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Saadoun D.,AP HP | Saadoun D.,University Pierre and Marie Curie | Pol S.,Hopital Necker | Thibault V.,Hopital Pitie Salpetriere | And 9 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.,Groupe Hospitalier Pitie Salpetriere | Saadoun D.,University Pierre and Marie Curie | Sene D.,Groupe Hospitalier Pitie Salpetriere | Terrier B.,Groupe Hospitalier Pitie Salpetriere | And 11 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.,Service de Medecine Interne | Saadoun D.,University Pierre and Marie Curie | Thibault V.,Groupe Hospitalier Pitie Salpetriere | Longuet M.,Service de Medecine Interne | And 9 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.


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.


PubMed | Pitie Salpetriere Hospital, Avicenne Hospital, Cochin Hospital, Meaux Hospital and 8 more.
Type: | Journal: Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver | Year: 2016

Perioperative chemotherapy with 5-fluorouracil and cisplatin, with or without epirubicin, improves overall survival in resectable gastroesophageal junction and gastric adenocarcinoma. The aim of this retrospective multicenter study was to evaluate the safety and efficacy of perioperative chemotherapy with a FOLFOX-based regimen.We enrolled patients with resectable gastric or gastroesophageal adenocarcinoma, who had at least 3 cycles of a pre-operative FOLFOX-based regimen. The primary end point was the feasibility of the peri-operative chemotherapy.We enrolled 109 patients from 2007 to 2012 in 12 centres. Their median age was 66, 67% were men and 73% had gastric tumours. The median number of chemotherapy courses was 6 with a median of 4 pre-operative cycles and 2 post-operative cycles. Twenty-three patients received at least 8 cycles of chemotherapy. In univariate analysis, the Karnofsky index at inclusion was the only factor associated with 8 cycles of chemotherapy. An R0 resection was achieved in 100 patients (95.2%).The FOLFOX-based perioperative regimen achieves favourable results in real life practice. The optimal number of chemotherapy cycle remains to be determined. FOLFOX regimen may be used as an alternative treatment option to a cisplatin-based regimen in resectable gastroesophageal adenocarcinoma. A prospective randomized trial is needed to confirm these results.


Saadoun D.,Groupe Hospitalier Pitie Salpetriere | Pineton De Chambrun M.,University Pierre and Marie Curie | Hermine O.,Groupe Hospitalier Pitie Salpetriere | Karras A.,Hopital Necker | And 4 more authors.
Arthritis Care and Research | Year: 2013

Objective Treatment of refractory mixed cryoglobulinemia (MC) with severe organ involvement remains challenging. Fludarabine, cyclophosphamide, and rituximab (FCR) treatment is highly effective for patients with chronic lymphocytic leukemia and marginal-zone lymphoma. We first report the safety and efficacy of FCR treatment in severe and refractory MC vasculitis associated with lymphoma. Methods We report the safety and efficacy of fludarabine (40 mg/m2 orally on days 2-4), cyclophosphamide (250 mg/m2 orally on days 2-4), and rituximab (375 mg/m2 on day 1), every 4 weeks, for 3 to 6 cycles in 7 consecutive patients with severe and refractory MC. Results Clinical features of MC included purpura (n = 7), polyneuropathy (n = 6), and kidney (n = 4) and cardiac involvement (n = 2). Previous treatment included rituximab (n = 5), corticosteroids (n = 5), antiviral therapy (n = 5), cyclophosphamide (n = 3), and plasmapheresis (n = 2). All patients achieved clinical response, with 3 patients (42.9%) achieving a complete remission and 4 patients (57.1%) a partial remission. Cryoglobulin decreased from 0.94 to 0.41 gm/liter (P = 0.015). After a followup of 27 months, 2 patients experienced a relapse of MC. Five patients (71.4%) experienced side effects, including cytopenia (n = 5), pneumopathy (n = 2), and serum sickness (n = 1). Conclusion The FCR regimen represents an effective treatment in severe and refractory MC. Copyright © 2013 by the American College of Rheumatology.


PubMed | Institute mutualiste Montsouris, Hopital Henri Mondor, Institute hospitalier franco britannique, Hopital europeen George Pompidou and 4 more.
Type: Journal Article | Journal: Bulletin du cancer | Year: 2015

Trastuzumab with 5-fluorouracil (5-FU) and cisplatin offers prolonged survival in patients with HER2-overexpressing advanced gastric cancer (AGC) and advanced gastro-oesophageal junction cancer (AGOJ). Oxaliplatin in combination with intravenous 5-FU plus leucovorin (LV; modified [m]FOLFOX6) or capecitabine (XELOX) improves tolerability compared with 5-FU/cisplatin regimen. There are few data available on the efficacy and safety of trastuzumab-oxaliplatin-based chemotherapy in previously untreated HER2-positive AGC and AGOJ patients.Clinical data were retrospectively analysed in patients receiving trastuzumab plus mFOLFOX6 or XELOX as first-line therapy between July 2009 and December 2012. Eligible patients had histologically proven AGC or AGOJ, HER2 overexpression, and no prior chemotherapy for metastatic disease.Thirty-four patients met the eligibility criteria. Median age was 63 years, 79% of patients had ECOG PS score of 0-1, and all had metastatic disease. Median duration of treatment was 7.5 months. Overall response rate was 41% (95% CI: 25-56). Median progression-free survival and overall survival were 9.0 months (95% CI: 5.6-12) and 17.3 months (95% CI: 13.5-32.3), respectively. Tolerability was acceptable. The most frequent grade 3-4 toxicities were neutropenia (8.8%) and neuropathy (17.6%).mFOLFOX6-trastuzumab combination is an efficient regimen with an acceptable safety profile for AGC and AGOJ patients. These results warrant further prospective study.


