase, MG = myasthenia gravis, MHC = major histocompatibility complex, MRI = magnetic resonance image, NCAM = neural cell adhesion molecules, OD450 = optical density at 450 nm, SRP = signal recognition particle.\n\nConflict of interest of interest disclosures: None reported.\n==== Refs\nREFERENCES\n1. Ganga HV Slim HB Thompson PD \nA systematic review of statin-induced muscle problems in clinical trials . Am Heart J \n2014 ; 168 :6 –15 .24952854 \n2. de Sousa E Howard J \nMore evidence for the association between statins and myasthenia gravis . Muscle Nerve \n2008 ; 38 :1085 –1086 .18720505 \n3. Mohassel P Mammen AL \nStatin-associated autoimmune myopathy and anti-HMGCR autoantibodies . Muscle Nerve \n2013 ; 48 :477 –483 .23519993 \n4. Mammen AL Chung T Christopher-Stine L \nAutoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy . Arthritis Rheum \n2011 ; 63 :713 –721 .21360500 \n5. Christopher-Stine L Casciola-Rosen LA Hong G \nA novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy . Arthritis Rheum \n2010 ; 62 :2757 –2766 .20496415 \n6. Drouot L Allenbach Y Jouen F \net al: Exploring necrotizing autoimmune myopathies with a novel immunoassay for anti-3-hydroxy-3-methyl-glutaryl-CoA reductase autoantibodies . Arthritis Res Ther \n2014 ; 16 :R39 .24484965 \n7. Allenbach Y Drouot L Rigolet A \nAnti-HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: inconstant exposure to statin . Medicine (Baltimore) \n2014 ; 93 :150 –157 .24797170 \n8. Musset L Miyara M Benveniste O \nAnalysis of autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase using different technologies . J Immunol Res \n2014 ; 405956 .\n9. Meriggioli MN Sanders DB \nAutoimmune myasthenia gravis: emerging clinical and biological heterogeneity . Lancet Neurol \n2009 ; 8 :475 –490 .19375665 \n10. Parmar B Francis PJ Ragge NK \nStatins, fibrates, and ocular myasthenia . Lancet \n2002 ; 360 :717 .12241896 \n11. Cartwright MS Jeffery DR Nuss GR \nStatin-associated exacerbation of myasthenia gravis . Neurology \n2004 ; 63 :2188 .15596782 \n12. Purvin V Kawasaki A Smith KH \nStatin-associated myasthenia gravis: report of 4 cases and review of the literature . Medicine (Baltimore) \n2006 ; 85 :82 –85 .16609346 \n13. Oh SJ Dhall R Young A \nStatins may aggravate myasthenia gravis . Muscle Nerve \n2008 ; 38 :1101 –1107 .18720508 \n14. Elsais A Lund C Kerty E \nPtosis, diplopia and statins: an association? \nEur J Neurol \n2008 ; 15 :e92 –e93 .18727677 \n15. Gale J Danesh-Meyer HV \nStatins can induce myasthenia gravis . J Clin Neurosci \n2014 ; 21 :195 –197 .24433954 \n16. Suzuki S Yonekawa T Kuwana M \nClinical and histological findings associated with autoantibodies detected by RNA immunoprecipitation in inflammatory myopathies . J Neuroimmunol \n2014 ; 274 :202 –208 .25064497 \n17. Hoogendijk JE Amato AA Lecky BR \n119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10-12 October 2003, Naarden, The Netherlands . Neuromuscul Disord \n2004 ; 14 :337 –345 .15099594 \n18. Hilton-Jones D Miller A Parton M \nInclusion body myositis: MRC Centre for Neuromuscular Diseases, IBM workshop, London 2008 . Neuromuscul Disord \n2010 ; 20 :142 –147 .20074951 \n19. Jaretzki A 3rdBarohn RJ Ernstoff RM \nMyasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America . Ann Thorac Surg \n2000 ; 70 :327 –334 .10921745 \n20. Suzuki S Utsugisawa K Iwasa K \nAutoimmunity to endoplasmic reticulum chaperone GRP94 in myasthenia gravis . J Neuroimmunol \n2011 ; 237 :87 –92 .21774995 \n21. Suzuki S Satoh T Yasuoka H \nNovel autoantibodies to a voltage-gated potassium channel Kv1.4 in a severe form of myasthenia gravis . J Neuroimmunol \n2005 ; 170 :141 –149 .16182377 \n22. Suzuki S Hayashi YK Kuwana M \nMyopathy associated with antibodies to signal recognition particle: disease progression and neurological outcome . Arch Neurol \n2012 ; 69 :728 –732 .22332183 \n23. Gilhus NE \nIs it safe to use statins in patients with myasthenia gravis? \nNat Clin Pract Neurol \n2009 ; 5 :8 –9 .19065133 \n24. Klein R Marx A Strobel P \nAutoimmune associations and autoantibody screening show focused recognition in patient subgroups with generalized myasthenia gravis . Hum Immunol \n2013 ; 74 :1184 –1193 .23792059 \n25. Mammen AL Pak K Williams EK \nRarity of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies in statin users, including those with self-limited musculoskeletal side effects . Arthritis Care Res (Hoboken) \n2012 ; 64 :269 –272 .21972203\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0025-7974",
"issue": "94(4)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000368:Aged; D001323:Autoantibodies; D015415:Biomarkers; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007150:Immunohistochemistry; D007564:Japan; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal; D009220:Myositis; D009336:Necrosis; D009460:Neurologic Examination",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e416",
"pmc": null,
"pmid": "25634171",
"pubdate": "2015-01",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": "19375665;18720505;24433954;19065133;15099594;23519993;25064497;18727677;23792059;21774995;10921745;16182377;12241896;24484965;24741598;15596782;24952854;21360500;24797170;18720508;20496415;22332183;20074951;16609346;21972203",
"title": "Statins and myotoxic effects associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies: an observational study in Japan.",
"title_normalized": "statins and myotoxic effects associated with anti 3 hydroxy 3 methylglutaryl coenzyme a reductase autoantibodies an observational study in japan"
} | [
{
"companynumb": "PHHY2015JP048665",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "OBJECTIVE\nTo describe new-onset inflammatory bowel diseases (new IBD) in patients treated with interleukin 17 inhibitors (IL-17i), to assess their incidence and to identify their risk factors in real life.\n\n\nMETHODS\nA French national registry (MISSIL) aimed to report all cases of new IBD in patients treated with IL-17i from January 2016 to December 2019. Using the estimated number of patients treated by IL-17 in France during the study period, the annual incidence rates of new IBD was reported in IL-17i-treated patients. A case-control study was performed with two controls per new IBD case matched by gender, age and underlying inflammatory disease.\n\n\nRESULTS\n31 cases of new IBD under IL-17i were collected: 27 patients treated for spondyloarthritis and 4 patients for psoriasis. All were observed with secukinumab (SEK). The median time to onset of new IBD symptoms was 4.0 (1.5-7.5) months. SEK was discontinued in all patients. The evolution was favourable with complete resolution (17/31), improvement (7/31) or stabilization (5/31). 2 patients died: one due to a massive myocardial infarction and one due to post-colectomy complications. The incidence of new IBD decreased from 0.69/100 PY (7/1010) in 2016, to 0.08/100PY (6/7951) in 2019. No previous treatment with etanercept (OR = 0.33, IC95% 0.14-0.80, p= 0.014) and low number of previous biological therapies (OR = 0.67, 95%CI 0.47-0.94, p= 0.021) were significantly associated with new IBD.\n\n\nCONCLUSIONS\nThe incidence of new IBD was low and decreased from 2016 to 2019. The outcome was favourable in 24 out of 31 patients, but two patients died.",
"affiliations": "Service de rhumatologie, Université de Lille, CHU Lille, Lille, France.;Service de rhumatologie, Aix Marseille University, APHM, Marseille, France.;Université de Lille, CHU Lille, ULR 2694-METRICS: évaluation des technologies de santé et des pratiques médicales, Lille, France.;Service de rhumatologie, Princess Grace Hospital Centre, Monaco, Monaco.;Service de rhumatologie, University Hospital Pitié Salpêtrière, APHP.;Université de Nantes, CHU Nantes, Service de dermatologie, UMR 1280 PhAN, INRAE, Nantes, France.;Service de rhumatologie, CHU Caen, Caen, France.;Service de rhumatologie, CHU de Nancy, Nancy, France.;Service de rhumatologie, Université Paris Est Créteil Val de Marne, EA 7379-Epiderme, AP-HP, Hôpital Henri-Mondor, Créteil, France.;Service de rhumatologie, CHU Toulouse, Toulouse, France.;Service de rhumatologie, CH Le Mans, Le Mans, France.;CHU de Strasbourg, Service de rhumatologie, Département Universitaire de Pharmacologie, Addictologie, Toxicologie et Thérapeutique, Université de Strasbourg, Strasbourg, France.;Service de rhumatologie, CHU Grenoble Alpes, Grenoble, France.;Service de dermatologie, CHU Montpellier, Montpellier, France.;Service de rhumatologie, CH La Rochelle, La Rochelle, France.;Service de rhumatologie, CHU de Tours, Tours, France.;Service de rhumatologie, Centre Hospitalier de Saint-Brieuc, Saint-Brieuc, France.;Service de rhumatologie, Centre Hospitalier Universitaire Amiens-Picardie, Amiens, France.;CHU Lyon, Service de dermatologie, Hôpital Edouard Herriot, Lyon, France.;Service de dermatologie, CH Lens, Lens, France.;Service de rhumatologie, Centre Hospitalier Intercommunal Alençon-Mamers, Alençon, France.;Service de rhumatologie, Polyclinique d'Henin-Beaumont, Hénin-Beaumont, France.;Service de rhumatologie, GHICL, Hôpital Saint-Philibert, Lomme, France.;Service de gastroentérologie, CH Colmar, Colmar, France.;CH Ouest-Réunion, Saint-Paul, La Réunion, France.;Service de pathologies digestives, HIA Sainte Anne, Toulon, France.;Service de rhumatologie, CHD Vendée, La Roche-sur-Yon, France.;CHU Besançon, Service de rhumatologie, EA 4266, Université de Franche-Comté, Besançon, France.;Centre régional de pharmacovigilance, Service de pharmacologie médicale, CHU de Lille, Lille, France.;Université de Lille, CHU Lille, Service de dermatologie, U1286 Inserm INFINITE, Lille, France.;Service de gastroentérologie, CHU de Nancy, Nancy, France.;Service de rhumatologie, Université de Lille, CHU Lille, Lille, France.",
"authors": "Letarouilly|Jean-Guillaume|JG|0000-0003-2793-6303;Pham|Thao|T|;Pierache|Adeline|A|;Acquacalda|Émilie|É|;Banneville|Beatrice|B|;Barbarot|Sébastien|S|;Baudart|Pauline|P|;Bauer|Élodie|É|;Claudepierre|Pascal|P|;Constantin|Arnaud|A|;Dernis|Emmanuelle|E|;Felten|Renaud|R|;Gaudin|Philippe|P|;Girard|Céline|C|;Gombert|Bruno|B|;Goupille|Philippe|P|;Guennoc|Xavier|X|;Henry-Desailly|Isabelle|I|;Jullien|Denis|D|;Karimova|Elena|E|;Lanot|Sylvain|S|;Le Dantec|Loïc|L|;Pascart|Tristan|T|;Plastaras|Laurianne|L|;Sultan|Nathalie|N|;Truchet|Xavier|X|;Varin|Stephane|S|;Wendling|Daniel|D|;Gaboriau|Louise|L|;Staumont-Sallé|Delphine|D|;Peyrin-Biroulet|Laurent|L|;Flipo|Rene-Marc|RM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/keab819",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-0324",
"issue": null,
"journal": "Rheumatology (Oxford, England)",
"keywords": "IL 17 inhibitor; inflammatory bowel disease; psoriasis; psoriatic arthritis; real-world; secukinumab; spondyloarthritis",
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": null,
"nlm_unique_id": "100883501",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34730790",
"pubdate": "2021-11-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "New-Onset Inflammatory Bowel Diseases Among IL-17 inhibitors-Treated Patients: Results From The Case-Control MISSIL Study.",
"title_normalized": "new onset inflammatory bowel diseases among il 17 inhibitors treated patients results from the case control missil study"
} | [
{
"companynumb": "NVSC2021FR052037",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SECUKINUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "BACKGROUND\nCoronavirus disease 2019 (COVID-19) has been demonstrated to be the cause of pneumonia. Nevertheless, it has not been reported as the cause of acute myocarditis or fulminant myocarditis.\n\n\nMETHODS\nA 63-year-old male was admitted with pneumonia and cardiac symptoms. He was genetically confirmed as having COVID-19 according to sputum testing on the day of admission. He also had elevated troponin I (Trop I) level (up to 11.37 g/L) and diffuse myocardial dyskinesia along with a decreased left ventricular ejection fraction (LVEF) on echocardiography. The highest level of interleukin-6 was 272.40 pg/ml. Bedside chest radiographs showed typical ground-glass changes indicative of viral pneumonia. Laboratory test results for viruses that cause myocarditis were all negative. The patient conformed to the diagnostic criteria of the Chinese expert consensus statement for fulminant myocarditis. After receiving antiviral therapy and mechanical life support, Trop I was reduced to 0.10 g/L, and interleukin-6 was reduced to 7.63 pg/mL. Moreover, the LVEF of the patient gradually recovered to 68%. The patient died of aggravation of secondary infection on the 33rd day of hospitalization.\n\n\nCONCLUSIONS\nCOVID-19 patients may develop severe cardiac complications such as myocarditis and heart failure. This is the first report of COVID-19 complicated with fulminant myocarditis. The mechanism of cardiac pathology caused by COVID-19 needs further study.",
"affiliations": "Department of Medical Ultrasonics, National Clinical Research Center for Infectious Disease, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, No. 29 Bulan Road, Shenzhen, 518112, People's Republic of China.;National Clinical Research Center for Infectious Disease, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, China.;Department of Infectious Disease, National Clinical Research Center for Infectious Disease, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, China.;Department of Infectious Disease, National Clinical Research Center for Infectious Disease, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, China.;Department of Infectious Disease, National Clinical Research Center for Infectious Disease, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, China.;Department of Intensive Care Unit, National Clinical Research Center for Infectious Disease, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, China.;Department of Radiology, National Clinical Research Center for Infectious Disease, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, China.;Department of Cardiology, National Clinical Research Center for Infectious Disease, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, China.;Department of Medical Ultrasonics, National Clinical Research Center for Infectious Disease, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, No. 29 Bulan Road, Shenzhen, 518112, People's Republic of China.;Department of Medical Ultrasonics, National Clinical Research Center for Infectious Disease, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, No. 29 Bulan Road, Shenzhen, 518112, People's Republic of China.;Department of Medical Ultrasonics, National Clinical Research Center for Infectious Disease, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, No. 29 Bulan Road, Shenzhen, 518112, People's Republic of China.;Department of Medical Ultrasonics, National Clinical Research Center for Infectious Disease, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, No. 29 Bulan Road, Shenzhen, 518112, People's Republic of China.;Department of Medical Ultrasonics, National Clinical Research Center for Infectious Disease, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, No. 29 Bulan Road, Shenzhen, 518112, People's Republic of China. chaosheng-01@szsy.sustech.edu.cn.;National Clinical Research Center for Infectious Disease, State Key Discipline of Infectious Disease, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, China. liulei3322@aliyun.com.",
"authors": "Zeng|Jia-Hui|JH|;Liu|Ying-Xia|YX|;Yuan|Jing|J|;Wang|Fu-Xiang|FX|;Wu|Wei-Bo|WB|;Li|Jin-Xiu|JX|;Wang|Li-Fei|LF|;Gao|Hong|H|;Wang|Yao|Y|;Dong|Chang-Feng|CF|;Li|Yi-Jun|YJ|;Xie|Xiao-Juan|XJ|;Feng|Cheng|C|;Liu|Lei|L|",
"chemical_list": "D000998:Antiviral Agents; D015415:Biomarkers; D004338:Drug Combinations; C508600:IL6 protein, human; D015850:Interleukin-6; D019210:Troponin I; C558899:lopinavir-ritonavir drug combination; D000077725:Piperacillin, Tazobactam Drug Combination; D061466:Lopinavir; D019438:Ritonavir",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-020-01424-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8126",
"issue": "48(5)",
"journal": "Infection",
"keywords": "COVID-19; Coronavirus; Echocardiography; Fulminant myocarditis; Infection",
"medline_ta": "Infection",
"mesh_terms": "D000208:Acute Disease; D000998:Antiviral Agents; D001442:Bacteroides Infections; D000073640:Betacoronavirus; D015415:Biomarkers; D000086382:COVID-19; D002177:Candidiasis; D018352:Coronavirus Infections; D004338:Drug Combinations; D004452:Echocardiography; D017809:Fatal Outcome; D006801:Humans; D015850:Interleukin-6; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D009205:Myocarditis; D058873:Pandemics; D000077725:Piperacillin, Tazobactam Drug Combination; D011024:Pneumonia, Viral; D019438:Ritonavir; D000086402:SARS-CoV-2; D013318:Stroke Volume; D014057:Tomography, X-Ray Computed; D019210:Troponin I",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "773-777",
"pmc": null,
"pmid": "32277408",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32946822;32955176;32966811;32870295;30519877;1309370;29324996;14535196;26922692;32598906;28466096;15602737;26505576;29863096",
"title": "First case of COVID-19 complicated with fulminant myocarditis: a case report and insights.",
"title_normalized": "first case of covid 19 complicated with fulminant myocarditis a case report and insights"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK202011130",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LOPINAVIR\\RITONAVIR"
},
"drugadditional... |
{
"abstract": "We studied the incidence of fatal adverse drug reactions (ADRs) in a tertiary hospital to find out which drugs were involved. The secondary objective was to compare the data from the same hospital published 12 years earlier. All 1708 death cases in the Helsinki University Central Hospital during the year 2012 were retrospectively evaluated. All suspected drug-related deaths, excluding suicides, were scrutinized by an expert panel using the WHO ADR probability classification. Of all cases, 52 (3.0%) were classified as certainly or probably drug related and 24 (1.4%) as possibly drug related. Together, these corresponded to 0.02% of all hospital admissions. The most commonly involved drugs in certain or probable cases were cytostatics (18 cases, 1.1% of all cases) and antithrombotics (17, 1.0%). Twelve years earlier, these caused 27 (1.8%) and 22 (1.5%) cases, respectively. Non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids caused less (2 and 0 cases) fatal ADRs than earlier (12 and 4 cases, p = 0.048 and p = 0.005, respectively). Most of the ADRs leading to death were present already in admission and affected seriously ill or elderly patients. Hospital-born fatal ADRs occurred in 0.003% of patients. In conclusion, cytostatics and antithrombotics are still the leading causes of fatal ADRs, but NSAIDs and glucocorticoids seem to cause fatal ADRs less often than previously. The incidence of fatal ADRs in 2012 was 3.0% of all deaths, suggesting a decline compared to the 2000 value (5.0%). Improved awareness, prevention and treatment of ADRs and safer medicines may explain these declining trends.",
"affiliations": "Department of Clinical Pharmacology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.;Department of Clinical Pharmacology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.;Department of Clinical Pharmacology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.;Department of Clinical Pharmacology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.;Department of Clinical Pharmacology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.",
"authors": "Lapatto-Reiniluoto|Outi|O|;Patinen|Laura|L|;Niemi|Mikko|M|;Backman|Janne T|JT|;Neuvonen|Pertti J|PJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bcpt.12435",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1742-7835",
"issue": "117(6)",
"journal": "Basic & clinical pharmacology & toxicology",
"keywords": null,
"medline_ta": "Basic Clin Pharmacol Toxicol",
"mesh_terms": "D000368:Aged; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005387:Finland; D017052:Hospital Mortality; D006785:Hospitals, University; D006801:Humans; D015994:Incidence; D008297:Male; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013405:Suicide; D013997:Time Factors",
"nlm_unique_id": "101208422",
"other_id": null,
"pages": "421-6",
"pmc": null,
"pmid": "26111726",
"pubdate": "2015-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Drug-Related Inadvertent Deaths in a University Hospital--A Declining Trend.",
"title_normalized": "drug related inadvertent deaths in a university hospital a declining trend"
} | [
{
"companynumb": "FI-PFIZER INC-2016098555",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREGABALIN"
},
"drugadditional": null,
... |
{
"abstract": "Macrolides have anti-inflammatory effects and have been used to treat diffuse panbronchiolitis, bronchiectasis, and cystic fibrosis. Lately, several cases of cryptogenic organizing pneumonia (COP) and radiotherapy-related organizing pneumonia (OP) that were successfully treated with macrolides considering their anti-inflammatory effects were reported. We report three cases of OP associated with rheumatoid arthritis (RA) successfully treated with clarithromycin (CAM) and prednisolone (PSL). Case 1: A 70-year-old woman suffering from RA was admitted with cough and severe dyspnea. She was diagnosed with OP associated with RA on the basis of computed tomography (CT) findings and transbronchial lung biopsy results. She was successfully treated with PSL and cyclosporine A. At the exacerbation of OP, she was successfully treated with CAM and PSL. Case 2: A 74-year-old man suffering from COP visited our department with arthralgia and articular swellings. He was diagnosed with RA, which was thought to be associated with OP. He was successfully treated with CAM and PSL. Case 3: A 54-year-old man suffering from RA presented with an exacerbation of arthralgia and articular swellings and cough. He was diagnosed with OP associated with RA on the basis of CT findings. He was successfully treated with CAM and PSL. The present cases suggest that CAM and PSL treatment may be effective in some cases of OP associated with RA.",
"affiliations": "Department of Internal Medicine, JCHO Hokkaido Hospital.;Department of Internal Medicine, JCHO Hokkaido Hospital.;Department of Internal Medicine, JCHO Hokkaido Hospital.;Department of Respiratory Medicine, JCHO Hokkaido Hospital.;Department of Diagnostic Radiology, JCHO Hokkaido Hospital.;Department of Pathology, JCHO Hokkaido Hospital.;Department of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine.",
"authors": "Ohe|Masashi|M|;Shida|Haruki|H|;Horita|Tetsuya|T|;Ito|Kenichiro|K|;Sugiura|Mitsuru|M|;Hattori|Atsuo|A|;Oku|Kenji|K|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005938:Glucocorticoids; D011239:Prednisolone; D017291:Clarithromycin",
"country": "Japan",
"delete": false,
"doi": "10.5582/ddt.2017.01043",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1881-7831",
"issue": "11(4)",
"journal": "Drug discoveries & therapeutics",
"keywords": "Rheumatoid arthritis; clarithromycin; organizing pneumonia; prednisolone",
"medline_ta": "Drug Discov Ther",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D001172:Arthritis, Rheumatoid; D017291:Clarithromycin; D018549:Cryptogenic Organizing Pneumonia; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D011239:Prednisolone; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101493809",
"other_id": null,
"pages": "218-222",
"pmc": null,
"pmid": "28867755",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of three patients with organizing pneumonia associated with rheumatoid arthritis using clarithromycin and prednisolone.",
"title_normalized": "successful treatment of three patients with organizing pneumonia associated with rheumatoid arthritis using clarithromycin and prednisolone"
} | [
{
"companynumb": "JP-BAUSCH-BL-2017-028025",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo determine the diagnostic value of apparent diffusion coefficient (ADC) maps in the assessment of response to chemotherapy in patients with multiple myeloma (MM).\n\n\nMETHODS\nFourteen patients (seven women) with MM underwent whole-body magnetic resonance imaging (WB-MRI) study on a 1.5T scanner, before and after chemotherapy. DWI with background body signal suppression (DWIBS) sequences (b values: 0, 500, and 1000 mm(2)/sec) were qualitatively analyzed, along with T1 turbo spine echo and short tau inversion recovery T2-weighted images, to evaluate bone lesions. On ADC maps, regions of interest were manually drawn along contours of lesions. The ADC values percentage variation (ΔADC) before (MR1) and after (MR2) chemotherapy were calculated and compared between responders (11 of 14) and nonresponders (3 of 14). The percentage of plasma cells by the means of the bone marrow aspirate was evaluated as parameter for response to chemotherapy.\n\n\nRESULTS\nTwenty-four lesions, hyperintense on DWIBS as compared to normal bone marrow, were evaluated. In responder group, the mean ADC values were 0.63 ± 0.24 × 10(-3) mm(2)/s on MR1 and 1.04 ± 0.46 × 10(-3) mm(2)/s on MR2; partial or complete signal intensity decrease during follow-up on DWIBS was found along with a reduction of plasma cells infiltration in the bone marrow. The mean ADC values for nonresponders were 0.61 ± 0.05 × 10(-3) mm(2)/s on MR1 and 0.69 ± 0.09 × 10(-3) mm(2)/s on MR2. The mean variation of ΔADC in responders (Δ = 66%) was significantly different (P < .05) than in nonresponders (Δ = 15%).\n\n\nCONCLUSIONS\nWB-MRI with DWIBS sequences, by evaluating posttreatment changes of ADC values, might represent a complementary diagnostic tool in the assessment of response to chemotherapy in MM patients.",
"affiliations": "School of Medicine, University of Milano-Bicocca, Via Pergolesi 33, 20900 Monza, Italy; Department of Diagnostic Radiology, H. San Gerardo, Monza, Italy; Department of Health Sciences, Tecnomed Foundation, University of Milano-Bicocca, Monza, Italy. Electronic address: pa.bonaffini@gmail.com.;School of Medicine, University of Milano-Bicocca, Via Pergolesi 33, 20900 Monza, Italy; Department of Diagnostic Radiology, H. San Gerardo, Monza, Italy.;School of Medicine, University of Milano-Bicocca, Via Pergolesi 33, 20900 Monza, Italy; Department of Diagnostic Radiology, H. San Gerardo, Monza, Italy.;School of Medicine, University of Milano-Bicocca, Via Pergolesi 33, 20900 Monza, Italy; Department of Diagnostic Radiology, H. San Gerardo, Monza, Italy.;School of Medicine, University of Milano-Bicocca, Via Pergolesi 33, 20900 Monza, Italy; Department of Diagnostic Radiology, H. San Gerardo, Monza, Italy.;School of Medicine, University of Milano-Bicocca, Via Pergolesi 33, 20900 Monza, Italy; Department of Diagnostic Radiology, H. San Gerardo, Monza, Italy.",
"authors": "Bonaffini|Pietro Andrea|PA|;Ippolito|Davide|D|;Casiraghi|Alessandra|A|;Besostri|Valeria|V|;Franzesi|Cammillo Talei|CT|;Sironi|Sandro|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1076-6332",
"issue": "22(9)",
"journal": "Academic radiology",
"keywords": "ADC; Multiple myeloma; chemotherapy; whole-body MRI",
"medline_ta": "Acad Radiol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001854:Bone Marrow Cells; D002452:Cell Count; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007089:Image Enhancement; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009367:Neoplasm Staging; D010950:Plasma Cells; D012074:Remission Induction; D051598:Whole Body Imaging",
"nlm_unique_id": "9440159",
"other_id": null,
"pages": "1163-71",
"pmc": null,
"pmid": "26182979",
"pubdate": "2015-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Apparent diffusion coefficient maps integrated in whole-body MRI examination for the evaluation of tumor response to chemotherapy in patients with multiple myeloma.",
"title_normalized": "apparent diffusion coefficient maps integrated in whole body mri examination for the evaluation of tumor response to chemotherapy in patients with multiple myeloma"
} | [
{
"companynumb": "IT-TAKEDA-2020TUS047839",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": "3",
... |
{
"abstract": "Atorvastatin and HMG-CoA reductase inhibitors are the most frequently used medication in the world due to very few adverse toxic side effects. One potentially life threatening adverse effect is caused by clinically significant statin induced rhabdomyolysis, either independently or in combination with fusidic acid. The patient in our case who previously had cardiac insufficiency, atrial fibrillation, and thoracic aorta aneurysm and was treated with insertion of an endovascular metallic stent in the aorta is presented in the report. He had an inoperable aortitis with an infected stent and para-aortic abscesses with no identified microorganism. The patient responded well to empirical antibiotic treatment with combination therapy of fusidic acid and moxifloxacin. This treatment was planned as a lifelong prophylactic treatment. The patient had been treated with atorvastatin for several years. He developed severe rhabdomyolysis when he was started on fusidic acid and moxifloxacin. The patient made a fast recovery after termination of treatment with atorvastatin and fusidic acid. We here report a life threatening complication of rhabdomyolysis that physicians must be aware of. This can happen either in atorvastatin monotherapy or as a complication of pharmacokinetic interaction between atorvastatin and fusidic acid.",
