CHRU de Grenoble

Grenoble, France

CHRU de Grenoble

Grenoble, France
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Duvoux C.,AP HP | Duvoux C.,University Paris Est Creteil | Roudot-Thoraval F.,University Paris Est Creteil | Decaens T.,AP HP | And 30 more authors.
Gastroenterology | Year: 2012

BACKGROUND & AIMS: The aim of this study was to generate an improved prognostic model for predicting recurrence in liver transplant candidates with hepatocellular carcinoma (HCC). METHODS: Predictors of recurrence were tested by a Cox model analysis in a training cohort of 537 patients transplanted for HCC. A prognostic score was developed and validated in a national cohort of 435 patients followed up prospectively. RESULTS: α-Fetoprotein (AFP) independently predicted tumor recurrence and correlated with vascular invasion and differentiation. At a Cox score threshold of 0.7 (area under the receiver operating characteristic curve, 0.701; 95% confidence interval, 0.63-0.76; accuracy, 75.8%), a model combining log10 AFP, tumor size, and number was highly predictive of tumor recurrence and death. By using a simplified version of the model, with untransformed AFP values, a cut-off value of 2 was identified. In the validation cohort, a score greater than 2 predicted a marked increase in 5-year risk of recurrence (50.6% ± 10.2% vs 8.8% ± 1.7%; P <.001) and decreased survival (47.5% ± 8.1% vs 67.8% ± 3.4%; P =.002) as compared with others. Among patients exceeding Milan criteria, a score of 2 or lower identified a subgroup of patients with AFP levels less than 100 ng/mL with a low 5-year risk of recurrence (14.4% ± 5.3% vs 47.6% ± 11.1%; P =.006). Among patients within Milan criteria, a score greater than 2 identified a subgroup of patients with AFP levels greater than 1000 ng/mL at high risk of recurrence (37.1% ± 8.9% vs 13.3% ± 2.0%; P <.001). Net reclassification improvement showed that predictability of the AFP model was superior to Milan criteria. CONCLUSIONS: Prediction of tumor recurrence is improved significantly by a model that incorporates AFP. We propose the adoption of new selection criteria for HCC transplant candidates, taking into account AFP. © 2012 AGA Institute.


Roux-buisson N.,French Institute of Health and Medical Research | Roux-buisson N.,French National Center for Scientific Research | Roux-buisson N.,Joseph Fourier University | Cacheux M.,French Institute of Health and Medical Research | And 39 more authors.
Human Molecular Genetics | Year: 2012

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease so far related to mutations in the cardiac ryanodine receptor (RYR2) or the cardiac calsequestrin (CASQ2) genes. Because mutations in RYR2 or in CASQ2 are not retrieved in all CPVT cases, we searched for mutations in the physiological protein partners of RyR2 and CSQ2 in a large cohort of CPVT patients with no detected mutation in these two genes. Based on a candidate gene approach, we focused our investigations on triadin and junctin, two proteins that link RyR2 and CSQ2. Mutations in the triadin (TRDN) and in the junctin (ASPH) genes were searched in a cohort of 97 CPVT patients. We identified three mutations in triadin which cosegregated with the disease on a recessive mode of transmission in two families, but no mutation was found in junctin. Two TRDN mutations, a 4 bp deletion and a nonsense mutation, resulted in premature stop codons; the third mutation, a p.T59R missense mutation, was further studied. Expression of the p.T59R mutant in COS-7 cells resulted in intracellular retention and degradation of the mutant protein. This was confirmed after in vivo expression of the mutant triadin in triadin knock-out mice by viral transduction. In this work, we identified TRDN as a new gene responsible for an autosomal recessive form of CPVT. The mutations identified in the two families lead to the absence of the protein, thereby demonstrating the importance of triadin for the normal function of the cardiac calcium release complex in humans. © The Author 2012. Published by Oxford University Press.


