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We assessed the prognostic and predictive value of β-tubulin III (TUBB3) expression, as determined by immunohistochemistry, in 412 non–small cell lung cancer (NSCLC) specimens from early-stage patients who received neoadjuvant chemotherapy (paclitaxel- or gemcitabine-based) in a phase III trial (IFCT-0002). We also correlated TUBB3 expression with K-Ras and EGF receptor (EGFR) mutations in a subset of 208 cryopreserved specimens. High TUBB3 protein expression was associated with nonsquamous cell carcinomas (P < 0.001) and K-Ras mutation (P < 0.001). The 127 (30.8%) TUBB3-negative patients derived more than 1 year of overall survival advantage, with more than 84 months median overall survival versus 71.7 months for TUBB3-positive patients [HR, 1.58; 95% confidence interval (CI), 1.11–2.25)]. This prognostic value was confirmed in multivariate analysis (adjusted HR for death, 1.51; 95% CI, 1.04–2.21; P = 0.031) with a bootstrapping validation procedure. TUBB3 expression was associated with nonresponse to chemotherapy (adjusted HR, 1.31; 95% CI, 1.01–1.70; P = 0.044) but had no predictive value (taxane vs. gemcitabine). Taking account of these clinical findings, we further investigated TUBB3 expression in isogenic human bronchial cell lines only differing by K-Ras gene status and assessed the effect of K-Ras short interfering RNA (siRNA) mediated depletion, cell hypoxia, or pharmacologic inhibitors of K-Ras downstream effectors, on TUBB3 protein cell content. siRNA K-Ras knockdown, inhibition of RAF/MEK (MAP–ERK kinase) and phosphoinositide 3-kinase (PI3K)/AKT signaling, and hypoxia were shown to downregulate TUBB3 expression in bronchial cells. This study is the first one to identify K-Ras mutations as determinant of TUBB3 expression, a chemoresistance marker. Our in vitro data deserve studies combining standard chemotherapy with anti-MEK or anti-PI3K drugs in patients with TUBB3-overexpressing tumors. Mol Cancer Ther; 11(5); 1203–13. ©2012 AACR.

PDF file - 144K, Representative SiRNA K-Ras depletion in HBEC and A549 (K-Ras mutated) cells

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PDF file - 60K, Flow-Chart

PDF file - 252K, TUBB3 protein expression in HBEC cells is reduced by hypoxia cells culture conditions

PDF file - 352K, TUBB3 mRNA and protein expression according to K-RAs Si-RNA

PDF file - 344K, Supplementary methods, suppl. Figure 1 with with the specimens flow-chart, suppl. Figure 2 with the diagram of the clinical trial IFCT 0002 and sampling timepoints, suppl. Figure 4 with RASSF1A interactome, suppl. Table 1 & 2 with primers used in the study, suppl. Table 3 with all the molecular analyses in the bio-IFCT 0002 study, suppl. Table 4 comparing patients with or without molecular analyses, suppl. Table 5 with all the HRs and p-values forthe molecular and clinical variables in the final prognostic analysis

PDF file - 21K, Acknowledegements to IFCT staff (administrative and CRAs), to expert pathological panel, and list of investigators of the phase 3 clinical trial IFCT 0002

PDF file - 205K, Correlation between RASSF1 promoter gene methylation and RASSF1A protein expression by immunoblotting

Purpose: To evaluate prognostic and predictive molecular biomarkers in early-stage non–small cell lung carcinoma (NSCLC) receiving neoadjuvant chemotherapy.Experimental Design: The IFCT-0002 trial compared two neoadjuvant regimens in 528 stages I to II NSCLC patients. DNA extraction of snap-frozen surgical samples taken from 208 patients receiving gemcitabine-cisplatin or paclitaxel-carboplatin regimens allowed for the identification of 3p allelic imbalance, Ras association domain family 1A (RASSF1A) and death-associated protein kinase 1 (DAPK1) promoter methylation, and epidermal growth factor receptor, K-ras, and TP53 mutations. Multivariate analysis identified prognostic and predictive effects of molecular alterations. A Bootstrapping approach was used to assess stability of the prognostic models generating optimism corrected indexes.Results: RASSF1A methylation correlated significantly with shorter disease-free survival (DFS; adjusted HR = 1.88, 95% CI: 1.25–2.82, P = 0.0048) and shorter median overall survival (OS; adjusted HR = 2.01, 95% CI: 1.26–3.20, P = 0.020). A computed bootstrap resampling strategy led to a prognostic model, including RASSF1A, DAPK1, and tumor stage, dividing patients into three prognostic groups, with median OS ranging from 34 months for high-risk patients (HR for death = 3.85, 95% CI: 1.79–6.40) to more than 84 months for moderate (HR = 1.85, 95% CI: 0.97–3.52) and low-risk patients (reference group; P = 0.00044). In addition, RASSF1A methylation predicted longer DFS in patients treated with paclitaxel-carboplatin compared with gemcitabine-cisplatin (adjusted HR = 0.47, 95% CI: 0.23–0.97, Pinteraction = 0.042).Conclusions: Following neoadjuvant chemotherapy, RASSF1A methylation negatively impacted prognosis of early-stage NSCLC. Along with DAPK1 methylation and tumor stage, RASSF1A methylation allowed definition of three subgroups with strikingly different prognosis. Conversely, significantly longer DFS following paclitaxel-based neoadjuvant chemotherapy for patients whose tumors showed RASSF1A methylation suggested its predictive interest in stages I and II NSCLC. Clin Cancer Res; 18(10); 2976–86. ©2012 AACR.