"affiliations": "Medical Department, Infectious Diseases Division, National Hospital Faroe Islands, Tórshavn, Faroe Islands.;Medical Department, Infectious Diseases Division, National Hospital Faroe Islands, Tórshavn, Faroe Islands; Infectious Diseases Research Unit, Odense University Hospital and University of Southern Denmark, Odense, Denmark; Faculty of Science and Technology, University of the Faroe Islands, Tórshavn, Faroe Islands.",
"authors": "Nandy|Anirban|A|0000-0002-3385-3777;Gaïni|Shahin|S|0000-0001-7752-0483",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2016/4705492",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 2811593810.1155/2016/4705492Case ReportSevere Rhabdomyolysis as Complication of Interaction between Atorvastatin and Fusidic Acid in a Patient in Lifelong Antibiotic Prophylaxis: A Dangerous Combination http://orcid.org/0000-0002-3385-3777Nandy Anirban \n1\n\n*\nhttp://orcid.org/0000-0001-7752-0483Gaïni Shahin \n1\n\n2\n\n3\n1Medical Department, Infectious Diseases Division, National Hospital Faroe Islands, Tórshavn, Faroe Islands2Infectious Diseases Research Unit, Odense University Hospital and University of Southern Denmark, Odense, Denmark3Faculty of Science and Technology, University of the Faroe Islands, Tórshavn, Faroe Islands*Anirban Nandy: anirban_198798@yahoo.co.inAcademic Editor: Mamede de Carvalho\n\n2016 27 12 2016 2016 470549228 9 2016 13 11 2016 4 12 2016 Copyright © 2016 A. Nandy and S. Gaïni.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.Atorvastatin and HMG-CoA reductase inhibitors are the most frequently used medication in the world due to very few adverse toxic side effects. One potentially life threatening adverse effect is caused by clinically significant statin induced rhabdomyolysis, either independently or in combination with fusidic acid. The patient in our case who previously had cardiac insufficiency, atrial fibrillation, and thoracic aorta aneurysm and was treated with insertion of an endovascular metallic stent in the aorta is presented in the report. He had an inoperable aortitis with an infected stent and para-aortic abscesses with no identified microorganism. The patient responded well to empirical antibiotic treatment with combination therapy of fusidic acid and moxifloxacin. This treatment was planned as a lifelong prophylactic treatment. The patient had been treated with atorvastatin for several years. He developed severe rhabdomyolysis when he was started on fusidic acid and moxifloxacin. The patient made a fast recovery after termination of treatment with atorvastatin and fusidic acid. We here report a life threatening complication of rhabdomyolysis that physicians must be aware of. This can happen either in atorvastatin monotherapy or as a complication of pharmacokinetic interaction between atorvastatin and fusidic acid.\n==== Body\n1. Introduction\nRhabdomyolysis is most commonly described by “lysis” or disintegration and breakdown of skeletal muscles and subsequent release of toxic intracellular components into the systemic circulation. The major causes of rhabdomyolysis include trauma, infections, hyperthermia, myopathies, and adverse drug-drug interactions of certain medications [1]. Statin myotoxicity is a well-known side effect and is related to serum levels of the drugs and can also be influenced by coprescription with other drugs, thus increasing the risk of side effects including rhabdomyolysis [2–4]. Although it has been reported previously that there is an increased risk of myopathy with coprescription of atorvastatin and fusidic acid, it was not before 2011 that the avoidance of coprescription of this drug combination was recommended [5–7]. We present a patient already on statin treatment who developed rhabdomyolysis apparently precipitated by fusidic acid. The potential life threatening interaction between atorvastatin and fusidic acid is highlighted in this case report.\n\n2. Case Presentation\nA Caucasian man aged 75 years presented to the Emergency Department at the National Hospital, Faroe Islands, with complaints of a two-week history of progressively severe diffuse myalgia, confined to the lower back and proximal lower muscles, reduced power in all four extremities, and generalized weakness, and he was immobile and bedridden. He was neurologically sound and there was no complaint regarding headache, numbness, tingling, or paraesthesia. He denied indulgence in any kind of vigorous physical exercise and over consumption of alcohol. He was already under medication for hypertension and in treatment with rivaroxaban due to atrial fibrillation and atorvastatin 80 mg daily for hyperlipidaemia and on lifelong prophylactic empirical antibiotic treatment with oral fusidic acid 500 mg twice a day combined with oral moxifloxacin 400 mg daily and for an infected aortic aneurysm, with an infected endovascular aortic stent and para-aortic abscesses. He had no familial or prior personal history of muscle disorder and no past history of muscular toxicity with statin or fibrate use. He had been in treatment with atorvastatin for several years. He had been treated with fusidic acid and moxifloxacin for 6 days before the day of admission.\n\nHe was afebrile with heart rate 75 beats/minute but hypotensive (103/42 mmHg). The cardiovascular, respiratory, and gastrointestinal tract examination was normal. He complained of moderate discomfort due to myalgia. The quadriceps muscles were tender to palpation and he had reduced power bilaterally. The cranial nerves 2–12 examination was normal. The power 5/5 strength in all the muscle groups was observed, except for the hip flexors and quadriceps which rated 3/5 bilaterally. He was immobile due to weakness. He had normal sensory examinations to light touch, pin prick, and proprioception.\n\nOn admission the laboratory measurements revealed the following: hemoglobin 6.4 mmol/L, total leukocyte count 7.8 × 109/L, potassium 4.4 mmol/L, sodium 140 mmol/L, urea 16.8 mmol/L, creatinine 128 micromol/L, and blood glucose 6.5 mmol/L. Serum muscle enzymes were markedly elevated: creatinine kinase (CK) 328 U/L (reference values: 40–208), LDH 266 U/L (reference values: 115–255), BNP 607 pmol/L (normal up to 28.9), elevated liver function test with ALAT 125 U/L (reference values: 10–70), alkaline phosphatases 232 U/L (reference values: 35–105), and normal bilirubin 9 U/L (reference values: 5–25). Table 1 describes the levels of CK, myoglobin, creatinine, and urea (the combination was stopped on 6th day after admission). Urine analysis showed no significant microscopic hematuria or proteinuria. The patient was also screened for autoimmune diseases: autoantibody p-ANCA (IgG) with medium positive result (nonconclusive), autoantibody c-ANCA (IgG) negative, and autoantibody ANA negative. These results made the differential diagnoses immunological vasculitis, granulomatosis with polyangiitis, and systemic lupus erythematosus (SLE) unlikely. The rheumatological differential diagnoses polymyositis and dermatomyositis were unlikely because of negative autoantibodies known to be associated to polymyositis and dermatomyositis (Table 2). A spinal tap was performed to rule out Guillain-Barré syndrome as differential diagnosis. The spinal tap showed no pleocytosis, normal protein, and normal glucose level in the cerebrospinal fluid. An MRI of the cervical spine showed a nonsignificant spinal stenosis at the C5/C6 level, which did not explain the symptomatology of the patient. Finally because of negative HMG-CoA reductase antibodies (IgG), associated to autoimmune statin induced rhabdomyolysis, this differential diagnosis was unlikely in our patient (Table 2). Therefore, considering the clinical development, the kinetics of the biochemical markers, and the medication history, we assume that the diagnosis of rhabdomyolysis as a consequence to combination therapy with atorvastatin and fusidic acid is highly likely. Treatment with atorvastatin and fusidic acid was halted on 6th day after admission and approximately 12th day since the combination started. Fusidic acid was changed to oral Co-amoxiclav 500/125 mg tid and the patient continued on atorvastatin and oral moxifloxacin 400 mg daily. The patient was treated with intravenous fluid and physiotherapy.\n\nThe patient was discharged after 5 weeks with remarkable improvement of symptoms. When he left hospital the biochemical markers revealed normal muscle enzymes with CK 71 U/L, myoglobin 94 ng/L, and normal transaminases (Table 1 and Figure 1). It was decided not to treat the patient with fusidic acid in the future.\n\n3. Discussion\nStatins are HMG-CoA inhibitors (hydroxymethylglutaryl/coenzyme A) and they lower the cholesterol levels by competitively inhibiting the HMG-CoA reductase, the final pathway in cholesterol biosynthesis [4, 8]. The three statins (lovastatin, simvastatin, and atorvastatin) are metabolized by the cytochrome p-450 3A4 (CYP-3A4) isoenzymes, whereas pravastatin is metabolized in the liver by sulfation and fluvastatin is metabolized by the cytochrome 2C9 isoenzyme (CYP-2C9) [8].\n\nRhabdomyolysis is one of the complications of myopathies. The risk of myopathies and rhabdomyolysis is increased by the concomitant administration of fusidic acid with statins [4]. Plasma concentration of statins significantly increases by coadministration of fusidic acid and HMG-CoA reductase inhibitor [4, 7, 9]. The mechanism of interaction, whether it is pharmacodynamics or pharmacokinetics or both, is still unknown. Reports have shown rhabdomyolysis, including some fatal cases, in patients receiving combination of fusidic acid and its salts with oral anticoagulants such as warfarin, other coumarin derivatives, or anticoagulant; this may also increase plasma concentration of these anticoagulant agents, thus enhancing the anticoagulant effects with risk of bleeding. An interaction between fusidic acid and drugs biotransformed via CYP-3A4 system is suspected. Apparently the mechanism of this interaction is possibly mutual inhibition of metabolism [9]. However, recent studies suggest fusidic acid inhibits hepatic transporters and metabolic enzymes which may cause drug-drug interaction with statin coadministration [10].\n\nThe mortality rate associated with statin induced rhabdomyolysis is approximately 0.15 deaths per 1 million [4, 11] and it is considered as a rare side effect involving less than 0.1% of patients on statin treatment. The FDA database reports a mortality rate of 7.8% in patients with rhabdomyolysis [4, 12]. Cerivastatin was previously one of the most commonly implicated statin [4, 11]. Due to more than 100 fatal outcomes linked to rhabdomyolysis, it was withdrawn from the market in August 2001 [4, 12].\n\nFactors increasing the plasma concentration of the statins increase the risk of rhabdomyolysis and hepatitis. These include concomitant use of lipid lowering drugs, hosts genetic factors, and drug interactions with other medications that are metabolized by the same cytochrome p-450 system of enzymes [7, 13]. Risk factors for these adverse effects include renal disease, hepatic dysfunction, diabetes, age above 80 years, and hypothyroidism [4, 14, 15]. The most common medications affecting statin metabolism, apart from fusidic acid, are fibrates (especially gemfibrozil), cyclosporine, warfarin, digoxin, macrolides, azole antifungals, calcium channel blockers, and amiodarone [2, 14–16].\n\nThe mainstay treatment of rhabdomyolysis is hydration and increasing diuresis. Diuresis protects the kidneys by diluting myoglobin in the renal tubules and hence prevents the toxic cast formation and also promotes the excretion [17]. Mannitol and urine alkalinization are also indicated in the treatment of rhabdomyolysis. To our knowledge there are no specific guidelines, but The American Academy of Clinical Toxicology and the European Association of Poisons Centre and Clinical Toxicologists have issued a paper recommending administration of a bolus of 225 mL of 8.4% sodium bicarbonate intravenously over 1 h, followed by additional intravenous boluses q. 1 h, to maintain pH between 7.5 and 8.5. Another regimen is to add 1–3 amps (50 mEq/50 cc) of sodium bicarbonate from 8.4% to 0.9% or 0.45% normal saline or 5% D5W [18]. In all regimes, high recommendations have been made to monitor the pH, serum potassium, and arterial pH hourly [7, 19].\n\n4. Conclusion\nThis case report is highlighting the importance of early recognition and treatment of this rare but potentially fatal side effect, rhabdomyolysis, caused by use of the statin group of drugs, either separately or combined with fusidic acid. If statins are used to treat patients, fusidic acid should not be used. In conditions where life threatening infection is involved and fusidic acid is the only antibiotic option available, it is suggested that all statin treatments should be set on a halt, as long as the patient is receiving fusidic acid.\n\nConsent\nWritten consent for a case report publication was obtained from the patient in April 2016.\n\nCompeting Interests\nThe authors declare that there is no conflict of interests regarding the publication of this article.\n\nAuthors' Contributions\nAnirban Nandy is involved in patient follow-up and wrote the manuscript. Shahin Gaïni treated and diagnosed the patient and contributed to the manuscript draft.\n\nFigure 1 The graph shows the levels of creatinine kinase (CK) and myoglobulin in the y-axis and the admission days in the x-axis. The rapid fall and normalization of the CK and myoglobulin in our patient, after cessation of treatment with atorvastatin and fusidic acid on 6th day prior to admission, clearly suggest the diagnosis of pharmacokinetic interaction between atorvastatin and fusidic acid as cause of rhabdomyolysis.\n\nTable 1 Muscle and kidney function biomarkers during the admission. The combination of atorvastatin and fusidic acid stopped at day 6 since admission.\n\nDays\n(according to admission)\tCreatinine kinase\n(normal 40–280 U/L) \tMyoglobulin \n(normal 24–77 ng/L) \tCreatinine \n(normal 60–105 micromole/L) \tUrea \n(normal 3.5–8.1 mmol/L) \t\n1\t—\t—\t128\t16.8\t\n2\t—\t—\t—\t—\t\n3\t—\t—\t—\t—\t\n4\t—\t—\t119\t—\t\n5\t10865\t—\t108\t—\t\n6\t10750\t—\t92\t—\t\n7\t22520\t—\t134\t—\t\n8\t35080\t—\t134\t—\t\n9\t>20000\t26300\t100\t22.2\t\n10\t8070\t7110\t85\t21.8\t\n11\t3350\t2590\t74\t19.5\t\n12\t1740\t—\t74\t17.0\t\n13\t755\t—\t62\t13.3\t\n14\t314\t—\t70\t10.4\t\n15\t197\t143\t68\t8.1\t\n16\t149\t89\t81\t7.7\t\n17\t112\t94\t79\t8.0\t\n22\t389\t—\t81\t8.0\t\n26\t72\t—\t85\t—\t\n29\t71\t—\t85\t—\t\nTable 2 Screening for autoantibodies known to be associated to polymyositis, dermatomyositis, and isolated statin (HMG-CoA reductase inhibitor) causing myalgia.\n\nAntibodies\tResults\t\nP-Glycyl-tRNA synthetase-Ab. (IgG)\tNegative\t\nP-Jo 1-antibody (IgG)\tNegative\t\nP-Histidine-tRNA-ligase (Jo1)-Ab. (IgG)\tNegative\t\nP-Isoleucyl-tRNA synth. cytop.-Ab. (IgG)\tNegative\t\nP-MDA5-antibody (IgG)\tNegative\t\nP-Mi-2a-antibody (IgG)\tNegative\t\nP-NXP2-antibody (IgG)\tNegative\t\nP-Polymyositis (Ku)-A (IgG)\tNegative\t\nP-Polymyositis (PL-12)-antibody\tNegative\t\nP-Polymyositis (PL-7)-Ab. (IgG)\tNegative\t\nP-Polymyositis (SRP)-Ab. (IgG)\tNegative\t\nP-SAE1-antibody (IgG)\tNegative\t\nP-TIF1 y-antibody (IgG)\tNegative\t\nHMG-CoA reductase-Ab. (IgG) (HMGCR), normal reference < 20\t<3\n==== Refs\n1 Graham D. J. Staffa J. A. Shatin D. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs The Journal of the American Medical Association 2004 292 21 2585 2590 10.1001/jama.292.21.2585 2-s2.0-9644252909 15572716 \n2 Omar M. A. Wilson J. P. Cox T. S. Rhabdomyolysis and HMG-CoA reductase inhibitors Annals of Pharmacotherapy 2001 35 9 1096 1107 10.1345/aph.10228 2-s2.0-0034821958 11573861 \n3 Ballantyne C. M. Corsini A. Davidson M. H. Risk for myopathy with statin therapy in high-risk patients Archives of Internal Medicine 2003 163 5 553 564 10.1001/archinte.163.5.553 2-s2.0-0037429617 12622602 \n4 Thompson P. D. Clarkson P. Karas R. H. Statin-associated myopathy JAMA 2003 289 13 1681 1690 10.1001/jama.289.13.1681 2-s2.0-0037414218 12672737 \n5 Burtenshaw A. J. Sellors G. Downing R. Presumed interaction of fusidic acid with simvastatin Anaesthesia 2008 63 656 658 18477279 \n6 Magee C. Medani S. A. Leavey S. F. Conlon P. J. Clarkson M. R. Severe rhabdomyolysis as a consequence of the interaction of fusidic acid and atorvastatin American Journal of Kidney Diseases 2010 56 e11 e15 20888103 \n7 Schreiber D. H. Anderson T. R. Statin-induced rhabdomyolysis Journal of Emergency Medicine 2006 31 2 177 180 10.1016/j.jemermed.2005.08.020 2-s2.0-33748090297 17044581 \n8 Knopp R. H. Drug treatment of lipid disorders The New England Journal of Medicine 1999 341 7 498 511 10.1056/nejm199908123410707 2-s2.0-0033549840 10441607 \n9 Wenisch C. Krause R. Fladerer P. El Menjawi I. Pohanka E. Acute rhabdomyolysis after atorvastatin and fusidic acid therapy American Journal of Medicine 2000 109, article no. 78 2-s2.0-0034725821 \n10 Gupta A. Harris J. J. Lin J. Bulgarelli J. P. Birmingham B. K. Grimm S. W. Fusidic acid inhibits hepatic transporters and metabolic enzymes: potential cause of clinical drug-drug interaction observed with statin coadministration Antimicrobial Agents and Chemotherapy 2016 60 12 5986 5994 10.1128/aac.01335-16 27458210 \n11 Chong P. H. Seeger J. D. Franklin C. Clinically relevant differences between the statins: implications for therapeutic selection American Journal of Medicine 2001 111 5 390 400 10.1016/s0002-9343(01)00870-1 2-s2.0-0035478637 11583643 \n12 Fuhrmans V. Bayer discloses higher death toll from Baycol Wall Street Journal 2002 A10 \n13 Martin J. Krum H. Cytochrome p450 drug interactions within the HMG-CoA reductase inhibitor class: are they clinically relevant? Drug Safety 2003 26 1 13 21 10.2165/00002018-200326010-00002 2-s2.0-0037229225 12495360 \n14 Deslypere J. P. Vermeulen A. Rhabdomyolysis and simvastatin Annals of Internal Medicine 1991 114 4 p. 342 2-s2.0-0025731860 \n15 Herman R. J. Drug interactions and the statins CMAJ 1999 161 10 1281 1286 2-s2.0-0033576261 10584091 \n16 Williams D. Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors Clinical Pharmacokinetics 2002 41 5 343 370 10.2165/00003088-200241050-00003 2-s2.0-0036291921 12036392 \n17 Bontempo L. J. Marx J. Walls R. Rhabdomyolysis Rosen's Emergency Medicine 2002 5th New York, NY, USA Mosby 1762 1769 \n18 Vanholder R. Sever M. S. Erek E. Lameire N. Rhabdomyolysis Journal of the American Society of Nephrology 2000 11 8 1553 1561 2-s2.0-0033928804 10906171 \n19 Haas C. E. Magram Y. Mishra A. González L. Kaiser J.-M. Rhabdomyolysis and acute renal failure following an ethanol and diphenhydramine overdose Annals of Pharmacotherapy 2003 37 4 538 542 10.1345/aph.1C241 2-s2.0-0037382080 12659612\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2016()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
"mesh_terms": null,
"nlm_unique_id": "101512910",
"other_id": null,
"pages": "4705492",
"pmc": null,
"pmid": "28115938",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "15572716;11573861;17044581;10441607;20888103;10991749;12036392;10584091;12659612;12495360;1987887;11583643;27458210;18477279;10906171;12622602;12672737",
"title": "Severe Rhabdomyolysis as Complication of Interaction between Atorvastatin and Fusidic Acid in a Patient in Lifelong Antibiotic Prophylaxis: A Dangerous Combination.",
"title_normalized": "severe rhabdomyolysis as complication of interaction between atorvastatin and fusidic acid in a patient in lifelong antibiotic prophylaxis a dangerous combination"
} | [
{
"companynumb": "PHHY2017FO020037",
"fulfillexpeditecriteria": "1",
"occurcountry": "FO",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "MOXIFLOXACIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Hydroxychloroquine (HCQ) has become the rheumatologists's \"Swiss army knife\" when it comes to managing the rheumatologic manifestations of SLE and other auto-immune disorders. By contrast, nephrologists are much less comfortable in managing the multifaceted effect of HCQ. As a result, nephrologists are inclined to abdicate their responsibility for HCQ management, if this therapy was initiated by a rheumatologist. This report describes such a situation, which had devastating consequences for the patient. On this basis we suggest that this report is a story worth telling, and should encourage the nephrologist to be more involved in their patients' HCQ management.",
"affiliations": null,
"authors": "Ayoub|Isabelle|I|;Singh|Priyamvada|P|;Ardoin|Stacy|S|;Brodsky|Sergey|S|;Hebert|Lee|L|",
"chemical_list": "D018501:Antirheumatic Agents; D006886:Hydroxychloroquine",
"country": "Germany",
"delete": false,
"doi": "10.5414/CN109976",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-0430",
"issue": "93(3)",
"journal": "Clinical nephrology",
"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D007668:Kidney; D008180:Lupus Erythematosus, Systemic; D000072104:Nephrologists; D012164:Retinal Diseases",
"nlm_unique_id": "0364441",
"other_id": null,
"pages": "149-151",
"pmc": null,
"pmid": "31983382",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "What every nephrologist needs to know about hydroxychloroquine toxicity
.",
"title_normalized": "what every nephrologist needs to know about hydroxychloroquine toxicity"
} | [
{
"companynumb": "US-MYLANLABS-2020M1072471",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugadditional": null... |
{
"abstract": "Immunosuppression is a significant parameter in the pathogenesis of brain abscesses (BA) and it could be the result of severe infections such as acquired immunodeficiency syndrome or drug-induced, by several medications used for systemic autoimmune diseases. Leflunomide is a pyrimidine synthesis inhibitor that affects the proliferation of lymphocytes and is used as a disease-modifying antirheumatic drug. Mild infections, particularly those of the respiratory tract and herpes zoster, are one of its most common adverse effects. However, atypical and severe infections have also been reported under treatment with leflunomide.\nA 70-year old female was referred to our hospital with headache, aphasia, and right-sided hemiparesis and a lesion of the left parietal lobe initially interpreted as a malignancy. Her medical history revealed a 12-year old history of rheumatoid arthritis under current treatment with leflunomide. A cerebral magnetic resonance imaging (MRI) revealed typical findings for a BA. She subsequently underwent a left craniotomy, which confirmed the MRI-based diagnosis. The abscess was evacuated and cultures were obtained intraoperatively. In the postoperative examination, the patient showed no neurological deficit.\nThe differential diagnostic considerations in immunocompromised patients with neurologic deficits should include focal central nervous system infections such as a BA, even in the absence of fever or immunosuppressant-induced leukopenia. It also demonstrates the importance of early neurosurgical intervention for the prevention of sequelae. To the best of our knowledge, this is the second-to-date reported case of a BA under immunomodulatory therapy with leflunomide.",
"affiliations": "Department of Neurology, Papageorgiou Hospital of Thessaloniki, Periferiaki Odos N. Efkarpia, Thessaloniki, Central Macedonia, Greece.;Department of Neurosurgery, Papageorgiou Hospital of Thessaloniki, Periferiaki Odos N. Efkarpia, Thessaloniki, Central Macedonia, Greece.;Department of Neurology, Papageorgiou Hospital of Thessaloniki, Periferiaki Odos N. Efkarpia, Thessaloniki, Central Macedonia, Greece.;Department of Neurology, Papageorgiou Hospital of Thessaloniki, Periferiaki Odos N. Efkarpia, Thessaloniki, Central Macedonia, Greece.;Department of Neurosurgery, Papageorgiou Hospital of Thessaloniki, Periferiaki Odos N. Efkarpia, Thessaloniki, Central Macedonia, Greece.;Department of Neurology, Papageorgiou Hospital of Thessaloniki, Periferiaki Odos N. Efkarpia, Thessaloniki, Central Macedonia, Greece.",
"authors": "Samara|Efthymia|E|;Siasios|Ioannis|I|;Katsiardanis|Konstantinos|K|;Liaptsi|Eirini|E|;Tsoleka|Kalliopi|K|;Deretzi|Georgia|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.25259/SNI_886_2020",
"fulltext": "\n==== Front\nSurg Neurol Int\nSurg Neurol Int\nSurgical Neurology International\n2229-5097\n2152-7806\nScientific Scholar USA\n\n10.25259/SNI_886_2020\n10.25259/SNI_886_2020\nCase Report\nBrain abscess in a rheumatoid arthritis patient treated with leflunomide – A case presentation and review\nSamara Efthymia 1effie.samara82@gmail.com\n\nSiasios Ioannis 2siasiosj@yahoo.gr\n\nKatsiardanis Konstantinos 1dinosgr@gmail.com\n\nLiaptsi Eirini 1liaptsi.eirini@hotmail.com\n\nTsoleka Kalliopi 2kaltso@otenet.gr\n\nDeretzi Georgia 1gderetzi@gmail.com\n\n1 Department of Neurology, Papageorgiou Hospital of Thessaloniki, Periferiaki Odos N. Efkarpia, Thessaloniki, Central Macedonia, Greece.\n2 Department of Neurosurgery, Papageorgiou Hospital of Thessaloniki, Periferiaki Odos N. Efkarpia, Thessaloniki, Central Macedonia, Greece.\n* Corresponding author: Efthymia Samara, Department of Neurology, Papageorgiou Hospital of Thessaloniki, Periferiaki Odos N. Efkarpia, Thessaloniki, Central Macedonia, Greece. effie.samara82@gmail.com\n2021\n17 3 2021\n12 9708 12 2020\n11 2 2021\nCopyright: © 2021 Surgical Neurology International\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.\nBackground:\n\nImmunosuppression is a significant parameter in the pathogenesis of brain abscesses (BA) and it could be the result of severe infections such as acquired immunodeficiency syndrome or drug-induced, by several medications used for systemic autoimmune diseases. Leflunomide is a pyrimidine synthesis inhibitor that affects the proliferation of lymphocytes and is used as a disease-modifying antirheumatic drug. Mild infections, particularly those of the respiratory tract and herpes zoster, are one of its most common adverse effects. However, atypical and severe infections have also been reported under treatment with leflunomide.\n\nCase Description:\n\nA 70-year old female was referred to our hospital with headache, aphasia, and right-sided hemiparesis and a lesion of the left parietal lobe initially interpreted as a malignancy. Her medical history revealed a 12-year old history of rheumatoid arthritis under current treatment with leflunomide. A cerebral magnetic resonance imaging (MRI) revealed typical findings for a BA. She subsequently underwent a left craniotomy, which confirmed the MRI-based diagnosis. The abscess was evacuated and cultures were obtained intraoperatively. In the postoperative examination, the patient showed no neurological deficit.\n\nConclusion:\n\nThe differential diagnostic considerations in immunocompromised patients with neurologic deficits should include focal central nervous system infections such as a BA, even in the absence of fever or immunosuppressant-induced leukopenia. It also demonstrates the importance of early neurosurgical intervention for the prevention of sequelae. To the best of our knowledge, this is the second-to-date reported case of a BA under immunomodulatory therapy with leflunomide.\n\nBrain abscess\nInfections\nLeflunomide\nRheumatoid arthritis\n==== Body\nINTRODUCTION\n\nBrain abscess (BA) is an intracranial, potentially lethal, space occupying inflammatory lesion with an estimated incidence of 0.3–1.3 per 100,000 people yearly in northern societies.[3] The non-specificity of the initial symptoms such as fatigue, headache, and dizziness can lead to a significant diagnostic delay. Patient may present with focal neurologic deficits correlated with the area of infection, epileptic seizures, a decreased level of consciousness, and other signs of increased intracranial pressure such as headache, vomiting, and papilledema. Absence of fever is very common (30–76% of all cases) and does not exclude the diagnosis. Meningeal signs, when present, are indicative of intraventricular abscess rupture.[5] The common diagnostic approach at the emergency department includes a brain computerized tomography (CT) scan with and without contrast as well as a brain magnetic resonance imaging (MRI) with and without gadolinium.[13]\n\nTrauma or commonly performed neurosurgical procedures have been associated with the emergence of BA by either direct contiguous microbial spread or hematogenous spread, while in almost 40% of the published cases the cause remains unknown.[11,12] The type of pathogens implicated in a BA can be highly variable and depends mostly on the route of spread as well as patient age, country of residence, previous medical history, and medications such as steroids. In up to 25% of the cases, no pathogen is detected.[14]\n\nIn addition, the literature supports that immunosuppression is also a significant parameter in the pathogenesis of BAs. Immunosuppression could be the result of severe infections such as acquired immunodeficiency syndrome or drug-induced, by several medications used for systemic autoimmune diseases, such as corticosteroids, calcineurin inhibitors, mTOR inhibitors, tumor necrosis factor (TNF) inhibitors, monoclonal antibodies, and antiproliferative agents. Leflunomide is a pyrimidine synthesis inhibitor that acts as an immunomodulator by affecting the proliferation of lymphocytes and is used in the treatment of active Rheumatoid and Psoriatic Arthritis. Susceptibility to infections, particularly those of the respiratory tract and herpes zoster, is one of its most common adverse effects and is mostly associated to leucopenia.\n\nHere, we present the case of a 70-year-old woman with a known history of rheumatoid arthritis (RA) under treatment with leflunomide, who was referred to our hospital of tertiary care with headache, aphasia, right-sided hemiparesis, and a left parietal lesion which was initially misdiagnosed as central nervous system (CNS) malignancy.