153 research outputs found

    Benefit of switching to mepolizumab from omalizumab in severe eosinophilic asthma based on patient characteristics

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    Asma; Tractament de l'asma; EosinĂČfilsAsma; Tratamiento del asma; EosinĂłfilosAsthma; Asthma treatment; EosinophilsBackground The OSMO study assessed the efficacy of switching to mepolizumab in patients with severe eosinophilic asthma that was uncontrolled whilst receiving omalizumab. The objective of this analysis was to assess the proportion of patients achieving pre-defined improvements in up to four efficacy outcomes and the relationship between patient baseline characteristics and treatment response. Methods This was a post hoc analysis of OSMO study data (GSK ID:204471; ClinicalTrials.gov No. NCT02654145). Patients with severe eosinophilic asthma uncontrolled by high-dose inhaled corticosteroids, other controller(s) and omalizumab subcutaneously (≄ 4 months) were switched to mepolizumab 100 mg administered subcutaneously. Endpoints included the proportion of responders—i.e. patients achieving a pre-defined clinical improvement in ≄ 1 of the following outcomes: (1) Asthma Control Questionnaire (ACQ)-5 score (≄ 0.5-points), (2) St George’s Respiratory Questionnaire (SGRQ) total score (≄ 4-points), (3) pre-bronchodilator forced expiratory volume in 1s (FEV1; ≄ 100 mL), all at Week 32, and (4) annualised rate of clinically significant exacerbations (≄ 50% reduction). Results Of the 145 patients included, 94%, 83%, 63% and 31% were responders for ≄ 1, ≄ 2, ≄ 3 and 4 outcomes, respectively; 75% and 78% were ACQ-5 and SGRQ score responders, and 50% and 69% were FEV1 and exacerbation responders. Subgroup analyses demonstrated improvements irrespective of baseline blood eosinophil count, prior omalizumab treatment regimen/duration, comorbidities, prior exacerbation history, maintenance oral corticosteroid use, ACQ-5 and SGRQ scores, and body weight/body mass index. Conclusions After switching to mepolizumab, almost all patients with uncontrolled severe eosinophilic asthma on omalizumab achieved a beneficial response in ≄ 1 clinical outcome. Improvements were observed regardless of baseline characteristics.This post hoc analysis and the parent study (GSK ID: 204471; ClinicalTrials.gov number: NCT02654145) were funded by GSK

    Pulmonary Sclerosing Hemangioma Detected by Fluorodeoxyglucose Positron Emission Tomography in Familial Adenomatous Polyposis: Report of a Case

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    We present a 53-year-old female suffering from familial adenomatous polyposis, who was found to have a positive nodus, lateral to the hilus of the left lung, on routine FDG-PET scan. This lesion was found to be a sclerosing hemangioma. We found an aberrant ÎČ-catenin expression on immunohistochemical staining, suggesting that sclerosing hemangioma and familial adenomatous polyposis share the same pathophysiology. It is important to be aware of the association of familial adenomatous polyposis and sclerosing hemangioma

    InforMing the PAthway of COPD Treatment (IMPACT Trial) Single-Inhaler Triple Therapy (Fluticasone Furoate/Umeclidinium/Vilanterol) Versus Fluticasone Furoate/Vilanterol and Umeclidinium/Vilanterol in Patients With COPD: Analysis o the Western Europe and North America Regions

