Sotteville-lès-Rouen, France
Sotteville-lès-Rouen, France

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Marie I.,University of Rouen | Hatron P.Y.,Lille University Hospital Center | Dominique S.,CHU Rouen | Cherin P.,Hopital Pitie Salpetriere | And 4 more authors.
Seminars in Arthritis and Rheumatism | Year: 2012

Objectives: The aims of the present study were to (1) assess clinical features and long-term outcome in anti-Jo1-positive patients with anti-Ro52 antibody; (2) compare characteristics of anti-Jo1-positive patients with and without anti-Ro52 antibody; and (3) compare features of anti-Ro52-positive patients with and without anti-Jo1 antibody. Methods: The medical records of 89 consecutive anti-Jo1-positive patients with antisynthetase syndrome (ASS) were reviewed; 36 of these patients had coexistent anti-Ro52 antibody. Furthermore, the medical records of 13 consecutive anti-Ro52-positive patients without anti-Jo1 antibody were also reviewed. Results: Nine anti-Jo1-positive patients (25%) with anti-Ro-52 antibody achieved remission of ASS, whereas 19 other patients (52.8%) improved and 8 patients (22.2%) worsened their clinical status. Anti-Jo1-positive patients with anti-Ro52 antibody experienced ASS-related complications: interstitial lung disease (n = 28), esophageal dysfunction (n = 9), and joint manifestations (n = 25), including periarticular hydroxyapatite calcifications and erosions of metacarpophalangeal and interphalangeal joints and wrists (n = 3); 7 anti-Ro52-positive patients (19.4%) had cancer. Anti-Jo1-positive patients with anti-Ro52 antibody, compared with those without, more commonly experienced deterioration of myositis and joint involvement, symptomatic form of ILD, and cancer; they also had decreased survival rate (P = 0.05). We further found that anti-Ro52-positive patients with anti-Jo1 antibody, compared with those without, were younger and more frequently exhibited ILD with poorer prognosis. Conclusions: Our series underlines that the presence of anti-Ro52 antibody is associated with a particular phenotype of ASS, leading to more severe myositis and joint impairment. Moreover, the coexistence of anti-Ro52 antibody seems to be associated with an increased risk of cancer. We therefore suggest that anti-Jo1-positive patients should routinely undergo the search for anti-Ro52 antibody, as this autoantibody appears to impact patients' prognosis. © 2012 Elsevier Inc.


Marie I.,CHU Rouen | Menard J.-F.,CHU Rouen | Hachulla E.,Lille University Hospital Center | Cherin P.,CHU Pitie Salpetriere | And 3 more authors.
Seminars in Arthritis and Rheumatism | Year: 2011

Objectives: To assess the prevalence and characteristics of severe pyogenic, nonpyogenic, and opportunistic infections in polymyositis and dermatomyositis (PM/DM) patients and to evaluate the predictive values for infections on clinical presentation and biochemical findings of PM/DM to detect patients at risk for such infections. Methods: The medical records of 279 consecutive PM/DM patients in 3 medical centers were reviewed. Results: One hundred four severe infections occurred in our patients (37.3%), ie, pyogenic (n = 71) and nonpyogenic/opportunistic infections (n = 33). Pyogenic infections were mainly due to aspiration pneumonia (n = 46) and calcinosis cutis infection. Thirty-three PM/DM patients developed nonpyogenic/opportunistic infections that were due to the following: Candida albicans, Pneumocystis jiroveci, Aspergillus fumigatus, Geotrichum capitatum, Mycobacterium (avium-intracellulare complex, xenopi, marinum, peregrinum, tuberculosis), Helicobacter heilmanii, cytomegalovirus, herpes simplex and zoster virus, hepatitis B and C, JC virus, Leishmania major, Strongyloides stercoralis. Esophageal dysfunction, ventilatory insufficiency, malignancy, and lymphopenia were significantly more frequent in the group of PM/DM patients with infections. Conclusion: Our study underscores the high frequency of infections in PM/DM, resulting in an increased mortality rate. Our results suggest that prophylaxis against pyogenic infections should be routinely recommended for patients with PM/DM, including regular physical examination of lungs to depict aspiration pneumonia as well as risk factors of aspiration pneumonia. Finally, because a great variety of micro-organisms may be responsible for opportunistic infections, it seems difficult to initiate primary prophylaxis in PM/DM patients exhibiting risk factors for opportunistic infections. © 2011 Elsevier Inc.


