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Murviel-lès-Montpellier, France

Toulmonde M.,Institute Bergonie | Bonvalot S.,Institute Gustave Roussy | Meeus P.,The Surgical Center | Stoeckle E.,Institute Bergonie | And 17 more authors.
Annals of Oncology

Background: Retroperitoneal sarcomas (RPS) are heterogeneous. No previous study has investigated the impact of specialized surgery, evaluated locoregional relapse (LRR), abdominal sarcomatosis and distant metastatic relapse as separate events, or considered histological subtypes separately. This study addresses these specific points in a homogeneous cohort of patients with completely resected primary RPS. Patients and methods: We conducted a retrospective analysis of adult patients diagnosed with a RPS between 1 January 1988 and 31 December 2008 and eventually referred to one of 12 centers of the French Sarcoma Group. All cases were centrally reviewed by an expert pathologist. Results: Five hundred eighty-six patients were included. Median follow-up was 6.5 years [95% confidence interval (CI) 5.9-7.1]. Five hundred thirty-seven patients had localized disease and 389 patients (76%) had macroscopically complete resection of the tumor. In this latter group, the 5-year LRR-free survival rate was 46% [41-52] and the 5-year overall survival (OS) rate was 66% [61-71]. In multivariate analysis, gender, adjacent organ involvement, specialization of the surgeon, piecemeal resection and perioperative radiotherapy were independently associated with LRR. Specialization of the surgeon and piecemeal resection were independently associated with abdominal sarcomatosis whereas histology and adjacent organ involvement were independently associated with distant metastasis. Age, gender, grade, adjacent organ involvement and piecemeal resection were significantly associated with OS. Prognostic factors for LRR and OS were analyzed in well-differentiated and dedifferentiated liposarcomas and leiomyosarcomas. Grade 3 was an independent prognostic factor for OS of dedifferentiated liposarcomas. Conclusion: This study underlines the crucial role of pretherapeutic assessment and meticulous histological examination of RPS as well as the need to consider histological subtypes separately. Surgery in a specialized center and avoidance of piecemeal resection stand out as the two most important prognostic factors for RPS and highlight the importance of treating these patients in specialized centers. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source

Toulmonde M.,Institute Bergonie | Bonvalot S.,Institute Gustave Roussy | Ray-Coquard I.,Center Leon Berard | Stoeckle E.,Institute Bergonie | And 17 more authors.
Annals of Oncology

Background: Retroperitoneal sarcomas (RPS) are heterogeneous. Advanced stages include unresectable locoregional (LR) disease, abdominal sarcomatosis and distant metastasis. There is no available report assessing palliative chemotherapy in advanced RPS. This study analyzes management and outcome in a large cohort of patients with advanced RPS, considering main histological subtypes separately. Patients and methods: We conducted a retrospective analysis of adult patients diagnosed with a RPS between 1 January 1988 and 31 December 2008 across 12 centers of the French Sarcoma Group. All cases were centrally reviewed by an expert pathologist. Results: Five-hundred eighty-six patients were included, 299 patients received palliative chemotherapy, with a median of two lines (range 0-8). Fifty patients underwent palliative surgery. Two hundred fifty-five patients (85%) were assessable for response after first line of chemotherapy. Among them, 69 patients (27%) had progressive disease, 145 (57%) had stable disease, 37 (14.5%) had partial response and 4 (1.5%) complete response. Median time from first line of palliative chemotherapy to progression was 5.9 months [4.9-7.3] and median overall survival (OS), 15.8 months [13-18]. In multivariate analysis, prognosis factors independently associated with poor OS were male gender, performance status (PS) >1 and grade >1. There was no difference according to stage of disease. Palliative surgery did not appear to add any survival benefit. Conclusion: These results emphasize the scarcity of available options for RPS in the advanced setting and the urgent need to develop new strategies. Patients with good PS should be included in clinical trials and best supportive care should be considered in those with poor PS. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source

Werbrouck J.,Belgian Cancer Registry | Bouche G.,Reliable Cancer Therapies | De Jonge E.,Gynecology Obstetrics | Jacomen G.,Anatomopathology | And 9 more authors.
Gynecologic Oncology