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    Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by airflow limitation and progressive respiratory symptoms.1 Global public health trends estimate that the COPD burden will continue to rise, with COPD deaths estimated to increase to 4.4% of all deaths in Europe and 6.3% in the World Health Organization-defined region of the Americas by 2060.2 There are differences in the COPD burden in different regions reflecting variations in etiology,3,4 disease severity,5 symptoms,6 medication use,7 and health care systems and utilization.7 These differences may help inform therapeutic strategies to optimize therapeutic approaches to reducing symptoms and exacerbation risk.1 In the global InforMing the PAthway of COPD Treatment (IMPACT) trial, single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduced moderate/severe exacerbation rates and improved lung function and health-related quality of life versus FF/VI or UMEC/VI dual therapy in patients ≄40 years of age with symptomatic COPD and a history of exacerbations.8 Within trial populations, regional differences such as patient characteristics, treatment patterns, access to care and cultural/socioeconomic factors may dictate treatment choices and influence disease severity and progression in particular geographical locations. For example, a meta-analysis conducted in 2015 comprising 123 studies between 1990 and 2010 found that the overall prevalence of COPD as well as the rate of increase was higher in the Americas (including both North and South America) compared with Europe.9 Furthermore, a cross-sectional study assessing the burden of COPD symptoms in the United States and Europe found variations between patients across countries who had experienced at least 1 symptom of COPD.10 In Europe, patients with more frequent symptoms were more likely to experience worsening of symptoms and unexpected hospitalization. Whereas in the United States, patients with more frequent symptoms were not only more likely to experience worsening of symptoms but also longer lasting symptoms and a longer length of exacerbations.10 A further difference was that treatment adherence was higher in the United States than Europe, however, adherence was consistent across patients in Europe when assessed by modified Global initiative for chronic Obstructive Lung Disease (GOLD) 2014 groups11 but varied in the United States with adherence highest in the GOLD Group C and lowest in Group A.10 Therefore, it is important to evaluate how overall population results pertain to patients treated in particular regions. As IMPACT is one of the largest trials conducted in patients with COPD to date, we have the unique opportunity to analyze study outcomes in patients enrolled in Western Europe and North America, the 2 main regions from an enrollment perspective

    Mise Ă  jour 2014 des recommandations du GEFPICS pour l’évaluation du statut HER2 dans les cancers du sein en France

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    De nouvelles recommandations internationales pour l’évaluation du statut HER2 dans les cancers du sein, basĂ©es sur plus de dix ans d’expĂ©rience et sur les rĂ©sultats d’études cliniques et de concordance entre les diffĂ©rentes techniques de dĂ©tection, viennent tout juste de voir le jour. Le prĂ©sent article a pour objet de faire le point sur ces nouvelles recommandations, Ă  la lumiĂšre de la publication rĂ©cente du groupe de travail de l’American Society of Clinical Oncology (ASCO) et du CollĂšge des pathologistes amĂ©ricains (CAP), adaptĂ©es Ă  la pratique de la pathologie en France et revues par le groupe GEFPICS. À l’ùre de la mĂ©decine personnalisĂ©e, la dĂ©termination du statut HER2 reste un Ă©lĂ©ment phare dans le panel des biomarqueurs thĂ©ranostiques des cancers du sein. Si l’interprĂ©tation du statut HER2 dans les cancers du sein est aisĂ©e dans la majoritĂ© des cas, un certain nombre de situations anatomocliniques est d’interprĂ©tation plus dĂ©licate, telles que la possibilitĂ© rare mais rĂ©elle de l’hĂ©tĂ©rogĂ©nĂ©itĂ© intra-tumorale du statut de HER2, les formes Ă  diffĂ©renciation micropapillaire ou la rĂ©-Ă©valuation du statut des biomarqueurs lors de la rechute mĂ©tastatique. Ces nouvelles recommandations abordent ces diffĂ©rentes questions, reprĂ©cisent les conditions prĂ©-analytiques optimales et les critĂšres d’interprĂ©tation (notamment des cas 2+), afin de rĂ©duire au maximum le risque de faux nĂ©gatifs. Plus que jamais, la mobilisation de la spĂ©cialitĂ© d’anatomo-cytopathologie autour de la qualitĂ© des tests thĂ©ranostiques tĂ©moigne de son implication dans la chaĂźne des soins en cancĂ©rologie., Summary International guidelines on HER2 determination in breast cancer have just been updated by the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP), on the basis of more than ten-year practice, results of clinical trials and concordance studies. The GEFPICS group, composed of expert pathologists in breast cancer, herein presents these recommendations, adapted to the French routine practice. These guidelines highlight the possible diagnosis difficulties with regards to HER2 status determination, such as intra-tumor heterogeneity, special histological subtypes and biomarker re-evaluation during metastatic relapse. Pre-analytical issues and updated scoring criteria (especially for equivocal cases) are detailed, in order to decrease the occurrence of false negative cases. In the era of personalized medicine, pathologists are more than ever involved in the quality of oncotheranostic biomarker evaluation.

