Hôpital-Camfrout, France
Hôpital-Camfrout, France

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Quoix E.,University of Strasbourg | Ramlau R.,Regional Center for Lung Disease | Westeel V.,University of Franche Comte | Papai Z.,Pulmonologiai Osztaly | And 16 more authors.
The Lancet Oncology | Year: 2011

Background: Chemotherapy is the standard of care for advanced stages of non-small-cell lung cancer (NSCLC). TG4010 is a targeted immunotherapy based on a poxvirus (modified vaccinia virus Ankara) that codes for MUC1 tumour-associated antigen and interleukin 2. This study assessed TG4010 in combination with first-line chemotherapy in advanced NSCLC. Methods: 148 patients with advanced (stage IIIB [wet] or IV) NSCLC expressing MUC1 by immunohistochemistry, and with performance status 0 or 1, were enrolled in parallel groups in this open-label, phase 2B study. 74 patients were allocated to the combination therapy group, and received TG4010 (108 plaque forming units) plus cisplatin (75 mg/m2 on day 1) and gemcitabine (1250 mg/m2 on days 1 and 8) repeated every 3 weeks for up to six cycles. 74 patients allocated to the control group received the same chemotherapy alone. Patients were allocated using a dynamic minimisation procedure stratified by centre, performance status, and disease stage. The primary endpoint was 6-month progression-free survival (PFS), with a target rate of 40% or higher in the experimental group. Analyses were done on an intention-to-treat basis. This study is completed and is registered with ClinicalTrials.gov, number NCT00415818. Findings: 6-month PFS was 43·2% (32 of 74; 95% CI 33·4-53·5) in the TG4010 plus chemotherapy group, and 35·1% (26 of 74; 25·9-45·3) in the chemotherapy alone group. Fever, abdominal pain, and injection-site pain of any grade according to National Cancer Institute Common Toxicity Criteria were more common in the TG4010 group than in the chemotherapy alone group: 17 of 73 patients (23·3%) versus six of 72 (8·3%), 12 (16·4%) versus two (2·8%), and four (5·5%) versus zero (0%), respectively. The most common grade 3-4 adverse events were neutropenia (33 [45·2%] of patients in the TG4010 plus chemotherapy group vs 31 [43·1%] in the chemotherapy alone group) and fatigue (18 [24·7%] vs 13 [18·1%]); the only grade 3-4 events that differed significantly between groups were anorexia (three [4·1%] vs 10 [13·9%]) and pleural effusion (none vs four [5·6%]). 38 of 73 patients (52·1%) in the TG4010 plus chemotherapy group and 34 of 72 (47·2%) in the chemotherapy alone group had at least one serious adverse event. Interpretation: This phase 2B study suggests that TG4010 enhances the effect of chemotherapy in advanced NSCLC. A confirmatory phase 2B-3 trial has been initiated. Funding: Transgene SA, Advanced Diagnostics for New Therapeutic Approaches (ADNA)/OSEO. © 2011 Elsevier Ltd.


Veauthier C.,Center Hospitalier Of Belfort Montbeliard | Paul F.,Charite University Medicine Berlin and Max Delbrueck Center for Molecular Medicine | Paul F.,Charité - Medical University of Berlin
Sleep Medicine | Year: 2014

Treatment of multiple sclerosis (MS)-related fatigue is still a challenging task, given that no proven therapies exist and its mechanisms are not known. Our review highlights the relationship between MS-related fatigue and sleep disorders (SD). Although many studies suggest a higher overall prevalence of SD in MS, there are no valid and robust data to confirm this hypothesis until now except for restless legs syndrome (RLS): the prevalence of RLS in MS patients-especially in those with severe pyramidal and sensory disability-seems to be four times higher than in controls subjects. RLS is sometimes difficult to distinguish from spasticity and in case of doubt, probatory dopaminergic therapy or polysomnographic (PSG) investigations may be helpful. Nocturia may impact MS-related fatigue and should be considered. The treatment of underlying SD led to an improvement of MS-related fatigue. From a scientific point of view, SD should be examined in all studies investigating MS-related fatigue and be considered as a relevant confounder. © 2013 Elsevier B.V.