Van Belle E.,Heart Catheterization Laboratory | Van Belle E.,Lille University | Juthier F.,Heart Catheterization Laboratory | Juthier F.,Lille University | And 23 more authors.
Circulation | Year: 2014

BACKGROUND-: Significant postprocedural aortic regurgitation (AR) is observed in 10% to 20% of cases after transcatheter aortic valve replacement (TAVR). The prognostic value and the predictors of such a complication in balloon-expandable (BE) and self-expandable (SE) TAVR remain unclear. METHODS AND RESULTS-: TAVR was performed in 3195 consecutive patients at 34 hospitals. Postprocedural transthoracic echocardiography was performed in 2769 (92%) patients of the eligible population, and these patients constituted the study group. Median follow-up was 306 days (Q1-Q3=178-490). BE and SE devices were implanted in 67.6% (n=1872) and 32.4% (n=897). Delivery was femoral (75.3%) or nonfemoral (24.7%). A postprocedural AR≥grade 2 was observed in 15.8% and was more frequent in SE (21.5%) than in BE-TAVR (13.0%, P=0.0001). Extensive multivariable analysis confirmed that the use of a SE device was one of the most powerful independent predictors of postprocedural AR≥grade 2. For BE-TAVR, 8 independent predictors of postprocedural grade 2 were identified including femoral delivery (P=0.04), larger aortic annulus (P=0.0004), and smaller prosthesis diameter (P=0.0001). For SE-TAVR, 2 independent predictors were identified including femoral delivery(P=0.0001). Aortic annulus and prosthesis diameter were not predictors of postprocedural AR for SE-TAVR. A postprocedural AR≥grade 2, but not a postprocedural AR=grade 1, was a strong independent predictor of 1-year mortality for BE (hazard ratio=2.50; P=0.0001) and SE-TAVR (hazard ratio=2.11; P=0.0001). Although postprocedural AR≥grade 2 was well tolerated in patients with AR grade 2 at baseline (1-year mortality=7%), it was associated with a very high mortality in other subgroups: renal failure (43%), AR


Mescam-Mancini L.,Grenoble University Hospital Center | Lantuejoul S.,Grenoble University Hospital Center | Lantuejoul S.,French Institute of Health and Medical Research | Moro-Sibilot D.,Grenoble University Hospital Center | And 11 more authors.
Lung Cancer | Year: 2014

Objectives: ROS1 proto-oncogene translocations define a new molecular subgroup in non-small cell lung cancers (NSCLC) and are associated with a response to the MET/ALK inhibitor, crizotinib. These rearrangements are described in 0.9-1.7% NSCLC, in wild-type EGFR, KRAS and ALK ("triple negative") lung adenocarcinomas. Rapid and efficient identification of these alterations is thus becoming increasingly important. Materials and methods: In this study, 121 triple negative lung adenocarcinomas were screened by both IHC with the ROS1 D4D6 antibody, and FISH using two commercially available ROS1 break-apart probes. To address a possible cross-reactivity of the ROS1 antibody with other protein kinase receptors, we screened 80 additional cases with known EGFR, KRAS, PI3KCA, BRAF, HER2 mutations or ALK-rearrangement. Results: We diagnosed 9 ROS1-rearranged adenocarcinomas, with both a positive FISH result (51-87% rearranged nuclei) and a positive IHC staining (2+/3+ cytoplasmic staining). Only one of the ROS1-positive FISH cases was characterized by a classical split pattern, the others showed a variant pattern, most commonly involving a loss of the 5' telomeric probe. Considering a positivity threshold of 2+ stained cells, the sensitivity of the ROS1 D4D6 antibody compared to FISH was 100% and the specificity 96.9%, as two HER2-mutated tumors were positive with D4D6 antibody, without any translocation in FISH. All the ROS1-positive cases were at an advanced stage, arising in never or light smokers. They were mainly solid cribriform and acinar adenocarcinomas, with signet ring cells noted in 5 cases, and calcifications in 3 cases. One positive case was an invasive mucinous carcinoma. Conclusion: Our results show that a screening algorithm based on an IHC detection of ROS1 fusion proteins, confirmed if positive or doubtful by a ROS1 break-apart FISH assay, is pertinent in advanced "triple negative" lung adenocarcinomas, since the prevalence of ROS1-positive cases in this selected population reaches 7.4% in our series. © 2013 Elsevier Ireland Ltd.