    Recommandations du GEFPICS concernant la phase prĂ©-analytique pour l’évaluation de HER2 et des rĂ©cepteurs hormonaux dans le cancer du sein : mise Ă  jour 2014

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    Les tumeurs fixĂ©es et incluses en paraffine sont quotidiennement utilisĂ©es pour l’évaluation des biomarqueurs nĂ©cessaires au traitement des patientes atteintes d’un cancer du sein invasif. Les nouvelles recommandations internationales sur la phase prĂ©-analytique ont Ă©tĂ© rĂ©cemment revues, confirmant l’importance de la prise en charge optimale des prĂ©lĂšvements pour garantir des tests d’immunohistochimie ou d’hybridation in situ de qualitĂ©, quel que soit le biomarqueur envisagĂ©. Incluant les procĂ©dĂ©s de fixation et de prĂ©paration des tissus, toutes les procĂ©dures prĂ©-analytiques doivent ĂȘtre validĂ©es, standardisĂ©es et tracĂ©es. Elles nĂ©cessitent la collaboration et la formation de toutes les personnes impliquĂ©es dans le circuit du prĂ©lĂšvement, du prĂ©leveur jusqu’au technicien de pathologie et au pathologiste en passant par l’infirmiĂšre, ou le coursier. La prise en charge initiale optimale des piĂšces et une fixation de qualitĂ© sont des Ă©tapes majeures Ă  maĂźtriser dans la phase prĂ©-analytique. Cette mise Ă  jour des recommandations du groupe d’étude des facteurs pronostiques immunohistochimiques dans le cancer du sein (GEFPICS) dĂ©taille et commente les diffĂ©rentes Ă©tapes prĂ©-analytiques. L’observation de ces rĂšgles de bonne pratique, l’utilisation rigoureuse de tĂ©moins internes et externes et la participation rĂ©guliĂšre Ă  des programmes d’assurance qualitĂ© sont autant de garanties pour une Ă©valuation correcte et pĂ©renne des biomarqueurs oncothĂ©ranostiques., Summary Biomarker assessment of breast cancer tumor samples is part of the routine workflow of pathology laboratories. International guidelines have recently been updated, with special regards to the pre-analytical steps that are critical for the quality of immunohistochemical and in situ hybridization procedures, whatever the biomarker analyzed. Fixation and specimen handling protocols must be standardized, validated and carefully tracked. Cooperation and training of the personnel involved in the specimen workflow (e.g. radiologists, surgeons, nurses, technicians and pathologists) are of paramount importance. The GEFPICS’ update of the recommendations herein details and comments the different steps of the pre-analytical process. Application of these guidelines and participation to quality insurance programs are mandatory to ensure the correct evaluation of oncotheranostic biomarkers

    BMJ Open

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    Objectives Presently, those outcomes that should be prioritised for chronic obstructive pulmonary disease (COPD) exacerbation studies remain unclear. In order to coordinate multicentre studies on eosinophilia-driven corticosteroid therapy for patients hospitalised for acute exacerbation of COPD (AECOPD), we aimed to find consensus among experts in the domain regarding the prioritisation of outcomes. Design A modified Delphi study was proposed to recognised COPD experts. Two brainstorming questionnaires were used to collect potential outcomes. Four subsequent rounds of questionnaires were used to rank items according to a six-point Likert scale for their importance in the protocol, as well as for being the primary outcome. Priority outcome criteria were predefined as those for which ≄70% of experts indicated that the outcome was essential for interpreting study results. Setting COPD exacerbation management in France. Participants 34 experts recommended by the French Language Pulmonology Society were invited to participate. Of the latter, 21 experts participated in brainstorming, and 19 participated in all four ranking rounds. Results 105 outcomes were ranked. Two achieved consensus as candidate primary outcomes: (1) treatment failure defined as death from any cause or the need for intubation and mechanical ventilation, readmission because of COPD or intensification of pharmacologic therapy, and (2) the time required to meet predefined discharge criteria. The 10 secondary priority outcomes included survival, time with no sign of improvement, episodes of hospitalisation, exacerbation, pneumonia, mechanical or non-invasive ventilation and oxygen use, as well as comorbidities during the initial hospitalisation. Conclusions This Delphi consensus project generated and prioritised a great many outcomes, documenting current expert views concerning a diversity of COPD endpoints. Among the latter, 12 reached consensus as priority outcomes for evaluating the efficacy of eosinophil-driven corticosteroid therapy in AECOPD inpatients

