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Brest P.,University of Nice Sophia Antipolis | Corcelle E.A.,Danish Cancer Society | Cesaro A.,University of Nice Sophia Antipolis | Chargui A.,University of Nice Sophia Antipolis | And 7 more authors.
Current Molecular Medicine | Year: 2010

Inflammatory bowel diseases (IBD) are common inflammatory disorders of the gastrointestinal tract that include ulcerative colitis (UC) and Crohn's disease (CD). The incidences of IBD are high in North America and Europe, affecting as many as one in 500 people. These diseases are associated with high morbidity and mortality. Colorectal cancer risk is also increased in IBD, correlating with inflammation severity and duration. IBD are now recognized as complex multigenetic disorders involving at least 32 different risk loci. In 2007, two different autophagy-related genes, ATG16L1 (autophagy-related gene 16-like 1) and IRGM (immunity-related GTPase M) were shown to be specifically involved in CD susceptibility by three independent genome-wide association studies. Soon afterwards, more than forty studies confirmed the involvement of ATG16L1 and IRGM variants in CD susceptibility and gave new information on the importance of macroautophagy (hereafter referred to as autophagy) in the control of infection, inflammation, immunity and cancer. In this review, we discuss how such findings have undoubtedly changed our understanding of CD pathogenesis. A unifying autophagy model then emerges that may help in understanding the development of CD from bacterial infection, to inflammation and finally cancer. The Pandora's box is now open, releasing a wave of hope for new therapeutic strategies in treating Crohn's disease. © 2010 Bentham Science Publishers Ltd.

Hofman V.,University of Nice Sophia Antipolis | Hofman V.,Laboratory of Clinical and Experimental Pathology | Hofman V.,French Institute of Health and Medical Research | Bonnetaud C.,Human Biobank | And 19 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Pathologic TNM staging is currently the best prognostic factor for non-small cell lung carcinoma (NSCLC). However, even in early-stage NSCLC, the recurrence rates after surgery range from 25% to 50%. The preoperative detection of circulating tumor cells (CTC) could be useful to tailor new therapeutic strategies in NSCLC. We assessed the presence of CTC in NSCLC patients undergoing surgery, using cytologic analyses, after their isolation by size of epithelial tumor cells (ISET method). The presence and the number of CTCs were considered and correlated with clinicopathologic parameters including patient follow-up. Experimental design: Of the 247 blood samples tested, 208 samples were from patients with resectable NSCLC and 39 from healthy subjects. The mean follow-up was 24 months. An image of detected cells with presumably nonhematologic features [initially defined as "circulating nonhematologic cells" (CNHC)] was recorded. The presence of CNHC was assessed blindly and independently by 10 cytopathologists, using cytologic criteria of malignancy on stained filters. The count of detected CNHCs was made for each filter. Results: One hundred two of 208 (49%) patients showed CNHCs corresponding to CNHC with malignant cytopathologic features in 76 of 208 (36%) cases. CNHCs were not detected in the control group. A level of 50 or more CNHCs corresponding to the third quartile was associated with shorter overall and disease-free-survival, independently of disease staging, and with a high risk of recurrence and death in early-stage I + II-resectable NSCLC. Conclusion: A high percentage of NSCLC patients show preoperative detection of CNHC by the ISET method. The presence and level of 50 or more CNHCs are associated with worse survival of patients with resectable NSCLC. ©2010 AACR.

Ilie M.,University of Nice Sophia Antipolis | Ilie M.,Laboratory of Clinical and Experimental Pathology | Long E.,University of Nice Sophia Antipolis | Long E.,Laboratory of Clinical and Experimental Pathology | And 12 more authors.
British Journal of Cancer | Year: 2014

