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Sainte-Anne-sur-Brivet, France

Goodwin G.M.,University of Oxford | Boyer P.,University of Ottawa | Boyer P.,University Paris Diderot | Emsley R.,Stellenbosch University | And 2 more authors.
International Clinical Psychopharmacology | Year: 2013

The present paper reports in parallel the findings of the two studies that evaluated the efficacy of agomelatine in preventing relapse of depression. It describes the methodological adjustments made between the first and the second trial, particularly in relation to patient selection and accuracy of diagnosis of depression. Patients with major depressive disorder who responded to an 8/10-week course of agomelatine 25-50 mg treatment were randomly assigned to receive continuation treatment with agomelatine or placebo during a 24-week, randomized, double-blind treatment period with an optional 18-or 20-week double-blind extension period. The cumulative probability of relapse was calculated using the Kaplan-Meier method of survival analysis. Study 1 lacked assay sensitivity because of an unexpectedly low relapse rate in the placebo arm, but was instructive in showing that the agomelatine effect was better than placebo only in those patients with higher symptom levels at baseline. Study 2 showed a robust benefit of agomelatine-a two-fold reduction in the relapse rate-observed at least up to 10 months in both the overall population and the more severely depressed patients. The methodological adjustments introduced in study 2 (e.g. a minimum subscore calculated from eight specific Hamilton Depression Rating Scale items, the use of the self-rating questionnaire Hospital Anxiety Depression Scale and the Sheehan questionnaire) have assured an adequate severity of depression not only on the basis of ratings of symptom severity but also on measures of functional impairment. We did not find increased severity of symptoms in study 2, but we hypothesize that the increased demands on investigators improved the quality of recruitment to represent more real-world patients. Adopting these innovations could contribute towards lower failure rates for future placebo-controlled clinical trials in the field. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Purpose: The high incidence of recurrence and unpredictable clinical outcome for pediatric ependymoma reflect the imprecision of current therapeutic staging and need for novel risk stratification markers. We therefore evaluated 1q25 gain across three age- and treatment-defined European clinical trial cohorts of pediatric intracranial ependymoma. Experimental Design: Frequency of 1q gain was assessed across 48 ependymomas (42 primary, 6 recurrent) using Affymetrix 500K single-nucleotide polymorphism arrays. Gain of 1q25 was then evaluated by interphase FISH across 189 tumors treated on the Children's Cancer Leukaemia Group/International Society for Pediatric Oncology (SIOP) CNS9204 (n = 60) and BBSFOP (n = 65) adjuvant chemotherapy trials, or with primary postoperative radiotherapy (SIOP CNS9904/RT, n=64). Results were correlated with clinical, histologic, and survival data. Results: Gain of 1q was the most frequent imbalance in primary (7/42, 17%) and recurrent ependymomas (2/6, 33%). Gain of 1q25 was an independent predictor of tumor progression across the pooled trial cohort [HR = 2.55; 95% confidence interval (CI): 1.56-4.16; P = 0.0002] and both CNS9204 (HR = 4.03; 95% CI: 1.88-8.63) and BBSFOP (HR = 3.10; 95% CI: 1.22-7.86) groups. The only clinical variable associated with adverse outcome was incomplete tumor resection. Integrating tumor resectability with 1q25 status enabled stratification of cases into disease progression risk groups for all three trial cohorts. Conclusions: This is the first study to validate a prognostic genomic marker for childhood ependymoma across independent trial groups. 1q25 gain predicts disease progression and can contribute to patient risk stratification. We advocate the prospective evaluation of 1q25 gain as an adverse marker in future international clinical trials. ©2012 AACR.

Chassoux F.,Sainte Anne Hospital | Chassoux F.,Center Hospitalier Sainte Anne | Daumas-Duport C.,Sainte Anne Hospital | Daumas-Duport C.,University of Paris Descartes
Epilepsia | Year: 2013

Dysembryoplastic neuroepithelial tumors (DNTs) belong to the surgically treatable long-term epilepsy-associated group of tumors. Based on cortical specimens provided through epilepsy surgery at Sainte-Anne hospital, three histologic subtypes (simple, complex, and nonspecific) have been described. Electroclinical data, imaging, intralesional recordings (stereo- electroencephalography [EEG]) and histologic correlations have been recently reviewed in order to assess the relationship between the epileptogenic zone (EZ), the tumor, and associated focal cortical dysplasia (FCD), and to determine optimal strategy for curing epilepsy. Based on a large series (78 patients, 50 male, aged 3-54 years, temporal location 73%, nonspecific forms 68%), we found similar electroclinical data in all DNT subtypes, and demonstrated that magnetic resonance imaging (MRI) features allow differentiation of histologic subtypes. Type 1 (cystic/polycystic-like) always corresponded to complex or simple forms, whereas type 2 (nodular-like) and type 3 (dysplastic-like) corresponded to nonspecific forms. It is notable that we demonstrated intrinsic epileptogenicity in all cases, but found that the EZ differed significantly according to MRI subtype, colocalizing with the tumor in type 1 MRI, including perilesional cortex in type 2 MRI, and involving extensive areas in type 3 MRI. The main prognostic factors for favorable outcome (83% of seizure-free patients) were complete tumor and EZ removal, short epilepsy duration, and lack of cortico-subcortical damage. According to these findings, surgical resection may be restricted to the tumor in type 1 MRI but should be more extensive in other MRI subtypes, especially in type 3 MRI. This MRI-based scheme may be helpful for optimal resection in epilepsy due to DNTs. In addition, we emphasize that early surgery is crucial in curing epilepsy. © 2013 International League Against Epilepsy.