To prevent the crisis-level shortage of beds in hospitals and for a more efficient support, it’s necessary to early identify coronavirus disease-19 (Covid-19) patients at risk to develop a severe form of the disease.The goal of our study was to determine whether biological markers, including the serum ferritin, could predict the severity of the Covid-19.One hundred and seventy-one patients, who were admitted to Caen University Hospital, were included retrospectively with a positive diagnosis of Covid-19 by RT-PCR. A serum ferritin measurement was performed for all patients. They were further classified either into a non-severe or a severe group based on their hospitalization in intense care unit (ICU) for mechanical ventilation or death.Univariate analysis revealed a significant association between increased serum ferritin and CRP levels, obesity, CT scan lesions, pathological respiratory rate, decreased PaO2/FiO2 ratio, the NEWS-2 score and the severe (n = 59) vs the non-severe (n = 112) outcome of Covid-19 patients. However, in a multivariate analysis, only CRP and obesity were associated with the severe form of Covid-19.While pathological level of serum ferritin at admission is associated with severe form of Covid-19, combination of increased CRP level and obesity would better predict the severity of the disease.Pour une meilleure prise en charge, il est nécessaire de pouvoir identifier précocement les patients atteints de la Covid-19 susceptibles de développer une forme sévère. L’objectif de notre étude était de déterminer si des marqueurs biologiques, notamment la ferritinémie, peuvent prédire la sévérité de la Covid-19. Nous avons inclus de manière rétrospective 171 patients au CHU de Caen avec un diagnostic de Covid-19. Les patients devaient avoir un bilan biologique incluant la ferritinémie à l’admission et ont été classés en formes sévères (n = 59, hospitalisation et ventilation invasive en soins intensifs ou en réanimation, et/ou décès) et non-sévères (n = 112, tous les autres patients). L’analyse univariée a montré une association entre les formes sévères de Covid-19 avec les niveaux élevés de ferritine et de CRP, l’obésité, les lésions pulmonaires, la fréquence respiratoire élevée, la diminution du ratio PaO2/FiO2 et le score de NEWS-2. Cependant, en analyse multivariée seules la CRP et l’obésité montraient une association avec les formes sévères. En conclusion, alors que la ferritinémie élevée est associée à un risque accru de développer une forme sévère de la Covid-19, la CRP et la présence d’une obésité seraient de meilleurs marqueurs prédictifs.

Background: The non-surgical solution for Pelvic Organ Prolapse (POP) typically consists of a pessary fitting. We aimed to assess patient satisfaction and symptom improvement 6 months after a pessary fitting and to identify risk factors associated with pessary failure. Methods: Six months after a pessary fitting, patient satisfaction was assessed by the PGII score; symptoms and quality of life were assessed using validated questionnaires (PFDI-20, ICIQ-SF, PISQ-12, USP, and PFIQ-7). Results: Of the 190 patients included in the study (mean age of 66.7 years), 141 (74%) and 113 (59%) completed the follow-up questionnaires at 1 and 6 months, respectively. Nearly all the women were menopausal (94.6%) and 45.2% declared being sexually active at inclusion. The satisfaction rate was 84.3% and 87.4% at 1 and 6 months, respectively. The global symptom score PFDI-20 had significantly improved at 6 months. A high body mass index (RR = 1.06, CI95%: [1.02–1.09]), as well as high PFDI-20 (1.05 [1.01–1.09]), PFIQ7 (1.04 [1.01, 1.08]), and PISQ12 scores at inclusion (0.75 [0.60, 0.93]), as well as higher GH and GH/TVL measurements (1.49 [1.25–1.78] and 1.39 [1.23–1.57], respectively) were associated with pessary failure. Conclusions: Pessary seems to be an effective treatment for POP with high patient satisfaction. Higher BMI, higher symptom scores, and greater genital hiatus measurements before insertion are risk factors for failure at 6 months.

Background Left ventricular remodelling that frequently occurs after acute myocardial infarction is associated with an increased risk of heart failure and cardiovascular death. Although several risk factors have been identified, there is still no marker in clinical use to predict left ventricular remodelling. Plasma concentration of coenzyme Q10, which plays a key role in mitochondrial energy production and as an antioxidant, seems to be negatively correlated with left ventricular function after acute myocardial infarction. Objective The goal of our study was to determine whether the plasma coenzyme Q10 baseline concentrations at time of the ST-elevation myocardial infarction (STEMI) could predict left ventricular remodelling at six months’ follow-up. Methods Sixty-eight patients who were admitted to hospital for STEMI and successfully revascularized with primary percutaneous coronary intervention were recruited. All patients underwent a 3D-echocardiography examination within the first four days after percutaneous coronary intervention and six months later then divided into two groups based on the presence or not of left ventricular remodelling. Plasma coenzyme Q10 concentration at the time of percutaneous coronary intervention was determined using high-performance liquid chromatography-tandem mass spectrometry. Results While we found similar plasma coenzyme Q10 concentrations compared with other studies, no association was evidenced between coenzyme Q10 concentrations and left ventricular remodelling ( P = 0.89). Conclusion We found no evidence for using plasma coenzyme Q10 concentration as an early prediction marker of left ventricular remodelling after STEMI.

Objective To describe the epidemiological, clinical, microbiological, and therapeutic features and outcomes of Rothia infective endocarditis (RIE) and extracardiac infections (ECRI). Methods We performed a systematic literature review of published cases of RIE and ECRI. Results After inclusion of a personal case report, 51 cases of RIE and 215 cases of ECRI were reported. Compared with ECRI patients, RIE patients were significantly more often males (80% versus 59%), intravenous drug users (IVDU) (20% versus 3%), immunocompetent (76% versus 31%), and infected with R. dentocariosa (55% versus 13%) but lacked significant differences with regard to median age (45 years [6–79]), rate of orodental abnormalities (33%), and six-month mortality (14%). Following microbiological documentation, RIE was most often treated with a beta-lactam antibiotic alone (39%) for a median duration of six weeks and required surgery in 39% of cases. Conclusion RIE is rare and likely secondary to a dental portal of entry or cutaneous inoculation in IVDU. Its prognosis seems to be favorable.

Background Among palliative care (PC) patients who are administered paracetamol, the subcutaneous (SC) route is often an alternative to the intravenous (IV) route. Yet pharmacological and clinical data on whether these are equivalent pharmacokinetically are lacking. Many French palliative teams are now empirically using paracetamol by the SC route, but there are no data to support this practice. This trial aims to compare the pharmacokinetic (PK) parameters of paracetomol between the IV and SC routes in PC patients. Methods/design This is a randomized, open, crossover study in two PC centers. The primary endpoints are AUC0-t, AUC0-∞, Cmax, Vd, and t1/2. All adverse events will be reported for a safety analysis. Twenty adult PC patients with an IV device having spontaneous pain not related to care, with a numeric pain rate scale > 3/10, or having a systematic prescription of paracetamol as the usual treatment will be included. All patients also have to meet all eligibility criteria. Conclusion This is the first study comparing PK parameters for IV paracetamol versus SC paracetamol in PC patients. Trial registration ClinicalTrials.gov, NCT03944044. Registered on 4 June 2019. Committee for the protection of persons (CPP) 18.09.05.58206 approval 4 October 2018. National Drug Safety Agency (ANSM; Agence Nationale de Sécurité Médicament) MEDAECNAT-2018-09-00009 approval 29 November 2018.