\n\nCASE PRESENTATION\n\nA 70-year old female was admitted to an outside hospital with a 14-days history of headache, dizziness, and a mild aphasia. A CT scan was performed [Figure 1] revealing a left parietal lesion, which was initially presumed as a tumor. An intravenous therapy with dexamethasone 8 mg IVq8H was initiated and the patient was referred to a tertiary hospital for further treatment.\n\nFigure 1: Axial brain CT with contrast demonstrates a poorly defined area of the left parietal lobe, with surrounding edema, and ring-like enhancement.\n\nOn admission at the emergency department and later on at the clinic, the patient had a Glasgow Coma Scale of 14/15 (Eyes:4, Verbal: 4, Movement: 6) with a mild aphasia, a right-sighted hemiparesis, and neglect.\n\nHer previous medical history revealed that she was diagnosed with RA at the age of 58 years old and was receiving orally 20 mg of leflunomide per day. She had been treated with methotrexate and hydroxychloroquine in the past, under which she had experienced many relapses that required oral corticosteroids. It was only when her antirheumatic therapy was switched to leflunomide that she had a long-term remission. The last time she had received oral corticosteroids was 3 years ago for a period of 6 months.\n\nInitial laboratory studies were normal, apart from a slightly elevated C-reactive protein (CRP) (CRP: 4.7 mg/dl, normal range: <0.5 mg/dl) with a normal white blood cell count (WBC: 6,9 × 103/μl) and no history of fever.\n\nIn the next 48 h a single fever wave of 39°C was documented, followed by subfebrile body temperatures, and a slight deterioration of her speech and orientation. A brain MRI demonstrated a left parietal, rim-enhancing collection of fluid with diffusion restriction and dimensions of 48 mm × 25 mm × 19 mm that resembled a BA [Figure 2a-d]. Blood cultures were obtained and a CT scan of the thorax, abdomen and pelvis as well as a transesophageal echocardiogram were performed, to rule out a possible primary location. The initial antibiotic regimen included ceftriaxone, metronidazole, and vancomycin. Due to the suspected BA, dexamethasone was discontinued and a prophylactic therapy with levetiracetam 1000 mgIVq 12H was initiated, given the high risk of seizure. In the next 48 h her hemiparesis improved, as well as her laboratory infection parameters. However, her aphasia deteriorated further and she additionally developed dyscalculia. This deterioration of the neurological status was attributed to the space-occupying effect of the BA during the stage of the early capsule formation, as well as the expansion of the surrounding edema, due to the discontinuation of dexamethasone. Neurosurgery consultation led to patient’s immediate surgical treatment. A left craniotomy was performed and an intraparechymal abscess was detected and evacuated. Cultures for common microbes as well as Mycobacterium tuberculosis and Nocardia were obtained intraoperatively from both the liquid and the solid part of the BA. The patient was extubated successfully and at her postoperative clinical evaluation she had a significant improvement of her neurological status. The intraoperatively obtained cultures came up negative, probably because of the early start of empirical antibiotic therapy. Histopathology revealed an aggregation of lymphocytes, macrophages, and neutrophils in a loose extracellular matrix, consistent with an abscess. No malignant cells were present.\n\nFigure 2: Axial brain MRI images demonstrate a rim-enhancing (a), collection of fluid which does not attenuate on FLAIR (b), with true diffusion restriction (c and d), indicative of a brain abscess. Postoperative image (e) was acquired 2 months after evacuation and demonstrates no signs of fluid collection or gadolinium enhancement.\n\nSeven days postoperatively only a slight paresis of patient’s right upper extremity remained. The patient was discharged 6 weeks after her surgery and she continued receiving an oral antibiotic therapy (amoxicillin/clavulanic acid in combination with levofloxacin) for another 4 weeks. At her follow-up examination (1 month postoperative) she did not have any focal neurological deficits and she was able to resume her daily activities. The postoperative brain MRI demonstrated only the usual postoperative changes of the brain without any sign of fluid collection or gadolinium enhancement [Figure 2e].\n\nDespite this incident, leflunomide was resumed after the termination of the antibiotic therapy, since her RA was refractory to the other antirheumatic therapies.\n\nMETHODS\n\nThe authors performed a review of the literature considering BA and other severe infections under treatment with leflunomide, published in PubMed, reported up to October 2020. Searching key words included “BA,” “RA,” “infections,” and “leflunomide.” A severe infection was defined as an infection requiring intravenous antibiotic therapy and hospitalization.\n\nRESULTS\n\nThe results of the search showed a total of five case reports/ series, two prospective studies, and one retrospective study in RA patients under treatment with leflunomide. Apart from our case, only one other case of a BA has been reported (Lee and Chang, 2003),[12] to the best of our knowledge. Tuberculosis reactivation and pneumonia are the most common severe infections that have been associated with the use of leflunomide, followed by herpes zoster, pyelonephritis, and cellulitis.[8,10,20] However, atypical and rare entities such as progressive multifocal leukoencephalopathy (PML), paravertebral abscess, pyomyositis, septic arthritis, and mediastinal abscess have also been reported.[1,7,18] These cases are summarized in [Table 1].\n\nTable 1: A summary of all PubMed reported cases of serious infections under treatment with leflunomide.\n\nDISCUSSION\n\nOur case illustrates that the differential diagnostic considerations in immunocompromised patients with neurologic deficits should include a focal CNS infection such as a BA, even in the absence of fever, and signs of a systemic infection or immunosuppressant-induced leucopenia.\n\nMRI is an indispensable tool in the differential diagnosis of a BA. MRI demonstrates a well-defined T1-weighted images (T1WI) hypointense and T2-weighted images (T2W1) hyperintense lesion with a rim, best seen on T2WI, enhancing intensely on postcontrast T1WI (ring enhancement),[4,14] resembling the appearance of a malignant tumor. However, the high viscosity and cellularity of an abscess usually results in truly restricted diffusion of the lesion in the diffusion-WI, helping differentiate these two entities, while the inflammation, microhemorrhages, and collagen deposition in the abscess wall lead to the formation of the rim seen on the MRI. Apart from the diffusion restriction, the so-called “dual rim sign” can help distinguish a BA from a brain malignancy; it consists of two concentric rims, an outer one, which is hypointense, and an inner one, which is relatively hyperintense on both T2W1 and susceptibility WI. As for the abscess cavity, its appearance on the MRI depends greatly on the stage of infection. In the initial phase, it may demonstrate a low signal on the T1W1 and a high signal on the T2W1. Later on, the low T1W1 signal becomes better demarcated, while the T2W2 signal remains high. The brain parenchyma surrounding the cavity may also demonstrate a high T2W1 signal.[16]\n\nDiagnostic delay may be caused by the non-specificity of the initial symptoms, such as dizziness and headache, and the absence of fever. Absence of fever can be seen in 30-76% of the cases,[6,9] particularly in immunocompromised patients, and it does not exclude a serious infection. Mild CRP elevation may be falsely attributed to the chronic inflammation in patients with RA.\n\nLeflunomide is a pyridine synthesis inhibitor used in the treatment of active RA. Its active metabolite reversely inhibits dihydroorotate dehydrogenase, resulting in the depletion of the pyrimidine supply to support the DNA synthesis and, subsequently, the proliferation of T-lymphocytes. It has also been implicated in the disruption of interleukin-1 and TNF-α pathways as well as in the glycosylation of adhesion molecules, thus reducing cell-cell contact activation during the inflammatory process.[2,19]\n\nRA is characterized by dysfunctional innate immunity, which increases the risk for infections and infection-related mortality.[15,17] This risk is exacerbated with the addition of disease-modifying antirheumatic drugs such as leflunomide. To date, only one case of BA in a rheumatoid patient has been previously reported by Lee and Chang in 2003.[12] [Table 1] summarizes all – to the best of our knowledge – published studies and case reports of serious infections in rheumatoid patients under treatment with leflunomide.\n\nOn review of this literature, a direct cause-and-effect relationship between leflunomide and severe infections cannot be verified. Disease activity and duration, age, other comorbidities, and combination therapy with corticosteroids and/or other immunosuppressants also play a significant role. Jenks et al. imply that infections under leflunomide have the tendency to progress rapidly, therefore a washout with cholestyramine or activated carbon should be considered.[10]\n\nThe successful management of this rare case was not only the result of early identification but also of the cooperation and coordinated exchange of information and expertise of the different medical specialties in a tertiary hospital, including a neurologist, a neuroradiologist, a rheumatologist, an infectiologist, and a neurosurgeon.\n\nDeclaration of patient consent\n\nPatient’s consent not required as patients identity is not disclosed or compromised.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n\nHow to cite this article: Samara E, Siasios I, Katsiardanis K, Liaptsi E, Tsoleka K, Deretzi G. Brain abscess in a rheumatoid arthritis patient treated with leflunomide – A case presentation and review. Surg Neurol Int 2021;12:97.\n==== Refs\nREFERENCES\n\n1 Balasanthiran A Vakilgilani T Darzy K Axon J A case of severe staphylococcal septicaemia: Septic arthritis and a mediastinal abscess following leflunamide therapy for rheumatoid arthritis BMJ Case Rep 2010 2010 bcr0720092082\n2 Breedveld FC Dayer JM Leflunomide: Mode of action in the treatment of rheumatoid arthritis Ann Rheum Dis 2000 59 841 9 11053058\n3 Brouwer MC Coutinho JM van de Beek D Clinical characteristics and outcome of brain abscess: Systematic review and meta-analysis Neurology 2014 82 806 13 24477107\n4 Carpenter J Stapleton S Holliman R Retrospective analysis of 49 cases of brain abscess and review of the literature Eur J Clin Microbiol Infect Dis 2007 26 1 11 17180609\n5 Chuang JM Lin WC Fang FM Huang YJ Ho JT Lu CH Bacterial brain abscess formation in post-irradiated patients: What is the possible pathogenesis? Clin Neurol Neurosurg 2015 136 132 8 26099700\n6 Dorsett M Liang SY Diagnosis and treatment of central nervous system infections in the emergency department Emerg Med Clin North Am 2016 34 917 42 27741995\n7 Grover R Dhir V Aneja R Arya V Galle A Marwaha V Severe infections following leflunomide therapy for rheumatoid arthritis Rheumatology (Oxford) 2006 45 918 20 16717066\n8 Hocevar A Rozman B Prapotnik S Lestan D Eržen V Petric M Leflunomide-associated tuberculosis? Rheumatology (Oxford) 2006 45 228 9 16319103\n9 Jameson JL Kasper DL Fauci AS Harrison’s Principles of Internal Medicine 2018 20th ed New York McGraw-Hill Education\n10 Jenks KA Stamp LK O’Donnell JL Savage RL Chapman P Leflunomide-associated infections in rheumatoid arthritis J Rheumatol 2007 34 2201 3 17937473\n11 Landriel F Ajler P Hem S Bendersky D Goldschmidt E Garategui L Supratentorial and infratentorial brain abscesses: Surgical treatment, complications and outcomes--a 10-year single-center study Acta Neurochir (Wien) 2012 154 903 11 22362051\n12 Lee CS Chang CK Brain abscess in rheumatoid arthritis Ann Rheum Dis 2003 62 689 90 12810444\n13 Lee TH Chang WN Su TM Chang HW Lui CC Ho JT Clinical features and predictive factors of intraventricular rupture in patients who have bacterial brain abscesses J Neurol Neurosurg Psychiatry 2007 78 303 9 17012340\n14 Leuthardt EC Wippold FJ Oswood MC Rich KM Diffusion-Weighted MR imaging in the preoperative assessment of brain abscesses Surg Neurol 2002 58 395 402 discussion 402 12517619\n15 Michaud K Wolfe F Comorbidities in rheumatoid arthritis Best Pract Res Clin Rheumatol 2007 21 885 906 17870034\n16 Miranda HA Castellar-Leones SM Elzain MA Brain abscess: Current management J Neurosci Rural Pract 2013 4 Suppl 1 S67 81 24174804\n17 Naz SM Symmons DP Mortality in established rheumatoid arthritis Best Pract Res Clin Rheumatol 2007 21 871 83 17870033\n18 Rahmlow M Shuster E Dominik J Deen HG Dickson DW Aksamit AJ Leflunomide-associated progressive multifocal leukoencephalopathy Arch Neurol 2008 65 1538 9 19001176\n19 Toh CH Wei KC Chang CN Hsu PW Wong HF Ng SH Differentiation of pyogenic brain abscesses from necrotic glioblastomas with use of susceptibility-weighted imaging AJNR Am J Neuroradiol 2012 33 1534 8 22422181\n20 Wolfe F Caplan L Michaud K Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: Associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy Arthritis Rheum 2006 54 628 34 16447241\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2152-7806",
"issue": "12()",
"journal": "Surgical neurology international",
"keywords": "Brain abscess; Infections; Leflunomide; Rheumatoid arthritis",
"medline_ta": "Surg Neurol Int",
"mesh_terms": null,
"nlm_unique_id": "101535836",
"other_id": null,
"pages": "97",
"pmc": null,
"pmid": "33880202",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "12517619;24477107;22422181;26099700;17937473;16717066;17180609;11053058;24174804;22766573;17870034;12810444;16447241;27741995;16319103;17012340;22362051;17870033;19001176",
"title": "Brain abscess in a rheumatoid arthritis patient treated with leflunomide - A case presentation and review.",
"title_normalized": "brain abscess in a rheumatoid arthritis patient treated with leflunomide a case presentation and review"
} | [
{
"companynumb": "GR-SA-2021SA120502",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEFLUNOMIDE"
},
"drugadditional": "1",
"dr... |
{
"abstract": "The syndrome of haemolysis, elevated liver enzymes and low platelets is a rare condition specific to pregnancy, affecting approximately 5-20% of all pre-eclamptic pregnancies. Described here is a woman in her first pregnancy, who experienced an intrauterine death following a significant hepatic haematoma and capsular rupture, in the absence of classical clinical features suggestive of pre-eclampsia. The events that followed suggested haemolysis, elevated liver enzymes and low platelets syndrome as the likely diagnosis. The patient's clinical course highlights the difficulties that may be encountered when making decisions about pregnant women with complicated medical and obstetric issues.",
"affiliations": "John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.;John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.",
"authors": "Frise|Charlotte J|CJ|;Davis|Peyton|P|;Barker|Graham|G|;Wilkinson|Douglas|D|;Mackillop|Lucy|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1753495X16670480",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1753-495X",
"issue": "9(4)",
"journal": "Obstetric medicine",
"keywords": "Liver failure; acute; elevated liver enzymes and low platelets syndrome; haemolysis; pregnancy",
"medline_ta": "Obstet Med",
"mesh_terms": null,
"nlm_unique_id": "101464191",
"other_id": null,
"pages": "185-188",
"pmc": null,
"pmid": "27829883",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports",
"references": "21356004;25732608;9362370;18332948;10877990;7055180;20977643;20203522;15121574;11305555;25667700;12427793;9215192;18388681;16150288;9392911",
"title": "Hepatic capsular rupture in pregnancy.",
"title_normalized": "hepatic capsular rupture in pregnancy"
} | [
{
"companynumb": "GB-MYLANLABS-2016M1053080",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLDOPA"
},
"drugadditional": null,
... |
{
"abstract": "We are reporting a rare case of acute liver injury that developed after an internal hemorrhoid treatment with the aluminum potassium sulfate and tannic acid (ALTA) regimen. A 41-year-old man developed a fever and liver injury after undergoing internal hemorrhoid treatment with a submucosal injection of ALTA with lidocaine. The acute liver injury was classified clinically as hepatocellular and pathologically as cholestastic. We could not classify the mechanism of injury. High eosinophil and immunoglobulin E levels characterized the injury, and a drug lymphocyte stimulation test was negative on postoperative day 25. Fluid replacement for two weeks after hospitalization improved the liver injury. ALTA therapy involves injecting chemicals into the submucosa, from the rectum to the anus, and this is the first description of a case that developed a severe liver disorder after this treatment; hence, an analysis of future cases as they accumulate is desirable.",
"affiliations": "Kenichi Yoshikawa, Reimi Kawashima, Yuki Hirose, Keiko Shibata, Takafumi Akasu, Noriko Hagiwara, Takeharu Yokota, Nami Imai, Akira Iwaku, Go Kobayashi, Hirohiko Kobayashi, Akiyoshi Kinoshita, Nao Fushiya, Hiroyuki Kijima, Kazuhiko Koike, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University Daisan Hospital, Tokyo 201-8601, Japan.;Kenichi Yoshikawa, Reimi Kawashima, Yuki Hirose, Keiko Shibata, Takafumi Akasu, Noriko Hagiwara, Takeharu Yokota, Nami Imai, Akira Iwaku, Go Kobayashi, Hirohiko Kobayashi, Akiyoshi Kinoshita, Nao Fushiya, Hiroyuki Kijima, Kazuhiko Koike, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University Daisan Hospital, Tokyo 201-8601, Japan.;Kenichi Yoshikawa, Reimi Kawashima, Yuki Hirose, Keiko Shibata, Takafumi Akasu, Noriko Hagiwara, Takeharu Yokota, Nami Imai, Akira Iwaku, Go Kobayashi, Hirohiko Kobayashi, Akiyoshi Kinoshita, Nao Fushiya, Hiroyuki Kijima, Kazuhiko Koike, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University Daisan Hospital, Tokyo 201-8601, Japan.;Kenichi Yoshikawa, Reimi Kawashima, Yuki Hirose, Keiko Shibata, Takafumi Akasu, Noriko Hagiwara, Takeharu Yokota, Nami Imai, Akira Iwaku, Go Kobayashi, Hirohiko Kobayashi, Akiyoshi Kinoshita, Nao Fushiya, Hiroyuki Kijima, Kazuhiko Koike, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University Daisan Hospital, Tokyo 201-8601, Japan.;Kenichi Yoshikawa, Reimi Kawashima, Yuki Hirose, Keiko Shibata, Takafumi Akasu, Noriko Hagiwara, Takeharu Yokota, Nami Imai, Akira Iwaku, Go Kobayashi, Hirohiko Kobayashi, Akiyoshi Kinoshita, Nao Fushiya, Hiroyuki Kijima, Kazuhiko Koike, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University Daisan Hospital, Tokyo 201-8601, Japan.;Kenichi Yoshikawa, Reimi Kawashima, Yuki Hirose, Keiko Shibata, Takafumi Akasu, Noriko Hagiwara, Takeharu Yokota, Nami Imai, Akira Iwaku, Go Kobayashi, Hirohiko Kobayashi, Akiyoshi Kinoshita, Nao Fushiya, Hiroyuki Kijima, Kazuhiko Koike, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University Daisan Hospital, Tokyo 201-8601, Japan.;Kenichi Yoshikawa, Reimi Kawashima, Yuki Hirose, Keiko Shibata, Takafumi Akasu, Noriko Hagiwara, Takeharu Yokota, Nami Imai, Akira Iwaku, Go Kobayashi, Hirohiko Kobayashi, Akiyoshi Kinoshita, Nao Fushiya, Hiroyuki Kijima, Kazuhiko Koike, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University Daisan Hospital, Tokyo 201-8601, Japan.;Kenichi Yoshikawa, Reimi Kawashima, Yuki Hirose, Keiko Shibata, Takafumi Akasu, Noriko Hagiwara, Takeharu Yokota, Nami Imai, Akira Iwaku, Go Kobayashi, Hirohiko Kobayashi, Akiyoshi Kinoshita, Nao Fushiya, Hiroyuki Kijima, Kazuhiko Koike, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University Daisan Hospital, Tokyo 201-8601, Japan.;Kenichi Yoshikawa, Reimi Kawashima, Yuki Hirose, Keiko Shibata, Takafumi Akasu, Noriko Hagiwara, Takeharu Yokota, Nami Imai, Akira Iwaku, Go Kobayashi, Hirohiko Kobayashi, Akiyoshi Kinoshita, Nao Fushiya, Hiroyuki Kijima, Kazuhiko Koike, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University Daisan Hospital, Tokyo 201-8601, Japan.;Kenichi Yoshikawa, Reimi Kawashima, Yuki Hirose, Keiko Shibata, Takafumi Akasu, Noriko Hagiwara, Takeharu Yokota, Nami Imai, Akira Iwaku, Go Kobayashi, Hirohiko Kobayashi, Akiyoshi Kinoshita, Nao Fushiya, Hiroyuki Kijima, Kazuhiko Koike, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University Daisan Hospital, Tokyo 201-8601, Japan.;Kenichi Yoshikawa, Reimi Kawashima, Yuki Hirose, Keiko Shibata, Takafumi Akasu, Noriko Hagiwara, Takeharu Yokota, Nami Imai, Akira Iwaku, Go Kobayashi, Hirohiko Kobayashi, Akiyoshi Kinoshita, Nao Fushiya, Hiroyuki Kijima, Kazuhiko Koike, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University Daisan Hospital, Tokyo 201-8601, Japan.;Kenichi Yoshikawa, Reimi Kawashima, Yuki Hirose, Keiko Shibata, Takafumi Akasu, Noriko Hagiwara, Takeharu Yokota, Nami Imai, Akira Iwaku, Go Kobayashi, Hirohiko Kobayashi, Akiyoshi Kinoshita, Nao Fushiya, Hiroyuki Kijima, Kazuhiko Koike, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University Daisan Hospital, Tokyo 201-8601, Japan.;Kenichi Yoshikawa, Reimi Kawashima, Yuki Hirose, Keiko Shibata, Takafumi Akasu, Noriko Hagiwara, Takeharu Yokota, Nami Imai, Akira Iwaku, Go Kobayashi, Hirohiko Kobayashi, Akiyoshi Kinoshita, Nao Fushiya, Hiroyuki Kijima, Kazuhiko Koike, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University Daisan Hospital, Tokyo 201-8601, Japan.;Kenichi Yoshikawa, Reimi Kawashima, Yuki Hirose, Keiko Shibata, Takafumi Akasu, Noriko Hagiwara, Takeharu Yokota, Nami Imai, Akira Iwaku, Go Kobayashi, Hirohiko Kobayashi, Akiyoshi Kinoshita, Nao Fushiya, Hiroyuki Kijima, Kazuhiko Koike, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University Daisan Hospital, Tokyo 201-8601, Japan.;Kenichi Yoshikawa, Reimi Kawashima, Yuki Hirose, Keiko Shibata, Takafumi Akasu, Noriko Hagiwara, Takeharu Yokota, Nami Imai, Akira Iwaku, Go Kobayashi, Hirohiko Kobayashi, Akiyoshi Kinoshita, Nao Fushiya, Hiroyuki Kijima, Kazuhiko Koike, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University Daisan Hospital, Tokyo 201-8601, Japan.;Kenichi Yoshikawa, Reimi Kawashima, Yuki Hirose, Keiko Shibata, Takafumi Akasu, Noriko Hagiwara, Takeharu Yokota, Nami Imai, Akira Iwaku, Go Kobayashi, Hirohiko Kobayashi, Akiyoshi Kinoshita, Nao Fushiya, Hiroyuki Kijima, Kazuhiko Koike, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University Daisan Hospital, Tokyo 201-8601, Japan.",
"authors": "Yoshikawa|Kenichi|K|;Kawashima|Reimi|R|;Hirose|Yuki|Y|;Shibata|Keiko|K|;Akasu|Takafumi|T|;Hagiwara|Noriko|N|;Yokota|Takeharu|T|;Imai|Nami|N|;Iwaku|Akira|A|;Kobayashi|Go|G|;Kobayashi|Hirohiko|H|;Kinoshita|Akiyoshi|A|;Fushiya|Nao|N|;Kijima|Hiroyuki|H|;Koike|Kazuhiko|K|;Saruta|Masayuki|M|",
"chemical_list": "D000534:Alum Compounds; D012597:Sclerosing Solutions; D013634:Tannins; C041524:aluminum sulfate; D008012:Lidocaine",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v23.i27.5034",
"fulltext": "\n==== Front\nWorld J GastroenterolWorld J. GastroenterolWJGWorld Journal of Gastroenterology1007-93272219-2840Baishideng Publishing Group Inc jWJG.v23.i27.pg503410.3748/wjg.v23.i27.5034Case ReportLiver injury after aluminum potassium sulfate and tannic acid treatment of hemorrhoids Yoshikawa Kenichi Kawashima Reimi Hirose Yuki Shibata Keiko Akasu Takafumi Hagiwara Noriko Yokota Takeharu Imai Nami Iwaku Akira Kobayashi Go Kobayashi Hirohiko Kinoshita Akiyoshi Fushiya Nao Kijima Hiroyuki Koike Kazuhiko Saruta Masayuki Kenichi Yoshikawa, Reimi Kawashima, Yuki Hirose, Keiko Shibata, Takafumi Akasu, Noriko Hagiwara, Takeharu Yokota, Nami Imai, Akira Iwaku, Go Kobayashi, Hirohiko Kobayashi, Akiyoshi Kinoshita, Nao Fushiya, Hiroyuki Kijima, Kazuhiko Koike, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University Daisan Hospital, Tokyo 201-8601, JapanMasayuki Saruta, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University School of Medicine, Tokyo 105-8471, JapanAuthor contributions: All authors contributed equally to this work; Yoshikawa K and Kawashima R conducted the medical examinations, analyzed the data, explained the condition to the patient, and provided the treatment; Yoshikawa K wrote the manuscript’s text; Kinoshita A wrote the supplementary information; all of the authors discussed the results and commented on the manuscript at all stages.\n\nCorrespondence to: Kenichi Yoshikawa, MD, PhD, Division of Gastroenterology and Hepatology, Internal Medicine, the Jikei University Daisan Hospital, 4-11-1 Izumihon-cho, Komae-shi, Tokyo 201-8601, Japan. kyoshikawa@jikei.ac.jp\n\nTelephone: +81-3-34801151 Fax: +81-3-34303611\n\n21 7 2017 21 7 2017 23 27 5034 5040 25 3 2017 9 6 2017 18 6 2017 ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.2017This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.We are reporting a rare case of acute liver injury that developed after an internal hemorrhoid treatment with the aluminum potassium sulfate and tannic acid (ALTA) regimen. A 41-year-old man developed a fever and liver injury after undergoing internal hemorrhoid treatment with a submucosal injection of ALTA with lidocaine. The acute liver injury was classified clinically as hepatocellular and pathologically as cholestastic. We could not classify the mechanism of injury. High eosinophil and immunoglobulin E levels characterized the injury, and a drug lymphocyte stimulation test was negative on postoperative day 25. Fluid replacement for two weeks after hospitalization improved the liver injury. ALTA therapy involves injecting chemicals into the submucosa, from the rectum to the anus, and this is the first description of a case that developed a severe liver disorder after this treatment; hence, an analysis of future cases as they accumulate is desirable.\n\nAluminum potassium sulfate and tannic acid injectionAluminum potassium sulfate and tannic acid therapyRectal submucosal injectionDrug-induced lymphocyte stimulation testDrug-induced liver injury\n==== Body\nCore tip: The definition of drug-induced liver injury has diversified in recent years. This report describes the characteristics of a case of acute liver injury that developed after internal hemorrhoid treatment using the aluminum potassium sulfate and tannic acid regimen, and it is the first report of a case of drug-induced liver injury caused by a rectal submucosal injection.\n\nINTRODUCTION\nDrug-induced liver injury (DILI) is a liver disorder caused by the administration of drugs, but in recent years the definition of this term has diversified to include supplements, health foods, and traditional Chinese medicines[1-3]. Drugs that cause hepatopathy are usually administered orally or intravenously, but there are few case reports that describe DILI cause by drugs administered by other routes, for example, subcutaneously or intravesically[4-6].\n\nIn this report, we describe a case of DILI that developed after internal hemorrhoid treatment with an aluminum potassium sulfate and tannic acid (ALTA) regimen with lidocaine. This is the first case report that describes the development and management of a severe liver disorder after ALTA therapy.\n\nCASE REPORT\nA 41-year-old Japanese man was admitted to our hospital with liver damage, itchy skin, and pyrexia. His medical history was unremarkable, but one year previously his gamma-glutamyl transpeptidase levels had risen to 271 IU/L (normal: < 30 IU/L). Prior to this, the patient had consumed 540 mL of sake three times a week, and he had been reducing the amount of alcohol he consumed for about one year. He did not smoke or take any recreational drugs. He was single, was not homosexual, and he had not had sexual intercourse for over one year.\n\nThe patient had undergone treatment of his internal hemorrhoids as an outpatient at a nearby hospital that comprised an aluminum potassium sulfate and tannic acid (ALTA) injection. He developed a fever of 38 °C, dark colored urine, and itchy skin on postoperative day (POD) 1, and he took loxoprofen sodium, as required. He consulted another doctor on POD 7, because the symptoms had not improved, and his blood test results led to a diagnosis of liver dysfunction. His liver dysfunction had not improved by POD 14, and he was admitted to our hospital on POD 15.\n\nThe patient was 167 cm tall and weighed 52.5 kg. He presented with a blood pressure of 103/59 mmHg, a heart rate of 82 beats per minute, a temperature of 36.6 °C, and 99% oxygen saturation in room air. No specific physical findings were evident during the clinical examination on the day of hospitalization, but the patient had a rash, edema, hepatosplenomegaly, lymphadenopathy, and jaundice. The subjective symptoms, comprising the fever, dark colored urine, and itchy skin, had disappeared by POD 10.