PubMed | 3 Federation francophone de cancerologie digestive FFCD, Autonomous University of Barcelona, Klinikum Wels Grieskirchen, Institute Of Cancerologie Of La Loire and 11 more.
Type: | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2016

RAS mutations have been shown to confer resistance to anti-EGFR treatment. We analyzed the results of the PETACC8 trial (cetuximab + FOLFOX vs FOLFOX) in full RAS and BRAF wildtype (WT) patients (pts) with resected stage III colon cancer.Exons 2, 3 and 4 of KRAS and NRAS, and BRAF exons 11 and 15, were sequenced using the Ampliseq colon-lung cancer panel version 2, in PETACC8 trial pts who consented to translational research. The impact of cetuximab on time to recurrence (TTR), disease-free survival (DFS) and overall survival (OS) was investigated in pts with tumors harboring RAS & BRAF WT and RAS mutations. The prognostic value of each individual mutation was also tested.Among the 2559 pts analyzed, 745 pts (29%) were known to have KRAS exon 2 mutations and 163 pts (6.4%) the BRAF V600E mutation. Of the remaining 1651 pts, 1054 were assessed by NGS, showing that a further 227 pts (21%) had KRAS exon 2,3,4 or NRAS exon 2,3,4 mutations, and that 46 pts (4.4%) had a newly diagnosed BRAF mutation. Cetuximab added to FOLFOX did not significantly improve TTR, DFS or OS in pts with RAS WT or RAS & BRAF WT tumors (HR 0.77 to 1.03, all P>0.05). Cetuximab addition was not either significantly deleterious in RAS mutant pts or in pts with rare RAS or BRAF mutations. In the overall trial population, NRAS and KRAS codon 61 mutations were the only rare mutations with the same pejorative prognostic value as KRAS exon 2 or BRAF V600E mutations.Though not significant, the clinically relevant 0.76 adjusted HR observed for DFS in favor of adding cetuximab to FOLFOX, in full RAS and BRAF WT stage III colon cancer pts, may justify a new randomized controlled trial testing EGFR inhibitors in this setting.Clinical trial number: This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.


Henrotin Y.,University of Liège | Chevalier X.,Hopital Henri Mondor | Deberg M.,Artialis S.A. | Balblanc J.C.,Center Hospitalier Of Belfort Montbeliard | And 7 more authors.
Journal of Orthopaedic Research | Year: 2013

To measure the evolution of the serum levels of specific Osteoarthritis (OA) biomarker, Coll2-1 and Coll2-1 NO2 in knee osteoarthritic patients after viscosupplementation (VS). Fifty-one patients with unilateral symptomatic knee were recruited for this prospective open label study. They received three intra-articular injections of 2 ml of hyaluronic acid (Hylan GF-20) and were followed for 3 months. Walking pain was evaluated and serum samples were taken at each visit. Coll2-1 and Coll2-1 NO2 were measured in the serum using specific immunoassays. Variations over time of each parameter and predictive factor of response were studied. Forty-five patients were analyzed. The serum concentrations of Coll2-1 and Coll2-1 NO2 were significantly higher in KL III/IV patients compared to KL I/II patients at baseline and decreased systematically over time after VS. Its effect was ever more pronounced in patients with KL III/IV. The serum concentration of Coll2-1 was significantly lower at baseline in responders than in non-responders. This study suggests a rapid slowdown of type II collagen degradation and joint inflammation after VS with Hylan G-20 and gives additional information for the validation of accurate biomarkers for OA. The serum level of Coll2-1 appeared to be a predictive factor for response to treatment. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.