Marie I.,University of Rouen | Leroi A.-M.,University of Rouen | Menard J.-F.,CHU Rouen | Levesque H.,University of Rouen | And 2 more authors.
Autoimmunity Reviews | Year: 2015

Fecal calprotectin (FC) is a simple, non-invasive and reproducible test, which has been described to be highly elevated in patients with active inflammatory bowel diseases. Recently, few authors have reported increased levels of FC in SSc patients, although the relationship between FC levels and the degree of gastrointestinal involvement has not yet been determined in patients with SSc. Thus, this prospective study aimed to: 1) determine the prevalence of increased fecal calprotectin (FC) levels in unselected patients with systemic sclerosis (SSc); 2) make prediction about which SSc patients exhibit increased levels of FC; and 3) evaluate the correlation between increased levels of FC and digestive symptoms, and gastrointestinal involvement, including the presence of small intestinal bacterial overgrowth (SIBO) using glucose H2/CH4 breath test.125 consecutive patients with SSc underwent FC levels and glucose H2/CH4 breath test. All of the patients with SSc also completed a questionnaire on digestive symptoms, and a global symptom score (GSS) was calculated.93 (74.4%) patients had abnormal levels of FC (>50μg/g); 68 patients (54.4%) exhibited highly elevated levels of FC (>200μg/g). A marked correlation was found between abnormal FC levels and GSS score of digestive symptoms, esophageal involvement and delayed gastric emptying. Moreover, we found a strong association between abnormal levels of FC and the presence of SIBO on glucose H2/CH4 breath test, with the higher correlation between the presence of SIBO and the level of FC ≥275μg/g with an area under the receiver operating characteristic curve of 0.97±0.001 (CI: 0.93-0.99; p<10-6); the sensitivity of FC level ≥275μg/g for predicting SIBO was as high as 0.93, while the specificity was 0.95. Finally, eradication of SIBO was obtained in 52.4% of the SSc patients with a significant improvement of intestinal symptoms. Finally, after 3months of rotating courses of alternative antibiotic therapy, eradication of SIBO was associated with significant decrease of FC levels in SSc patients.The current study underscores that abnormal FC levels were correlated with gastrointestinal impairment, especially SIBO. Because FC levels ≥. 275. μg/g were markedly associated with the presence of SIBO, our findings suggest that FC may be a helpful test in identifying the group of SSc patients at high risk for SIBO requiring glucose breath test to detect SIBO. Finally, we also suggest that FC levels may be helpful in SSc patients to assess SIBO eradication, as long-term antibiotic therapy is costly and carries risks such as the onset of pseudo-membranous colitis and SIBO-related antibiotic resistance. © 2014 Elsevier B.V.


Marie I.,University of Rouen | Gehanno J.-F.,CHU Rouen
Seminars in Immunopathology | Year: 2015

Systemic sclerosis (SSc) has a complex pathogenesis. Although, there is a growing evidence that environmental factors have an impact on alterations and modulation of epigenetic determinants, resulting in SSc onset and progression. A marked correlation has thus been found between SSc onset and occupational exposure to crystalline silica and the following organic solvents: white spirit, aromatic solvents, chlorinated solvents, trichloroethylene, and ketones; the risk associated with high cumulative exposure to silica and organic solvents further appears to be strongly increased in SSc. Altogether, occupational exposure should be systematically checked in all SSc patients at diagnosis, as (1) exposed patients seem to develop more severe forms of SSc and (2) the identification of the occupational agents will allow its interruption, which may lead to potential improvement of SSc outcome. By contrast, based on current published data, there is insufficient evidence that exposure to other chemical agents (including notably pesticides as well as personal care such as silicone and hair dye), physical agents (ionizing radiation, ultraviolet radiation, electric and magnetic fields), and biological agents (infections and diet, foods, and dietary contaminants) is a causative factor of SSc. Further investigations are still warranted to identify other environmental factors that may be associated with SSc onset and progression. © 2015, Springer-Verlag Berlin Heidelberg.