\n\nThe laboratory test results showed that the patient’s complete blood count was almost normal with a white blood cell count of 6900 cells/μL, a hemoglobin concentration of 14.7 g/dL, a hematocrit level of 43.1%, and a platelet count of 3.98 × 105 cells/μL, but a higher percentage of eosinophils was present (6.8%) (normal: 1.0%-5.0%), which peaked at 13.9% on POD 20. The patient’s serum liver enzyme and bilirubin levels were elevated at the time of admission. The aspartate aminotransferase (AST) level was 432 IU/L (normal: 10-40 IU/L), the alanine aminotransferase (ALT) level was 911 IU/L (normal: 10-40 IU/L), the alkaline phosphatase (ALP) level was 473 IU/L (normal: 115-359 IU/L), and the total bilirubin level was 1.3 mg/dL (normal: 0.2-1.2 mg/dL). Thus, compared with the ALP level, the AST and ALT levels showed greater magnitudes of elevation. The patient’s other blood test results were within the normal ranges, as follows: serum albumin: 4.0 g/dL (normal: 3.8-5.2 g/dL); serum creatinine: 0.86 mg/dL (normal: 0.65-1.09 mg/dL); C-reactive protein: 0.1 mg/dL (normal: 0-0.3 mg/dL); prothrombin time: 100% (normal: 80%-120 %); thyroid-stimulating hormone: 0.5 μIU/mL (normal: 0.34-4.04 μIU/mL); triiodothyronine: 2.98 pg/dL (normal: 2.36-5.00 pg/dL); and thyroxin: 1.18 ng/dL (normal: 0.88-1.67 ng/dL). The serological tests for autoantibodies generated weakly positive results (1:40) for anti-nuclear antibodies, and negative results for anti-smooth muscle and anti-mitochondrial antibodies. Negative results were obtained from the tests for the hepatitis B virus surface antigen, the hepatitis C virus antibody, rapid plasma reagin, the anti-Epstein-Barr virus immunoglobulin M (IgM) antibody, and the anti-cytomegalovirus IgM antibody, and from the Treponema pallidum hemagglutination test. The IgG level was within the normal range at 1415 mg/dL (normal: 800-1600 mg/dL) and the IgM level was within the normal range at 100 mg/dL (normal: 60-250 mg/dL). The IgE level was elevated at 1333 mg/dL (normal: < 250 mg/dL). Chest radiography did not reveal any abnormalities. No morphological changes were evident following abdominal ultrasonography, magnetic resonance cholangiopancreatography, and abdominal computed tomography (Figure 1).\n\nFigure 1 Abdominal computed tomography scans did not show any morphological changes on admission.\n\nWhen the patient was hospitalized, we considered viral, alcohol-induced, autoimmune, drug-induced, biliary tract, and thyroid function-based diseases as frequent causes of acute liver dysfunction for the differential diagnosis, and, based on the patient’s medical history, and the serological and imaging results, we considered that alcohol and DILI were highly likely causes of the patient’s acute liver dysfunction. However, the patient had stopped drinking during the past year, so we thought that there was a high likelihood of DILI. Therefore, we began conservative treatment with a small amount of extracellular fluid replacement.\n\nFigure 2 presents the patient’s symptoms, laboratory test results, and treatment over the entire course. The liver transaminase and bilirubin levels decreased rapidly after admission, and the maximum levels were as follows: ALT: 950 IU/L on POD 15; AST: 470 IU/L on POD 17; and total bilirubin: 2.1 mg/dL on POD 17. The ALP and gamma-glutamyl transpeptidase levels showed consistent downward trends from POD 7. The patient's symptoms disappeared on POD 10, and no new symptoms appeared after hospitalization. We performed a liver biopsy on POD 25, and a drug-induced lymphocyte stimulation test (DLST) of the components of the ALTA injection and lidocaine on POD 28. The patient was discharged on POD 29, and he was managed as an outpatient without any prescriptions. At the time of the patient’s first outpatient appointment on POD 35, his liver transaminase and bilirubin levels had declined and were almost within the normal ranges.\n\nFigure 2 Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, and gamma-glutamyl transpeptidase levels in the patient at presentation and in response to treatment. AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; γGTP: Gamma-glutamyl transpeptidase; T-Bil: Total bilirubin; DLST: Drug lymphocyte stimulation test.\n\nFigure 3 presents hematoxylin and eosin (H and E)-stained sections of the liver biopsy performed on POD 25. The H and E staining showed that the basic structure of the liver had been maintained without any hepatocyte dropout or disruption, and that the bile duct had not been disrupted. At a higher magnification, the H and E staining showed that the parenchymal cells were partially dilated and that a mild inflammatory cell infiltration was present in the area of the central vein. Neither eosinophil nor plasma cell infiltrations were detected within the liver tissue. Bile plugs were found at multiple sites within the parenchyma and sinusoids. Masson staining did not show the presence of liver tissue fibrosis.\n\nFigure 3 Micrographs of a liver biopsy specimen. A: Fibrosis around the central vein area and the fibrous expansion of the portal region were not detected (Masson staining × 40); B: Swelling of the parenchymal cells and a mild infiltration of inflammatory cells around the central vein area were evident (green arrows). Destruction of the bile duct had not occurred (hematoxylin-eosin staining × 40); C: Bile plugs were found in multiple sites within the hepatocytes and sinusoids (green arrows). (hematoxylin-eosin staining × 200). CV: Central vein; PV: Portal vein.\n\nThe lymphocyte proliferation activity levels, which were determined from the DLST performed on POD 28, were 676 counts per minute (cpm) for the control and 871 cpm for the ALTA with lidocaine. The stimulation index, which was calculated as the ALTA with lidocaine cpm divided by the control cpm, was 1.29 (normal in Japanese people: < 1.8).\n\nDISCUSSION\nThis is the first case report that describes suspected severe acute liver injury caused by ALTA therapy for the treatment of internal hemorrhoids. Our discussion focusses on the cause of the acute liver injury, the components of the ALTA regimen used to treat the hemorrhoids in this case, the positions of the biopsy and the DLST in the diagnosis, and the properties of the administration route.\n\nWe primarily suspected DILI caused by the ALTA therapy in this case. The laboratory test results ruled out viral, autoimmune, and biliary tract diseases, and a thyroid gland malfunction as causes of the acute hepatic injury. Given that the IgG levels were normal and the autoantibody test results were negative or only weakly positive in this case, a comprehensive judgement based on a histopathological evaluation was necessary[7]. Accounting for the consumption of alcohol during the pathological assessments was necessary based on the patient’s history. Interface hepatitis with lymphocytic/lymphoplasmacytic inflammatory activity, rosettes, and emperipolesis, which are characteristic of autoimmune hepatitis[8,9], and lobular neutrophilic infiltration, ballooning degeneration with apoptosis, and Mallory bodies, which are characteristic of alcoholic liver injury[10], were not observed in the pathological specimens from this case. Therefore, we diagnosed the patient as having DILI, which was a diagnosis of exclusion. This patient did not regularly use supplements or health foods, so the suspect drugs were loxoprofen and the ALTA with lidocaine injection. Loxoprofen is a non-steroidal anti-inflammatory agent, is one of the most frequently used drugs by patients with DILI[11], and it was used once by this patient. Given that it was used to treat the symptoms after their onset, we decided that loxoprofen did not cause this patient’s liver injury. Therefore, we concluded that the ALTA with lidocaine injection caused the acute liver injury in this case.\n\nALTA is an improved formulation of Xiaozhiling®[12], and ALTA injections were approved by the Japanese Government in 2005 for the treatment of hemorrhoids. Traditionally, 5% phenol almond oil was injected into the submucosal layer to treat internal hemorrhoids, which reduced the blood flow to the thick hemorrhoidal vein by causing an inflammatory reaction in the surrounding area and promoting fibrosis, and the short-term one-year results were good[12]. However, the long-term outcomes from phenol almond oil injections were not positive in relation to curing hemorrhoids or regarding the treatment of internal Goligher grade III and IV hemorrhoids. On the other hand, ALTA sclerotherapy is now widely used to treat internal hemorrhoids in Japan, because it performs well over one-to-five years, with cumulative successive rates at one, three, and five years of 95.9%, 89.3%, and 89.3%, respectively, for grade II hemorrhoids, and 93.1%, 83.7%, and 78.2%, respectively, for grade III hemorrhoids[13]. The treatment comprises a four-step process, and it is injected locally into the submucosa of the rectum and the anus via the lamina propria, and not into the vascular lumen[14]. Aluminum potassium sulfate causes inflammation inside the hemorrhoids followed by sclerosis, and tannic acid is an anti-inflammatory substance that prevents excessive inflammation. The complications associated with this treatment include bleeding (1.4%), pyrexia (1.4%), and rectal ulcers (1.4%)[15]; however, no case reports that describe acute liver injury following ALTA injections have been published.\n\nThe formulation used to treat the current case comprised aluminum potassium sulfate, tannic acid, and lidocaine. This patient had undergone local anesthesia involving the use of lidocaine in the past; hence, we considered that the likelihood of lidocaine involvement in the acute liver injury was low. Aluminum is less essential in living organisms, and it is generally considered to be less toxic. Clinically, aluminum encephalopathy can become a problem in dialysis patients, and the possibility of its accumulation in the central nervous system has been noted when renal excretion becomes insufficient[16]. Aluminum as aluminum chloride is used in an external preparation to manage hyperhidrosis, and sucralfate is a sucrose sulfate-aluminum complex that is used to treat peptic ulcers. Although a case report has been published that describes liver injury following sucralfate treatment[17], it is very rare and the underlying mechanism is unknown. There are no data that describe the transferability of aluminum into the blood following its external application or oral administration. In a rat model, intraperitoneal administrations of aluminum increased the aluminum concentrations in the blood and caused morphological changes in the liver, but the mechanism that underlies these changes remains unclear[18,19]. Tannic acid is used to treat gastric bleeding, diarrhea, and ulcerative colitis[20,21]. Although a liver disorder has been described that involved an advanced degree of destruction in the region of the central vein following the administration of a barium enema containing tannic acid, the causative component was not identified. Lidocaine is used as an anesthetic or as an antiarrhythmic agent, and only two cases of hepatopathy caused by tocainide, which is a lidocaine analog that is used as an oral preparation for ventricular arrhythmias, have been published[22,23].\n\nSome scoring systems have been used to diagnose DILI[24], and the Digestive Disease Week Japan 2004 scale and the Roussel-Uclaf Causality Assessment Method are considered particularly useful[25-27]. The current case scored six points using these scoring systems, which suggested that DILI was probable in this patient. DILI is classified in several ways based on its clinical presentation, histological findings, and the hepatotoxicity mechanism[28]. When the current case was admitted, the R value, defined as the ALT level/the upper limit of the normal (ULN) ALT level divided by the ALP level/the ULN ALP level, was 17.3, and given that it was ≥ 5, we diagnosed DILI with a hepatocellular injury pattern[27]. DILI mechanisms can be separated into the “intrinsic” type, which is dose-dependent and can be predicted, and the “idiosyncratic” type, which is dose-independent and unpredictable, and the idiosyncratic type can be further classified into the immune-mediated and metabolic types[29]. Immune-mediated DILI develops one-to-eight weeks after the administration of the drug, and T-cell-dependent liver injury is accompanied by a positive DLST, because the drug or its metabolite binds to protein to acquire antigenicity. Metabolic DILI develops against a background of the genetic variations in the enzymes that metabolize drugs, it develops after the long-term oral administration of drugs, and the DLST is often negative, because the mechanism is not mediated by T cells. A mechanism has not been described for any hepatic disorder caused by the drugs used to treat this case. The DLST was negative at one-to-two weeks after the administration of the drugs, and the elevated eosinophil and IgE levels suggested that the DILI was immune mediated. The mechanism underlying this patient’s DILI cannot be specified, because there was a problem relating to the timing of the DLST that is described below; however, given that the DILI developed in association with specific agents, we think the mechanism was idiosyncratic hepatotoxicity in this case.\n\nThe histopathological patterns in DILI can be classified as the hepatocellular type, the cholestatic type, and the mixed type. A characteristic pathological feature of the hepatocellular type is cyclic necrosis in the central vein zone (zone 3), and biliary plugs in the bile capillaries are a characteristic pathological feature of the cholestatic type. The histological pattern is basically classified as cholestatic in the idiosyncratic clinical disease type[30], and the current case seemed to be consistent with the idiosyncratic type. A report that compares the clinical disease and the pathological types[31] explains that a pathological image can exhibit the cholestatic type, even if the clinical disease type is hepatocellular, which corresponds to the current case. Although the scoring systems can diagnose DILI with high levels of sensitivity and specificity, they may produce high scores for autoimmune hepatitis[31]. Drugs may cause autoimmune hepatitis, therefore, careful evaluations must be undertaken[32]. We confirmed the liver biopsy findings while taking this fact into account.\n\nA DLST determines the proliferative response by lymphocytes to the addition of drugs. Based on the observed responses of sensitized T cells, positive DLST results tend to be generated by immune-mediated DILI[33]. Currently, DLST is positioned as one item that contributes to the scoring systems used to diagnose DILI, because it is only positive in association with some types of DILI[34], and because of the diversification of substances that have been determined to cause DILI in recent years. The number of reports describing DILI caused by supplements and health foods has increased in recent years[1-3], and the causal agents include garlic, egg yolk, turmeric, glucosamine, and noni juice[35]. Moreover, traditional Chinese medicine is thought to generate false-positive results from DLSTs[36], and their interpretation is often difficult. The DLST positive response rate for DILI overall is 45.7%[1].\n\nOn the other hand, Popple et al[37] and Pichler and Tilch[38] suggested that DLSTs should be undertaken following remission, that is, at about four-to-eight weeks, as the tests may generate false-negative results, because of the strong activation of regulatory T cells or the uneven distribution of memory T cells caused by ongoing hypersensitivity reactions[37,38]. Because the patient consent is not obtained, a second DLST cannot be conducted on samples from that patient. However, if the test appears to be positive, it may be possible to determine whether or not the mechanism is immune mediated.\n\nDILI usually occurs following the oral or intravenous administration of drugs or when they are administered as suppositories. In relation to intravesical instillations, 18 cases (0.7%) of pneumonia or hepatitis occurred following Bacillus Calmette-Guérin therapy for bladder cancer[4]. Regarding the subcutaneous administration of drugs, insulin and interferon injections can cause hepatic injury[5,6]. This is the first report that describes a case of hepatic injury caused by the administration of drugs to the rectal submucosa. The median rectal vein and the inferior rectal vein are present in the middle-to-lower regions of the rectum, and it is possible that the administered drugs entered the systemic circulation from the submucosal blood vessels and caused DILI in this patient.\n\nWe have described the first case of DILI following an ALTA injection to treat internal hemorrhoids. The accumulation and analysis of further cases are necessary to clarify the mechanism, frequency, and the clinical variations of this disease type.\n\nACKNOWLEDGMENTS\nMy deepest appreciation goes to Professor Masayuki Saruta whose comments and suggestions were of inestimable value to my report.\n\nCOMMENTS\nCase characteristics\nA Japanese male patient presented with fever, dark-colored urine, and itchy skin.\n\nClinical diagnosis\nThe authors diagnosed acute liver disorder after aluminum potassium sulfate and tannic acid (ALTA) therapy.\n\nDifferential diagnosis\nThe diseases to be considered are liver injury induced by autoimmune hepatitis, alcohol, and other drugs, which can be estimated by liver biopsy.\n\nLaboratory diagnosis\nThe patient had elevated liver enzymes, with an aspartate aminotransferase level of 432 IU/L, an alanine aminotransferase level of 911 IU/L, an alkaline phosphatase level of 473 IU/L, and a total bilirubin level of 1.3 mg/dL.\n\nImaging diagnosis\nComputed tomography scan showed no morphological changes.\n\nPathological diagnosis\nHistological examination showed liver injury of the cholestatic type characterized by bile plugs within the parenchyma and sinusoids, with mild inflammation of hepatocytes around the area of the central vein.\n\nTreatment\nThe patient received conservative treatment, with a small amount of extracellular fluid replacement.\n\nRelated reports\nThere is no other case report of acute liver injury associated with ALTA therapy. There are reports of a case of liver injury accompanying barium enema containing tannic acid and of two cases of liver injury accompanying lidocaine, but neither pathophysiology nor pathological features have been elucidated.\n\nTerm explanation\nALTA sclerotherapy is now widely used to treat internal hemorrhoids in Japan and consists of aluminum potassium sulfate, tannic acid and lidocaine.\n\nExperiences and lessons\nThis is the first case of drug-induced liver injury following an ALTA injection to treat internal hemorrhoids and discusses the clinical and pathological features. The accumulation and analysis of further cases are necessary to clarify the mechanism, frequency and clinical variations of this disease type.\n\nPeer-review\nThis case report is very informative and well written. It should be worth sharing to people in the field as well as to the general public.\n\nManuscript source: Unsolicited manuscript\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry of origin: Japan\n\nPeer-review report classification\n\nGrade A (Excellent): A\n\nGrade B (Very good): 0\n\nGrade C (Good): 0\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nInstitutional review board statement: The study was reviewed and approved by the IRB of the Jikei University School of Medicine.\n\nInformed consent statement: We received patient consent with regard to this manuscript.\n\nConflict-of-interest statement: The authors declare that they have no conflicts of interest.\n\nPeer-review started: March 29, 2017\n\nFirst decision: May 12, 2017\n\nArticle in press: June 19, 2017\n\nP- Reviewer: Leardkamolkarn V S- Editor: Ma YJ L- Editor: A E- Editor: Li D\n==== Refs\n1 Takikawa H Murata Y Horiike N Fukui H Onji M Drug-induced liver injury in Japan: An analysis of 1676 cases between 1997 and 2006 Hepatol Res 2009 39 427 431 19207579 \n2 Stickel F Patsenker E Schuppan D Herbal hepatotoxicity J Hepatol 2005 43 901 910 16171893 \n3 Navarro VJ Seeff LB Liver injury induced by herbal complementary and alternative medicine Clin Liver Dis 2013 17 715 735, x 24099027 \n4 Lamm DL van der Meijden PM Morales A Brosman SA Catalona WJ Herr HW Soloway MS Steg A Debruyne FM Incidence and treatment of complications of bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer J Urol 1992 147 596 600 1538436 \n5 Quesada JR Talpaz M Rios A Kurzrock R Gutterman JU Clinical toxicity of interferons in cancer patients: a review J Clin Oncol 1986 4 234 243 2418169 \n6 Tawata M Ikeda M Kodama Y Aida K Onaya T A type 2 diabetic patient with liver dysfunction due to human insulin Diabetes Res Clin Pract 2000 49 17 21 10808059 \n7 Balitzer D Shafizadeh N Peters MG Ferrell LD Alshak N Kakar S Autoimmune hepatitis: review of histologic features included in the simplified criteria proposed by the international autoimmune hepatitis group and proposal for new histologic criteria Mod Pathol 2017 30 773 783 28106105 \n8 Papamichalis PA Zachou K Koukoulis GK Veloni A Karacosta EG Kypri L Mamaloudis I Gabeta S Rigopoulou EI Lohse AW The revised international autoimmune hepatitis score in chronic liver diseases including autoimmune hepatitis/overlap syndromes and autoimmune hepatitis with concurrent other liver disorders J Autoimmune Dis 2007 4 3 17603886 \n9 Qiu D Wang Q Wang H Xie Q Zang G Jiang H Tu C Guo J Zhang S Wang J Validation of the simplified criteria for diagnosis of autoimmune hepatitis in Chinese patients J Hepatol 2011 54 340 347 21056494 \n10 Singal AK Kodali S Vucovich LA Darley-Usmar V Schiano TD Diagnosis and Treatment of Alcoholic Hepatitis: A Systematic Review Alcohol Clin Exp Res 2016 40 1390 1402 27254289 \n11 Björnsson ES Hepatotoxicity by Drugs: The Most Common Implicated Agents Int J Mol Sci 2016 17 224 26861310 \n12 Lim SW Aluminum potassium sulfate and tannic Acid injection for hemorrhoids J Korean Soc Coloproctol 2012 28 73 77 22606645 \n13 Miyamoto H Hada T Ishiyama G Ono Y Watanabe H Aluminum potassium sulfate and tannic acid sclerotherapy for Goligher Grades II and III hemorrhoids: Results from a multicenter study World J Hepatol 2016 8 844 849 27458504 \n14 Takano M Iwadare J Ohba H Takamura H Masuda Y Matsuo K Kanai T Ieda H Hattori Y Kurata S Sclerosing therapy of internal hemorrhoids with a novel sclerosing agent. Comparison with ligation and excision Int J Colorectal Dis 2006 21 44 51 15843937 \n15 Abe T Hachiro Y Ebisawa Y Hishiyama H Kunimoto M Distal hemorrhoidectomy with ALTA injection: a new method for hemorrhoid surgery Int Surg 2014 99 295 298 24833156 \n16 Alfrey AC LeGendre GR Kaehny WD The dialysis encephalopathy syndrome. Possible aluminum intoxication N Engl J Med 1976 294 184 188 1244532 \n17 Odeh M Oliven A Hepatotoxicity related to sucralfate Hepatol Res 2001 20 255 258 11348860 \n18 Kutlubay R Oguz EO Abban G Turgut S Amelioration of aluminium-induced liver damage by vitamin E Saudi Med J 2007 28 197 200 17268696 \n19 Abubakar MG Taylor A Ferns GA Aluminium administration is associated with enhanced hepatic oxidant stress that may be offset by dietary vitamin E in the rat Int J Exp Pathol 2003 84 49 54 12694486 \n20 Lucke HH Hodge KE Patt NL Fatal Liver Damage After Barium Enemas Containing Tannic Acid Can Med Assoc J 1963 89 1111 1114 14079135 \n21 Hupkens P Boxma H Dokter J Tannic acid as a topical agent in burns: historical considerations and implications for new developments Burns 1995 21 57 61 7718122 \n22 Higa K Hirata K Dan K Mexiletine-induced severe skin eruption, fever, eosinophilia, atypical lymphocytosis, and liver dysfunction Pain 1997 73 97 99 9414061 \n23 Geisler C Keiding S [Cholestatic hepatitis during treatment with mexiletine/lidocaine] Ugeskr Laeger 1984 146 1212 1213 6730049 \n24 Lucena MI Camargo R Andrade RJ Perez-Sanchez CJ Sanchez De La Cuesta F Comparison of two clinical scales for causality assessment in hepatotoxicity Hepatology 2001 33 123 130 11124828 \n25 Tajiri K Shimizu Y Practical guidelines for diagnosis and early management of drug-induced liver injury World J Gastroenterol 2008 14 6774 6785 19058303 \n26 Hanatani T Sai K Tohkin M Segawa K Kimura M Hori K Kawakami J Saito Y A detection algorithm for drug-induced liver injury in medical information databases using the Japanese diagnostic scale and its comparison with the Council for International Organizations of Medical Sciences/the Roussel Uclaf Causality Assessment Method scale Pharmacoepidemiol Drug Saf 2014 23 984 988 24596340 \n27 Chalasani NP, Hayashi PH, Bonkovsky HL, Navarro VJ, Lee WM, Fontana RJ; Practice Parameters Committee of the American College of Gastroenterology ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury Am J Gastroenterol 2014 109 950 966; quiz 967 24935270 \n28 Chang CY Schiano TD Review article: drug hepatotoxicity Aliment Pharmacol Ther 2007 25 1135 1151 17451560 \n29 Suk KT Kim DJ Drug-induced liver injury: present and future Clin Mol Hepatol 2012 18 249 257 23091804 \n30 Maddur H Chalasani N Idiosyncratic drug-induced liver injury: a clinical update Curr Gastroenterol Rep 2011 13 65 71 21049293 \n31 Tsutsui A Nakanuma Y Takaguchi K Nakamura S Shibata H Baba N Senoh T Nagano T Ikeda H Comparison of Liver Biopsy Findings with the Digestive Disease Week Japan 2004 Scale for Diagnosis of Drug-Induced Liver Injury Mediators Inflamm 2015 2015 913793 26783385 \n32 Teschke R Frenzel C Drug induced liver injury: do we still need a routine liver biopsy for diagnosis today? Ann Hepatol 2013 13 121 126 24378275 \n33 Shibuya A Watanabe M Fujita Y Saigenji K Kuwao S Takahashi H Takeuchi H An autopsy case of troglitazone-induced fulminant hepatitis Diabetes Care 1998 21 2140 2143 9839107 \n34 Maria VA Pinto L Victorino RM Lymphocyte reactivity to ex-vivo drug antigens in drug-induced hepatitis J Hepatol 1994 21 151 158 7989705 \n35 Mrzljak A Kosuta I Skrtic A Kanizaj TF Vrhovac R Drug-Induced Liver Injury Associated with Noni (Morinda citrifolia) Juice and Phenobarbital Case Rep Gastroenterol 2013 7 19 24 23467452 \n36 Mantani N Kogure T Sakai S Goto H Shibahara N Kita T Shimada Y Terasawa K Incidence and clinical features of liver injury related to Kampo (Japanese herbal) medicine in 2,496 cases between 1979 and 1999: problems of the lymphocyte transformation test as a diagnostic method Phytomedicine 2002 9 280 287 12120808 \n37 Popple A Williams J Maxwell G Gellatly N Dearman RJ Kimber I The lymphocyte transformation test in allergic contact dermatitis: New opportunities J Immunotoxicol 2016 13 84 91 25655136 \n38 Pichler WJ Tilch J The lymphocyte transformation test in the diagnosis of drug hypersensitivity Allergy 2004 59 809 820 15230812\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1007-9327",
"issue": "23(27)",
"journal": "World journal of gastroenterology",
"keywords": "Aluminum potassium sulfate and tannic acid injection; Aluminum potassium sulfate and tannic acid therapy; Drug-induced liver injury; Drug-induced lymphocyte stimulation test; Rectal submucosal injection",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000328:Adult; D000534:Alum Compounds; D056486:Chemical and Drug Induced Liver Injury; D005334:Fever; D006484:Hemorrhoids; D006801:Humans; D015552:Injections, Intralesional; D008012:Lidocaine; D008099:Liver; D008111:Liver Function Tests; D008297:Male; D011183:Postoperative Complications; D012597:Sclerosing Solutions; D015911:Sclerotherapy; D013634:Tannins",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "5034-5040",
"pmc": null,
"pmid": "28785156",
"pubdate": "2017-07-21",
"publication_types": "D016428:Journal Article",
"references": "28106105;7989705;24833156;16171893;24099027;27254289;9414061;23467452;1538436;2418169;17451560;22606645;15843937;10808059;17268696;23091804;21056494;9839107;11348860;15230812;12694486;6730049;19207579;26783385;27458504;7718122;19058303;24596340;21049293;11124828;24378275;14079135;1244532;26861310;24935270;12120808;17603886;25655136",
"title": "Liver injury after aluminum potassium sulfate and tannic acid treatment of hemorrhoids.",
"title_normalized": "liver injury after aluminum potassium sulfate and tannic acid treatment of hemorrhoids"
} | [
{
"companynumb": "JP-DENTSPLY-2021SCDP000093",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditional": null,
... |
{
"abstract": "Rhabdomyolysis is defined as dissolution of striped muscle characterized by leakage of intracellular muscle components into the circulation, which can ultimately lead to renal failure with a possible fatal outcome. This is an uncommon side effect of trabectedin which is used in second-line therapy of metastatic sarcoma after anthracycline and ifosfamide failure. Here, we describe a case of reversible rhabdomyolysis in a male patient with recurrent metastatic synovial sarcoma of the hand, with marked 18F-FDG uptake into his skeletal muscles, after 4 cycles of trabectedin, and who at the same time was taking an alternative medicine (bioflavonoids) suspected of triggering this adverse event.",
"affiliations": "aMedical Oncology Unit, Clinical Cancer Centre, IRCCS Arcispedale S. Maria Nuova, Reggio Emilia, Italy.;aMedical Oncology Unit, Clinical Cancer Centre, IRCCS Arcispedale S. Maria Nuova, Reggio Emilia, Italy.;aMedical Oncology Unit, Clinical Cancer Centre, IRCCS Arcispedale S. Maria Nuova, Reggio Emilia, Italy.;bNuclear Medicine Unit, IRCCS Arcispedale S. Maria Nuova, Reggio Emilia, Italy.;aMedical Oncology Unit, Clinical Cancer Centre, IRCCS Arcispedale S. Maria Nuova, Reggio Emilia, Italy.;bNuclear Medicine Unit, IRCCS Arcispedale S. Maria Nuova, Reggio Emilia, Italy.",
"authors": "Damato|Angela|A|;Larocca|Mario|M|;Rondini|Ermanno|E|;Menga|Massimo|M|;Pinto|Carmine|C|;Versari|Annibale|A|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000464440",