PubMed | Polycliniques Ken Val Site Valdegour, Medical Oncology, Institute Of Cancerologie Of La Loire, Limoges University Hospital Center and 15 more.
Type: | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2016

To assess the efficacy and tolerability of sunitinib rechallenge in the third-line or later setting in patients with metastatic renal cell carcinoma (mRCC).This observational study comprised 61 mRCC patients at 19 centres in France who received sunitinib rechallenge between January 2006 and May 2013. Patients received first-line sunitinib, 1 different targeted therapies, and then sunitinib rechallenge. Patient/disease characteristics, tolerability, treatment modalities, and outcomes of therapeutic lines were recorded. The primary end-point was progression-free survival (PFS) in sunitinib rechallenge.Analyses included 52 patients; median age was 59 years, 75% were male, and 98% had clear-cell mRCC and prior nephrectomy. At sunitinib rechallenge versus first-line, patients had poorer performance (Karnofsky performance status 90-100: 30% versus 81%) and Memorial Sloan Kettering Cancer Centre prognostic risk (poor risk: 18% versus 3%). Overall, 20%, 65%, 12%, and 4% received sunitinib rechallenge as third-, fourth-, fifth-, and sixth-line therapy, respectively, at 14.6 months (median) after stopping initial treatment. With first-line sunitinib and rechallenge, median PFS was 18.4 and 7.9 months, respectively; objective response rate was 54% and 15%. Two of eight rechallenge responders had not achieved first-line response. Median overall survival was 55.9 months. The sunitinib rechallenge safety profile was as expected, with no new adverse events reported.Sunitinib rechallenge is a feasible treatment option with potential clinical benefit for mRCC patients. Disease progression with first-line sunitinib may not be associated with complete or irreversible resistance to therapy.


PubMed | Hopital Bichat, University of Versailles, University of Nantes, Bordeaux University Hospital Center and 9 more.
Type: | Journal: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons | Year: 2016

Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation (LT). CLAD manifests as Bronchiolitis Obliterans Syndrome (BOS) or Restrictive Allograft Syndrome (RAS). Alloimmune reactions and epithelial-to-mesenchymal transition have been suggested in BOS. However, little is known regarding the role of allogenicity on epithelial cell differentiation. Primary human bronchial epithelial cells (BEC) were treated with activated T cells in the presence or absence of TGF-. The expression of epithelial and mesenchymal markers was investigated. The secretion of inflammatory cytokines and matrix metalloproteinase (MMP)-9 was measured in culture supernatants and in plasma from 49 stable, 29 BOS and 16 RAS lung transplant recipients (LTR). We demonstrated that C-C motif chemokine 2 (CCL2) secreted by T cells supports TGF--induced MMP-9 production by BEC after binding to C-C chemokine receptor type 2 (CCR2). Longitudinal investigation in LTR revealed a rise in plasma MMP-9 before CLAD onset. Multivariate analysis showed that plasma MMP-9 was independently associated with BOS (OR 6.19 p=0.002) or RAS (OR 3.9, p=0.024), and predicted the occurrence of CLAD twelve months before the functional diagnosis. Thus, immune cells support airway remodelling through the production of MMP-9. Plasma MMP-9 is a potential predictive biomarker of CLAD. This article is protected by copyright. All rights reserved.


Epinette J.-A.,Orthopaedic Research and Imaging Center in Arthroplasty Clinique Medico Chirurgicale | Beracassat R.,Clinique Bonnefon 45 av Carnot | Tracol P.,Clinique Saint Roch 235 | Pagazani G.,Clinique du Docteur Montagard 23 boulevard Gambetta | Vandenbussche E.,Hopital Europeen George Pompidou
Journal of Arthroplasty | Year: 2014

Hip instability after total hip replacement has been shown to be a critical cause of failure. The use of dual mobility has been classically restricted to patients "at risk", over 70. years of age. The question rises up about extended indications of so-called "modern" second generation dual mobility cups. This prospective multicenter study reports on first results at 2-5. years of the HA anatomical ADM cup upon two comparative groups of patients under 70. years (112 hips) vs. over 70. years of age (325 hips). No dislocation, migration, tilting, wear, or intra-prosthetic dislocation was recorded within each of the two cohorts. Survivorship for cup failures at this 4-year period was ideal at 100% in the younger patients, and 99.7% in the older group of patients. © 2014 Elsevier Inc.

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