Marie I.,CHU Rouen | Marie I.,University of Rouen | Gehanno J.-F.,CHU Rouen | Bubenheim M.,CHU Rouen | And 11 more authors.
Autoimmunity Reviews | Year: 2014

Introduction: Systemic sclerosis (SSc) has complex pathogenesis and likely multifactorial causes. Environmental exposures have been suggested to play a role in SSc pathogenesis, including occupational exposure to pollutants and chemicals as well as use of drugs leading to modulation of immune response. Thus, this case-control study aimed to assess: the relationship between SSc and occupational exposure; and the risk of SSc related to occupational exposure in male and female patients. Methods: From 2005 to 2008, 100 patients with a definite diagnosis of SSc were included in the study; 3 age, gender, and smoking habits matched controls were selected for each patient. A committee of experts evaluated blindly occupational exposure to crystalline silica, white spirit, organic solvents, ketones, welding fumes, epoxy resins, and pesticides; an occupational exposure score was calculated for all subjects. Our findings were compared with previous data in the literature. Results: Increased ORs for SSc were found for: crystalline silica (p < 0.0001), white spirit (p < 0.0001), aromatic solvents (p = 0.0002), chlorinated solvents (p = 0.014), trichlorethylene (p = 0.044), ketones (p = 0.002) and welding fumes (p = 0.021). Elevated risk associated with high final cumulative score in SSc was observed for: crystalline silica, white spirit, chlorinated solvents, trichlorethylene, aromatic solvents, any type of solvents, ketones and welding fumes. A marked association between SSc and occupational exposure was further found for: 1) crystalline silica, chlorinated solvents, trichloroethylene, white spirit, ketones and welding fumes in male patients; and 2) white spirit, aromatic solvents, any type of solvent and ketones in female patients. Finally, we did not find an association between SSc and: 1) the use of drugs that have been speculated to play a role in SSc onset (anorexigens, pentazocine, bromocriptine, l-tryptophan); 2) implants - that are prosthesis, silicone implants, and contact lenses; and 3) dyeing hair. In the literature, SSc has been associated with occupational exposure to silica and solvents, while the association between SSc and specific organic solvents and welding fumes has been anecdotally reported. Conclusion: The following occupational factors have an impact in the development of SSc: crystalline silica, white spirit, aromatic solvents, chlorinated solvents, trichlorethylene, ketones and welding fumes. The risk of SSc appears to be markedly associated with high cumulative exposure. Finally, the association between SSc and occupational exposure may be variable according to gender. © 2013 Elsevier B.V.


Kerebel D.,French Army Hospital Sainte Anne | Joly L.-M.,CHU Rouen | Honnart D.,CHU Dijon | Schmidt J.,CHU Clermont Ferrand | And 4 more authors.
Critical Care | Year: 2013