"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 10.1159/000464440cro-0010-0258Case ReportSevere Rhabdomyolysis during Treatment with Trabectedin in Combination with a Herbal Drug in a Patient with Metastatic Synovial Sarcoma: A Case Report Damato Angela a*Larocca Mario aRondini Ermanno aMenga Massimo bPinto Carmine aVersari Annibale baMedical Oncology Unit, Clinical Cancer Centre, IRCCS Arcispedale S. Maria Nuova, Reggio Emilia, ItalybNuclear Medicine Unit, IRCCS Arcispedale S. Maria Nuova, Reggio Emilia, Italy*Angela Damato, Medical Oncology Unit, Clinical Cancer Centre, IRCCS Arcispedale S. Maria Nuova, Viale Risorgimento, IT–42123 Reggio Emilia (Italy), E-Mail angela.damato@asmn.re.itJan-Apr 2017 28 3 2017 28 3 2017 10 1 258 264 22 2 2017 22 2 2017 Copyright © 2017 by S. Karger AG, Basel2017This 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.Rhabdomyolysis is defined as dissolution of striped muscle characterized by leakage of intracellular muscle components into the circulation, which can ultimately lead to renal failure with a possible fatal outcome. This is an uncommon side effect of trabectedin which is used in second-line therapy of metastatic sarcoma after anthracycline and ifosfamide failure. Here, we describe a case of reversible rhabdomyolysis in a male patient with recurrent metastatic synovial sarcoma of the hand, with marked 18F-FDG uptake into his skeletal muscles, after 4 cycles of trabectedin, and who at the same time was taking an alternative medicine (bioflavonoids) suspected of triggering this adverse event.\n\nKey Words\nRhabdomyolysisSarcomaTrabectedinHerbal drug\n==== Body\nCase Presentation\nThis is the case of a 50-year-old Caucasian man from Italy, nonsmoker, with no alcohol or illicit drug intake. His oncology history began in July 2007 in another cancer center, after the surgical removal of an expansive lesion on his left hand achieving a complete negative margin (R0) resection. Histological findings of the lesion highlighted a monophasic synovial sarcoma. He was administered adjuvant local radiotherapy and was then followed up. In June 2008, a computed tomography (CT) scan detected local recurrence of the disease and appearance of new nodules in the middle and apical right pulmonary lobe; therefore, the patient underwent another surgery of the hand and local excision of the lung tumor, which was confirmed by the previous histological diagnosis. Taking into account the dissemination of the disease, in August 2008, he was treated with systemic chemotherapy including 4 cycles of epirubicin in combination with ifosfamide. After about 1 year, in May 2009, progression of the disease into the right lung was recorded; therefore, the patient underwent another 3 wedge resections (anterior segment of the lower and upper right lobe), which is a diagnostic for metastasis of synovial sarcoma. He was followed up with only clinical and instrumental controls (CT scan and laboratory tests). After several years, in June 2012, a contralateral progression of the pulmonary disease was detected (1 lesion in the lower left lobe) and CT scan showed pathological mediastinal lymph nodes. A wedge resection of the dorsal segment of the lower lobe was performed, histologically compatible with metastases, and 2 hilar and lobar lymph nodes, which had become inflammatory, were removed. According to the patient, he continued to be followed up until December 2015 when he was submitted once again to a wedge resection of the middle lobe for sarcoma metastases. After 10 months, the patient reported intermittent episodes of hemoptysis in the absence of other symptoms; the CT scan showed significant thoracic disease progression associated with pulmonary artery compression. Therefore, in October 2016, he started chemotherapy with trabectedin at a dose of 1.5 mg/m2, administered as a 24-h continuous intravenous infusion repeated every 21 days. The treatment was well tolerated for the first 3 cycles in the absence of toxicity. He continued with 4 cycles of trabectedin in December of last year. After 2 weeks, the patient began to complain of sudden weakness, difficulty walking and diffuse muscle pain until it became unbearable. The patient was referred to the emergency department of our hospital and then admitted to start symptomatic therapy and supportive care. The ECOG performance status was grade 3. The laboratory test was found to mark an increase in serum levels of myoglobin, creatine phosphokinase (CPK), and liver function (Table 1). No kidney function injury was present. Fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography was performed and showed an intense widespread tracer uptake in the skeletal muscles, particularly in the upper extremities, sternocleidomastoid muscle, the long muscles of the neck, the muscle groups of the scapular tracks bilaterally, certain muscles of the chest wall, the rectus abdominis muscles, the iliopsoas muscles, and almost all the muscle groups of the upper and lower limbs (Fig. 1), according to the clinical history and laboratory data. When asking the patient about his medical history, he did not report any muscle trauma but he had been taking a herbal drug for hemorrhoids (diosmin) during the last course of trabectedin. After hospitalization and stopping the intake of diosmin with parenteral hydration, a complete normalization of the laboratory findings was obtained (Table 1) associated with a progressive recovery of muscle strength and mobilization of the patient starting from day 10 with a walking aid until complete full functional recovery and a recovery of ECOG performance status grade 0 by day 15.\n\nDiscussion\nTrabectedin is an effective drug in patients with advanced sarcoma who previously failed standard of care chemotherapy [1]. It has a manageable safety profile with common toxicities including reversible low absolute neutrophil count, anemia, thrombocytopenia, and hepatotoxicity and rare, severe clinical consequences such as elevated serum CPK and rhabdomyolysis. Its etiology is unclear and is an uncommon side effect of trabectedin with an incidence of 0.5–0.7% [2, 3]; during preclinical studies, only sporadically increased CPK was found. Rhabdomyolysis is an injury of skeletal muscle that releases potentially toxic muscle cell components (e.g., myoglobin, other intracellular proteins, and electrolytes) into the extracellular fluid and blood stream, which may result in renal damage [1, 4, 5]. Rhabdomyolysis may have a number of causes, including direct trauma, excessive muscular activity, body temperature extremes, muscle hypoxia, infections, metabolic and electrolyte disorders, endocrine disorders, connective tissue disorders, drugs, and toxins. Overall, the clinical features of rhabdomyolysis are quite variable and they can be summarized as muscular signs and symptoms (pain, weakness, tenderness, and contractures) and other symptoms (illness, fatigue, fever, tachycardia, nausea, and vomiting). Rhabdomyolysis can result in life-threatening renal and multiorgan failure with hypovolemia, hyperkalemia, metabolic acidosis, disseminated intravascular coagulation, and compartment syndrome, secondary arrhythmias, or cardiac arrest [3, 567]. Biochemically, rhabdomyolysis is defined by marked blood CPK elevation (typically greater than 10 times the upper limit of normal) with creatinine increase [8, 9]. CPK elevation is the most sensitive marker for skeletal muscle injury [10]. Trabectedin is eliminated through hepatic metabolism and CYP3A4 is the principal responsible enzyme. As a high number of drugs are also metabolized by this enzyme, interactions with multiple concomitant drugs could arise. According to in vitro data, trabectedin exposure could be increased in the presence of CYP3A4 inhibitors [11]. Therefore, coadministration of trabectedin with potent CYP34A inhibitors should be avoided or, if this is not possible, closer patient monitoring is required. The literature described a case of an association of trabectedin with a “natural foe” such as chokeberry (Aronia melanocarpa) extract derived from the black fruit of this shrub [12], which has a long tradition in European and North American folk medicine [13]. It is a relatively concentrated source of flavonoids such as quercetin, and is also reported to strongly inhibit CYP3A4 activity in the liver. It is capable of increasing the bioavailability of different chemotherapeutic agents [14]. Technical data are not listed among the flavonoid inhibitors of CYP3A4. There are several causes of exaggerated physiological 18F-FDG uptake. It may occur if there is activity before, during, or after the injection of the tracer; however, this typically involves the entire muscle more or less uniformly, unlike the patchy appearance in this case. Furthermore, our patient could not move. There may also be preferential uptake of 18F-FDG into muscles in hyperinsulinemic states, for example after the use of corticosteroids. The present patient had a normal glucose level at the time of tracer injection and was not taking any medications that might have affected his glucose metabolism. In the literature, several reports of tracer uptake in muscles have been described, e.g., in a patient taking some drugs such as tacrolimus, which was hypothesized to be due to altered glucose metabolism [15] and in a patient with statin-induced rhabdomyolysis [16]. In conclusion, in our case, according to Strippoli et al. [12], it is possible to assume a role of drug-drug interactions in the pathogenesis of this rare trabectedin side effect. Furthermore, in the presence of unexpected toxicity during conventional anticancer treatment, the simultaneous use by the patient of alternative drugs should be suspected. Although this is a rare side effect of herbal drug use, these medications are in widespread use and it is very important to remember the drug interactions and in particular inhibition of the CYP3A4 isoenzyme by several medications. It is clinically important that there is prevention and early recognition and accurate diagnosis of rhabdomyolysis. This condition may become apparent with abnormal imaging findings and the radiologist should be aware of this possible mode of presentation, which is useful for making a definitive diagnosis.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFig. 1 Anteroposterior maximum intensity projection 18F-FDG positron emission tomography image showing intense abnormal tracer uptake into the skeletal muscles, in particular, into the muscles of the upper extremities, the long muscles of the neck, muscles of the chest wall, and sternocleidomastoid muscle (a, b) as well as the muscle groups of the lower limbs (c).\n\nTable 1 Laboratory parameters related to rhabdomyolysis starting from the first day of hospitalization\n\nLaboratory test\tNormal range\tDay 1\tDay 5\tDay 9\tDay 17\tDay 24\t\nMyoglobin, ng/ml\t0.00–110.0\t14,869.5\t2,511.1\t310.8\t230.5\t94.7\t\nCreatine phosphokinase, U/L\t32–294\t3,009\t1,306\t217\t211\t76\t\nAspartate aminotransferase, U/L\t2.0–40.0\t428\t214\t62\t40\t23\t\nAlanine aminotransferase, U/L\t4.0–49.0\t497\t330\t177\t61\t31\t\nAlkaline phosphatase, U/L\t90–360\t756\t803\t578\t454\t.333\t\nGamma glutamyl transpeptidase, U/L\t5.0–73.0\t918\t789\t511\t288\t154\t\nLactate dehydrogenase, U/L\t208–379\t1,640\t1,751\t1,312\t1,197\t804\n==== Refs\nReferences\n1 Demetri GD Chawla SP von Mehren M Ritch P Baker LH Blay JY Hande KR Keohan ML Samuels BL Schuetze S Lebedinsky C Elsayed YA Izquierdo MA Gomez J Park YC Le Cesne A Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different schedules. J Clin Oncol 2009 27 4188 4196 19652065 \n2 Grosso F D'Incalci M Problems in dealing with very rare adverse effects of new anticancer drugs: the example of trabectedin. Tumori 2011 97 256 21617728 \n3 Khan FY Rhabdomyolysis: a review of the literature. Neth J Med 2009 67 272 283 19841484 \n4 Singh D Chander V Chopra K Rhabdomyolysis. Methods Find Exp Clin Pharmacol 2005 27 39 48 15834458 \n5 Bosh X Poch E Grau JM Rhabdomyolysis and acute kidney injury. N Eng J Med 2012 361 62 72 \n6 Chatzizisis YS Misirli G Hatzitolios AI Giannoglou GD The syndrome of rhabdomyolysis: complications and treatment. Eur J Intern Med 2008 19 568 574 19046720 \n7 Grosso F D'Incalci M Cartoafa M Nieto A Fernandez-Teruel C Alfaro V Lardelli P Roy E Gomez J Kahatt C Soto-Matos A Judson I A comprehensive safety analysis confirms rhabdomyolysis as an uncommon adverse reaction in patients treated with trabectedin. Cancer Chemother Pharmacol 2012 69 1557 1565 22484722 \n8 Cziraky MJ Willey VJ McKenney JM Kamat SA Fisher MD Guyton JR Jacobson TA Davidson MH Statin safety: an assessment using an administrative claims database. Am J Cardiol 2006 97 61C 68C 16377285 \n9 Pasternak RC Smith SC Jr Bairey-Merz CN Grundy SM Cleeman JI Lenfant C ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation 2002 106 1024 1028 12186811 \n10 Cervellin G Comelli I Lippi G Rhabdomyolysis: historical background, clinical, diagnostic and therapeutic features. Clin Chem Lab Med 2010 48 749 756 20298139 \n11 Brandon EF Sparidans RW Guijt KJ Lowenthal S Meijerman I Beijnen JH Schellens JH In vitro characterization of the human biotransformation and CYP reaction phenotype of ET-743 (Yondelis, Trabectidin), a novel marine anti-cancer drug. Invest New Drugs 2006 24 3 14 16379042 \n12 Strippoli S Lorusso V Albano A Guida M Herbal-drug interaction induced rhabdomyolysis in a liposarcoma patient receiving trabectedin. BMC Complement Altern Med 2013 13 199 23899130 \n13 Kulling SE Rawel HM Chokeberry (Aronia melanocarpa ) – a review on the characteristic components and potential health effects. Planta Med 2008 74 1625 1634 18937167 \n14 Choi JS Piao YJ Kang KW Effects of quercetin on the bioavailability of doxorubicin in rats: role of CYP3A4 and P-gp inhibition by quercetin. Arch Pharm Res 2011 34 607 613 21544726 \n15 Groves AM Cheow HK Win T Extensive skeletal muscle uptake of 18 F-FDG: relation to immunosuppressants? J Nucl Med Technol 2004 32 206e8 15576342 \n16 Sheehy N Israel DA Findings on 18 FDG-PET imaging in statin-induced rhabdomyolysis. Clin Radiol 2007 62 1012 1014 17765468\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "10(1)",
"journal": "Case reports in oncology",
"keywords": "Herbal drug; Rhabdomyolysis; Sarcoma; Trabectedin",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "258-264",
"pmc": null,
"pmid": "28512407",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "19652065;17765468;19046720;16379042;21617728;15834458;20298139;22484722;12186811;19571284;21544726;16581331;23899130;19841484;18937167;15576342",
"title": "Severe Rhabdomyolysis during Treatment with Trabectedin in Combination with a Herbal Drug in a Patient with Metastatic Synovial Sarcoma: A Case Report.",
"title_normalized": "severe rhabdomyolysis during treatment with trabectedin in combination with a herbal drug in a patient with metastatic synovial sarcoma a case report"
} | [
{
"companynumb": "IT-JNJFOC-20170126994",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LANSOPRAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of culture-negative aortic valve endocarditis secondary to Tropheryma whipplei infection. Our patient underwent aortic valve replacement after 4 weeks of antibiotic therapy with persistently negative blood culture results. Despite a technically uneventful operation, the patient showed continued sepsis and was unresponsive to a broad-spectrum of antibiotic therapy with subsequent multiorgan failure. He died on the 5th postoperative day, and diagnosis was established at postmortem examination. In this case report, we discuss the diagnosis and treatment of a rare type of endocarditis caused by T. whipplei.",
"affiliations": "Department of Cardiothoracic Surgery, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.;Department of Cardiothoracic Anesthesia, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.;Department of Microbiology and Infectious Diseases, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.;Department of Cardiothoracic Surgery, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.",
"authors": "Muretti|Mirko|M|http://orcid.org/0000-0002-0483-7372;Keiralla|Amar|A|;Jeffery|Katie|K|;Krasopoulos|George|G|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.1111/jocs.14467",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0886-0440",
"issue": "35(4)",
"journal": "Journal of cardiac surgery",
"keywords": "endocarditis; tropheryma whipplei; valve repair/replacement",
"medline_ta": "J Card Surg",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001021:Aortic Valve; D004697:Endocarditis, Bacterial; D017809:Fatal Outcome; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure; D035583:Rare Diseases; D054851:Tropheryma; D008061:Whipple Disease",
"nlm_unique_id": "8908809",
"other_id": null,
"pages": "923-925",
"pmc": null,
"pmid": "32058604",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Tropheryma whipplei endocarditis: An uncommon infection with potentially fatal consequences.",
"title_normalized": "tropheryma whipplei endocarditis an uncommon infection with potentially fatal consequences"
} | [
{
"companynumb": "GB-PFIZER INC-2020181307",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GENTAMICIN SULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "Device based closure of the left atrial appendage (LAA) has emerged as a viable approach for stroke prevention in atrial fibrillation (AF) patients with contraindications to chronic oral anticoagulation. One of the most feared complications is device related thrombus formation. We present a 66-year-old male with chronic AF who developed a life-threatening intracranial bleed on oral anti-coagulation. He subsequently underwent LAA closure using an Amplatzer muscular ventricular septal defect closure device for stroke prevention. However, he was found to have a large thrombus attached to the device a year later. We present a review of the various LAA closure devices, importance of periodic surveillance via echocardiography and management options to prevent this complication. Also, the case highlights the importance of contrast-enhance echocardiography in diagnosis of LAA closure device thrombus.",
"affiliations": "Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA.;Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA.;Department of Cardiology, Henry Ford Hospital, Detroit, MI, USA.;Department of Cardiology, Henry Ford Hospital, Detroit, MI, USA.",
"authors": "Jain|Tarun|T|;Shah|Jainil|J|;Shah|Sunay|S|;Modi|Shalini|S|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.4250/jcu.2016.24.1.60",
"fulltext": "\n==== Front\nJ Cardiovasc UltrasoundJ Cardiovasc UltrasoundJCUJournal of Cardiovascular Ultrasound1975-46122005-9655Korean Society of Echocardiography 10.4250/jcu.2016.24.1.60Case ReportHeart within a Heart Jain Tarun MD1Shah Jainil MD1Shah Sunay MD2Modi Shalini MD21 Department of Internal Medicine, Henry Ford Hospital, Detroit, MI, USA.2 Department of Cardiology, Henry Ford Hospital, Detroit, MI, USA.\nAddress for Correspondence: Tarun Jain, Department of Internal Medicine, Henry Ford Hospital, 1350 W Bethune St, Apt 1609, Detroit, MI 48202, USA. Tel: +1-708-527-5753, Fax: +1-313-916-4513, tarun93@hotmail.com3 2016 24 3 2016 24 1 60 63 24 6 2015 09 12 2015 01 2 2016 Copyright © 2016 Korean Society of Echocardiography2016This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Device based closure of the left atrial appendage (LAA) has emerged as a viable approach for stroke prevention in atrial fibrillation (AF) patients with contraindications to chronic oral anticoagulation. One of the most feared complications is device related thrombus formation. We present a 66-year-old male with chronic AF who developed a life-threatening intracranial bleed on oral anti-coagulation. He subsequently underwent LAA closure using an Amplatzer muscular ventricular septal defect closure device for stroke prevention. However, he was found to have a large thrombus attached to the device a year later. We present a review of the various LAA closure devices, importance of periodic surveillance via echocardiography and management options to prevent this complication. Also, the case highlights the importance of contrast-enhance echocardiography in diagnosis of LAA closure device thrombus.\n\nAtrial fibrillationLeft atrial appendageTranscatheter occlusion device\n==== Body\nIntroduction\nAtrial fibrillation (AF) is a common disease associated with developing strokes. The main-stay therapy for this condition is chronic oral anticoagulation, however, in patients with a high bleeding risk profile or prior life-threatening bleed, conventional therapy may not be ideal. New advanced technologies such as transcatheter closure of the left atrial (LA) appendage (LAA) provides clinicians an alternative therapy to reduce the stroke risk in patients with contraindications to chronic oral anticoagulation. In this case, we present a 66-year-old male with chronic AF who underwent LAA closure and was found to have a large thrombus attached to the device a year later. This case is valuable for dealing with thrombus formation even after one year device closure. Several studies of the percutaneous transcatheter delivery of dedicated LAA occlusion devices have shown promising results that offer an alternative to warfarin therapy for selected patients. Despite the encouraging results of several studies about the procedure, additional studies are needed to verify the safety and effectiveness of the devices. As in the present case, thrombosis might be a possible late complication and information to guide imaging monitoring and treatment is lacking.\n\nCase\nA 66-year-old male with an extensive past medical history including hypertension, hyperlipidemia, diabetes, metastatic prostate cancer treated with prostatectomy along with radiation and chemotherapy, previous ischemic stroke, known severe 3-vessel coronary artery disease with coronary bypass grafting surgery after myocardial infarction, preserved ejection fraction of 50%, and chronic AF on anti-coagulation with warfarin. The patient suffered a fall resulting in left cerebellar hemorrhage, left temporal lobe subarachnoid hemorrhage as well as encephalomalacia of posterior right frontal lobe due to intraparenchymal hemorrhage. Due to his inability to tolerate long-term anticoagulation and high CHADS2 score of 5, he underwent percutaneous LAA closure using a 16 mm Amplatzer muscular ventricular septal defect closure device (AGA Medical Corp., Plymouth, MN, USA). He was not a candidate for Lariat device (SentreHEART, Redwood City, CA, USA) due to prior cardiac surgery. The device was deployed with no complications and no residual flow. The patient was placed on life-long daily aspirin 81 mg and a three-month course of clopidogrel 75 mg.\n\nTransthoracic 2D-echocardiogram performed post-procedure, 45 days, and at 6 month follow-up was unremarkable for device complications. However, the 1 year follow-up transthoracic 2D-echocardiogram revealed a spherical echo dense structure measuring 2.38 × 1.42 cm suggestive of clot in the left atrium (Fig. 1, 2, and 3, Supplementary movie 1 and 2). Transesophageal echocardiogram demonstrated a bilobed echo dense mass in the LA, the smaller being 1.53 × 1.87 cm and the larger mass being 2.45 × 2.33 cm (Fig. 4 and 5, Supplementary movie 3). The mass was found to be attached to the closure device. The patient had no coagulation abnormalities. The patient was bridged to warfarin with heparin and anticoagulation was resumed. There were no early complications as a result of the treatment. Repeat transthoracic echocardiogram six months later did not reveal any evidence of residual thrombus on contrast imaging. His warfarin was subsequently discontinued and he has been maintained on daily 81 mg aspirin. He has remained asymptomatic from a cardiac and neurological standpoint and is regularly followed by cardiology.\n\nDiscussion\nAF is the most common sustained cardiac arrhythmia and increases the risk for stroke.1) LAA is the site of around 75–90% of thrombus formation in non-valvular AF, and thus obliteration or exclusion of this structure, at least in theory, should lead to stroke risk reduction.2) Three devices have been specifically designed for LAA occlusion: the percutaneous left atrial appendage transcatheter occlusion (PLAATO), the Watchman (Atritech, Boston Scientific, Natick, MA, USA) LAA system, and the Amplatzer Cardiac Plug (ACP) (AGA, St. Jude Medical, Minneapolis, MN, USA).3) The PLAATO device has been discontinued for commercial reasons. The embolic protection in patients with atrial fibrillation trial compared closure of the LAA with the Watchman device with long-term warfarin therapy and found it was non-inferior to standard anticoagulant therapy for stroke prophylaxis in high-risk AF patients.4) Recently, the ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology study found that LAA closure with the Watchman device can be safely performed without a warfarin transition, and is a reasonable alternative to consider for patients at high risk for stroke but with contraindications to systemic oral anticoagulation.5)\n\nA variety of Amplatzer septal occluder devices (AGA, St. Jude Medical, St. Paul, MN, USA) have been available for many years and used extensively for closure of atrial and ventricular septal defects and other cardiac shunts. Eventually, a novel device, the ACP, was developed for the purpose of closing the LAA. Similar to prior trans-catheter LAA closure devices, the ACP system is delivered into the left atrium via a trans-septal approach. The relatively short length of the ACP device allows for implantation into shallow LAA variants, which gives it an advantage over the PLAATO and Watchman devices that require a deeper LAA anatomy because of their longer profiles.3)\n\nThe incidence of thrombus formation on devices is relatively uncommon with prior studies showing an incidence for the Watchman device thrombus formation between 2–4%.5)6)7) In a study by Urena et al.,8) none of the 52 patients developed a device thrombus on the Amplatzer device; however, there have been two case reports from Europe.9)10) Prior studies demonstrate high stroke risk score, high pre-procedural platelet count, and low left ventricular ejection fraction as independent risk factors for the formation of thrombus on the ACP device.7)\n\nTransthoracic echocardiogram has a lower sensitivity to identify LA thrombus. Use of contrast-enhanced echocardiography significantly improves the sensitivity for identifying intra-cardiac masses when standard imaging does not reveal diagnostic information.11)\n\nIndividuals who will benefit from LAA closure are probably those who are at the highest risk for both stroke and hemorrhagic complications; therefore, patient selection is of paramount importance in order to realize the optimal device and antithrombotic strategy. As in the present case, thrombosis might be a rare, but possible complication of device-based antithrombotic therapy, and additional studies are needed to know if the current practice of treating patients only with double-antiplatelet therapy before endothelization of the device is sufficient, or if one should use oral anticoagulation in the first 3 months as is advised in biological prostheses. In addition, periodic surveillance by echocardiography with contrast should be recommended to monitor the formation of thrombus in all types of devices. The frequency, duration, and type of echocardiogram (transthoracic or transesophageal) for thrombus formation monitoring still needs further research.\n\nSupplementary movie legends\nMovie 1\nThree chamber view movie clip showing a stalk with pedunculated thrombus\n\n Movie 2\nContrast-enhanced echocardiogram movie clip showing enhanced view of thrombus\n\n Movie 3\nTransesophageal echocardiogram movie clip confirms a large bi-lobed thrombus\n\n Fig. 1 Zoom in of atrium from apical four chamber view. Unable to\nappreciate thrombus in this view without the use of contrast.\nFig. 2 Heart within a heart. Three chamber view showing a stalk with\npedunculated thrombus (arrow).\nFig. 3 Contrast-enhanced echocardiogram enhances view of thrombus\n(arrow).\nFig. 4 Transesophageal echocardiogram confirms a large bi-lobed thrombus (arrows).\nFig. 5 Transesophageal 3D image shows thrombus attached to ventricular septal defect occluder device (arrow).\n==== Refs\n1 Roger VL Go AS Lloyd-Jones DM Adams RJ Berry JD Brown TM Carnethon MR Dai S de Simone G Ford ES Fox CS Fullerton HJ Gillespie C Greenlund KJ Hailpern SM Heit JA Ho PM Howard VJ Kissela BM Kittner SJ Lackland DT Lichtman JH Lisabeth LD Makuc DM Marcus GM Marelli A Matchar DB McDermott MM Meigs JB Moy CS Mozaffarian D Mussolino ME Nichol G Paynter NP Rosamond WD Sorlie PD Stafford RS Turan TN Turner MB Wong ND Wylie-Rosett J American Heart Association Statistics Committee and Stroke Statistics Subcommittee Heart disease and stroke statistics--2011 update: a report from the American Heart Association Circulation 2011 123 e18 e209 21160056 \n2 Blackshear JL Odell JA Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation Ann Thorac Surg 1996 61 755 759 8572814 \n3 Lardizabal JA Sharma S Mechanical approaches to stroke prevention in atrial arrhythmias J Innov Cardiac Rhythm Manage 2012 3 809 813 \n4 Holmes DR Reddy VY Turi ZG Doshi SK Sievert H Buchbinder M Mullin CM Sick P PROTECT AF Investigators Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial Lancet 2009 374 534 542 19683639 \n5 Reddy VY Möbius-Winkler S Miller MA Neuzil P Schuler G Wiebe J Sick P Sievert H Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology) J Am Coll Cardiol 2013 61 2551 2556 23583249 \n6 De Backer O Arnous S Ihlemann N Vejlstrup N Jørgensen E Pehrson S Krieger TD Meier P Søndergaard L Franzen OW Percutaneous left atrial appendage occlusion for stroke prevention in atrial fibrillation: an update Open Heart 2014 1 e000020 25332785 \n7 Plicht B Konorza TF Kahlert P Al-Rashid F Kaelsch H Jánosi RA Buck T Bachmann HS Siffert W Heusch G Erbel R Risk factors for thrombus formation on the Amplatzer Cardiac Plug after left atrial appendage occlusion JACC Cardiovasc Interv 2013 6 606 613 23787233 \n8 Urena M Rodés-Cabau J Freixa X Saw J Webb JG Freeman M Horlick E Osten M Chan A Marquis JF Champagne J Ibrahim R Percutaneous left atrial appendage closure with the AMPLATZER cardiac plug device in patients with nonvalvular atrial fibrillation and contraindications to anticoagulation therapy J Am Coll Cardiol 2013 62 96 102 23665098 \n9 Cardona L Ana G Luísa B Leal A António F Lídia S Cruz FR Thrombus formation on a left atrial appendage closure device Circulation 2011 124 1595 1596 21969319 \n10 Lammers J Elenbaas T Meijer A Thrombus formation on an Amplatzer closure device after left atrial appendage closure Eur Heart J 2013 34 741 23242193 \n11 Mulvagh SL Rakowski H Vannan MA Abdelmoneim SS Becher H Bierig SM Burns PN Castello R Coon PD Hagen ME Jollis JG Kimball TR Kitzman DW Kronzon I Labovitz AJ Lang RM Mathew J Moir WS Nagueh SF Pearlman AS Perez JE Porter TR Rosenbloom J Strachan GM Thanigaraj S Wei K Woo A Yu EH Zoghbi WA American Society of Echocardiography American society of echocardiography consensus statement on the clinical applications of ultrasonic contrast agents in echocardiography J Am Soc Echocardiogr 2008 21 1179 1201 quiz 1281 18992671\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1975-4612",
