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Le Touquet – Paris-Plage, France

Fouret R.,Telecom ParisTech | Laffaire J.,Programme Carte dIdentite des Tumeurs | Hofman P.,Nice University Hospital Center | Beau-Faller M.,CHU Strasbourg | And 10 more authors.
Clinical Cancer Research | Year: 2012

Purpose: To identify genetic changes that could drive cancer pathogenesis in never and ever smokers with lung adenocarcinoma. Experimental Design: We analyzed the copy number and gene expression profiles of lung adenocarcinomas in 165 patients and related the alterations to smoking status. Having found differences in the tumor profiles, we integrated copy number and gene expression data from 80 paired samples. Results: Amplifications at 8q24.12 overlapping MYC and ATAD2 were more frequent in ever smokers. Unsupervised analysis of gene expression revealed two groups: in the group with mainly never smokers, the tumors expressed genes common to normal lung; in the group with more ever smokers, the tumors expressed "proliferative" and "invasive" gene clusters. Integration of copy number and gene expression data identified one module enriched in mitotic genes and MYC targets. Its main associated modulator was ATAD2, a cofactor of MYC. A strong dose-response relationship between ATAD2 and proliferation-related gene expression was noted in both never and ever smokers, which was verified in two independent cohorts. Both ATAD2 and MYC expression correlated with 8q24.12 amplification and were higher in ever smokers. However, only ATAD2, and not MYC, overexpression explained the behavior of proliferation-related genes and predicted a worse prognosis independently of disease stage in a large validation cohort. Conclusions: The likely driving force behind MYC contribution to uncontrolled cell proliferation in lung adenocarcinoma is ATAD2. Deregulation of ATAD2 is mainly related to gene amplification and is more frequent in ever smokers. ©2012 AACR.

Verschuren F.,Catholic University of Louvain | Bonnet M.,Catholic University of Louvain | Benoit M.-O.,Hopital Europeen George Pompidou | Gruson D.,Catholic University of Louvain | And 7 more authors.
Thrombosis Research | Year: 2013

Aims To assess the clinical performance of pro-B-type natriuretic peptide 1-108 (proBNP) for the prognosis of acute pulmonary embolism. Methods This study was ancillary to a recently published multicentre study including 570 patients with acute pulmonary embolism. ProBNP values were analysed using a new sandwich immunoassay proBNP1-108, Bioplex2200™ (Bio-Rade Laboratories). Data was compared with BNP and N-terminal (NT) proBNP values. Adverse outcomes at 30 days were defined as death, secondary cardiogenic shock, or recurrent venous thromboembolism. Résults ProBNP values were analysed in 549 patients, with 39 (7.1%) presenting adverse outcomes. All three natriuretic peptides were significantly elevated in these 39 patients compared with the group without adverse outcomes (BNP: p < 0.001; NT-proBNP: p < 0.001; proBNP: 0.044), with median proBNP values being 605 pg/ml (113-1437) and 109 pg/ml (30-444), respectively. Multivariate analyses revealed that proBNP significantly depended on patient age (p < 0.001) and renal failure (p = 0.001), with proBNP values increasing with both factors. The areas under the receiver operating curve were 0.74 (95% CI 0.69-0.79) for BNP, 0.76 (95% CI 0.72-0.80) for NT-proBNP, and 0.70 (95% CI 0.65-0.75) for proBNP, meaning that the performance of proBNP was significantly lower than that of the two other peptides (p = 0.017). Conclusion ProBNP, BNP, and NT-proBNP values were significantly increased in patients with adverse outcomes after acute pulmonary embolism. However, the prognostic performance of proBNP for predicting adverse versus favourable outcomes was lower than that of the other natriuretic peptides, thus limiting the clinical relevance of proBNP as a prognostic marker in pulmonary embolism. © 2013 Elsevier Ltd.

Saadoun D.,Assistance Publique Hopitaux de Paris | Saadoun D.,University Pierre and Marie Curie | Sene D.,Assistance Publique Hopitaux de Paris | Terrier B.,Assistance Publique Hopitaux de Paris | And 8 more authors.
Blood | Year: 2010