Degrassat-Thas A.,University of Paris Dauphine | Bensadon M.,Technical Agency of Information on Hospitals ATIH | Rieu C.,Sainte Anne Hospital | Angalakuditi M.,Eisai Inc | And 2 more authors.
PharmacoEconomics | Year: 2012

In 2005, the French Government implemented a new way of financing high-cost drugs for hospitals in order to promote innovation. Such drugs are gathered on a positive list, established by the Ministry of Health, with a reimbursement price cap. Hospitals still negotiate with pharmaceutical firms, who set their prices freely, and then charge the national health insurance according to their consumption, without budgetary constraints, but on the condition of good use of care. They are not allowed to charge a price higher than this ceiling price, which is called the 'responsibility tariff' (RT). This measure is included in another, larger reform, which concerns hospital financing through allotted amounts at a specific diagnosis-based level. The purpose of this add-on payment on top of the health funds is firstly to avoid heterogeneity in costs per diagnostic-related group and secondly to avoid an uncontrolled increase of prices due to a lack of interest in negotiation from hospitals, as supplementary funding could reduce hospital price sensitivity. Objectives: The aim of this work was to assess the bargaining power of hospitals with the pharmaceutical firms in the monopoly market of innovative cancer drugs since the implementation of this reimbursement price cap. Methods: This study used data from the French Technical Agency of Information on Hospitals (ATIH; Agence Technique de l'Information sur l'Hospitalisation) and included 487 hospitals, which were public and non-profit private. The analysis was conducted on the cancer drugs of the regulated list. An index representing the ratio of the purchase prices to the RT was built from 2004 to 2007 in order to make a 'beforeα;ndα; fter' comparison. Results: Results showed a transient price decrease in 2005 before an alignment of patented drugs with regulated prices in the context of a dynamic market with a 22.5% yearly growth rate in value between 2004 and 2007.Conclusion: Hospitals are able to impose the RT for single-brand drugs. However, they are no longer able to negotiate below the RT except for generic drugs. Negotiations take place upstream for setting the RT between the public authorities and the firms. Adis © 2012 Springer International Publishing AG.

Pallud J.,Sainte Anne Hospital | Pallud J.,University Paris - Sud | Varlet P.,Sainte Anne Hospital | Varlet P.,University of Paris Descartes | And 10 more authors.
Neurology | Year: 2010

BACKGROUND: Imaging determinations of the spatial extent of diffuse low-grade gliomas (DLGGs) are of paramount importance in evaluating the risk-to-benefit ratio of surgical resection. However, it is not clear how accurately preoperative conventional MRI can delineate DLGGs. METHODS: We report a retrospective histologic and imaging correlation study in 16 adult patients who underwent serial stereotactic biopsies for the diagnosis of untreated supratentorial well-defined and non-contrast-enhanced DLGG, in whom biopsy samples were taken within and beyond (OutBSs) MRI-defined abnormalities. RESULTS: Thirty-seven OutBSs that extended from 10 to 26 mm beyond MRI-defined abnormalities were studied. Immunostaining revealed MIB-1-positive cells (i.e., cycling cells) in all but 2 of the OutBSs. None of the MIB-1-positive cells coexpressed glial fibrillary acidic protein, and all of them coexpressed OLIG2. MIB-1-positive cells were cycling isolated tumor cells, because 1) their morphologic characteristics reflected those of tumor cells, 2) the number of MIB-1-positive cells per square centimeter was significantly higher than that of controls, 3) the number of MIB-1-positive cells per square centimeter was positively correlated with the tumor growth fraction (p = 0.012), and 4) the number of MIB-1-positive cells per square centimeter in OutBSs decreased with distance from the tumor (p = 0.003). CONCLUSIONS: This study demonstrates, using a multiscale correlative approach, that conventional MRI underestimates the actual spatial extent of diffuse low-grade gliomas (DLGGs), even when they are well delineated. These results suggest that an extended resection of a margin beyond MRI-defined abnormalities, whenever feasible in noneloquent brain areas, might improve the outcome of DLGGs Copyright © 2010 by AAN Enterprises, Inc.

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