"issue": "24(1)",
"journal": "Journal of cardiovascular ultrasound",
"keywords": "Atrial fibrillation; Left atrial appendage; Transcatheter occlusion device",
"medline_ta": "J Cardiovasc Ultrasound",
"mesh_terms": null,
"nlm_unique_id": "101477138",
"other_id": null,
"pages": "60-3",
"pmc": null,
"pmid": "27081446",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports",
"references": "23242193;23787233;25332785;18992671;19683639;21160056;23583249;23665098;21969319;8572814",
"title": "Heart within a Heart.",
"title_normalized": "heart within a heart"
} | [
{
"companynumb": "US-CIPLA LTD.-2016US04235",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
... |
{
"abstract": "Chronic granulomatous disease (CGD) is a primary immunodeficiency associated to multiple life-threatening bacterial and fungal infections, beginning in childhood. There are rare cases of diagnosis in adulthood. We describe here two cases of late diagnosis in adults: a 45-year-old woman and 59-year-old-man. CGD diagnosis should be considered in adult patients with unexplained infectious diseases with tissue granuloma.",
"affiliations": "Respiratory Diseases Department, Foch Hospital, Suresnes, France.;Internal Medicine Department, Strasbourg University Hospital, Strasbourg, France.;Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, Paris, France.;Respiratory Diseases Department, Foch Hospital, Suresnes, France.;Clinical Immunology and Internal Medicine, Center for Rare Autoimmune Diseases, Strasbourg University Hospital, CNRS 3572, Strasbourg, France.;Respiratory Diseases Department, Foch Hospital, Suresnes, France.;Respiratory Diseases Department, Foch Hospital, Suresnes, France.;Respiratory Diseases Department, Foch Hospital, Suresnes, France.;Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children, Paris, France. jacinta.bustamante@inserm.fr.;Clinical Immunology and Internal Medicine, Center for Rare Autoimmune Diseases, Strasbourg University Hospital, CNRS 3572, Strasbourg, France.",
"authors": "Colin de Verdière|Sylvie|S|;Noel|Esther|E|;Lozano|Claire|C|;Catherinot|Emilie|E|;Martin|Mickael|M|;Rivaud|Elisabeth|E|;Couderc|Louis-Jean|LJ|;Salvator|Hélène|H|;Bustamante|Jacinta|J|;Martin|Thierry|T|",
"chemical_list": "D015415:Biomarkers",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10875-017-0370-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0271-9142",
"issue": "37(2)",
"journal": "Journal of clinical immunology",
"keywords": "CGD; NCF1; Pantoea; ROS; colitis; inflammatory bowel disease; pulmonary aspergillosis; pulmonary disease",
"medline_ta": "J Clin Immunol",
"mesh_terms": "D015415:Biomarkers; D005260:Female; D006105:Granulomatous Disease, Chronic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009504:Neutrophils; D055732:Pulmonary Aspergillosis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8102137",
"other_id": null,
"pages": "113-116",
"pmc": null,
"pmid": "28130637",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": "25614174;8551880;9311521;18094446;25537876;23351990;20700078;19381301;23791514;15286231;10879644;16123991;26090111;26185411;24942036",
"title": "Respiratory Complications Lead to the Diagnosis of Chronic Granulomatous Disease in Two Adult Patients.",
"title_normalized": "respiratory complications lead to the diagnosis of chronic granulomatous disease in two adult patients"
} | [
{
"companynumb": "FR-JNJFOC-20170317216",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Psychiatric and behavioral side effects (PBSEs) are common, undesirable effects associated with antiepileptic drug (AED) use. The objective of the study was to compare the PBSE profiles of older and newer AEDs in a large specialty practice-based sample of patients diagnosed with epilepsy.\n\n\n\nAs part of the Columbia and Yale AED Database Project, we reviewed patient records including demographics, medical history, AED use, and side effects for 4085 adult patients (age: 18 years) newly started on an AED regimen. Psychiatric and behavioral side effects were determined by patient or physician report in the medical record, which included depressive mood, psychosis, anxiety, suicidal thoughts, irritability, aggression, and tantrum. Significant non-AED predictors of PBSE rate were first determined from 83 variables using logistic regression. Predictors were then controlled for in the comparison analysis of the rate of PBSEs and intolerable PBSEs (PBSEs that led to dosage reduction or discontinuation) between 18 AEDs.\n\n\n\nPsychiatric and behavioral side effects occurred in 17.2% of patients and led to intolerability in 13.8% of patients. History of psychiatric condition(s), secondary generalized seizures, absence seizures, and intractable epilepsy were associated with increased incidence of PBSE. Levetiracetam (LEV) had the greatest PBSE rate (22.1%). This was statistically significant when compared with the aggregate of the other AEDs (P<0.001, OR=6.87). Levetiracetam was also significantly (P<0.001) associated with higher intolerability rate (17.7%), dose decreased rate (9.4%), and complete cessation rate (8.3%), when compared with the aggregate of the other AEDs. Zonisamide (ZNS) was also significantly associated with a higher rate of PBSE (9.7%) and IPBSE (7.9%, all P<0.001). On the other hand, carbamazepine (CBZ), clobazam (CLB), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OXC), phenytoin (PHT), and valproate (VPA) were significantly associated with a decreased PBSE rates (P<0.001). Carbamazepine, GBP, LTG, PHT, and VPA were also associated with lower IPBSE rates when compared individually with the aggregate of other AEDs. All other AEDs were found to have intermediate rates that were not either increased or decreased compared with other AEDs. When each AED was compared to LTG, only CBZ had a significantly lower PBSE rate. The main limitations of this study were that the study design was retrospective and not blinded, and the AEDs were not randomly assigned to patients.\n\n\n\nPsychiatric and behavioral side effects occur more frequently in patients taking LEV and ZNS than any other AED and led to higher rates of intolerability. Lower PBSE rates were seen in patients taking CBZ, CLB, GBP, LTG, OXC, PHT, and VPA. Our findings may help facilitate the AED selection process.",
"affiliations": "Comprehensive Epilepsy Center, Dept. of Neurology, Yale University, New Haven, CT, USA; William Beaumont School of Medicine, Oakland University, Rochester, MI, USA. Electronic address: baibing.chen@yale.edu.;Comprehensive Epilepsy Center, Dept. of Neurology, Columbia University, New York, NY, USA.;Comprehensive Epilepsy Center, Dept. of Neurology, Yale University, New Haven, CT, USA.;Comprehensive Epilepsy Center, Dept. of Neurology, Yale University, New Haven, CT, USA.;Comprehensive Epilepsy Center, Dept. of Neurology, Columbia University, New York, NY, USA.;Comprehensive Epilepsy Center, Dept. of Neurology, Columbia University, New York, NY, USA.;Comprehensive Epilepsy Center, Dept. of Neurology, Yale University, New Haven, CT, USA.",
"authors": "Chen|Baibing|B|;Choi|Hyunmi|H|;Hirsch|Lawrence J|LJ|;Katz|Austen|A|;Legge|Alexander|A|;Buchsbaum|Richard|R|;Detyniecki|Kamil|K|",
"chemical_list": "D000927:Anticonvulsants",
"country": "United States",
"delete": false,
"doi": "10.1016/j.yebeh.2017.08.039",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-5050",
"issue": "76()",
"journal": "Epilepsy & behavior : E&B",
"keywords": "Antiepileptic drug; Comparison; Epilepsy; Intolerability; Predictor; Psychiatric behavioral side effect",
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D000069279:Drug Resistant Epilepsy; D004361:Drug Tolerance; D064420:Drug-Related Side Effects and Adverse Reactions; D004827:Epilepsy; D004832:Epilepsy, Absence; D005260:Female; D006801:Humans; D008297:Male; D001523:Mental Disorders; D008875:Middle Aged; D012189:Retrospective Studies",
"nlm_unique_id": "100892858",
"other_id": null,
"pages": "24-31",
"pmc": null,
"pmid": "28931473",
"pubdate": "2017-11",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy.",
"title_normalized": "psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy"
} | [
{
"companynumb": "US-JNJFOC-20171117660",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": "3",
"... |
{
"abstract": "Ocrelizumab is a humanized CD20 monoclonal antibody which was approved for management of Relapsing Remitting Multiple Sclerosis (RRMS) and Primary Progressive Multiple Sclerosis (PPMS) in 2017. We present 2 patients, a 67-year-old woman with history of PPMS and a 42-year-old woman with RRMS, who were started on ocrelizumab and were diagnosed with invasive ductal cell breast carcinoma after 2 years of ocrelizumab infusion followed by discontinuation of the drug. Large trials conducted for ocrelizumab showed malignancies in a total of 4 cases with RRMS in OPERA 1 trial conducted over 2 years from 2011 to 2013 (breast cancer, renal cell carcinoma, and melanomas) and in 11 cases with PPMS seen in ORATORIO trial conducted in 2017. There are currently no other published case reports of breast cancer in setting of ocrelizumab use for MS outside of large trials on literature review.",
"affiliations": "Department of Neurology, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA.;Department of Neurology, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA.;Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.;Department of Neurology, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA.",
"authors": "Kelsey|Andrew|A|;Casinelli|Gabriella|G|;Tandon|Medha|M|;Sriwastava|Shitiz|S|https://orcid.org/0000-0001-6844-3287",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/11795735211037785",
"fulltext": "\n==== Front\nJ Cent Nerv Syst Dis\nJ Cent Nerv Syst Dis\nspcns\nCNS\nJournal of Central Nervous System Disease\n1179-5735\nSAGE Publications Sage UK: London, England\n\n10.1177_11795735211037785\n10.1177/11795735211037785\nCase Series\nBreast Carcinoma After Ocrelizumab Therapy in Multiple Sclerosis Patients: A Case Series and Literature Review\nKelsey Andrew MD 1\nCasinelli Gabriella MD 1\nTandon Medha MD 2\nhttps://orcid.org/0000-0001-6844-3287\nSriwastava Shitiz MD 13\n1 Department of Neurology, Rockefeller Neuroscience Institute, 5631 West Virginia University , Morgantown, WV, USA\n2 Department of Neurology, 6595 University of Pittsburgh Medical Center , Pittsburgh, PA, USA\n3 West Virginia Clinical and Translational Science Institute , Morgantown, WV, USA\nShitiz Sriwastava, MD, Department of Neurology, Rockefeller Neuroscience Institute, West Virginia University Phone: 813-410-2578. Email: shitiz.sriwastava@hsc.wvu.edu\n2021\n2 9 2021\n13 11795735211037785© The Author(s) 2021\n2021\nSAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nOcrelizumab is a humanized CD20 monoclonal antibody which was approved for management of Relapsing Remitting Multiple Sclerosis (RRMS) and Primary Progressive Multiple Sclerosis (PPMS) in 2017. We present 2 patients, a 67-year-old woman with history of PPMS and a 42-year-old woman with RRMS, who were started on ocrelizumab and were diagnosed with invasive ductal cell breast carcinoma after 2 years of ocrelizumab infusion followed by discontinuation of the drug. Large trials conducted for ocrelizumab showed malignancies in a total of 4 cases with RRMS in OPERA 1 trial conducted over 2 years from 2011 to 2013 (breast cancer, renal cell carcinoma, and melanomas) and in 11 cases with PPMS seen in ORATORIO trial conducted in 2017. There are currently no other published case reports of breast cancer in setting of ocrelizumab use for MS outside of large trials on literature review.\n\nocrelizumab\nmultiple sclerosis\nin situ breast carcinoma\nmalignancy in MS\ndisease-modifying therapies\ncover-dateJanuary-December 2021\ntypesetterts10\n==== Body\npmcIntroduction\n\nMultiple sclerosis (MS) is a debilitating disease caused by an autoimmune demyelinating process affecting the central nervous system (CNS). MS commonly affects women 2–3 times more than men, with peak ages of onset between 20 and 50 years.1\n\nDespite the aggressive nature of the disease, there have been vast developments of key immunomodulation therapies in the form of disease modifying therapies (DMTs) to help prevent deterioration and disability in the disease process by preventing further inflammatory reactions. The DMTs act by suppressing the immune response against brain cells and to reduce the inflammatory cascade.2 Over the years, there has been an evolution of various DMTs with different mechanisms of action that have changed the long-term prognosis of MS.\n\nHowever, with the increasing use of DMTs for disease control, neurologists must also be mindful of the suspected increased risks associated with DMT use. The disease itself inadvertently increases the risk of infection and malignancy, which is subsequently exaggerated by the additional factors of immunosuppression in patients being managed with DMTs.3-5 Unfortunately, there are no clear guidelines with regard to screening or management of malignancy in the setting of DMT related to MS or how to manage a new diagnosis of malignancy in these subgroups of patients. Depending upon the type of malignancy, there have been varying studies showing increased, decreased, or similar risk of developing cancer in MS patients as compared to the general population.3,6-8 There have been overall consensus for certain immunosuppressants such as fingolimod, natalizumab, and alemtuzumab, leading to an increased risk of malignancy with increasing duration of treatment and cumulative dose.4,9-15\n\nOcrelizumab, an immunosuppressive DMT used in the management of MS, is a humanized monoclonal antibody that targets the pre-B and mature B cells expressing the CD20 antigen on their cell surface. Through modulation of the immune response, ocrelizumab interferes with the disease process at many levels including antigen presentation, cytokine release, antibody production, and aggregation of lymphocytes. Common adverse reactions associated with ocrelizumab are mostly related to increased infections including skin infections and upper respiratory infections; however, malignancy particularly of the breast has been reported earlier in the clinical trials.16-18\n\nHere, we present 2 interesting and unique cases of middle-aged women on ocrelizumab for management of MS who eventually developed breast cancer. We also present various associations of malignancies in patients diagnosed with MS (refer Table 1) and the associations of various malignancies with usage of several DMT medications (refer Table 2). We conducted a thorough literature review in April 2021 using the terms “DMTs and malignancy”; “DMTs and breast cancer”; “Ocrelizumab and breast cancer.” We searched PubMed and Scopus databases for identifying case series and case reports published between January 01, 1995, and March 15, 2021, whereas review articles and consensus statements were excluded from the analysis.Table 1. Large Cohort Studies Highlighting the Mean Age at the Diagnosis of Malignancy, Type of MS Medication, Type of Malignancy, and Duration from the Medication Start to the Onset of Malignancy.\n\nAuthor/Study Year\tStudy Type\tMedication Studied\tNumber of MS Cases with (Gender)\tNumber of Cases with Malignancy\tMean Age of Patients at Malignancy Diagnosis\tType of Malignancy\t\nMidgard et al6\tRetrospective study\tNA\t1271 (530 M/741 F)\t73\tNA\tBreast cancer; cancer of urinary tract\t\nEtemadifar et al21\tCohort study\tNA\t1718 (388 M/1330 F)\t23\tF = 44.1 ± 9.9\t11 had breast cancer, 3 lymphoma, 3 nervous system cancer, and 6 had other types of cancer (endocrine glands, bone, connective tissue, and secondary and unspecified sites)\t\nM = 34 ± 4\t\nMøller et al7\tCohort\tNA\t5359 (NA)\t210\t(0–49 years: 55%; 50+ years: 45%)\tNon‐melanoma skin cancer, urinary tract, and nasopharyngeal carcinomas\t\nSumelahti et al22\tCohort prospective\tNA\t1597 (NA)\t85\tNA\tHematological\t\nNervous system\t\nKingwell et al27\tCohort prospective\tNA\t6820(NA)\t410\tNA\tNon-melanoma skin cancer\t\nHajiebrahimi et al20\tCohort\tNA\t19330 (NA)\t471\t<18 =1\tBreast cancer\t\n18–40 = 121\t\n41–54 = 205\t\n55–64 = 87\t\n>65 y = 57\t\nNørgaard et al24\tCohort study\tNA\t10752 (NA)\t608\t<25 = 8\tMelanoma\t\n25–29 = 18\t\n30–34 = 34\t\n35–39 = 65\t\n40–44 = 91\t\n45–49 = 103\t\n50–54 = 109\t\n55–59 = 96\t\n60–64 = 44\t\n65–69 = 26\t\n70–74 = 10\t\n75–79 = 4\t\nNielsen et al8\tPopulation based register\tNA\t11817 (NA)\t1037\tNA\tBreast cancer\t\nAchiron et al25\tCohort\tNA\t1338 (NA)\t63\tNA\tNon-statistically significant breast cancer\t\nF, female; M, male; MS, multiple sclerosis; NA, not available.\n\nTable 2. Case Report and Case Series Highlighting the Age, Type of MS Medication, Type of Malignancy, and Duration from the Medication Start to the Onset of Malignancy.\n\nAuthor/Study Year\tStudy Type\tMedication Studied\tGender\tAge\tType of Malignancy\t\nAmaria RN et al/2008\tCase report\tPatient 1: IFN-β1a\t2 F\tPt 1= 53\tBreast cancer\t\nPatient 2: Glatiramer acetate\tPt 2= 48\t\nMadray et al15\tCase report\tGlatiramer acetate\tF\t33\tCutaneous anaplastic large cell\t\nLymphoma\t\nWalker et al26\tCase report\tGlatiramer acetate\tF\t43\tMelanoma\t\nLandais et al16\tCase report\tTeriflunomide\tF\t54\tLymphoma\t\nMahajan et al17\tCase report\tFingolimod\tM\t61\tMerkel cell carcinoma\t\nKillestein et al9\tCase report\tFingolimod\t1 M/4F\tPt1=44\tMelanoma\t\nPt2=38\t\nPt3=44\t\nPt4=32\t\nPt5=45\t\nConzett et al18\tCase report\tFingolimod\tF\t39\tMelanoma\t\nPapathemeli et al27\tCase report\tFingolimod\tF\t69\tPrimary cutaneous CD30(+) anaplastic large-cell T-cell lymphoma\t\nCohan et al28\tCase report\tFingolimod\tM\t34\tAcute lymphoblastic leukemia\t\nWalker et al29\tCase report\tFingolimod\tM\t46\tKaposi sarcoma\t\nPace et al11\tCase report\tAlemtuzumab\tF\t34\tMelanoma\t\nBergamaschi et al30\tCase report\tNatalizumab\tF\t39\tMelanoma\t\nSchweikert et al10\tCase report\tNatalizumab\tM\t40\tPrimary central nervous system lymphoma\t\nPhan-Ba R et al31\tCase report\tNatalizumab\tM\t40\tPrimary central nervous system lymphoma\t\nF, female; M, male; MS, multiple sclerosis.\n\nCase Report #1\n\nA 67-year-old Caucasian woman with hypertension and hyperlipidemia with a prior clinical history of bilateral optic neuritis and balance difficulty since 2003 was diagnosed with PPMS based on MRI and CSF findings. CSF analysis showed isolated oligoclonal bands 7, IgG index of 0.56, protein 38 mg/dl, CSF ACE 1.7, WBC 0, and glucose 52 mg/dl. MRI showed T2/FLAIR changes in periventricular region and MRI cervical spine showed T2 plaque at C5-C6 (refer Figure 1).Figure 1. Sagittal (A) and axial (B) FLAIR MRI shows right sided irregular hyperintensity in periventricular region. (C) T2 weighted MRI sagittal section shows hyperintensity in spinal cord at the level of C5 and C6 vertebrae. MRI, magnetic resonance imaging.\n\nShe had no past or family history of melanoma or breast cancer which was clearly documented and confirmed prior to starting any therapy. She underwent menopause in her 50s and was not on any hormone replacement therapy. She did not consume alcohol, but she used to smoke cigarettes less than 1/2 pack/day for 3 years, 25 years ago. From December 2017, she was started on ocrelizumab infusions, every 6 months, in view of her persisting balance problems due to her PPMS. Patients’ prior annual mammogram reports before starting ocrelizumab and up till 2018 showed symmetric fibro-glandular breast tissue pattern with no suspicious microcalcification and no mass or skin changes.\n\nShe denies any hospital admissions in the past for MS exacerbations. In August 2019, she underwent routine bilateral screening mammogram that revealed architectural distortion in the right breast in the form of a 9 mm × 6 mm irregularly shaped, non-parallel hypoechoic mass with angular margins and no suspicious finding in the left breast. Subsequent ultrasound showed 9 × 9 × 6 mm irregularly shaped hypoechoic mass in the right breast 2 cm deep to the nipple. A biopsy of the mass was performed and she was diagnosed with ER+/PR+/HER2-invasive ductal carcinoma of the right breast T1N0M0 stage 1. She was started on anastrozole 1 mg daily and underwent right partial mastectomy for the management of this condition. Ocrelizumab was discontinued following the diagnosis of malignancy as this correlation has been found in earlier clinical trials of ocrelizumab.17,18\n\nFollowing the surgery, she was counseled about the suspected increased risk of breast cancer with ocrelizumab. Her diagnosis of breast cancer significantly reduced available treatment options and all other DMTs for MS were discussed with her. She opted of on any other MS medications and preferred to be monitored clinically. She was asked to report any new neurological symptom, which could be indicative of a relapse upon which she would be started on steroids. She is currently monitored clinically and radiologically (MRI scan) at an interval of 12 months. She is clinically stable and not currently on any DMT.\n\nCase Report #2\n\nA 42-years old Caucasian woman with history of RRMS with prior clincial events of bilateral lower extremity weakness and right lower extremity numbness in 1999 and cognitive impairment with memory loss.MS diagnosed based on MRI imaging and CSF study. As diagnosis was established at an outside facility, the patient’s diagnostic CSF labs are not available at the time. MRI performed in 2019 showed T2/FLAIR changes in the large centimeter size tumefactive lesion in the bilateral periventricular area in the frontal lobe in the atrium and with corresponding patchy enhancement of the left periventricular lesion with a few other discrete lesions in the deep white matter and the frontal white matter. MRI of the T-spine shows T2 plaque at the T10-T11 level (Figure 2).Figure 2. Sagittal (A) and axial (B) FLAIR MRI shows 2 discrete irregular hyperintensity in periventricular region. (C) T2 weighted MRI sagittal section shows hyperintensity in spinal cord at the level of T9 and T10 vertebrae. MRI, magnetic resonance imaging.\n\nShe had no past personal history of malignancy and no family history of breast cancer. She had a history of excessive menorrhagia requiring radiofrequency ablation therapy, following which she stopped menstruating while using Depo-Provera as birth control. She has never been on any hormone replacement therapy. She has minimal alcohol use and remote tobacco use, having quit in 2011 with only episodic tobacco use prior to this.\n\nHer current treatment includes ocrelizumab infusions, every 6 months, starting October 2019. She was previously on Copaxone and Avonex. She required hospitalization for MS exacerbation in June 2019, when she transferred care to our facility. She was undergoing annual mammogram and ultrasound for the last 10 years due to dense breasts with last negative screening being in February 2020. In October 2020, there was a lesion on left breast concerning for a nodule 11 mm in size with some microcalcification on routine mammogram. On follow-up breast ultrasound, there was a 6 mm nodule in the right breast and an 11 mm × 9 mm solid nodule with calcification and vascularity in the left breast. A complex cystic aspiration was performed to evaluate the right breast nodule, and a core sample biopsy along with a sentinel lymph node biopsy was performed for the left breast nodule followed by left complete mastectomy. Left breast nodule was histologically consistent with ER+/PR+/HER2-invasive ductal carcinoma with focal associated ductal carcinoma in situ (DCIS) of the left breast T1N0M0 stage 1 with negative margin from resection. All 4 sentinel lymph nodes were negative for metastatic disease. As per radiation oncology, she completed 6 cycles of adjuvant whole breast radiation for the left breast carcinoma. Right breast was biopsy confirmed benign cyst.\n\nAs with Case #1, ocrelizumab was discontinued following the diagnosis of malignancy as correlation has been found in earlier clinical trials of ocrelizumab after counseling on suspected increased risk of breast cancer with ocrelizumab.17,18 Her diagnosis of breast cancer and plan for neoadjuvant chemotherapy significantly reduced available treatment options, and all other disease modifying therapies for MS were discussed with her. It was decided to start Solu-Medrol 1 g IV monthly and restart Copaxone as disease modifying therapy. She is currently followed clinically every 6 months and radiologically (MRI) yearly. She is currently stable and remains on Copaxone with monthly Solu-Medrol infusions at this time.\n\nDiscussion\n\nIn this case series, we present 2 cases of breast cancer that are suspected to have developed following ocrelizumab therapy in patients with MS after its FDA approval for RRMS and PPMS since 2017.16 The use of DMT in MS patients has significantly changed the management of the disease and has shown promising results for reducing the morbidity associated with the disease. Monoclonal antibodies against CD20 cell surface marker such as rituximab, second generation ocrelizumab approved by FDA in 2017 for RRMS and PPMS, and third generation ofatumumab, which was recently approved by the FDA in 2020 for RRMS, have revolutionized the treatment of MS.16 However, the modulation of the innate immune mechanism and the suppression of the immune system caused by the use of DMT is postulated to contribute to an increased risk of malignancy in patients who are on long-term treatment with these drugs.4,5 Most of the studies report that there is no significant difference from the general population, but a few studies and clinical trials have documented a significant increased risk of developing varied malignancies with the usage of DMTs, such as melanoma, lymphoma, and breast carcinoma4,19-22 (refer Table 2).\n\nSeveral mechanisms of actions have been postulated for various DMTs, including activity on the CD20 receptors for the medications like rituximab, ocrelizumab, and ofatumumab. Rituximab is also being increasingly used for management against many carcinomas (ie, B-cell lymphomas, Hodgkin lymphoma, Burkitt lymphoma, and B-cell lymphoblastic leukemias) as malignant B cells vastly express CD20 receptors.23 However, despite the use of anti-CD20 therapies in some cancers, it may also increase the risk for other cancers in treated patients.5\n\nOcrelizumab is a relatively newer generation immunomodulator acting against the CD20 monoclonal antibody.16,17 Large trials conducted for ocrelizumab showed malignancies in a total of 4 cases with RRMS in OPERA 1 trial conducted over 2 years from 2011 to 2013 (breast cancer, renal cell carcinoma, and melanomas) and in 11 cases with PPMS seen in ORATORIO trial conducted in 2017.17,18 The is likely related to the predisposition of malignancies by the deactivation of the protective mechanisms of the normal B cells against tumor production and lysis of tumor. Recent studies have shown that B-cell suppression can lead to worsening of outcomes in breast cancer patients.4 There are no currently published cases documenting development of breast cancer after treatment with ocrelizumab for MS outside of large trials on literature review.\n\nThe protective role of CD20 B cells along with cytotoxic T cells plays an important role in prevention of development of malignancies, and their reduced presence in these patients could be detrimental in this population. Moreover, it has been found that timing of initiation of anti-CD20 therapy plays an important role in cancer development. It was shown in mice that starting anti-CD20 therapy prior to tumor initiation decreased the chance of metastatic involvement, whereas initiation after tumor increased the cancer growth and survival with metastasis.4 This should be taken into consideration with MS patients in the context of the stage of cancer when deciding treatment.