Background: Among palliative care (PC) patients who are administered paracetamol, the subcutaneous (SC) route is often an alternative to the intravenous (IV) route. Yet pharmacological and clinical data are lacking. Many French palliative teams are now empirically using paracetamol by the SC route, but there are no data to support this practice.Aim: Compare pharmacokinetic (PK) parameters between the IV and SC routes for PC patients.Design: A randomized, open, crossover study in two PC centers. The primary endpoints are AUC0-t, AUC0-, Cmax, and Vd et t1/2. All adverse events will be reported for a safety analysis.Setting/participants: 20 adult PC patients with an IV device, having spontaneous pain, not related to care, with a numeric pain rate scale > 3/10, or having a systematic prescription of paracetamol in the usual treatment. They also have to meet all eligibility criteria.Conclusion: First study comparing PK parameters for IV paracetamol versus SC paracetamol.Trial registration:Clinical trial register number NCT03944044, 2019-06-04https://clinicaltrials.gov/ct2/show/NCT03944044Committee for the protection of persons (CPP) 18.09.05.58206 approval 2018/10/4National Drug Safety Agency (ANSM: Agence Nationale de Sécurité Médicament) MEDAECNAT-2018-09-00009 approval 2018/11/29

Background Despite the emergence of new therapies, Pulmonary Hypertension (PH) still has a high mortality. Several clinical, echocardiographic, biological or hemodynamic prognostic factors have been identified but are of limited predictive value for survival. We aimed to assess whether heart rate (HR) and all ECG abnormalities measured on a 12-lead ECG may help to better identify patients at high risk of death in this population. Methods and results 296 patients followed in a registry were included with all types of PH, except group 2 of the WHO clinical classification. After a median follow-up of 10 years, age, male sex, NYHA III/IV status and, among all ECG parameters, HR and corrected QT interval were associated with mortality. In multivariate analysis, HR, age and male sex remained significant independent predictors of mortality. HR has a higher predictive value in the 238 patients in sinus rhythm. In addition, only HR was significantly correlated with clinical and hemodynamic PH prognostic factors. Conclusion HR measured on a 12-lead ECG at the time of the diagnosis is a strong independent predictor of mortality in PH patients.

Background Preterm birth causes parenting stress and increases the risk of developmental disorders in children. Our objective was to assess the impact of an early psychological intervention, Triadic parent-infant Relationship Therapy (TRT), on parenting stress, parental mental health and preterm infant development in the motor, language, social, behavioral and emotional domains at a corrected age of 18months. Methods Sixty-five families of preterm infants were randomly assigned to the intervention group ( n =33) or the control group ( n =32). Families of full-term children ( n =24) were also recruited. Intervention focused on the triadic relationship and aimed to improve parenting stress by supporting parental mental health to promote infant development. The main outcome was assessed with the Parenting Stress Index Short Form (PSI-SF). Results Highly significant differences at 18months were observed for the mother and father in overall PSI-SF scores, with 16.6, and 11.7 points, respectively, in favor of the intervention group. Children in the intervention group demonstrated higher full-scale developmental quotients than the preterm controls (an 8.7-point difference) along with lower scores on behavioral tests (a 5.8-point difference at 18months). At 18months, results for children in the intervention group showed no significant differences compared to the full-term group or were even better. Conclusions Our study provides sound evidence for the efficiency of the TRT program to reduce parenting stress and improve parental mental health for both parents, thus fostering the infant's overall development.

Ras association domain family (RASSF)/Hippo pathway alterations are poorly characterized in diffuse gliomas. We assayed promoter methylation of LATS1/2, MST1(STK4)/MST2(STK3), RASSF1, RASSF2, Nore1A/RASSF5, RASSF6, and RASSF10 genes in 133 diffuse gliomas. The RASSF/Hippo pathway was highly silenced in gliomas, particularly RASSF1A (79.4%) and LATS2 (35.9%). The most frequent combination of promoter hypermethylation of one RASSF gene and one Hippo pathway member's gene was RASSF1/LATS2-coupled hypermethylation [n = 44 (33.08%)]. Hypermethylated profiles were related to IDH mutation, yet not randomly in IDH-mutated gliomas, because LATS2 promoter hypermethylation was more frequent in oligodendroglioma than in astrocytoma. RASSF1 and LATS2 promoter hypermethylation predicted a longer overall survival (OS). Considering hypermethylation of these two promoters, Cox proportional hazard regression analysis categorized the patients into three prognostic groups: i) high risk of death (n = 24; both RASSF1 and LATS2 unmethylated promoters; median OS, 13 months); ii) intermediate risk of death (n = 65; RASSF1 or LATS2 hypermethylated promoter; median OS, 50.5 months; HR = 3.3; 95% CI, 1.6–6.4; P = 0.001); and iii) low risk of death (n = 44; both RASSF1 and LATS2 hypermethylated promoters; median OS, 119 months; HR = 75.1; 95% CI, 3.3–15.1; P = 0.001). We have thus highlighted a simple two-gene (RASSF1/LATS2) methylation signature as a tool to stratify different prognostic groups of patients with diffuse glioma, adding further prognostic information within the IDH-mutated group.

CERVOXY; International audience; Background: The Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456) phase 3 trial demonstrated the superiority of bevacizumab plus pemetrexed–cisplatin triplet over chemotherapy alone in 448 malignant pleural mesothelioma (MPM) patients. Here, we evaluated the prognostic role of Hippo pathway gene promoter methylation.Methods: Promoter methylations were assayed using methylation-specific polymerase chain reaction in samples from 223 MAPS patients, evaluating their prognostic value for overall survival (OS) and disease-free survival in univariate and multivariate analyses. MST1 inactivation effects on invasion, soft agar growth, apoptosis, proliferation, and YAP/TAZ activation were investigated in human mesothelial cell lines.Results: STK4 (MST1) gene promoter methylation was detected in 19/223 patients tested (8.5%), predicting poorer OS in univariate and multivariate analyses (adjusted HR: 1.78, 95% CI (1.09–2.93), p = 0.022). Internal validation by bootstrap resampling supported this prognostic impact. MST1 inactivation reduced cellular basal apoptotic activity while increasing proliferation, invasion, and soft agar or in suspension growth, resulting in nuclear YAP accumulation, yet TAZ cytoplasmic retention in mesothelial cell lines. YAP silencing decreased invasion of MST1-depleted mesothelial cell lines.Conclusions: MST1/hippo kinase expression loss is predictive of poor prognosis in MPM patients, leading to nuclear YAP accumulation and electing YAP as a putative target for therapeutic intervention in human MPM.