Audigier-Valette C.,CHITS Toulon | Girard N.,University Claude Bernard Lyon 1 | Cortot A.B.,University of Lille Nord de France | Mennecier B.,Nouvel Hopital Civil | And 6 more authors.
Bulletin du Cancer | Year: 2014

Crizotinib (XALKORI™, Pfizer) is a tyrosine kinase inhibitor of ALK, MET, and ROS1, which is currently approved for the second line treatment for ALK-rearranged lung cancer. This work from an expert group, based on the review of the data from the Profile studies, aims to provide practical elements in order to optimize the tolerability of crizotinib. Specific major or frequent side effects of crizotinib are discussed: visual disturbances, cardiac effects, elevated transaminases, and hypogonadism. In the routine practice, patients should be advised about visual disturbances, especially with regard to driving in low brightness. Digestive disorders related to crizotinib are exceptionally persistent or severe. Dietary measures and symptomatic treatments usually control these disorders. It is recommended to perform an electrocardiogram before introduction of crizotinib, to identify prolonged QT interval. Torsades de pointes may produce dizziness or syncope. Hypogonadism should be considered in case of fatigue, decreased libido, and even depression, taking into account that these symptoms may be related to cancer; testosterone serum level should be measured to identify patients that may be eligible to receive a supplementation. Monitoring of liver function tests, including transaminases and bilirubin, is necessary. To conclude, these practical elements are helpful to optimize treatment with crizotinib in patients with ALK-rearranged lung cancer; in the future, academic initiatives should be taken to study these aspects, based on the monitoring of large cohorts of patients treated with crizotinib. © John Libbey Eurotext


Decaens T.,AP HP | Decaens T.,University Paris Est Creteil | Decaens T.,French Institute of Health and Medical Research | Roudot-Thoraval F.,University Paris Est Creteil | And 18 more authors.
Liver International | Year: 2011

To generate a new score with improved accuracy compared with Milan criteria to select patients. Patients: The training cohort comprised 373 patients transplanted for hepatocellular carcinoma (HCC) between 1988 and 1998 (cohort 1). An algorithm was derived from the analysis of patient data by the proportional hazard Cox regression model. The area under the receiver operating characteristic (AUROC) was used to determine a cut-off value. The validation cohort comprised 140 patients transplanted between 1999 and 2001 (cohort 2). Results: Multivariate analysis identified three predictors of 5-year tumour-free survival: tumour differentiation (P=0.02), diameter (P<0.0001) and number of nodules (P=0.04). A cut-off value of 4 was derived from the AUROC of the final score. Five-year tumour-free survival was 60.2 ± 3.1% in patients with as score <4 and 36.4 ± 4.7% in individuals with a score ≥4, P<0.0001. In the validation cohort, 5-year tumour-free survival was 82.8 ± 3.6% (score <4) and 50.0 ± 10.7% (score ≥4), P=0.0003. In patients with a score <4, there was no significant difference in 5-year tumour-free survival between Milan+ and Milan- patients, either in cohort 1 or 2. Five-year tumour-free survival of Milan- patients was significantly better in individuals with a score <4 compared with those with a score ≥4, both in cohort 1 (61.5 ± 9.1 vs 31.4 ± 4.6%, P=0.009) and in cohort 2 (P=0.02). Conclusion: A novel score taking into account tumour differentiation shows higher accuracy than Milan criteria in predicting 5-year tumour-free survival following liver transplantation for HCC. Prospective studies should validate these findings. © 2011 John Wiley & Sons A/S.


Roux-Buisson N.,French Institute of Health and Medical Research | Gandjbakhch E.,French Institute of Health and Medical Research | Donal E.,Service de Cardiologie | Probst V.,Nantes University Hospital Center | And 15 more authors.
Heart rhythm : the official journal of the Heart Rhythm Society | Year: 2014

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a genetic disease predominantly caused by desmosomal gene mutations that account for only ~50% of cases. Ryanodine receptor 2 (RYR2) gene mutations usually cause catecholaminergic polymorphic ventricular tachycardia but have been associated with a peculiar phenotype named ARVC2.OBJECTIVE: We aimed to determine the prevalence and phenotype associated with RYR2 mutations in a large ARVC/D population.METHODS: We analyzed the whole RYR2 coding sequence by Sanger sequencing in 64 ARVC/D probands without desmosomal gene mutations.RESULTS: We have identified 6 rare missense variants: p.P1583S, p.A2213S, p.G2367R, p.Y2932H, p.V3219M, and p.L4670V. It corresponds to a 9% prevalence of rare RYR2 variants in the ARVC/D population (6 of 64 probands), which is significantly higher than the estimated frequency of rare RYR2 variants in controls (Fisher exact test, P = .03). Phenotypes associated with RYR2 variants were similar to desmosome-related ARVC/D, associating typical electrocardiographic abnormalities at rest, frequent monomorphic ventricular tachycardia, right ventricular dilatation, wall motion abnormalities, and fibrofatty replacement when histopathological examination was available.CONCLUSION: In this first systematic screening of the whole coding region of the RYR2 gene in a large ARVC/D cohort without mutation in desmosomal genes, we show that putative RYR2 mutations are frequent (9% of ARVC/D probands) and are associated with a conventional phenotype of ARVC/D, which is in contrast with previous findings. The results support the role of the RYR2 gene in conventional ARVC/D. Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.