    Endothelial Dysfunction and Specific Inflammation in Obesity Hypoventilation Syndrome

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    BACKGROUND: Obesity hypoventilation syndrome (OHS) is associated with increased cardiovascular morbidity. What moderate chronic hypoventilation adds to obesity on systemic inflammation and endothelial dysfunction remains unknown. QUESTION: To compare inflammatory status and endothelial function in OHS versus eucapnic obese patients. METHODOLOGY: 14 OHS and 39 eucapnic obese patients matched for BMI and age were compared. Diurnal blood gazes, overnight polysomnography and endothelial function, measured by reactive hyperemia peripheral arterial tonometry (RH-PAT), were assessed. Inflammatory (Leptin, RANTES, MCP-1, IL-6, IL-8, TNFalpha, Resistin) and anti-inflammatory (adiponectin, IL-1Ra) cytokines were measured by multiplex beads immunoassays. PRINCIPAL FINDINGS: OHS exhibited a higher PaCO(2), a lower forced vital capacity (FVC) and tended to have a lower PaO(2) than eucapnic obese patients. (HS)-CRP, RANTES levels and glycated haemoglobin (HbA1c) were significantly increased in OHS (respectively 11.1+/-10.9 vs. 5.7+/-5.5 mg x l(-1) for (HS)-CRP, 55.9+/-55.3 vs 23.3+/-15.8 ng/ml for RANTES and 7.3+/-4.3 vs 6.1+/-1.7 for HbA1c). Serum adiponectin was reduced in OHS (7606+/-2977 vs 13,660+/-7854 ng/ml). Endothelial function was significantly more impaired in OHS (RH-PAT index: 0.22+/-0.06 vs 0.51+/-0.11). CONCLUSIONS: Compared to eucapnic obesity, OHS is associated with a specific increase in the pro-atherosclerotic RANTES chemokine, a decrease in the anti-inflammatory adipokine adiponectin and impaired endothelial function. These three conditions are known to be strongly associated with an increased cardiovascular risk. TRIAL REGISTRATION: ClinicalTrials.gov NCT00603096

    EMT Inducers Catalyze Malignant Transformation of Mammary Epithelial Cells and Drive Tumorigenesis towards Claudin-Low Tumors in Transgenic Mice

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    The epithelial-mesenchymal transition (EMT) is an embryonic transdifferentiation process consisting of conversion of polarized epithelial cells to motile mesenchymal ones. EMT–inducing transcription factors are aberrantly expressed in multiple tumor types and are known to favor the metastatic dissemination process. Supporting oncogenic activity within primary lesions, the TWIST and ZEB proteins can prevent cells from undergoing oncogene-induced senescence and apoptosis by abolishing both p53- and RB-dependent pathways. Here we show that they also downregulate PP2A phosphatase activity and efficiently cooperate with an oncogenic version of H-RAS in malignant transformation of human mammary epithelial cells. Thus, by down-regulating crucial tumor suppressor functions, EMT inducers make cells particularly prone to malignant conversion. Importantly, by analyzing transformed cells generated in vitro and by characterizing novel transgenic mouse models, we further demonstrate that cooperation between an EMT inducer and an active form of RAS is sufficient to trigger transformation of mammary epithelial cells into malignant cells exhibiting all the characteristic features of claudin-low tumors, including low expression of tight and adherens junction genes, EMT traits, and stem cell–like characteristics. Claudin-low tumors are believed to be the most primitive breast malignancies, having arisen through transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Challenging this prevailing view, we propose that these aggressive tumors arise from cells committed to luminal differentiation, through a process driven by EMT inducers and combining malignant transformation and transdifferentiation
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