Summary Background Malignant pleural mesothelioma is an aggressive cancer with poor prognosis, linked to occupational asbestos exposure. Vascular endothelial growth factor is a key mitogen for malignant pleural mesothelioma cells, therefore targeting of vascular endothelial growth factor might prove effective. We aimed to assess the effect on survival of bevacizumab when added to the present standard of care, cisplatin plus pemetrexed, as first-line treatment of advanced malignant pleural mesothelioma. Methods In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged 18–75 years with unresectable malignant pleural mesothelioma who had not received previous chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0–2, had no substantial cardiovascular comorbidity, were not amenable to curative surgery, had at least one evaluable (pleural effusion) or measurable (pleural tumour solid thickening) lesion with CT, and a life expectancy of >12 weeks from 73 hospitals in France. Exclusion criteria were presence of central nervous system metastases, use of antiaggregant treatments (aspirin ≥325 mg per day, clopidogrel, ticlopidine, or dipyridamole), anti-vitamin K drugs at a curative dose, treatment with low-molecular-weight heparin at a curative dose, and treatment with non-steroidal anti-inflammatory drugs. We randomly allocated patients (1:1; minimisation method used [random factor of 0·8]; patients stratified by histology [epithelioid vs sarcomatoid or mixed histology subtypes], performance status score [0–1 vs 2], study centre, or smoking status [never smokers vs smokers]) to receive intravenously 500 mg/m 2 pemetrexed plus 75 mg/m 2 cisplatin with (PCB) or without (PC) 15 mg/kg bevacizumab in 21 day cycles for up to six cycles, until progression or toxic effects. The primary outcome was overall survival (OS) in the intention-to treat population. Treatment was open label. This IFCT-GFPC-0701 trial is registered with ClinicalTrials.gov, number NCT00651456. Findings From Feb 13, 2008, to Jan 5, 2014, we randomly assigned 448 patients to treatment (223 [50%] to PCB and 225 [50%] to PC). OS was significantly longer with PCB (median 18·8 months [95% CI 15·9–22·6]) than with PC (16·1 months [14·0–17·9]; hazard ratio 0·77 [0·62–0·95]; p=0·0167). Overall, 158 (71%) of 222 patients given PCB and 139 (62%) of 224 patients given PC had grade 3–4 adverse events. We noted more grade 3 or higher hypertension (51 [23%] of 222 vs 0) and thrombotic events (13 [6%] of 222 vs 2 [1%] of 224) with PCB than with PC. Interpretation Addition of bevacizumab to pemetrexed plus cisplatin significantly improved OS in malignant pleural mesothelioma at the cost of expected manageable toxic effects, therefore it should be considered as a suitable treatment for the disease. Funding Intergroupe Francophone de Cancerologie Thoracique (IFCT).

Memantine, an uncompetitive antagonist of N-methyl- d -aspartate (NMDA)-type glutamate receptors that was approved for the treatment of moderate to severe Alzheimer's disease, has been negatively evaluated for the treatment of cognitive disorders of multiple sclerosis, but these studies were conducted only during short-term administration and on a heterogeneous group of patients with different forms of the disease. In addition, many adverse reactions were observed in these patients. Aims The purpose of the “EMERITE” (NCT01074619) study was to examine the efficacy and safety of the long-term administration of memantine as a symptomatic treatment for cognitive disorders in patients with relapsing-remitting multiple sclerosis (RR-MS). Methods The study was supported by the French Ministry of Health and received additional support from Lundbeck. In this double-blind, placebo-controlled, parallel group, randomized trial, the participants were assigned to receive memantine (20 mg/day) or a placebo for 52 weeks. The participants included males and females, 18–60 years of age, with a diagnosis of RR-MS and presenting with a cognitive complaint and/or demonstrating moderate cognitive impairment. The data were collected in the Department of Neurology in 19 French centers. The primary outcome was the Paced Auditory Serial Addition Test (PASAT) score at week 52. Secondary measurements included additional neuropsychological tests and the annualized relapse rate. The scores were adjusted according to the baseline scores in the analysis. The safety was assessed by the number of adverse events. The random sequence was generated using the Excel software. At each center, only the pharmacist had access to the allocation sequence and could be asked to unblind the trial. Results Fifty patients were allocated to the memantine group, and 43 to the placebo group. The intent-to-treat (ITT) population included 31 patients in each group. After adjusting for the PASAT scores at baseline, the PASAT scores at the end point did not differ between the memantine and the placebo groups (p = 0.88). Adjusted mean score difference (memantine minus placebo), was − 0.40 (95% confidence interval: -5.5; + 4.7). No significant differences were observed for the secondary outcomes (short term memory and attention scores, EDSS, and relapse rate). The findings remained unchanged after multiple imputation of the missing values. Neurological and psychiatric adverse events were significantly higher in the memantine group than in the placebo group, and these parameters were higher than those reported in the product literature of memantine. Conclusions No differences between the placebo and memantine groups were observed. Nevertheless, the tolerability of memantine was significantly worse than expected.

Introduction/objectifs L’essai clinique MAPS ayant demontre le benefice de l’association du Bevacizumab au doublet Pemetrexed-Cisplatine chez 448 patients atteints de mesotheliome pleural malin (MPM), il avait egalement pour objectif d’identifier de nouveaux biomarqueurs du MPM, notamment parmi les membres de la voie de signalisation Hippo, dont la kinase MST1. Materiels/Patients et methodes Le statut de methylation du promoteur de MST1 a ete determine par MS-PCR et correle aux survies globales et sans progression en analyses univariee et multivariee avant validation par Boostrap. L’impact de l’inactivation de MST1, mimee en transfectant des cellules de lignees mesotheliales (MSTO-211H/H2452/H28 et H2052) par un siARN (inactif ou anti-MST1), sur l’activite apoptotique, la proliferation cellulaire, la capacite d’invasion, la croissance en agar ou suspension et l’activation de YAP/TAZ (effecteurs terminaux de la voie Hippo) a ete teste. Resultats L’hypermethylation frequente de la kinase MST1, detectee chez 19 des 203 patients testes soit 9,4 %, predit une moins bonne survie (globale et sans progression) des patients atteints de MPM en analyse univariee (survie globale diminuee par 1,4 fois, HR 2,33, IC95 [1,42 ; 3,80], p = 0,001) et multivariee (p = 0,026). In cell, l’inactivation de MST1 diminue significativement leur activite apoptotique basale, augmente leur proliferation, leur invasion en Matrigel®, leur capacite a croitre en agar ou en suspension, cela parce que dans ces cellules, YAP s’accumule sous sa forme active. Conclusions La perte d’expression de la kinase MST1 est un facteur de mauvais pronostic chez les patients atteints de MPM, car en regulant YAP, MST1 controle l’apoptose, la proliferation et la capacite migratoire des cellules mesotheliales. En son absence, ces processus cellulaires sont deregules.