PubMed | Paris-Sorbonne University, Hopital de Mulhouse, Caen University Hospital Center, University Claude Bernard Lyon 1 and 6 more.
Type: Consensus Development Conference | Journal: Bulletin du cancer | Year: 2014

Crizotinib (XALKORI(), Pfizer) is a tyrosine kinase inhibitor of ALK, MET, and ROS1, which is currently approved for the second line treatment for ALK-rearranged lung cancer. This work from an expert group, based on the review of the data from the Profile studies, aims to provide practical elements in order to optimize the tolerability of crizotinib. Specific major or frequent side effects of crizotinib are discussed: visual disturbances, cardiac effects, elevated transaminases, and hypogonadism. In the routine practice, patients should be advised about visual disturbances, especially with regard to driving in low brightness. Digestive disorders related to crizotinib are exceptionally persistent or severe. Dietary measures and symptomatic treatments usually control these disorders. It is recommended to perform an electrocardiogram before introduction of crizotinib, to identify prolonged QT interval. Torsades de pointes may produce dizziness or syncope. Hypogonadism should be considered in case of fatigue, decreased libido, and even depression, taking into account that these symptoms may be related to cancer; testosterone serum level should be measured to identify patients that may be eligible to receive a supplementation. Monitoring of liver function tests, including transaminases and bilirubin, is necessary. To conclude, these practical elements are helpful to optimize treatment with crizotinib in patients with ALK-rearranged lung cancer; in the future, academic initiatives should be taken to study these aspects, based on the monitoring of large cohorts of patients treated with crizotinib.


Chantry A.A.,French Institute of Health and Medical Research | Chantry A.A.,University Pierre and Marie Curie | Deneux-Tharaux C.,French Institute of Health and Medical Research | Deneux-Tharaux C.,University Pierre and Marie Curie | And 7 more authors.
Revue d'Epidemiologie et de Sante Publique | Year: 2012

Background: The organization of obstetric care in France brings all women in contact with the hospital system. Thus, hospital discharge data from the Program of Medicalization of the Information System (PMSI) constitute a potentially valuable source of information, particularly regarding rare events such as severe maternal morbidity. These data cover a large population but their quality has not been assessed in that field. Our objectives were to study the processes of production and the validity of PMSI data related to severe maternal morbidity. Methods: The study was conducted in four French tertiary teaching hospitals (Caen, Cochin [AP-HP, Paris], Grenoble and Lille). First, the organization of each step of the medical information process -production, formatting, verification and processing- was detailed in each center with a standardized form. Second, the validation study was based on the comparison of data related to severe maternal morbid events in the PMSI from these centers for 2006 and 2007, with the content of medical records which constituted the gold standard. Indicators of sensitivities and positive predictive values of PMSI were calculated. Results: The processes of PMSI data production showed major differences between the four centers. In hospital discharge data, diagnoses (eclampsia and pulmonary embolism) had a high proportion of false-positives (68%). Inversely, procedures (four procedures for management of severe haemorrhage) had less than 1% of false-positives, but a low sensitivity with 37% false-negatives which could be corrected in 95%. Regarding intensive care provision, all indicators of hospital data quality were very high. In addition, the validity of hospital data in centers 1 and 2 was higher for all events. Conclusion: The heterogeneity of the process of PMSI data production is associated with a variable quality of these data. Intensive care provision can be used in the PMSI, as well as procedures after correction. For diagnoses, the quality of the PMSI data is better in centers having both computerized medical records and steps for verification of medical information. © 2012 Elsevier Masson SAS.