Wagner S.,Center Hospitalier Of Belfort Montbeliard | Vianey-Saban C.,Lyon University Hospital Center | Salomons G.-S.,VU University Amsterdam | Schmitt E.,Nancy University Hospital Center | Feillet F.,Nancy University Hospital Center
Archives de Pediatrie | Year: 2014

L-2-hydroxyglutaric aciduria is a rare genetic neurometabolic disease. It occurs in childhood with mental retardation, cerebellar ataxia, and epilepsy. Macrocephaly is present in half of the cases. Diagnosis is based on clinical symptoms, biological and radiological findings, and molecular testing. Specific treatments can improve the spontaneous progression of the disease. We examined two independent patients who presented with L-2-hydroxyglutaric aciduria. Clinical presentation led to cerebral MRI and urinary organic acid chromatography. The genetic analysis confirmed the diagnosis. Under specific treatment, the progression of the disease was subsequently stopped. L-2-hydroxyglutaric aciduria shares common symptoms with other genetic and metabolic diseases. However, the association of a distinct phenotype and typical MRI abnormalities (such as a high signal in the subcortical white matter, pallidum, and dentate nuclei) should draw the clinician's attention to this diagnosis. It can easily be suspected with a simple urinary analysis and can then be confirmed by genetic testing. With this case report, we show the importance of genetic identification to begin treatment with riboflavin. Early detection of L-2-hydroxyglutaric aciduria based on MRI abnormalities can enable rapid initiation of treatment and prevent disease progression. © 2013 Elsevier Masson SAS.


PubMed | Nancy University Hospital Center, Lyon University Hospital Center, VU University Amsterdam and Center Hospitalier Of Belfort Montbeliard
Type: Case Reports | Journal: Archives de pediatrie : organe officiel de la Societe francaise de pediatrie | Year: 2014

L-2-hydroxyglutaric aciduria is a rare genetic neurometabolic disease. It occurs in childhood with mental retardation, cerebellar ataxia, and epilepsy. Macrocephaly is present in half of the cases. Diagnosis is based on clinical symptoms, biological and radiological findings, and molecular testing. Specific treatments can improve the spontaneous progression of the disease. We examined two independent patients who presented with L-2-hydroxyglutaric aciduria. Clinical presentation led to cerebral MRI and urinary organic acid chromatography. The genetic analysis confirmed the diagnosis. Under specific treatment, the progression of the disease was subsequently stopped. L-2-hydroxyglutaric aciduria shares common symptoms with other genetic and metabolic diseases. However, the association of a distinct phenotype and typical MRI abnormalities (such as a high signal in the subcortical white matter, pallidum, and dentate nuclei) should draw the clinicians attention to this diagnosis. It can easily be suspected with a simple urinary analysis and can then be confirmed by genetic testing. With this case report, we show the importance of genetic identification to begin treatment with riboflavin. Early detection of L-2-hydroxyglutaric aciduria based on MRI abnormalities can enable rapid initiation of treatment and prevent disease progression.


PubMed | Charité - Medical University of Berlin and Center Hospitalier Of Belfort Montbeliard
Type: Journal Article | Journal: Sleep medicine | Year: 2014

Treatment of multiple sclerosis (MS)-related fatigue is still a challenging task, given that no proven therapies exist and its mechanisms are not known. Our review highlights the relationship between MS-related fatigue and sleep disorders (SD). Although many studies suggest a higher overall prevalence of SD in MS, there are no valid and robust data to confirm this hypothesis until now except for restless legs syndrome (RLS): the prevalence of RLS in MS patients-especially in those with severe pyramidal and sensory disability-seems to be four times higher than in controls subjects. RLS is sometimes difficult to distinguish from spasticity and in case of doubt, probatory dopaminergic therapy or polysomnographic (PSG) investigations may be helpful. Nocturia may impact MS-related fatigue and should be considered. The treatment of underlying SD led to an improvement of MS-related fatigue. From a scientific point of view, SD should be examined in all studies investigating MS-related fatigue and be considered as a relevant confounder.


Feissel M.,Center Hospitalier Of Belfort Montbeliard | Kalakhy R.,Center Hospitalier Of Belfort Montbeliard | Banwarth P.,Center Hospitalier Of Belfort Montbeliard | Badie J.,Center Hospitalier Of Belfort Montbeliard | And 3 more authors.
Journal of Critical Care | Year: 2013