Purpose Our aim was to evaluate the rate of occurrence of chromosomal abnormalities, associated findings, and outcome in a series of cases of prenatally diagnosed clubfoot. Methods We conducted a retrospective study of all cases of clubfoot diagnosed prenatally in the ultrasound unit of a French tertiary center from January 2004 through December 2011. Clubfoot was scored as complex or isolated depending on the presence or absence of another structural abnormality observed on sonographic examination. Results Data from 90 fetuses prenatally diagnosed with clubfoot were included in this study. Thirty-four cases were considered complex (38%) and 56 were considered isolated (62%). A chromosomal abnormality was identified in 10 of 33 of the fetuses with complex clubfoot and in 1 of 45 of those with isolated clubfoot (p

Resume Objectif Comparer le devenir obstetrical et neonatal selon le type de cicatrice uterine : myomectomie versus cesarienne. Methodes Etude de cohorte retrospective realisee dans un service universitaire de type 3 entre le 1er janvier 2006 et le 1er janvier 2012. Nous avons compare 18 femmes ayant accouche apres myomectomie (groupe expose) a 72 femmes ayant accouche apres cesarienne (groupe non expose). Les femmes de moins de 43 ans ayant beneficie d’une myomectomie par voie cœlioscopique ou laparotomique etaient incluses. Le critere principal de jugement etait le taux d’accouchement par voie basse. La voie d’accouchement, le taux de ruptures uterines, les complications de la delivrance et le devenir neonatal etaient etudies. Resultats Le taux d’acceptation de la tentative de voie basse etait de 55,6 % apres myomectomie contre 84,7 % apres cesarienne (p = 0,005). La reussite de la tentative de voie basse etait de 88,9 % apres myomectomie versus 73,9 % apres cesarienne (NS). Aucune rupture uterine n’est survenue apres myomectomie contre 3 ruptures sous-peritoneales apres cesarienne. La survenue d’une hemorragie du post-partum ne differait pas significativement entre les deux groupes (11,1 % chez les exposes versus 6,9 % chez les non-exposes). Le taux de cesarienne etait d’autant plus eleve que le nombre d’hysterotomies etait eleve (p = 0,0047). Conclusion Cette etude semble montrer que l’accouchement par voie basse apres myomectomie est possible avec un taux de reussite similaire a celui d’un uterus cicatriciel post-cesarienne.

Aim The aim of this study was to evaluate two regimens of administration of sustained-release dinoprostone on the need for oxytocin induction of labor. Material and Methods We carried out an open prospective study comparing labor, maternal and neonatal outcomes after 12 h of prostaglandin cervical ripening insert versus 24 h of prostaglandin cervical ripening insert in 284 patients (142 ripenings at 12 h [P12 group] and 142 ripenings at 24 h [P24 group]). Results The two groups were demographically similar. There was a significant difference in the need for artificial rupture of membranes/oxytocin induction of labor between the groups (49.3% for the P12 group vs 38% for the P24 group, P = 0.03). The delay between the beginning of ripening and delivery was significantly decreased in the P12 group, but the duration of active labor (6.6 h), the dose of oxytocics used (1326 UI), the rate of cesarean section, the rate of uterine hyperstimulation, the rates of hemorrhaging from delivery, the neonatal state and the experience of induction were similar in the two groups. Conclusion This study allows us to show for the first time that sustained-release of dinoprostone leads to spontaneous induction of labor without increasing the obstetrical risk in a majority of patients.

The treatment of acquired hemophilia (AH) involves discussing whether corticosteroids should be administered alone or combined with immunosuppressant drugs, which increase the risk of infection especially in elderly patients and/or those with autoimmunity or neoplastic diseases, who represent the target population of the disease. Prognostic factors highlighting adequate responses to corticosteroids alone must be identified for satisfactory clinical response and lower infectious risk. We aimed to evaluating the efficacy of corticosteroids alone in the management of AH depending on factor VIII (FVIII, ≥ or 20 Bethesda units per milliliter [BU/mL]) titer. We conducted a retrospective single-center study including 24 patients treated for AH with corticosteroids alone. Time to achieve partial remission (PR: absence of hemorrhage and FVIII levels >50 IU/dL) was significantly shorter in the FVIII ≥ 1 IU/dL group than in the FVIII 20 BU/mL group (15 [11–35] vs 41 [20–207] days, P = 0.003). In both subgroups, time to achieve complete remission (CR: negative INH and corticosteroids below 10 mg/d) was also significantly shorter than that observed in the opposite subgroups. INH titer, considered alone, did not affect the length of time to onset of PR or CR. CR and PR rates did not differ significantly depending on these variables. Our study suggests that in AH, patients with FVIII levels ≥1 IU/dL considered alone or combined with INH titer ≤20 BU/mL could be treated by corticosteroids alone, given that this subgroup of patients displayed faster therapeutic responses to this strategy.