\n\nIn a large cohort study, 11,817 patients enrolled in the Danish Multiple Sclerosis Registry showed an increased risk of breast cancer by 1.6-fold (relative risk [RR], 1.56). On the contrary, it showed 16% decreased risk of all cancers in men, whereas the study did not show an increase in overall risk of cancer in women except for breast cancer risk. It was also noted that tumor size tended to have larger sizes in MS patients when compared to patients without MS. Sixteen percent of women with MS in their studies had tumors ≥5 cm compared with 11% in the non-MS population.8\n\nIn the literature review summarized in Table 1, there are multiple studies, including retrospective, cohort, and registries that evaluate hundreds to thousands of MS patients that eventually developed malignancies during treatment and specifically the commonly diagnosed malignancies. For example, in the studies of Midgard and Etemadifar, there was a higher likelihood of breast cancer diagnosis within the MS patients. Other malignancies were found but were not deemed significant when compared to the general population, including urinary tract, skin cancers, nervous system, or hematological disease such as lymphoma. Hajiebrahimi focused on premenopausal and postmenopausal breast cancer among MS patients,24 which showed an overall increase in postmenopausal breast cancer. As seen with Moller cohort study, the diagnosis of uncommon malignancies may in part be due to over diligence in screening. In Kingswell cohort prospective study, there were 6820 patients, with 410 of them being diagnosed with malignancies, and demonstrated an overall lower cancer risk in this population. Nørgaard demonstrated an overall increase in melanoma compared to other malignancies within thousands of MS patients in the Danish population6-8,25-29 (refer Table 1).\n\nOverall, there has been an increase in incidence of malignancy seen in MS patients treated on with immunomodulant therapies that need further investigation9-12,19-22,30-34 (refer Table 2). Given that MS patients can be exposed to many medications over the course of the disease with different mechanisms of action, these can eventually alter the immune system, which indirectly increases their cancer potential. One study demonstrated the higher risk of cancer in MS patients due to prior exposure to DMTs, rather than the disease itself.35 It is clearly evident that these patients need extra caution when selecting therapies, and benefits vs. risks must be weighed on an individual basis. Further large-scale studies are required to formulate proper guidelines in screening and monitoring of the patients with MS on DMTs. Additionally, more studies can be helpful for the clinicians to better understand the available alternatives of DMTs after an association with malignancy has been found.\n\nConclusion\n\nAs immunosuppressive therapy for MS becomes more prevalent, long-term follow-up studies documenting the incidence and prognosis of breast cancer in this cohort are needed. Current data in the literature reflect the need for further study in ascertaining the risk of biologically poor prognosis breast cancer development in patients with MS treated with immunosuppressive therapy. There has been an increase in cancers seen in MS patients treated with immunosuppressive therapies, that needs further investigation. Most of the studies report that there is no significant difference from the general population, but a few studies have demonstrated a significant increased risk of developing breast cancer.\n\nAcknowledgments\n\nWest Virginia Clinical and Translational Science Institute, Morgantown, SS supported in part by WVCTSI via US National Institute of General Medical Sciences of National Institute of Health under award under 5U54GM104942-05.\n\nORCID iD\n\nShitiz Sriwastava https://orcid.org/0000-0001-6844-3287\n\nAuthor Contributions: Conceptualization: SS.Drafting the manuscript: AK, GC, MT, and SS. Final edits: SS.\n\nDeclaration of conflicting interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The authors received no financial support for the research, authorship, and/or publication of this article.\n\nETHICS STATEMENT: The authors obtained approval by the WVU institutional review board (approval #2011176554) and the article complies with the WVY institutional review board guidelines. Both patients provided informed consent.\n==== Refs\nReferences\n\n1 Weinshenker BG . Epidemiology of multiple sclerosis. Neurol Clin. 1996;14 (2 ):291-308. doi:10.1016/s0733-8619(05)70257-7.8827172\n2 Smith AL Cohen JA Hua LH . Therapeutic targets for multiple sclerosis: current treatment goals and future directions. Neurotherapeutics. 2017;14 (4 ):952-960. doi:10.1007/s13311-017-0548-5.28653282\n3 Bahmanyar S Montgomery SM Hillert J Ekbom A Olsson T . Cancer risk among patients with multiple sclerosis and their parents. Neurology. 2009;72 (13 ):1170-1177. doi:10.1212/01.wnl.0000345366.10455.62.19332695\n4 Melamed E Lee MW . Multiple sclerosis and cancer: The Ying-Yang effect of disease modifying therapies. Front Immunol. 2020;10 :2954. doi:10.3389/fimmu.2019.02954.31998289\n5 Ragonese P Aridon P Vazzoler G Mazzola MA Lo Re V Lo Re M , et al . Association between multiple sclerosis, cancer risk, and immunosuppressant treatment: a cohort study. BMC Neurol. 2017;17 (1 ):155. doi:10.1186/s12883-017-0932-0.28789625\n6 Midgard R Glattre E Grønning M Riise T Edland A Nyland H . Multiple sclerosis and cancer in Norway. A retrospective cohort study. Acta Neurol Scand. 1996;93 (6 ):411-415. doi:10.1111/j.1600-0404.1996.tb00019.x.8836302\n7 Møller H Kneller RW Boice JD Jr Olsen JH . Cancer incidence following hospitalization for multiple sclerosis in Denmark. Acta Neurol Scand. 1991;84 (3 ):214-220. doi:10.1111/j.1600-0404.1991.tb04941.x.1950464\n8 Nielsen NM Rostgaard K Rasmussen S Koch-Henriksen N Storm HH Melbye M , et al . Cancer risk among patients with multiple sclerosis: a population-based register study. Int J Canc. 2006;118 (4 ):979-984. doi:10.1002/ijc.21437.\n9 Killestein J Leurs CE Hoogervorst ELJ van Eijk J Mostert JP van den Eertwegh AJM , et al . Five cases of malignant melanoma during fingolimod treatment in Dutch patients with MS. Neurology. 2017;89 (9 ):970-972. doi:10.1212/WNL.0000000000004293.28768850\n10 Schweikert A Kremer M Ringel F Liebig T Duyster J Stüve O , et al . Primary central nervous system lymphoma in a patient treated with natalizumab. Ann Neurol. 2009;66 (3 ):403-406. doi:10.1002/ana.21782.19798640\n11 Pace A Zajicek JP . Melanoma following treatment with alemtuzumab for multiple sclerosis. Eur J Neurol. 2009;16 (4 ):e70-e71. doi:10.1111/j.1468-1331.2009.02552.x.19222552\n12 Bergamaschi R Montomoli C . Melanoma in multiple sclerosis treated with natalizumab: causal association or coincidence?. Mult Scler. 2009;15 (12 ):1532-1533. doi:10.1177/1352458509347154.20019096\n13 Polman CH O'Connor PW Havrdova E Hutchinson M Kappos L Miller DH , et al . A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354 (9 ):899-910. doi:10.1056/NEJMoa044397.16510744\n14 Castela E Lebrun-Frenay C Laffon M Rocher F Cohen M Leccia NC , et al . Evolution of nevi during treatment with natalizumab: A prospective follow-up of patients treated with natalizumab for multiple sclerosis. Arch Dermatol. 2011;147 (1 ):72-76. doi:10.1001/archdermatol.2010.243.20855675\n15 Sartori DC Westerberg C Grundmark B . Natalizumab and rapidly evolving central nervous system lymphoma in VigiBase. InDrug Safety. 2017;40 (10 ):974.\n16 Florou D Katsara M Feehan J Dardiotis E Apostolopoulos V . Anti-CD20 Agents for Multiple Sclerosis: Spotlight on Ocrelizumab and Ofatumumab. Brain Sci. 2020;10 (10 ):758. doi:10.3390/brainsci10100758.\n17 Hauser SL Bar-Or A Comi G Giovannoni G Hartung HP Hemmer B , et al . OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2017;376 (3 ):221-234. doi:10.1056/NEJMoa1601277.28002679\n18 Gelfand JM Cree BAC Hauser SL . Ocrelizumab and Other CD20+ B-Cell-Depleting Therapies in Multiple Sclerosis. Neurotherapeutics. 2017;14 (4 ):835-841. doi:10.1007/s13311-017-0557-4.28695471\n19 Madray MM Greene JF Jr Butler DF . Glatiramer acetate-associated, CD30+, primary, cutaneous, anaplastic large-cell lymphoma. Arch Neurol. 2008;65 (10 ):1378-1379. . doi:10.1001/archneur.65.10.1378.18852356\n20 Landais A Alhendi R Gouverneur A Teron-Aboud B . A case of lymphoma in a patient on teriflunomide treatment for relapsing multiple sclerosis. Mult Scler Relat Disord. 2017;17 :92-94. doi:10.1016/j.msard.2017.07.001.29055483\n21 Mahajan KR Ko JS Tetzlaff MT Hudgens CW Billings SD Cohen JA . Merkel cell carcinoma with fingolimod treatment for multiple sclerosis: A case report. Mult Scler Relat Disord. 2017;17 :12-14. doi:10.1016/j.msard.2017.06.004.29055440\n22 Conzett K Kolm I Jelcic I Kamarachev J Dummer R Braun R , et al . Melanoma occurring during treatment with fingolimod for multiple sclerosis: a case report. Arch Dermatol. 2011;147 (8 ):991-992. doi:10.1001/archdermatol.2011.212.21844470\n23 Salles GA-O Barrett M Foà R Maurer J O’Brien S Valente N , et al . Rituximab in B-Cell hematologic malignancies: A review of 20 years of clinical experience. Adv Ther. 2017;34 (10 ):2232-2273. doi:10.1007/s12325-017-0612-x.28983798\n24 Hajiebrahimi MA-O Montgomery S Burkill S Bahmanyar S . Risk of Premenopausal and Postmenopausal Breast Cancer among Multiple Sclerosis Patients. PloS One. 2016;11 (10 ):e0165027. doi:10.1371/journal.pone.0165027.27776164\n25 Etemadifar M Jahanbani-Ardakani H Ghaffari S Fereidan-Esfahani M Changaei H Aghadoost N , et al . Cancer risk among patients with multiple sclerosis: A cohort study in Isfahan, Iran. Caspian J Intern Med. 2017;8 (3 ):172-177. doi:10.22088/cjim.8.3.172.28932368\n26 Sumelahti ML Pukkala E Hakama M . Cancer incidence in multiple sclerosis: a 35-year follow-up. Neuroepidemiology. 2004;23 (5 ):224-227. doi:10.1159/000079947.15316248\n27 Kingwell E Bajdik C Phillips N Zhu F Oger J Hashimoto S , et al . Cancer risk in multiple sclerosis: findings from British Columbia, Canada. Brain. 2012;135 (Pt 10 ):2973-2979. doi:10.1093/brain/aws148.22730559\n28 Nørgaard M Veres K Didden EM Wormser D Magyari M . Multiple sclerosis and cancer incidence: A Danish nationwide cohort study. Mult Scler Relat Disord. 2019;28 :81-85. doi:10.1016/j.msard.2018.12.014.30576846\n29 Achiron A Gail M Mandel M Pee D Ayyagari R Rotstein Z . Cancer incidence in multiple sclerosis and effects of immunomodulatory treatments. Breast Canc Res Treat. 2005;89 (3 ):265-270. doi:10.1007/s10549-004-2229-4.\n30 Walker J Smylie A Smylie M . An Association Between Glatiramer Acetate and Malignant Melanoma. J Immunother. 2016;39 (7 ):276-278. doi:10.1097/CJI.0000000000000131.27404942\n31 Papathemeli D Hildebrandt U Zettl UK Ulrich J . Development of a primary cutaneous CD30(+) anaplastic large-cell T-cell lymphoma during treatment of multiple sclerosis with fingolimod. Mult Scler. 2016;22 (14 ):1888-1890. doi:10.1177/1352458516645868.27207455\n32 Cohan S Godwin J Gaedeke L . Acute lymphoblastic leukemia in a man treated with fingolimod for relapsing multiple sclerosis. J Investig Med High Impact Case Rep. 2015;3 (1 ):2324709615575551. doi:10.1177/2324709615575551.\n33 Walker S Brew B . Kaposi sarcoma in a fingolimod-treated patient with multiple sclerosis. J Clin Neurosci. 2016;31 :217-218. doi:10.1016/j.jocn.2016.03.001.27168454\n34 Phan-Ba R Fau - Bisig B Deprez M De Prijck B Delrue G Herens C Moonen G , et al . Primary central nervous system lymphoma in a patient treated with natalizumab. Ann Neurol. 2011;69 (6 ):1060-1061. doi:10.1002/ana.22296.21328606\n35 D'Amico E Chisari CG Arena S Zanghì A Toscano S Lo Fermo S , et al . Cancer risk and multiple sclerosis: Evidence from a large italian cohort. Front Neurol. 2019;10 :337. doi:10.3389/fneur.2019.00337.31024431\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-5735",
"issue": "13()",
"journal": "Journal of central nervous system disease",
"keywords": "disease-modifying therapies; in situ breast carcinoma; malignancy in MS; multiple sclerosis; ocrelizumab",
"medline_ta": "J Cent Nerv Syst Dis",
"mesh_terms": null,
"nlm_unique_id": "101595026",
"other_id": null,
"pages": "11795735211037785",
"pmc": null,
"pmid": "34497472",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "28983798;29055440;31998289;1950464;31024431;29055483;16510744;21328606;16152598;30576846;27207455;8836302;19332695;27168454;28653282;27776164;28768850;15754125;19222552;19798640;20855675;21844470;15316248;33092190;8827172;22730559;26425635;18852356;27404942;28789625;28695471;28932368;20019096;28002679",
"title": "Breast Carcinoma After Ocrelizumab Therapy in Multiple Sclerosis Patients: A Case Series and Literature Review.",
"title_normalized": "breast carcinoma after ocrelizumab therapy in multiple sclerosis patients a case series and literature review"
} | [
{
"companynumb": "US-ROCHE-2912215",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ANASTROZOLE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Pediatric patients with pulmonary alveolar proteinosis require whole lung lavage to clear the accumulation of lipoproteinaceous material within the alveoli, to maintain respiratory function. Anesthesia for this presents a challenge due to preexisting respiratory failure, and the small diameter and length of the pediatric airway, which is often unable to accommodate existing one-lung isolation and ventilation equipment. Novel techniques to facilitate lung lavage on seven occasions are described and placed in the context of the existing literature to date.",
"affiliations": "Department of Paediatric Anaesthesia, Great Ormond Street Hospital, London, UK.",
"authors": "Wilson|Caroline A|CA|;Wilmshurst|Sally L|SL|;Black|Ann E|AE|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1111/pan.12626",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1155-5645",
"issue": "25(6)",
"journal": "Paediatric anaesthesia",
"keywords": "anesthesia; children; lung lavage; pediatrics; pulmonary alveolar proteinosis; pulmonary ventilation",
"medline_ta": "Paediatr Anaesth",
"mesh_terms": "D058109:Airway Management; D000758:Anesthesia; D018893:Bronchoalveolar Lavage; D002648:Child; D006801:Humans; D011649:Pulmonary Alveolar Proteinosis; D012131:Respiratory Insufficiency",
"nlm_unique_id": "9206575",
"other_id": null,
"pages": "546-53",
"pmc": null,
"pmid": "25664978",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Anesthetic techniques to facilitate lung lavage for pulmonary alveolar proteinosis in children-new airway techniques and a review of the literature.",
"title_normalized": "anesthetic techniques to facilitate lung lavage for pulmonary alveolar proteinosis in children new airway techniques and a review of the literature"
} | [
{
"companynumb": "GB-BAXTER-2015BAX030117",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXYGEN"
},
"drugadditional": null,
"... |
{
"abstract": "The regimen of oxaliplatin with 5-fluorouracil plus l-leucovorin (FOLFOX) has become one of the most commonly used first-line chemotherapy for patients with advanced colorectal cancer and it provides an increase in disease-free survival as well as an overall survival benefit. Although FOLFOX chemotherapy has helped to improve the clinical outcomes in these patients, the regimen is associated with some therapeutic issues or uncontrolled side effects. Gastrointestinal, neurosensory, and hematological toxicities have frequently been observed in patients treated with FOLFOX, and consequently, some palliative treatment has been established to combat such complications. However, pulmonary toxicities including drug-induced interstitial pneumonia (DI-IP) is rarely observed in these patients and a curative treatment is yet to be established. DI-IP due to chemotherapy is most commonly observed in patients treated with mitomycin, paclitaxel, docetaxel, or gemcitabine. Steroid therapy is mostly used to treat DI-IP, although the efficacy of such treatments is not supported with adequate evidence. FOLFOX-induced interstitial pneumonia (FIIP) is rarely observed, and several case reports of FIIP treated with steroids have been published previously that showed the mortality is extremely high. Here, we present a 74-year-old woman who received modified FOLFOX6 as adjuvant chemotherapy after rectal cancer surgery. The patient experienced FIIP, which improved after application of steroid pulse (high-dose methylprednisolone at 1,000 mg/day for 3 days) and tapering (starting with prednisolone at 40 mg/day) therapy. Our data suggest that such a steroid therapy could represent an effective treatment option for FIIP.",
"affiliations": "Department of Surgery, Yoshida General Hospital, Akitakata City, Japan.;Department of Surgery, Yoshida General Hospital, Akitakata City, Japan.;Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Surgery, Yoshida General Hospital, Akitakata City, Japan.;Department of Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Surgery, Yoshida General Hospital, Akitakata City, Japan.",
"authors": "Yanagawa|Senichiro|S|;Karakuchi|Nozomi|N|;Mochizuki|Tetsuya|T|;Kodama|Shinya|S|;Takeshima|Yukio|Y|;Sumimoto|Kazuo|K|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000507985",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000507985\ncro-0013-0768\nCase Report\nDrug-Induced Interstitial Pneumonia due to Application of FOLFOX as Adjuvant Chemotherapy after Rectal Cancer Surgery: A Case Report and Literature Review\nYanagawa Senichiro a* Karakuchi Nozomi a Mochizuki Tetsuya c Kodama Shinya a Takeshima Yukio b Sumimoto Kazuo ac aDepartment of Surgery, Yoshida General Hospital, Akitakata City, Japan\nbDepartment of Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan\ncDepartment of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan\n*Senichiro Yanagawa, Department of Surgery, Yoshida General Hospital, 3666 Yoshida, Yoshida-Chou, Akitakata City, Hiroshima 731-0595 (Japan), qqry3v7d@silk.ocn.ne.jp\nMay-Aug 2020 \n2 7 2020 \n2 7 2020 \n13 2 768 773\n17 4 2020 17 4 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.The regimen of oxaliplatin with 5-fluorouracil plus l-leucovorin (FOLFOX) has become one of the most commonly used first-line chemotherapy for patients with advanced colorectal cancer and it provides an increase in disease-free survival as well as an overall survival benefit. Although FOLFOX chemotherapy has helped to improve the clinical outcomes in these patients, the regimen is associated with some therapeutic issues or uncontrolled side effects. Gastrointestinal, neurosensory, and hematological toxicities have frequently been observed in patients treated with FOLFOX, and consequently, some palliative treatment has been established to combat such complications. However, pulmonary toxicities including drug-induced interstitial pneumonia (DI-IP) is rarely observed in these patients and a curative treatment is yet to be established. DI-IP due to chemotherapy is most commonly observed in patients treated with mitomycin, paclitaxel, docetaxel, or gemcitabine. Steroid therapy is mostly used to treat DI-IP, although the efficacy of such treatments is not supported with adequate evidence. FOLFOX-induced interstitial pneumonia (FIIP) is rarely observed, and several case reports of FIIP treated with steroids have been published previously that showed the mortality is extremely high. Here, we present a 74-year-old woman who received modified FOLFOX6 as adjuvant chemotherapy after rectal cancer surgery. The patient experienced FIIP, which improved after application of steroid pulse (high-dose methylprednisolone at 1,000 mg/day for 3 days) and tapering (starting with prednisolone at 40 mg/day) therapy. Our data suggest that such a steroid therapy could represent an effective treatment option for FIIP.\n\nKeywords\nFOLFOXDrug-induced pneumoniaRectal cancerSteroid therapy\n==== Body\nIntroduction\nIn recent decades, the chemotherapy treatment for colorectal cancer (CRC) has undergone substantial development, including the application of effective new drugs [1, 2]. Oxaliplatin with 5-fluorouracil plus l-leucovorin (FOLFOX) is used as adjuvant chemotherapy in patients with pathological stage III colon cancer (CC), and FOLFOX is also a promising chemotherapeutic regimen in treating advanced or metastatic and unresectable CRC [1, 2, 3, 4]. In addition, the FOLFOX regimen has also been used for the treatment of advanced gastric cancer cases [5], and its indications have been expanding.\n\nWhile the FOLFOX regimen is associated with adverse effects (gastrointestinal, neurosensory, and hematological toxicities), drug-induced interstitial pneumonia (DI-IP) is rarely observed in patients treated with the FOLFOX regimen. There are no established guidelines or curative treatment of DI-IP; as such, the onset of FOLFOX-induced interstitial pneumonia (FIIP) could lead to acute respiratory failure and death. Oxaliplatin has been identified as the potential causative agent of DI-IP in patients treated with FOLFOX or FOLFIRI regimens [6]. However, its mortality rate is high and its mechanism remains elusive.\n\nHere, we present a case where a combination of steroid pulse and tapering therapy was effective in treating DI-IP related to modified FOLFOX6 (mFOLFOX6).\n\nCase Report\nA 74-year-old woman had a history of hypertension and chronic obstructive pulmonary disease. Her arterial blood gas analysis showed that the partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2) were 65.7 and 35.8 mm Hg on room air, respectively, which did not impact her daily life activities. She underwent Hartmann's procedure and lymph node resection for the treatment of rectal cancer in our hospital. The final pathological diagnosis was classified as pT3N2bM0 pStage IIIC in accordance with the Union for International Cancer Control (UICC) tumor node metastasis (TNM) classification.\n\nTwo months after surgery, she received mFOLFOX6 as adjuvant chemotherapy. The mFOLFOX6 therapy consisted of l-leucovorin (200 mg/m2) infusion over 2 h and oxaliplatin (85 mg/m2) on day 1, followed by bolus injection of 5-fluorouracil (5-FU) (400 mg/m2) and 46 h infusion of 5-FU (2,400 mg/m2). This regimen was repeated every 2 weeks, and 12 cycles of the treatment were administered.\n\nThe day after the completion of adjuvant chemotherapy she was hospitalized due to cough (day 0). Three days later, this condition deteriorated and fine crackles were heard in both lungs (day 3). The peripheral oxygen saturation (SpO2) level measured by a pulse oximeter was 77% and her arterial blood gas analysis showed that the PaO2 and PaCO2 were 42.9 and 34 mm Hg on room air, respectively. In both lungs, chest X-ray demonstrated diffuse ground-glass opacities (Fig. 1a) and chest computed tomography (CT) scan showed severe disorder of lung architecture including honeycombing (Fig. 1b). Laboratory data showed that the white blood cell count was 4.4 × 103/μL, C-reactive protein level was 3.01 mg/dL (normal value <0.1 mg/dL), lactate dehydrogenase (LDH) level was 739 U/L (normal range 120–220 U/L), Krebs von den Lungen-6 (KL-6) concentration was 654 U/mL (normal value <500 U/mL), procalcitonin concentration was <0.5 ng/mL (normal value <0.5 ng/dL), and β-D glucan concentration was 11.1 pg/mL (normal range 0–20 pg/mL). All cultures and stains for infectious etiologies, including common bacteria, fungi, pneumocystis, and legionella, were negative. Although transbronchial lung biopsy (TBLB) and bronchoalveolar lavage (BAL) were not performed, we diagnosed the patient's condition as FIIP based on these examination results and clinical course.\n\nIn addition to supplemental oxygen (2 L/min), steroid therapy was started with a combination of broad-spectrum antibiotics (meropenem) and sivelestat sodium (4.8 mg/kg). Intravenous administration of steroid pulse (high-dose methylprednisolone at 1,000 mg/day for 3 days) was performed, followed by the administration of prednisolone (40 mg/day) for 1 month, and then gradually decreased as the respiratory condition improved. The duration of steroid therapy was three and a half months. Subsequently, supplemental oxygen (0.5–1 L/min) and respiratory rehabilitation were continued for 4 months. In contrast, broad-spectrum antibiotics and sivelestat sodium were used for only 2 weeks.\n\nSix months after the completion of the steroid therapy, her arterial blood gas analysis showed that the SpO2 was 92%, while PaO2 and PaCO2 were 62.3 and 34.8 mm Hg on room air, respectively, and she did not require supplemental oxygen. Her respiratory condition was almost as stable as before the rectal cancer surgery, and chest X-ray and CT scans showed significant improvements (Fig. 2a, b).\n\nMoreover, there has been no recurrence of cancer for 20 months after the rectal cancer surgery.\n\nDiscussion/Conclusion\nChemotherapy for CRC has recently undergone substantial development, including the application of effective new drugs [1, 2]. The FOLFOX regimen has been effective as adjuvant chemotherapy in patients with stage III CC and became one of the most commonly used first-line chemotherapies for patients with unresectable or metastatic CRC [1, 2, 3, 4].\n\nThe widely known FOLFOX-induced side effects are neurological, hematopoietic, and gastrointestinal toxicities. Pulmonary toxicities, including DI-IP, have been noted in less than 1% of CRC treated with the FOLFOX regimen during clinical trials. It is often difficult to differentiate DI-IP from other lung diseases and thus, DI-IP diagnosis remains a challenge. While TBLB or BAL may be helpful in DI-IP diagnosis, the accuracy rate of these diagnostic procedures is not high and they could only rule out other causes [7]. Steroid therapy is generally used for DI-IP; however, no prospective studies have examined the outcomes of such a therapy in these patients [7].\n\nAlthough several case reports on FIIP have been published [8, 9, 10, 11, 12, 13, 14], currently, there is no established guideline for the management of FIIP. Most of the published reports on FIIP primarily focused on the application of steroid treatment. One specific report showed some improvements in FIIP with steroid pulse therapy alone [8], but other reports showed no improvements with intensive care and steroid pulse therapy [9, 10, 11, 12].\n\nWhile the pathogenesis of FIIP is unknown, oxaliplatin is considered to be the causative drug linked to FIIP in these reports [8, 9, 10, 11, 12, 13, 14]. The mechanism of oxaliplatin-induced pneumonia is not yet determined; however, data suggest that oxaliplatin could cause glutathione depletion, which could be involved in the pathogenesis of liver injury leading to hepatic sinusoidal obstruction associated with endothelial injury and perivenular fibrosis [15]. Since glutathione acts as a protector against oxidative damage in the lungs, depletion of the same caused by oxaliplatin could trigger pulmonary lesions leading to interstitial pulmonary disorder or subsequent pulmonary fibrosis. Currently, it remains elusive if treatment with antioxidant agents (such as N-acetylcysteine) that replenish glutathione deposits could be beneficial in treating FIIP. However, since glutathione protects against oxidative damages, its supplementation could have a positive impact on FIIP patients. This hypothesis is supported by studies that showed N-acetylcysteine, with or without steroid pulse therapy, administration improved FIIP [13, 14].\n\nIn our case, after the clinical diagnosis of FIIP, steroid pulse therapy (intravenous administration of high-dose methylprednisolone at 1,000 mg/day) followed by steroid tapering therapy (starting with prednisolone at 40 mg/day) gradually improved the respiratory status in the patient. The steroid therapy brought the serum level of KL-6 and LDH within the normal range and this effect sustained even after the completion of the therapy (Fig. 3). Bacterial pneumonia that developed twice after the completion of steroid treatment improved rapidly with ampicillin administration.\n\nCollectively, these data suggest that a combination of steroid pulse and tapering therapy could be an effective treatment option for FIIP, and if such a therapy is insufficient, application of antioxidants could become another treatment option.\n\nStatement of Ethics\nWritten informed consent was obtained from the patient and her family.\n\nConflict of Interest Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nThe authors received no financial support for the research, authorship, or publication of this article.\n\nAuthor Contributions\nS.Y. made a substantial contribution toward the concept and design of the study and in data acquisition and interpretation. N.K., T.M., S.K., Y.T., and K.S. were involved in drafting the manuscript and critical revision of the intellectual content. S.Y. approved the final version of the manuscript submitted for publication. All authors read and approved the manuscript.\n\nAcknowledgement\nThe authors would like to thank the patient for providing consent to publish clinical information and data. We would like to thank Editage (www.editage.com) for English language editing.\n\nFig. 1 Chest X-ray (a) and CT scan (b) of the patient at the onset of FIIP. a Reticular shadows with ground-glass opacities could be observed mainly in the middle and lower zones of both lungs. b Diffuse ground-glass infiltration with honeycomb-like shadow could be observed in both lungs.\n\nFig. 2 Chest X-ray (a) and CT scan (b) of the patient 6 months after the completion of the steroid therapy. a In both lungs, reticular shadows with ground-glass opacities improved. b Although the old inflammation remained in the right lung, the honeycomb-like shadow had almost disappeared in both lungs.\n\nFig. 3 Changes in the serum level of LDH and KL-6 between post-hospitalization day 3 and day 252 and the clinical course of steroid therapy.\n==== Refs\nReferences\n1 Ciombor KK Wu C Goldberg RM Recent therapeutic advances in the treatment of colorectal cancer Annu Rev Med 2015 66 83 95 25341011 \n2 Das S Ciombor KK Haraldsdottir S Goldberg RM Promising new agents for colorectal cancer Curr Treat Options Oncol 2018 May 11 19 (6) 29 29752549 \n3 Reynolds J Chamberland-Tremblay A Herrington JD Munoz Maldonado Y Wong L High- versus low-dose leucovorin in the modified FOLFOX6 regimen for first-line treatment of metastatic colorectal cancer J Oncol Pharm Pract 2017 4 23 (3) 173 8 26786027 \n4 Gustavsson B Carlsson G Machover D Petrelli N Roth A Schmoll HJ A review of the evolution of systemic chemotherapy in the management of colorectal cancer Clin Colorectal Cancer 2015 3 14 (1) 1 10 25579803 \n5 Masuishi T Kadowaki S Kondo M Komori A Sugiyama K Mitani S FOLFOX as first-line therapy for gastric cancer with severe peritoneal metastasis Anticancer Res 2017 12 37 (12) 7037 42 29187492 \n6 Shimura T Fuse N Yoshino T Minashi K Tahara M Doi T Clinical features of interstitial lung disease induced by standard chemotherapy (FOLFOX or FOLFIRI) for colorectal cancer. Ann Oncol 2010 10 21 (10) 2005 10 20305036 \n7 Skeoch S Weatherley N Swift AJ Oldroyd A Johns C Hayton C Drug-induced interstitial lung disease: a systematic review J Clin Med 2018 Oct 15 7 (10) 356 \n8 Soon WC West K Gibeon D Bowen EF Pulmonary fibrosis secondary to FOLFOX chemotherapy: a case report Case Rep Oncol 2014 Sep 24 7 (3) 662 8 25408660 \n9 Ishizone S Koide N Akita N Karasawa F Kobayashi N Koizumi T Fatal interstitial pneumonia associated with oxaliplatin-based therapy in a patient with metastatic rectal cancer Clin J Gastroenterol 2011 6 4 (3) 157 61 26189347 \n10 Vargas A Montironi C Buxó E Organizing pneumonia with fatal outcome after adjuvant chemotherapy with FOLFOX Arch Bronconeumol 2015 11 51 (11) 610 26163115 \n11 Moskovitz M Wollner M Haim N Oxaliplatin-induced pulmonary toxicity in gastrointestinal malignancies: two case reports and review of the literature Case Rep Oncol Med 2015 2015 341064 26064729 \n12 Sánchez Cendra C Juez Martel I Gutierrez Abad D Interstitial lung disease caused by oxaliplatin. An uncommon but not unknown complication Arch Bronconeumol 2017 4 53 (4) 213 5 27756654 \n13 Wilcox BE Ryu JH Kalra S Wang S Guo J Exacerbation of pre-existing interstitial lung disease after oxaliplatin therapy: a report of three cases Respir Med 2008 2 102 (2) 273 9 17945475 \n14 De Weerdt A Dendooven A Snoeckx A Pen J Lammens M Jorens PG Prognosis and treatment of FOLFOX therapy related interstitial pneumonia: a plea for multimodal immune modulating therapy in the respiratory insufficient patient BMC Cancer 2017 Aug 29 17 (1) 586 28851379 \n15 Rubbia-Brandt L Audard V sartoretti P Roth AD Brezault C Le Charpentier M Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 2004 3 15 (3) 460 6 14998849\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "13(2)",