Background: Previous studies indicate that endothelial injury, as demonstrated by the presence of circulating endothelial cells (CECs), may predict clinical outcome in cancer patients. In addition, soluble CD146 (sCD146) may reflect activation of angiogenesis. However, no study has investigated their combined clinical value in patients undergoing resection for non-small cell lung cancer (NSCLC). Methods: Data were collected from preoperative blood samples from 74 patients who underwent resection for NSCLC. Circulating endothelial cells were defined, using the CellSearch Assay, as CD146+CD105+CD45-DAPI+. In parallel, sCD146 was quantified using an ELISA immunoassay. These experiments were also performed on a group of 20 patients with small-cell lung cancer, 60 healthy individuals and 23 patients with chronic obstructive pulmonary disease. Results: The CEC count and the plasma level of sCD146 were significantly higher in NSCLC patients than in the sub-groups of controls (P<0.001). Moreover, an increased CEC count was associated with higher levels of sCD146 (P=0.010). Both high CEC count and high sCD146 plasma level at baseline significantly correlated with shorter progression-free survival (P<0.001, respectively) and overall survival (P=0.005; P=0.009) of NSCLC patients. Conclusions: The present study provides supportive evidence to show that both a high CEC count and a high sCD146 level at baseline correlate with poor prognosis and may be useful for the prediction of clinical outcome in patients undergoing surgery for NSCLC. © 2014 Cancer Research UK.

Doyen J.,Antoine Lacassagne Cancer Center | Doyen J.,University of Nice Sophia Antipolis | Doyen J.,French National Center for Scientific Research | Alix-Panabieres C.,Montpellier University Hospital Center | And 12 more authors.
Critical Reviews in Oncology/Hematology | Year: 2012

Prostate-specific antigen (PSA) levels in blood are widely used in prostate cancer (PCa) for the management of this disease at every stage of progression. Currently, PSA levels combined with clinical stage and Gleason score provide the best predictor of survival and the main element to monitor treatment efficiency. However, these areas could be improved by utilizing emerging biomarkers. Recently, circulating tumor cells (CTCs) and disseminating tumor cells (DTCs) have been detected in PCa and may be a new surrogate candidate. Here we provide a systematic review of the literature in order to describe the current evidence of CTC/DTC surrogacy regarding outcome of prostate cancer patients. We also discuss several markers that could be used to increase the sensitivity and specificity of CTC/DTC detection. CTC/DTC detection is performed using a wide variety of techniques. Initially, reverse transcriptase polymerase chain reaction (RT-PCR) based methods were utilized with weak correlation between their positive detection and patients' outcome. More recent immunological techniques have indicated a reproducible correlation with outcome. Such surrogate markers may enable clinicians to provide early detection for inefficient treatments and patients with poor prognosis that are candidates for treatment intensification. Dissecting the micrometastasis phenomenon in CTCs/DTCs is a key point to increase surrogacy of this biomarker. © 2011 Elsevier Ireland Ltd.

Ilie M.I.,Laboratory of Clinical and Experimental Pathology | Ilie M.I.,University of Nice Sophia Antipolis | Bence C.,Laboratory of Clinical and Experimental Pathology | Hofman V.,Laboratory of Clinical and Experimental Pathology | And 12 more authors.
Annals of Oncology | Year: 2015

Background: Patients with advanced lung adenocarcinomas expressing ALK rearrangements are highly responsive to crizotinib, a dual ALK/c-MET inhibitor. Immunohistochemistry (IHC) is an easy clinically and routinely applicable costeffective assay for ALK, c-MET and ROS1 protein expression for potential treatment with crizotinib. The purpose of this study was to evaluate the percentage and the pattern of ALK-rearranged cells, the variation in the native ALK copy number, as well as ALK, c-MET and ROS1 protein expression, and their significance on outcome of crizotinib-treated lung adenocarcinoma patients. Patients and methods: Consecutive lung adenocarcinoma specimens (n = 176) 'double-negative' (wild-type EGFR and KRAS) were tested for ALK rearrangements/copy number alterations and for ALK, c-MET and ROS1 protein expression using automated standardized protocols. Preliminary data on the outcome of crizotinib-treated patients were recorded. Results: FISH analysis identified 26/176 (15%) cases with ALK rearrangements. Seven cases had discordant results between the ALK FISH and IHC. Five cases with discordant FISH-positive/IHC-negative revealed FISH 'borderline' positivity (15%-20%). Three cases overexpressed c-MET and responded to crizotinib, and two cases with ALK-'borderline' rearranged cells only, not associated with c-MET expression, progressed under crizotinib. Two cases with discordant FISH-negative/IHC-positive revealed ALK gene amplification without associated c-MET or ROS1 protein expression. Conclusions: The discrepancies observed between the IHC and FISH data revealed unexpected biological events, rather than technical issues, which potentially can have a strong impact on the therapeutic strategy with crizotinib. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

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