Introduction/objectifs Bien que l’activite oncogenique de l’amphireguline (AREG) ait deja ete decrite dans de nombreux cancers humains [1] , son role dans l’histoire naturelle du mesotheliome pleural malin (MPM), un cancer rare mais agressif et de mauvais pronostic, principalement cause par une exposition professionnelle a l’amiante [2] , reste controversee. L’objectif de ce travail etait d’etudier le possible role de l’AREG dans le developpement du MPM. Patients et methodes L’AREG plasmatique et l’expression tumorale de l’AREG ont ete quantifiees par dosage ELISA (Amphiregulin DuoSet, RD score : 59,87 ± 26,92, mediane : 70). La mediane de survie globale des patients exprimant une AREG cytosolique est de 24,8 mois, contre 15,9 mois lorsque l’AREG se trouve dans un autre compartiment cellulaire (HR ajuste : 0,62, IC95 % [0,44–0,86], p = 0,005). La mediane de survie sans progression des patients exprimant un AREG cytosolique est de 10,4 mois contre 8,2 mois pour les autres localisations subcellulaires (HR ajuste : 0,61, IC95 % [0,45–0,84], p = 0,0007). Aucune correlation entre les quantites plasmatiques et tissulaires d’AREG n’a ete trouvee (coefficient de correlation = 0,007, p = 0,91). Conclusions L’expression cytoplasmique d’AREG s’avere donc etonnamment etre un facteur de bon pronostic chez les patients atteints de MPM. N’etant pas retrouvee dans le plasma de ces patients, nous supposons qu’il existe un defaut de relargage de l’AREG par les cellules de MPM, l’empechant ainsi d’agir sur son recepteur membranaire.

Resume Introduction Le surdon intellectuel – aussi appele « precocite intellectuelle » ou « haut potentiel intellectuel » – chez l’enfant est souvent considere comme un facteur de risque psychopathologique. Le but de cette etude etait de mesurer l’anxiete trait – envisagee comme un marqueur psychopathologique general – dans un groupe d’enfants surdoues et de le comparer a la norme. Methode Cent onze enfants ayant un quotient intellectuel superieur ou egal a 130 ont repondu a la version francaise de la Revised-Children's Manifest Anxiety Scale (R-CMAS ; 33). Analyse des donnees Les scores moyens a la R-CMAS et ses sous-echelles ont ete compares aux donnees normatives francaises (33) par le calcul d’intervalles de confiance a 95 %. Les proportions des enfants ayant obtenu des scores et sous-scores superieurs aux seuils d’anxiete ont ete comparees aux memes donnees normatives par des tests du Khi2. Resultats Les intervalles de confiance obtenus pour la totalite du groupe etudie et selon le sexe et l’âge, ainsi que les comparaisons pour les scores et sous-scores excedant les seuils, indiquaient que l’ensemble des resultats ne differait pas statistiquement des valeurs normatives. Conclusion Le niveau d’anxiete trait chez les enfants surdoues etudies ne semble pas exceder celui de la population generale. Cela ne tend pas a confirmer l’hypothese selon laquelle le surdon intellectuel chez l’enfant constituerait un facteur de risque psychopathologique. Pour autant, des etudes supplementaires seraient necessaires afin de mieux caracteriser ce risque chez les enfants surdoues.

The objective of this study is primarily to compare the performance of the VIDAS(®) Measles immunoglobulin (Ig)G assay to that of two other serological assays using an immunoassay technique, Enzygnost(®) Anti-measles Virus/IgG (Siemens) and Measles IgG CAPTURE EIA(®) (Microimmune). The sensitivity and the agreement of the VIDAS(®) Measles IgG assay compared to the Enzygnost(®) Anti-measles Virus/IgG assay and the Measles IgG CAPTURE EIA(®) assay are 100%, 97.2% and 99.0%, 98.4%, respectively. The very low number of negative sera for IgG antibodies does not allow calculation of specificity. As a secondary objective, we have evaluated the ability of the VIDAS(®) Measles IgG assay to measure anti-measles virus IgG antibody avidity with the help of the VIDAS(®) CMV IgG Avidity reagent, using 76 sera from subjects with measles and 238 other sera. Different groups of populations were analyzed. In the primary infection measles group, the mean IgG avidity index was 0.16 (range of 0.07 to 0.93) compared to 0.79 (range of 0.25 to 1) in the serum group positive for IgG antibodies and negative for IgM. These data allow to define a weak anti-measles virus IgG antibody avidity as an avidity index (AI)0.3 and a strong avidity as an AI0.6. The VIDAS(®) Measles IgG assay has a performance equivalent to that of other available products. Its use, individual and quick, is well adapted to testing for anti-measles immunity in exposed subjects.

Resume L'essor des therapeutiques ciblees tres efficaces dans les carcinomes bronchiques non a petites cellules (CBNPC) a modifie le pronostic de certains sous-groupes de patients avec des survies tres prolongees. L'identification a priori (au moment du diagnostic) des patients qui beneficient le plus de ces therapeutiques souvent couteuses, constitue le nouvel enjeu de la cancerologie thoracique. Pour les inhibiteurs de la tyrosine kinase (ITK) de l'EGFR, la situation est desormais claire et le ciblage repose sur l'identification de mutations de l'EGFR, a l'origine de la premiere AMM conditionnee par le diagnostic moleculaire en cancerologie thoracique. Ce ciblage est facilite en France en routine par l'effort considerable de financement de l'INCa des 28 plates-formes regionales de biologie moleculaire. D'autres therapies ciblees sont en developpement en essai de phase 2 et 3, voire, deja en ATU de cohorte, ciblant les mutations de K-Ras, B-Raf, MEK1, ou les rearrangements de ALK. L'Intergroupe francophone de cancerologie thoracique (IFCT) avec le soutien de l'INCa, a initie une large etude prospective, Biomarqueurs-France, pour analyser l'impact des 17 000 analyses de routine annuelles de biomarqueurs des plates-formes regionales, sur la prise en charge des patients francais, etude qui contribuera a valider l'utilisation des le diagnostic, des biomarqueurs que nous utiliserons demain en routine dans le cancer bronchique.

Objective. To determine risk factors for anal sphincter laceration and define situations with a high risk for such trauma in vacuum-assisted deliveries. Design. Retrospective observational study of 1961 vacuum-assisted deliveries over a period of 5 years. Setting. French university hospital. Population. All women who delivered with vacuum assistance. Methods. Third- and fourth-degree perineal tears were reviewed. The factors studied through univariate and multivariate logistic regression were the mother's age, parity, history of assisted delivery, cesarean section, gestational age, uterine fundal height, duration of the second stage of labor, head position at expulsion, epidural anesthesia, episiotomy, biparietal diameter and birthweight. Main outcome measures. Third- and fourth-degree perineal tears. Results. There were 1.9% third-degree and no fourth-degree perineal tears. Risk factors identified were occipito-posterior position (odds ratio 4.7, p < 0.001), biparietal diameter (odds ratio 2.0 for each 5 mm increase, p= 0.004), duration of second stage (only significant when parity was ≥1; odds ratio 1.3 for each 10 min increase, p= 0.004) and nulliparity (decreasing effect according to duration of the second stage). The patterns of the association between these factors and the risk of perineal tears were different for nulli- and multiparous women. Conclusions. In a targeted population of women having vacuum-assisted deliveries, the association of specific risk factors allows clinicians to identify women who are at high risk of anal sphincter laceration.