Purpose: Feasibility study examining whether plethysmographic variability index (PVI) can predict fluid responsiveness in mechanically ventilated patients in the early phase of septic shock in the emergency department. Materials and Methods: Monocentric, prospective, observational study that included 31 mechanically ventilated and sedated patients with septic shock in whom volume expansion was planned. The patients were equipped with a pulse oximeter that automatically calculated and displayed PVI. The intervention consisted in infusing 8 mL/kg of hydroxylethyl starch over a 20-minute period. Before and after intervention, we recorded PVI and measured the aortic velocity-time integral (VTIao) using transthoracic echocardiography. Responders were defined as patients who increased their VTIao by 15% or higher after fluid infusion. Results: Sixteen patients were classified as responders, and 15 as nonresponders. Mean PVI values before intervention were significantly higher in responders vs nonresponders (30% ± 9% vs 8% ± 5%, P < .001). Plethysmographic variability index values before intervention were correlated with percent changes in VTIao induced by intervention (R2 = 0.67; P < .001). A PVI threshold value of 19% discriminates responders from nonresponders with a sensitivity of 94% and a specificity of 87% (area under the curve, 0.97; P < .001). Conclusion: Our study suggests that PVI is a feasible and interesting method to predict fluid responsiveness in early phase septic shock patients in the emergency department. © 2013 Elsevier Inc.


Purpose: The diagnosis of fever or inflammation of unknown origin (FUO/IUO) is guided by the search of clinical clues. Lymphadenopathy is thought to be helpful but its actual contribution has never been tested, and little is known about the main causes of FUO/IUO with lymphadenopathy. The aim of this study was to clarify these issues from the experience of two departments of internal medicine. Methods: We retrospectively studied a cohort of 69 consecutive inpatients with FUO or IUO and lymphadenopathy, hospitalized from January 2002 to February 2008. The patients were coded according to the final diagnosis and age. Recorded data included lymph node location, fever, CRP level, lymphocyte and platelet counts, presence of hyperbasophilic cells, hypogammaglobulinemia, monoclonal gammopathy, LDH level, and the results of histological and or cytological lymph node examination. Results: Malignancy accounted for 54%, granulomatosis for 23%, mainly of infectious (60%) or malignancy-related origin (18%), the group classified as non-specific adenitis represented 17% of the cases and systemic diseases 4%. Diagnosis was obtained by histological examination of a lymph node biopsy in 80% and by cytology alone in 13% of the patients; no correlation was found between anatomic location, clinical and biological data and any pathological group. Univariate age-independent analysis showed significant correlation between intra-abdominal lymphadenopathy (P = 0.05), increased serum CRP (P = 0.01) and LDH levels (P = 0.05) and malignancy, whereas superficial unique lymph node location (P< 0.05), absence of deep site location (P< 0.01), and presence of hyperbasophilic cells (P< 0.01) were all related to benign non specific adenitis. Conclusion: FUO/IUO with lymphadenopathy must be considered as a separate entity, mostly represented by malignancies and granulomatosis, mainly of infectious or malignancy related origin. Fever, intra-abdominal lymphadenopathy, serum CRP and LDH levels and hyperbasophilic cells are relevant indicators. © 2011 Société nationale française de médecine interne (SNFMI).


Rinaudo M.,Biomaterials Applications | Lardy B.,Joseph Fourier University | Grange L.,Center Hospitalier University Amichallon | Conrozier T.,Center Hospitalier Of Belfort Montbeliard
Polymers | Year: 2014

In this paper, we propose the evaluation of the mannitol's ability to reduce hyaluronic acid (HA) degradation using two different models of oxidative stress. Firstly, a solution of hyaluronan and a solution of the same HA including mannitol in PBS buffer were submitted to an oxidative stress generated by the addition of xanthine + xanthine oxidase generating oxygen free radicals. Different enzyme concentrations were used and the HA properties were studied after 24 h of contact at ambient temperature. Decreases of the viscosity of the solution were assessed by rheometry (viscous and elastic module) and that of HA molecular weight was determined by steric exclusion chromatography. Rheologic behavior was assessed on identical HA solutions subjected to another model of oxidative stress imposed by addition of hydrogen peroxide. The influence of mannitol concentration on HA degradation was also demonstrated. Whatever the stress applied, it appears very clearly that mannitol protects hyaluronic acid from mediated oxygen free radicals degradation. These in vitro results suggest that mannitol could be a simple way to significantly increase the intra-articular residence time of the injected hyaluronic acid and therefore might improve viscosupplementation effectiveness. © 2014 by the authors.

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