Treatment of hepatitis C (HCV)-mixed cryoglobulinemia (MC) may target either the viral trigger (HCV) or the downstream B-cell clonal expansion. Prospective cohort study of 38 HCV-MC patients who received a combination of rituximab (375 mg/m2) once a week for 1 month followed by Peg-interferon-α (Peg-IFN-α; 2a, 180 μg or 2b, 1.5 μg/kg) weekly plus ribavirin (600-1200 mg) daily for 48 weeks were compared with 55 HCV-MC patients treated by Peg-IFN-α/ribavirin with the same modalities. In the whole population of HCV-MC patients (n = 93), a complete clinical response was achieved in 73.1% (68 of 93), cryoglobulin clearance in 52.7% (49 of 93), and a sustained virologic response in 59.1% (55 of 93). Compared with Peg-IFN-α/ribavirin, rituximab plus Peg-IFN-α/ribavirin-treated patients had a shorter time to clinical remission (5.4 ± 4 vs 8.4 ± 4.7 months, P = .004), better renal response rates (80.9% vs 40% of complete response, P = .040), and higher rates of cryoglobulin clearance (68.4% vs 43.6%, P = .001) and clonal VH1-69+ B-cell suppression (P < .01). Treatment was well tolerated with 11% of discontinuation resulting from antiviral therapy and no worsening of HCV RNA under rituximab. Our findings indicate that rituximab combined with Peg-IFN-α/ribavirin is well tolerated and more effective than Peg-IFN-α/ribavirin in HCV-MC. © 2010 by The American Society of Hematology.

Saadoun D.,AP HP | Saadoun D.,University Pierre and Marie Curie | Karras A.,Hopital Europeen George Pompidou | Bazin-Kara D.,Hopital de la Robertsau | And 6 more authors.
Journal of Hepatology | Year: 2015

Background & Aims The aim of this study was to analyse the safety and efficacy of the PegIFNα/ribavirin/protease inhibitor combination in severe and/or refractory hepatitis C virus (HCV)-mixed cryoglobulinemia (MC) vasculitis.Methods This prospective cohort study included 30 patients (median age 59 years [53-66] and 57% of women) with HCV-MC vasculitis. PegIFNα/ribavirin (for 48 weeks) was associated with telaprevir (375 mg three times daily, for 12 weeks, [n = 17]) or boceprevir (800 mg three times daily, for 44 weeks, (n = 13]).Results Twenty three patients (76.7%) were non-responders to previous antiviral therapy. At week 72, twenty patients (66.7%) were complete clinical and sustained virological responders. The cryoglobulin level decreased from 0.45 to 0 g/L (p <0.0001) and the C4 level increased from 0.09 to 0.14 g/L (p = 0.017). Complete clinical responders had a higher frequency of purpura (16/20 [80%] vs. 4/10 [40%], p = 0.045), and a trend towards lower frequency of neuropathy (9/20 (45%) vs. 8/10 [80%], p = 0.12) compared with partial responders. Serious adverse events occurred in 14 patients (46.6%) during the 72 weeks of follow-up. Twenty eight patients (93.3%) received erythropoietin, 14 (46.6%) had red blood cell transfusion and 2 (6.6%) received granulocyte stimulating agent. The baseline factors associated with serious adverse events included liver fibrosis (p = 0.045) and a low platelet count (p = 0.021).Conclusions The PegIFNα/ribavirin/protease inhibitor combination is highly effective in severe and/or refractory HCV-MC at the cost of frequent side effects. Baseline platelet count and liver fibrosis are useful in guiding treatment decisions. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Saadoun D.,Service de Medecine Interne | Saadoun D.,University Pierre and Marie Curie | Thibault V.,Groupe Hospitalier Pitie Salpetriere | Longuet M.,Service de Medecine Interne | And 8 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Background The standard-of-care treatment of patients with hepatitis C virus (HCV)-mixed cryoglobulinemia (MC) vasculitis includes pegylated interferon a (PegIFN)-a plus ribavirin and/or rituximab. About 30-40% of patients are non-responders or relapsers to such combination. Objective To analyse the safety and efficacy of Peg-IFNa/ribavirin/protease inhibitor combination in HCV-MC vasculitis. Patients and methods Open-label, prospective, cohort study including 23 patients with HCV-MC vasculitis. Peg-IFNa/ribavirin was associated to telaprevir (375 mg three times daily, for 12 weeks, (n=15)) or boceprevir (800 mg three times daily, for 44 weeks, (n=8)) for 48 weeks. Results The median age was 59 (52.5-66) years, with 48.8% women. Thirteen patients (56.5%) were complete clinical responders, and 10 (43.5%) were partial responders at week 24. The virological response (ie, HCV RNA negativation) was of 69.6% at week 24 (p=0.005). The cryoglobulin level decreased from 0.44 to 0.06 g/l (p=0.0006) and the C4 level increased from 0.09 to 0.15 g/l (p=0.045). Grades 3 and 4 adverse events (mainly anaemia, neutropenia and thrombocytopenia) were observed in 10 cases (43.5%). Twenty patients (87%) received erythropoietin, 9 (39.1%) had red cell transfusion, and 2 (8.7%) had granulocyte stimulating agents. Antiviral therapy discontinuation was required in 8 (34.7%) patients for virological non-response (n=5), virological relapse (n=2) and depression (n=1). Conclusions Peg-IFNa/ribavirin/protease inhibitor combination seems highly effective in HCV-MC. Such therapeutic regimen should be administered cautiously considering the high rate of side effects.

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