Background The aim of this work was to evaluate myocardial strain analysis as a tool for the early detection of left ventricular functional changes in patients with cystic fibrosis. Methods A total of 42 consecutive patients (mean age, 24 ± 7.5 years; 52% men) diagnosed with cystic fibrosis and referred for echocardiographic cardiac function assessment were prospectively enrolled. A group of healthy age-matched and gender-matched volunteers ( n = 42) formed the reference population for echocardiographic comparisons. Results Left ventricular ejection fraction was conserved in both groups but was significantly lower in the cystic fibrosis group. Cardiac function assessment using Doppler tissue imaging parameters revealed that both systolic and diastolic measurements differed between the two groups: mitral peak systolic and diastolic velocities, as well as septal and lateral wall strain rates, were decreased in patients with cystic fibrosis, as was longitudinal strain of both the septal and lateral walls. Conclusions Using strain measurements, subclinical changes in left ventricular function were found in patients with cystic fibrosis. These parameters were correlated with the degree of pulmonary involvement severity. These findings have potentially significant clinical implications for the outcomes and follow-up of patients with cystic fibrosis, meriting further studies.

Targeted therapies booming and new efficacious cytotoxics emergence in non-small cell lung cancers (NSCLC) deeply changed prognosis in some subsets of patients experiencing long survival. A priori identification (at time of diagnosis) of patients the most beneficiating from those often costly therapies is the new issue in thoracic oncology. For EGFR tyosine kinase inhibitors (TKI), molecular targeting relies on EGFR mutations diagnosis, that led to the first conditioned molecular-based registration for a drug in thoracic oncology, that was made easier in France by French NCI huge effort to sponsor the 28 regional molecular biology platforms. For the majority of classical cytotoxics used in adjuvant treatment after lung cancer surgical resection, biomarkers relying on immunohistochemistry still need further prospective validation steps before routine use. Prospective validation studies aimed to evaluate the ability of those biomarkers to predict not only response to therapy, but also survival with a specific treatment (predictive value), need large phase 3 trials with centralized biomarker analyses and rigorous statistical methods. French Intergroup (IFCT) has initiated such studies that will help to validate new biomarkers that we may use routinely in lung cancer in near future.

PURPOSE OF REVIEW To summarize the major methodological issues concerning prognostic biomarkers in nonsmall cell lung cancers (NSCLCs) and to discuss integration of biomarkers into clinical trials. RECENT FINDINGS Large phase 3 trials have recently been published in early-resected NSCLC with studies of biomarkers identifying subsets of patients that benefited most from the experimental perioperative strategy. The IALT-bio study reported that ERCC1 DNA-repair protein had prognostic and predictive implications. Other studies reported on the prognostic role of TUBB3 expression in stages I-III NSCLCs. The IPASS study reported the predictive and prognostic impact of epidermal growth factor receptor (EGFR) mutations in stage IV patients treated with EGFR tyrosine kinase inhibitor or platinum-based chemotherapy. Whereas EGFR mutations studies received prospective validation with trials in which treatment allocation was based on biomarker status, chemotherapy biomarkers still need such prospective confirmations, and many biases were still encountered in recent published studies. SUMMARY Biomarkers of treatment efficacy will help to tailor treatment in NSCLCs. EGFR mutations have reached that point. Markers of chemotherapy efficacy still need validation studies before coming into routine practice. Stringent methodological recommendations should avoid most of the possible pitfalls of those studies and allow clinical applicability of such biomarkers.

OBJECTIVE. To record feto-maternal complications following the use of selective prophylactic transfusions in women with major sickle cell disease (SCD) and determine whether selective prophylactic transfusion reduces these complications, through a comparison with a population of women who received transfusions for complications only. DESIGN. A retrospective cohort study. SETTING. Public regional referral hospital in western French Guyana. POPULATION. Between 1992 and 2004, in all 29 women, 55 pregnancies, and 56 neonates. METHODS. Close obstetric follow-up and selective prophylactic transfusions after 26 weeks. Main outcome measures. Adverse obstetric outcome (pre-eclampsia, preterm delivery, intrauterine growth restriction (IUGR), intrauterine fetal death (IUFD), cesarean delivery, neonatal and maternal mortality) and end-points for SCD outcome (vaso-occlusive crisis (VOC), acute chest syndrome, and infections). RESULTS. Complications involved the different major SCD types to an equal extent. Comparison with the control group showed that women who had received prophylactic transfusions had lower rates of VOC (p=0.002) and preterm deliveries (p=0.036), but a significant increase in IUGR cases (p=0.048). CONCLUSION. Selective prophylactic transfusion seems to reduce certain maternal and fetal complications in women with severe forms of SCD. These results can only be confirmed through a randomized prospective study.

Resume But Evaluer la faisabilite et l’efficacite de la radiofrequence (TUNA™) en chirurgie ambulatoire chez le sujet jeune souffrant d’hypertrophie benigne de prostate. Materiels et methodes Neuf patients, d’âge moyen 59,7 ans (valeurs extremes : 55-68) souffrant d’hypertrophie benigne de prostate, ont ete traites par radiofrequence entre mai 2004 et mai 2005 en chirurgie ambulatoire. Le statut mictionnel des patients a ete evalue par le score international symptomatique de la prostate (IPSS), le score de qualite de vie liee aux symptomes urinaires (QdV), la debitmetrie et le residu post-mictionnel. La fonchtion erectile a ete evaluee par l’Index International de la Fonction Erectile (IIEF-5). Resultats Les scores IPSS moyen et de QdV moyen preoperatoires etaient respectivement de 25,2 et de 5,6. Le debit urinaire maximal moyen preoperatoire etait de 6 ml/s et le residu post-mictionnel moyen etait de 167,1 ml. Le score moyen IIEF-5 etait de 20,2. Les patients traites par radiofrequence ont ete revus tous les trois mois. Avec un recul moyen de 9,5 mois, huit patients ont eu une amelioration de leur statut urinaire, avec des scores moyens IPSS et de QdV respectivement de 9,5 et de 1,6 (p Conclusion A l’issue de cette evaluation initiale, le TUNA™ etait une technique fiable, qui a permis de preserver les fonctions sexuelles des sujets jeunes. Sa faible morbidite pourrait permettre sa pratique en chirurgie ambulatoire.