Objective Describe the methodology and selection of quality indicators (QI) to be implemented in the EFFECT (EFFectiveness of Endometrial Cancer Treatment) project. EFFECT aims to monitor the variability in Quality of Care (QoC) of uterine cancer in Belgium, to compare the effectiveness of different treatment strategies to improve the QoC and to check the internal validity of the QI to validate the impact of process indicators on outcome. Methods A QI list was retrieved from literature, recent guidelines and QI databases. The Belgian Healthcare Knowledge Center methodology was used for the selection process and involved an expert's panel rating the QI on 4 criteria. The resulting scores and further discussion resulted in a final QI list. An online EFFECT module was developed by the Belgian Cancer Registry including the list of variables required for measuring the QI. Three test phases were performed to evaluate the relevance, feasibility and understanding of the variables and to test the compatibility of the dataset. Results 138 QI were considered for further discussion and 82 QI were eligible for rating. Based on the rating scores and consensus among the expert's panel, 41 QI were considered measurable and relevant. Testing of the data collection enabled optimization of the content and the user-friendliness of the dataset and online module. Conclusions This first Belgian initiative for monitoring the QoC of uterine cancer indicates that the previously used QI selection methodology is reproducible for uterine cancer. The QI list could be applied by other research groups for comparison. © 2013 Elsevier Inc. Source

Cubizolle A.,Institute Of Genetique Moleculaire Of Montpellier | Cubizolle A.,Montpellier University | Serratrice N.,Institute Of Genetique Moleculaire Of Montpellier | Serratrice N.,Montpellier University | And 24 more authors.
Molecular Therapy

Severe deficiency in lysosomal β-glucuronidase (β-glu) enzymatic activity results in mucopolysaccharidosis (MPS) VII, an orphan disease with symptoms often appearing in early childhood. Symptoms are variable, but many patients have multiple organ disorders including neurological defects. At the cellular level, deficiency in β-glu activity leads to abnormal accumulation of glycosaminoglycans (GAGs), and secondary accumulation of GM2 and GM3 gangliosides, which have been linked to neuroinflammation. There have been encouraging gene transfer studies in the MPS VII mouse brain, but this is the first study attempting the correction of the >200-fold larger and challenging canine MPS VII brain. Here, the efficacy of a helper-dependent (HD) canine adenovirus (CAV-2) vector harboring a human GUSB expression cassette (HD-RIGIE) in the MPS VII dog brain was tested. Vector genomes, β-glu activity, GAG content, lysosome morphology and neuropathology were analyzed and quantified. Our data demonstrated that CAV-2 vectors preferentially transduced neurons and axonal retrograde transport from the injection site to efferent regions was efficient. HD-RIGIE injections, associated with mild and transient immunosuppression, corrected neuropathology in injected and noninjected structures throughout the cerebrum. These data support the clinical evaluation of HD CAV-2 vectors to treat the neurological defects associated with MPS VII and possibly other neuropathic lysosomal storage diseases. © The American Society of Gene & Cell Therapy. Source

Chaib-Mezrag H.,University of Kansas Medical Center | Lemacon D.,Institute Of Recherche En Cancerologie Of Montpellier | Lemacon D.,French Institute of Health and Medical Research | Lemacon D.,Montpellier University | And 13 more authors.
Molecular Cancer

Background: Human T-cell leukemia virus type 1 (HTLV-I) is a human retrovirus associated with adult T-cell leukemia (ATL), an aggressive CD4 T-cell proliferative disease with dismal prognosis. The long latency preceding the development of the disease and the low incidence suggests that the virus itself is not sufficient for transformation and that genetic defects are required to create a permissive environment for leukemia. In fact, ATL cells are characterized by profound genetic modifications including structural and numerical chromosome alterations. Results: In this study we used molecular combing techniques to study the effect of the oncoprotein Tax on DNA replication. We found that replication forks have difficulties replicating complex DNA, fork progression is slower, and they pause or stall more frequently in the presence of Tax expression. Our results also show that Tax-associated replication defects are partially compensated by an increase in the firing of back-up origins. Consistent with these effects of Tax on DNA replication, an increase in double strand DNA breaks (DDSB) was seen in Tax expressing cells. Tax-mediated increases in DDSBs were associated with the ability of Tax to activate NF-kB and to stimulate intracellular nitric oxide production. We also demonstrated a reduced expression of human translesion synthesis (TLS) DNA polymerases Pol-H and Pol-K in HTLV-I-transformed T cells and ATL cells. This was associated with an increase in DNA breaks induced by Tax at specific genome regions, such as the c-Myc and the Bcl-2 major breakpoints. Consistent with the notion that the non-homologous end joining (NHEJ) pathway is hyperactive in HTLV-I-transformed cells, we found that inhibition of the NHEJ pathway induces significant killing of HTLV-I transformed cells and patient-derived leukemic ATL cells. Conclusion: Our results suggest that, replication problems increase genetic instability in HTLV-I-transformed cells. As a result, abuse of NHEJ and a defective homologous repair (HR) DNA repair pathway can be targeted as a new therapeutic approach for the treatment of adult T-cell leukemia. © 2014 Chaib-Mezrag et al.; licensee BioMed Central Ltd. Source

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