Introduction: Prothrombin complex concentrates (PCC) are haemostatic blood preparations indicated for urgent anticoagulation reversal, though the optimal dose for effective reversal is still under debate. The latest generation of PCCs include four coagulation factors, the so-called 4-factor PCC. The aim of this study was to compare the efficacy and safety of two doses, 25 and 40 IU/kg, of 4-factor PCC in vitamin K antagonist (VKA) associated intracranial haemorrhage.Methods: We performed a phase III, prospective, randomised, open-label study including patients with objectively diagnosed VKA-associated intracranial haemorrhage between November 2008 and April 2011 in 22 centres in France. Patients were randomised to receive 25 or 40 IU/kg of 4-factor PCC. The primary endpoint was the international normalised ratio (INR) 10 minutes after the end of 4-factor PCC infusion. Secondary endpoints were changes in coagulation factors, global clinical outcomes and incidence of adverse events (AEs).Results: A total of 59 patients were randomised: 29 in the 25 IU/kg and 30 in the 40 IU/kg group. Baseline demographics and clinical characteristics were comparable between the groups. The mean INR was significantly reduced to 1.2 - and ≤1.5 in all patients of both groups - 10 minutes after 4-factor PCC infusion. The INR in the 40 IU/kg group was significantly lower than in the 25 IU/kg group 10 minutes (P = 0.001), 1 hour (P = 0.001) and 3 hours (P = 0.02) after infusion. The 40 IU/kg dose was also effective in replacing coagulation factors such as PT (P = 0.038), FII (P = 0.001), FX (P <0.001), protein C (P = 0.002) and protein S (0.043), 10 minutes after infusion. However, no differences were found in haematoma volume or global clinical outcomes between the groups. Incidence of death and thrombotic events was similar between the groups.Conclusions: Rapid infusion of both doses of 4-factor PCC achieved an INR of 1.5 or less in all patients with a lower INR observed in the 40 IU/kg group. No safety concerns were raised by the 40 IU/kg dose. Further trials are needed to evaluate the impact of the high dose of 4-factor PCC on functional outcomes and mortality.Trial registration: Eudra CT number 2007-000602-73. © 2013 Kerebel et al.; licensee BioMed Central Ltd.


Resection of pancreatic adenocarcinoma is the only chance for cure giving a survival for resectable tumors between 20 and 30 months after adjuvant therapy. The primary driver of clinical management is the feasability of surgical resection. To guide surgical indications, resectability criteria have been defined, but the literature and published data are heterogeneous. Several groups have formulated their criteria to describe pancreatic tumors in terms of operability, each focusing on the anatomic interface between the tumor and its surrounding critical structures. These include the MD Anderson Cancer Center (MDACC), American Hepato Pancreato Biliary Assocation (AHPBA) and National Comprehensive Cancer Network (NCCN) criteria. These systems define resectable disease, borderline resectable disease and locally advanced unresectable disease. These classification systems are based on standardized CT-scan analysis. American recommandations have been updated in early 2014. Although these classifications are informative, they should not be used without analysis of clinical and laboratory data which are required for therapeutic decision Recent advances in terms of chemotherapy based on FOLFIRINOX and nabpaclitaxel suggest the interest of sequential management for unresectable disease with firstly neoadjuvant treatment, secondly repeated monitoring and evaluation of resectability and thirdly surgery for well selected candidates. The evaluation of tumor's resectability is currently the key criteria guiding oncological management according to the tumoral stage.


Marie I.,CHU Rouen | Dominique S.,CHU Rouen | Janvresse A.,CHU Rouen | Levesque H.,CHU Rouen | Menard J.-F.,CHU Rouen
Respiratory Medicine | Year: 2012

Objective: To report our experience using rituximab as therapy for refractory antisynthetase syndrome (ASS)-associated interstitial lung disease. Methods: We retrospectively evaluated the medical records of 7 ASS patients with refractory interstitial lung disease, which had previously failed to respond to prednisone and/or other cytotoxic drugs. All 7 patients received rituximab therapy, i.e.: 1 g at days 0 and 14 and at 6-month follow-up. Data on pulmonary symptoms, pulmonary function tests and high resolution computed tomography (HRCT) scan of the lungs were collected: 1) before rituximab initiation; and 2) at 6-month and one-year follow-up after the first infusion of rituximab. Results: At one-year follow-up, ASS patients had resolution (n = 2) or improvement of pulmonary clinical manifestations. Patients also exhibited significant improvement of interstitial lung disease parameters: 1) on pulmonary function tests: FVC (p = 0.03) and DLCO (p = 2 × 10 -5); 2) and HRCT-scan of the lungs. Due to clinical resolution/improvement of interstitial lung disease, the median daily dose of oral prednisone could be reduced in these 7 ASS patients at one-year follow-up, compared with baseline (20 mg/day vs. 9 mg/day; p = 0.015). Conclusion: Our findings suggest that rituximab may be a helpful therapy for refractory interstitial lung disease in patients with ASS. © 2012 Elsevier Ltd. All rights reserved.

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