To assess the risk of uterine rupture of the scarred uterus according to mode of delivery in subsequent births recorded as spontaneous labour, labour induced by oxytocin, labour after ripening with prostaglandin E2, and planned cesarean section.Retrospective study of 2,128 births with a low transversal scar after a previous cesarean section. The study population was realised in a level III university hospital from 1995 to 2003. The association between mode of delivery and uterine rupture was studied in a multivariate logistic regression model, and adjusted for specific antenatal confounding factors.Over 9 years, we collected 22 cases (1%), including 11 asymptomatic ruptures in a population of 2,128 scarred uteri out of 28,248 deliveries. Uterine rupture occurred at a rate of 0.3 per 100 among women with repeated cesarean delivery without labour, 1 per 100 among women with spontaneous onset of labour, 1.4 per 100 among women with oxytocin-induced labour, and 2.2 per 100 among women with prostaglandin cervical ripening. Compared to women with a planned cesarean section, women with spontaneous onset of labour were more likely to have uterine rupture (OR: 4.0; 95% CI: 0.8-42.0). A greater relative risk was observed among women with oxytocin-induced labour (OR: 4.3; 95% CI: 0.3-60.0), and particularly those with prostaglandin-induced labour (OR: 8.7; 95% CI: 1.5-97.3, p=0.01).In women with a scarred uterus, prostaglandin E2 induction of labour is a risk factor for uterine rupture. The practice of a systematic cesarean section in cases with Bishop score3, appropriate induction procedure, and rigorous monitoring of the labour, could make for a safer delivery.

Objective This article investigates the effects of antenatal depression and anxiety on spontaneous preterm birth resulting either from preterm labor or preterm premature rupture of membranes. Methods We conducted a prospective cohort study of 681 women with singleton pregnancies consecutively recruited between 20 and 28 weeks of gestation in the Obstetrics Department of the French University Hospital of Caen. Most were of European ethnic origin and received early and regular antenatal care. The assessment of gestational age was based on ultrasound examination (occurring before 13 weeks of gestation for 94.9% of the women). Depression and anxiety were assessed using self-administered questionnaires: the Edinburgh Postnatal Depression Scale and the Spielberger State-Trait Anxiety Inventory. Logistic regression analysis, controlling for sociodemographic factors (e.g., maternal age, occupation) and obstetric factors (e.g., previous preterm birth, cervical or vaginal infection), provided adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results Spontaneous preterm birth occurred in 31 women (4.8%). The rate of spontaneous preterm birth was significantly higher among women with high depression scores (9.7%) as opposed to other women (4.0%) even after adjustment for potential confounding factors (adjusted OR = 3.3, 95% CI = 1.2-9.2, p = .020). Anxiety was not significantly associated with the outcome. There were no significant interaction effects between psychological and biomedical factors. Conclusions These findings provide evidence that antenatal depression is significantly associated with spontaneous preterm birth in a population of European women receiving early and regular care.

Introduction La mediane de survie globale (SG) dans le MPM n’excedait pas 13 mois avec le doublet pemetrexed–cisplatine. Le vascular endothelial growth factor (VEGF) est un facteur de croissance autocrine des cellules mesotheliales malignes. Methodes Dans cette phase 3 multicentrique academique francaise, les patients etaient eligibles s’ils avaient un MPM juge non resecable, histologiquement prouve, un âge Resultats Au total, 448 patients ont ete inclus (73 centres). Hommes : 75,4 % ; âge median : 65,7 ans ; PS 0–1 : 96,7 %. La SG s’est averee significativement plus longue dans le bras B, mediane : 18,8 mois vs 16,1 mois pour le bras A (HR aj. = 0,77, 95 % IC [0,62–0,95], p = 0,015). La survie sans progression (SSP) mediane etait de 9,2 mois, dans le bras B vs 7,3 mois, dans le bras A (HR aj = 0,62, 95 % IC [0,51–0,75], p Conclusion L’addition du bevacizumab au doublet de pemetrexed/cisplatine allonge significativement la SG comme la SSP chez les patients avec MPM, avec un profil de toxicite acceptable, sans impact deletere sur la qualite de vie, ce qui fait de ce triplet le nouveau traitement de reference du mesotheliome.

Resume L’innervation sympathique du tissu osseux a ete tres recemment demontree. La stimulation de la voie beta-adrenergique est une des mediations impliquees dans les mecanismes de perte osseuse par decouplage entre la fonction osteoclastique et la fonction osteoblastique. Objectif. – Nous avons emis l’hypothese qu’en utilisant un antagoniste non specifique de la voie β-adrenergique du systeme sympathique (propranolol per os), nous pourrions freiner la perte osseuse dans un modele de rate suspendue simulant les effets sur l’os de l’absence de contraintes mecaniques et de l’apesanteur par le meme mecanisme cellulaire de decouplage. Materiel et methodes. – Vingt-deux rates Wistar âgees de 12 semaines sont reparties en trois groupes : huit rates non suspendues (RNS), huit rates suspendues (RS) et six rates suspendues traitees par propranolol per os (RSP) pendant 30 jours. Une mesure de la densite minerale osseuse (DMO, g/cm2) par DXA (Hologic QDR-4500A) est realisee a j0 et a j30 au niveau de la metaphyse distale femorale (MDF), de la diaphyse femorale (DF), du corps entier (CE) ainsi qu’une mesure de la composition corporelle. Resultats. – Entre j0 et j30, au niveau de la MDF, la variation de DMO est differente entre le groupe RS et le groupe RNS (RNS : +15,6 ± 3,1 % vs RS : –1,0 ± 1,4 %, p Conclusion. – Nous demontrons que la voie β-adrenergique du systeme nerveux sympathique est une voie de mediation majeure des facteurs de contrainte mecanique dans le tissu osseux chez le rat. Une etude specifique est necessaire pour analyser un eventuel effet systemique du propranolol sur le tissu osseux. Une molecule bloquant la voie β-adrenergique de maniere non specifique pourrait etre utilisee pour lutter contre la perte osseuse liee a l’apesanteur.