Nguyen T.D.,Institute Jean Godinot | Azria D.,Center Val dAurelle | Brochon D.,CHRU de Grenoble | Poortmans P.,Dr B Verbeteen Institute | And 9 more authors.
Critical Reviews in Oncology/Hematology | Year: 2010

Purpose: To analyse tolerance and outcome of patients over 80 years of age who choose external beam radiation therapy to the prostate as a curative treatment. Methods and material: We evaluated acute and late side effects, biological DFS (bDFS) and actuarial survival as well as causes of death in relation to the clinical status including co-morbidity, PSA value, Gleason score and modalities of external radiotherapy in patients with localised prostate cancer >80 years of age. Results: From January 1990 to December 2000, 65 eligible cases (median age: 81) were treated by 12 different participating institutions in the Rare Cancer Network. Tumour stage was T1N0M0, T2N0M0 and T3N0M0 for 10, 40, and 15 patients, respectively. Median follow-up was 65 months (range 22-177). Five-year overall survival rate was 77% with a 5-year bDFS rate of 73%. The incidence of grade 3 early toxicity was 12% and 9% for urinary and digestive tract, respectively. Conclusions: Radiation therapy given with curative intent is well tolerated in this selected group of patients aged over 80 years with localised prostate cancer. Results in terms of survival do not suggest a deleterious impact of this treatment. Therefore the authors recommend that radiation therapy with curative intent should not be withheld in selected elderly patients with localised prostate cancer. © 2009 Elsevier Ireland Ltd. All rights reserved.


PubMed | University of Versailles, Joseph Fourier University, Hopital University Pitie Salpetriere, CHRU de Grenoble and 6 more.
Type: Journal Article | Journal: Heart rhythm | Year: 2014

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a genetic disease predominantly caused by desmosomal gene mutations that account for only ~50% of cases. Ryanodine receptor 2 (RYR2) gene mutations usually cause catecholaminergic polymorphic ventricular tachycardia but have been associated with a peculiar phenotype named ARVC2.We aimed to determine the prevalence and phenotype associated with RYR2 mutations in a large ARVC/D population.We analyzed the whole RYR2 coding sequence by Sanger sequencing in 64 ARVC/D probands without desmosomal gene mutations.We have identified 6 rare missense variants: p.P1583S, p.A2213S, p.G2367R, p.Y2932H, p.V3219M, and p.L4670V. It corresponds to a 9% prevalence of rare RYR2 variants in the ARVC/D population (6 of 64 probands), which is significantly higher than the estimated frequency of rare RYR2 variants in controls (Fisher exact test, P = .03). Phenotypes associated with RYR2 variants were similar to desmosome-related ARVC/D, associating typical electrocardiographic abnormalities at rest, frequent monomorphic ventricular tachycardia, right ventricular dilatation, wall motion abnormalities, and fibrofatty replacement when histopathological examination was available.In this first systematic screening of the whole coding region of the RYR2 gene in a large ARVC/D cohort without mutation in desmosomal genes, we show that putative RYR2 mutations are frequent (9% of ARVC/D probands) and are associated with a conventional phenotype of ARVC/D, which is in contrast with previous findings. The results support the role of the RYR2 gene in conventional ARVC/D.


Escoffier J.,French Institute of Health and Medical Research | Escoffier J.,Joseph Fourier University | Couvet M.,Joseph Fourier University | Couvet M.,French Institute of Health and Medical Research | And 12 more authors.
Biochimie | Year: 2010

The goal of this study was to identify new compounds from venoms able to modulate sperm physiology and more particularly sperm motility. For this purpose, we screened the effects of 16 snake venoms cleared of molecules higher than 15 kDa on sperm motility. Venoms rich in neurotoxins like those from Oxyuranus scutellatus scutellatus or Daboia russelii, were highly potent inhibitors of sperm motility. In contrast, venoms rich in myotoxins like those from Echis carinatus, Bothrops alternatus and Macrovipera lebetina, were inactive. From the main pharmacologically-active fraction of the Taipan snake O. scutellatus s., a proteomic approach allowed us to identify 16 different proteins, among which OS1 and OS2, two secreted phospholipases A2 (sPLA2). Purified OS1 and OS2 mimicked the inhibitory effect on sperm motility and were likely responsible for the inhibitory effect of the active fraction. OS1 and OS2 triggered sperm acrosome reaction and induced lipid rearrangements of the plasma membrane. The catalytic activity of OS2 was required to modulate sperm physiology since catalytically inactive mutants had no effect. Finally, sperm treated with OS2 were less competent than control sperm to initiate in vitro normal embryo development. This is the first report characterizing sPLA2 toxins that modulate in vitro sperm physiology. © 2010 Elsevier Masson SAS.

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