"journal": "Case reports in oncology",
"keywords": "Drug-induced pneumonia; FOLFOX; Rectal cancer; Steroid therapy",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "768-773",
"pmc": null,
"pmid": "32774274",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "26064729;26163115;25579803;25341011;27756654;26786027;20305036;26189347;29752549;30326612;14998849;28851379;25408660;17945475;29187492",
"title": "Drug-Induced Interstitial Pneumonia due to Application of FOLFOX as Adjuvant Chemotherapy after Rectal Cancer Surgery: A Case Report and Literature Review.",
"title_normalized": "drug induced interstitial pneumonia due to application of folfox as adjuvant chemotherapy after rectal cancer surgery a case report and literature review"
} | [
{
"companynumb": "JP-PFIZER INC-2020332849",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MEROPENEM"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSome reports have suggested an association between dopamine agonists and hiccups, involuntary contractions that merit full clinical attention because they can be very debilitating. Many drugs frequently used to treat hiccups are formally contraindicated in Parkinson's disease due to their liability to worsen motor symptoms, making the treatment of hiccups problematic in this disease. The objective of the present study was to analyze all spontaneous reports of hiccups from the European Pharmacovigilance Database in patients with Parkinson's disease and/or on dopaminergic drugs. Finally, we sought to identify evidence-based recommendations on the management of hiccups in Parkinson's disease.\n\n\nMETHODS\nWe searched for all reports of hiccups in the European Pharmacovigilance Database (EudraVigilance) and calculated proportional reporting ratios for dopamine agonists and hiccups. We reviewed the literature on Parkinson's disease, dopamine agonists, and hiccups, searching for specific treatment recommendations for hiccups in this disease.\n\n\nRESULTS\nBoth rotigotine and pramipexole fulfilled the criteria to generate a safety signal. We found 32 and 13 cases of hiccups associated with dopamine agonists in EudraVigilance and the literature, respectively. There were no specific recommendations for the management of hiccups in Parkinson's disease in the clinical guidelines consulted.\n\n\nCONCLUSIONS\nWe have found evidence that rotigotine and pramipexole are associated with the appearance of hiccups and that this adverse reaction occurs predominantly in males. Given the scarce information available, specific recommendations are needed in clinical guidelines for the adequate management of hiccups in Parkinson's disease.",
"affiliations": "Pharmacy Service, Araba Mental Health Network, C/Alava 43, 01006, Vitoria-Gasteiz, Alava, Spain. Unax.lertxundietxebarria@osakidetza.net.;Pharmacokinetic, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Lascaray Research Center, University of the Basque Country UPV/EHU, Paseo de la Universidad, 7, 01006, Vitoria-Gasteiz, Spain.;Pharmacy Service, Alto Deba Integrated Health Organization, Avda. Nafarroa 16, 20500, Arrasate Gipuzkoa, Spain.;Pharmacokinetic, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Lascaray Research Center, University of the Basque Country UPV/EHU, Paseo de la Universidad, 7, 01006, Vitoria-Gasteiz, Spain.;Pharmacokinetic, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Lascaray Research Center, University of the Basque Country UPV/EHU, Paseo de la Universidad, 7, 01006, Vitoria-Gasteiz, Spain.;Pharmacokinetic, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Lascaray Research Center, University of the Basque Country UPV/EHU, Paseo de la Universidad, 7, 01006, Vitoria-Gasteiz, Spain.;Basque Pharmacovigilance Unit, Hospital de Galdakao-Usansolo, Galdakao, Spain.;Basque Pharmacovigilance Unit, Hospital de Galdakao-Usansolo, Galdakao, Spain.;Pharmacokinetic, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, Lascaray Research Center, University of the Basque Country UPV/EHU, Paseo de la Universidad, 7, 01006, Vitoria-Gasteiz, Spain.",
"authors": "Lertxundi|U|U|;Marquínez|A C|AC|;Domingo-Echaburu|S|S|;Solinís|M Á|MÁ|;Calvo|B|B|;Del Pozo-Rodríguez|A|A|;García|M|M|;Aguirre|C|C|;Isla|A|A|",
"chemical_list": "D052160:Benzothiazoles; D018491:Dopamine Agonists; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; D000077487:Pramipexole; C047508:rotigotine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00228-017-2275-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-6970",
"issue": "73(9)",
"journal": "European journal of clinical pharmacology",
"keywords": "Adverse drug reaction; Dopamine agonist; Hiccups; Parkinson’s disease (PD); Pharmacovigilance",
"medline_ta": "Eur J Clin Pharmacol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D052160:Benzothiazoles; D018491:Dopamine Agonists; D005260:Female; D006606:Hiccup; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease; D060735:Pharmacovigilance; D000077487:Pramipexole; D013764:Tetrahydronaphthalenes; D013876:Thiophenes",
"nlm_unique_id": "1256165",
"other_id": null,
"pages": "1159-1164",
"pmc": null,
"pmid": "28600702",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "12242206;25970275;19735905;20728400;26596880;20310014;25904081;19185020;28065403;16534128;11828828;26307025;17534966;10216420;18281732;18329942;20056471",
"title": "Hiccups in Parkinson's disease: an analysis of cases reported in the European pharmacovigilance database and a review of the literature.",
"title_normalized": "hiccups in parkinson s disease an analysis of cases reported in the european pharmacovigilance database and a review of the literature"
} | [
{
"companynumb": "ES-AMGEN-USASP2017125352",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
"drugadditional": "3",
... |
{
"abstract": "Tremor is an underrecognized feature in certain neuropathy subtypes.\n\n\n\nWe show a patient with a disabling neuropathic tremor and mild cerebellar syndrome associated with chronic inflammatory demyelinating polyneuropathy (CIDP) and anti-neurofascin-155 (NF155) antibodies.\n\n\n\nAnti-NF155 testing should be considered in patients with CIDP and disabling tremor because of therapeutic implications.",
"affiliations": "Department of Neurology, AP-HP, Pitié-Salpêtrière Hospital, Paris, FR.;Department of Neurology, AP-HP, Pitié-Salpêtrière Hospital, Paris, FR.;Department of Neurology, AP-HP, Pitié-Salpêtrière Hospital, Paris, FR.;Faculty of Medicine of Sorbonne University, UMRS 1127 and Inserm U 1127, CNRS UMR 7225, ICM, F-75013, Paris, FR.;Department of Hemo-biotherapies, AP-HP, Pitié Salpêtrière Hospital, University of Paris VI, Paris, FR.;Department of Neurology, AP-HP, Pitié-Salpêtrière Hospital, Paris, FR.;Department of Neurology, AP-HP, Pitié-Salpêtrière Hospital, Paris, FR.",
"authors": "Bailly|Laurent|L|;Mongin|Marie|M|;Delorme|Cecile|C|;Apartis|Emmanuelle|E|;Saheb|Samir|S|;Viala|Karine|K|;Roze|Emmanuel|E|",
"chemical_list": "D001323:Autoantibodies; D015815:Cell Adhesion Molecules; C054305:NFASC protein, human; D009414:Nerve Growth Factors",
"country": "England",
"delete": false,
"doi": "10.7916/D81560ZW",
"fulltext": "\n==== Front\nTremor Other Hyperkinet Mov (N Y)Tremor Other Hyperkinet Mov (N Y)TOHMTremor and Other Hyperkinetic Movements2160-8288Columbia University Libraries/Information Services 10.7916/D81560ZWVideo AbstractsTremor Associated with Chronic Inflammatory Demyelinating Polyneuropathy and Anti‐Neurofascin‐155 Antibodies Tremor, CIDP, and Anti‐NF155 AntibodiesBailly Laurent 1Mongin Marie 12Delorme Cecile 12Apartis Emmanuelle 23Saheb Samir 4Viala Karine 15Roze Emmanuel 12*1 Department of Neurology, AP‐HP, Pitié‐Salpêtrière Hospital, Paris, FR2 Faculty of Medicine of Sorbonne University, UMRS 1127 and Inserm U 1127, CNRS UMR 7225, ICM, F‐75013, Paris, FR3 Department of Neurophysiology, AP‐HP, Saint‐Antoine Hospital, Paris, FR4 Department of Hemo‐biotherapies, AP‐HP, Pitié Salpêtrière Hospital, University of Paris VI, Paris, FR5 Department of Neurophysiology, AP‐HP, Pitié‐Salpêtrière Hospital, Paris, FRLouis Elan D. Yale University, USA*To whom correspondence should be addressed. E-mail: flamand.roze.75012@gmail.com2018 4 12 2018 8 6068 9 2018 18 10 2018 © 2018 D’Bailly et al.2018D’Bailly et al.This is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommerical–No Derivatives License, which permits the user to copy, distribute, and transmit the work provided that the original author and source are credited; that no commercial use is made of the work; and that the work is not altered or transformed.Background\nTremor is an underrecognized feature in certain neuropathy subtypes.\n\nPhenomenology shown\nWe show a patient with a disabling neuropathic tremor and mild cerebellar syndrome associated with chronic inflammatory demyelinating polyneuropathy (CIDP) and anti‐neurofascin‐155 (NF155) antibodies.\n\nEducational value\nAnti‐NF155 testing should be considered in patients with CIDP and disabling tremor because of therapeutic implications.\n\nNeuropathic tremorneurofascin‐155chronic inflammatory demyelinating polyneuropathy\n==== Body\nWe report the case of a 64‐year‐old female with type 2 diabetes and a longstanding history of bipolar disorder treated with valproate and venlafaxine on stable doses. She presented with gait ataxia and distal limb paresthesia that had gradually worsened over 2 months. She then noticed bilateral upper limb tremor and dysarthria. Clinical examination showed a mild proximal and distal quadriparesis, absent deep tendon reflexes, dysmetria, ataxic dysarthria, and mixed proprioceptive and cerebellar gait ataxia. She had a predominantly action tremor (kinetic, postural, and intentional) with proximal and distal involvement and a mild rest tremor (Video 1). Electroneuromyography showed motor and sensory demyelinating neuropathy in the upper and lower limbs with proximal and distal involvement, consistent with CIDP. Cerebrospinal fluid examination showed an increased protein level (0.67 g/L) with a normal cell count. Polymyographic recording revealed a rest and action tremor with a 5‐Hz frequency intermingled with occasional subcortical myoclonus. Brain magnetic resonance imaging and dopamine transporter scan results were normal. Antibody testing was positive for anti‐neurofascin‐155 (NF155) antibodies. We made the diagnosis of CIDP associated with anti‐NF155 antibodies causing a pronounced neuropathic tremor and cerebellar syndrome. The subacute presentation while on stable doses argues against roles of sodium valproate and venlafaxine in the tremor and myoclonic jerks, but a mild effect cannot be excluded. She did not respond to intravenous immunoglobulins (IVIg). Corticosteroids given with rituximab and plasma exchange allowed partial improvement of sensory and motor manifestations, tremor severity, and neurophysiological parameters. NF155 is an adhesion molecule expressed at paranodes at the terminal loops of myelin, where it plays a key role in promoting rapid nerve impulse propagation.1 CIDP with anti‐NF155 antibodies is frequently associated with disabling neuropathic tremor. It is described as an action tremor with low frequency, high amplitude, and marked postural and intention components.2 Mild rest component and jerks could also be a feature of neuropathic tremor. In a recently described cohort, some patients with NF‐155 antibodies (5/38) had an additional cerebellar syndrome with gait ataxia, dysarthria, and nystagmus. In addition, some patients also had central nervous system (CNS) demyelination (3/38), which may be related to the presence of an NF155 antigen in the CNS.2 Disabling action tremor in the context of a demyelinating neuropathy is a clue for anti‐NF155 antibody‐associated CIDP. This has important therapeutic implications as this condition does not usually respond to IVIg but may improve with plasmapheresis and rituximab.2\n\nVideo 1. Tremor Associated with Chronic Inflammatory Demyelinating Polyneuropathy and Anti‐neurofascin‐155 Antibodies in a 64‐year‐old Patient. Action and rest tremor, predominating on the right side with an occasional myoclonic component. Ataxic dysarthria and gait ataxia are also observed.\nFunding: None.\n\nFinancial Disclosures: L. Bailly has nothing to disclose M. Mongin received travel support from Merz‐Pharma C. Delorme received travel support from Merz‐Pharma and Elivie. E. Apartis received research support from APTES S. Saheb received research support from Octapharma, CSL Bering, Terumo BCT, Amgen, and Sanofi E. Roze received research support from Merz‐Pharma, Orkyn, Aguettant, Elivie, Ipsen, Ultragenix, Fondation Desmarest, AMADYS, Fonds de Dotation Brou de Laurière, and Agence Nationale de la Recherche; has served on scientific advisory boards for Orkyn, Aguettant, and Merz‐Pharma; and has received honoraria for speeches from Orkyn, Aguettant, Merz‐Pharma, and Medday‐Pharma.\n\nConflicts of Interest: The authors report no conflict of interest.\n\nEthics Statement: All patients that appear on video have provided written informed consent; authorization for the videotaping and for publication of the videotape was provided.\n==== Refs\nReferences\n1 Querol L Devaux J Rojas‐Garcia R Illa I Autoantibodies in chronic inflammatory neuropathies: diagnostic and therapeutic implications Nat Rev Neurol 2017 13 533 47 10.1038/nrneurol.2017.84 28708133 \n2 Devaux JJ Miura Y Fukami Y Inoue T Manso C Belghazi M et al Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy Neurology 2016 86 800 7 10.1212/WNL.0000000000002418 26843559\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2160-8288",
"issue": "8()",
"journal": "Tremor and other hyperkinetic movements (New York, N.Y.)",
"keywords": "Neuropathic tremor; chronic inflammatory demyelinating polyneuropathy; neurofascin‐155",
"medline_ta": "Tremor Other Hyperkinet Mov (N Y)",
"mesh_terms": "D001323:Autoantibodies; D015815:Cell Adhesion Molecules; D005260:Female; D006801:Humans; D008875:Middle Aged; D009414:Nerve Growth Factors; D020277:Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; D014202:Tremor",
"nlm_unique_id": "101569493",
"other_id": null,
"pages": "606",
"pmc": null,
"pmid": "30619643",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26843559;28708133",
"title": "Tremor Associated with Chronic Inflammatory Demyelinating Polyneuropathy and Anti-Neurofascin-155 Antibodies.",
"title_normalized": "tremor associated with chronic inflammatory demyelinating polyneuropathy and anti neurofascin 155 antibodies"
} | [
{
"companynumb": "FR-PFIZER INC-2019371673",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "This case describes almost continual daptomycin use for approximately 18 months in a patient with osteomyelitis caused by methicillin-resistant Staphylococcus aureus. The case is notable for only a brief episode of myalgia-associated creatine kinase elevations, which quickly resolved. Daptomycin demonstrated efficacy against this strain, which was tolerant to other antibiotics.",
"affiliations": "Ocala Regional Medical Center, Ocala, Florida, USA. dorchak2003@yahoo.com",
"authors": "Burns|Cheryl A|CA|",
"chemical_list": "D000900:Anti-Bacterial Agents; D017576:Daptomycin",
"country": "England",
"delete": false,
"doi": "10.1080/00365540701633038",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0036-5548",
"issue": "40(2)",
"journal": "Scandinavian journal of infectious diseases",
"keywords": null,
"medline_ta": "Scand J Infect Dis",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D001170:Arthritis, Infectious; D017576:Daptomycin; D004334:Drug Administration Schedule; D006801:Humans; D008297:Male; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D010019:Osteomyelitis; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus",
"nlm_unique_id": "0215333",
"other_id": null,
"pages": "183-6",
"pmc": null,
"pmid": "17852899",
"pubdate": "2008",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Long-term use of daptomycin for MRSA osteomyelitis and joint infection.",
"title_normalized": "long term use of daptomycin for mrsa osteomyelitis and joint infection"
} | [
{
"companynumb": "US-PFIZER INC-2020273772",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": "1",
... |
{
"abstract": "Background The aim of this study was to compare the immediate and long-term clinical outcomes of medical therapy and percutaneous patent foramen ovale (PFO) closure as secondary prevention strategies in patients younger than 55 years of age presenting with cryptogenic stroke and PFO. Methods Between January 2006 and April 2015, all patients with the diagnosis of cryptogenic stroke and PFO were analysed and prospectively followed. Stroke was confirmed in 159 out of 309 patients (51%). In the remaining cases, other neurological conditions were found and therefore excluded from further analysis. Patients received PFO closure or medical therapy on the basis of a pre-specified algorithm. Primary outcome was the assessment of recurrent ischaemic events at follow-up. Results Percutaneous PFO closure was performed in 77 patients (48%) and 82 (52%) were treated medically. Mean follow-up was 51.6 ± 34.8 months. Two ischaemic strokes occurred in the medical group only (2.4% vs 0%; P = 0.16) and no complications related to the invasive procedure were observed. Conclusions The diagnosis of stroke in patients with PFO could be confirmed in 50% of cases only, underlining the importance of a multidisciplinary evaluation of these patients. A very low ischaemic recurrence rate was observed in the medical therapy group, suggesting that a personalized treatment based on a prespecified diagnostic algorithm yields good clinical results irrespective of the treatment modality. Given the low number of recurrences, larger cohorts may be needed to prove significant differences.",
"affiliations": "a Department of Neurological, Neuropsychological, Morphological and Movement Sciences, Section of Clinical Neurology , University Hospital of Verona , Italy.;b Division of Neurology , Rovereto Hospital , Trento, Verona , Italy.;c Department of Neurosciences , Stroke Unit, Verona Hospital , Verona , Italy.;d Division of Cardiology, Department of Medicine , University Hospital of Verona.;a Department of Neurological, Neuropsychological, Morphological and Movement Sciences, Section of Clinical Neurology , University Hospital of Verona , Italy.;d Division of Cardiology, Department of Medicine , University Hospital of Verona.;d Division of Cardiology, Department of Medicine , University Hospital of Verona.;e Cardiology Unit , San Bonifacio Hospital , Verona , Italy.;a Department of Neurological, Neuropsychological, Morphological and Movement Sciences, Section of Clinical Neurology , University Hospital of Verona , Italy.;d Division of Cardiology, Department of Medicine , University Hospital of Verona.;c Department of Neurosciences , Stroke Unit, Verona Hospital , Verona , Italy.;c Department of Neurosciences , Stroke Unit, Verona Hospital , Verona , Italy.;c Department of Neurosciences , Stroke Unit, Verona Hospital , Verona , Italy.;a Department of Neurological, Neuropsychological, Morphological and Movement Sciences, Section of Clinical Neurology , University Hospital of Verona , Italy.;d Division of Cardiology, Department of Medicine , University Hospital of Verona.;d Division of Cardiology, Department of Medicine , University Hospital of Verona.",
"authors": "Danese|Alessandra|A|;Stegagno|Chiara|C|;Tomelleri|Giampaolo|G|;Piccoli|Anna|A|;Turri|Giulia|G|;Carletti|Monica|M|;Variola|Andrea|A|;Anselmi|Maurizio|M|;Mazzucco|Sara|S|;Ferrara|Angela|A|;Bovi|Paolo|P|;Micheletti|Nicola|N|;Cappellari|Manuel|M|;Monaco|Salvatore|S|;Vassanelli|Corrado|C|;Ribichini|Flavio|F|;|||",
"chemical_list": "D000925:Anticoagulants; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1080/00015385.2017.1307668",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5385",
"issue": "72(4)",
"journal": "Acta cardiologica",
"keywords": "Cryptogenic stroke; patent foramen ovale; percutaneous atrial septal repair",
"medline_ta": "Acta Cardiol",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000925:Anticoagulants; D006328:Cardiac Catheterization; D005260:Female; D005343:Fibrinolytic Agents; D054092:Foramen Ovale, Patent; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D011446:Prospective Studies; D012008:Recurrence; D012307:Risk Factors; D055502:Secondary Prevention; D020521:Stroke; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0370570",
"other_id": null,
"pages": "410-418",
"pmc": null,
"pmid": "28705105",
"pubdate": "2017-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Clinical outcomes of secondary prevention strategies for young patients with cryptogenic stroke and patent foramen ovale.",
"title_normalized": "clinical outcomes of secondary prevention strategies for young patients with cryptogenic stroke and patent foramen ovale"
} | [
{
"companynumb": "PHHY2019IT183976",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": "3",
"drugadmi... |
{
"abstract": "High-dose chemotherapy and autologous stem cell transplant (ASCT) remains a cornerstone of treatment in relapsed/refractory (R/R) aggressive-histology lymphomas. This retrospective study examined efficacy and safety of peripheral blood stem cell (PBSC) mobilization using cyclophosphamide/etoposide and GCSF (CE + GCSF, n = 129) versus gemcitabine, dexamethasone and cisplatin and GCSF (GDP + GCSF, n = 210). All patients received first salvage with GDP. Patients mobilized with CE + GCSF required fewer days of leukapheresis (median 1 vs 2 day; p = .001) and achieved higher total CD34+ yield than GDP + GCSF patients (8.5 vs 7.1 × 106 CD34+ cells/kg, p = .001). Rates of febrile neutropenia and CD34+ collection ≥5 × 106 CD34+ cells/kg were similar (OR 1.19, 95% CI: 0.54-2.6, p = .66). In multivariable analysis, days to engraftment and admission duration were not statistically different between the two mobilization strategies. While CE + GCSF appeared more efficacious for mobilization after GDP salvage, this did not translate to significant differences in clinical outcomes.",
"affiliations": "Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, Canada.;Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Canada.;Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, Canada.;Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, Canada.;Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, Canada.;Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, Canada.;Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, Canada.;Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, Canada.;Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, Canada.",
"authors": "Tang|Catherine|C|0000-0002-0223-8341;Espin-Garcia|Osvaldo|O|;Prica|Anca|A|;Kurkreti|Vishal|V|;Kridel|Robert|R|;Keating|Armand|A|;Patriquin|Christopher J|CJ|;Kuruvilla|John|J|;Crump|Michael|M|",
"chemical_list": "D003841:Deoxycytidine; D005047:Etoposide; D003907:Dexamethasone; C056507:gemcitabine; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2020.1762882",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "61(9)",
"journal": "Leukemia & lymphoma",
"keywords": "Autologous stem cell transplant; lymphoma; salvage chemotherapy; stem cell mobilization",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D003841:Deoxycytidine; D003907:Dexamethasone; D005047:Etoposide; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008223:Lymphoma; D012189:Retrospective Studies; D016879:Salvage Therapy",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "2153-2160",
"pmc": null,
"pmid": "32482114",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy and safety of stem cell mobilization following gemcitabine, dexamethasone, cisplatin (GDP) salvage chemotherapy in patients with relapsed or refractory lymphoma.",
"title_normalized": "efficacy and safety of stem cell mobilization following gemcitabine dexamethasone cisplatin gdp salvage chemotherapy in patients with relapsed or refractory lymphoma"
} | [
{
"companynumb": "CA-AMGEN-CANSP2020150893",
"fulfillexpeditecriteria": "2",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nChemotherapy with oxaliplatin is used for a wide range of malignancies. Unlike other platinum derivatives, oxaliplatin has less nephrotoxicity. However, in recent years, there have been multiple reports of different forms of renal toxicity related to this agent.\n\n\nMETHODS\nA 40-year-old woman with colon adenocarcinoma developed jaundice, hematuria, and oliguria after the 36th cycle of oxaliplatin chemotherapy. Laboratory data revealed severe anemia, thrombocytopenia, increased creatinine, indirect hyperbilirubinemia, and high lactate dehydrogenase. A negative direct antiglobulin test and presence of <1% schistocytes in the peripheral blood smear stood against the diagnosis of immune-mediated hemolytic anemia or hemolytic uremic syndrome/thrombotic thrombocytopenic purpura. Renal biopsy was consistent with interstitial nephritis with tubular vacuolization in favor of drug-induced renal injury. Based on the Naranjo Probability Scale, the likelihood of oxaliplatin-induced renal injury in this case was probable.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first case report of renal tubular vacuolization with symptoms mimicking thrombotic microangiopathy in a patient on long-term chemotherapy with oxaliplatin.\n\n\nCONCLUSIONS\nOxaliplatin can induce various forms of nephrotoxicity such as renal tubular vacuolization, acute tubular necrosis, renal tubular acidosis, and acute kidney injury secondary to hematological toxicity. Monitoring for renal function abnormalities and hemolysis should be considered during oxaliplatin-based chemotherapy.",
"affiliations": "Shahid Beheshti University of Medical Sciences, Tehran, Iran.",
"authors": "Joybari|Ali Yaghobi|AY|;Sarbaz|Samaneh|S|;Azadeh|Payam|P|;Mirafsharieh|S Abbas|SA|;Rahbari|Ali|A|;Farasatinasab|Maryam|M|;Mokhtari|Majid|M|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028014526160",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "48(6)",
"journal": "The Annals of pharmacotherapy",
"keywords": "AKI; HUS; Oxaliplatin; RTA; TTP",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000970:Antineoplastic Agents; D003110:Colonic Neoplasms; D005260:Female; D006801:Humans; D007668:Kidney; D007674:Kidney Diseases; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "796-800",
"pmc": null,
"pmid": "24615628",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Oxaliplatin-induced renal tubular vacuolization.",
"title_normalized": "oxaliplatin induced renal tubular vacuolization"
} | [
{
"companynumb": "IR-ACTAVIS-2015-02007",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.