Pottier C.,University of Rouen |
Hannequin D.,University of Rouen |
Coutant S.,University of Rouen |
Rovelet-Lecrux A.,University of Rouen |
And 21 more authors.
Molecular Psychiatry | Year: 2012
Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n1) or missense (n4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD. © 2012 Macmillan Publishers Limited All rights reserved.
Dhedin N.,University Paris Diderot |
Huynh A.,Institut Universitaire de France |
Maury S.,University Hospital Henri Mondor |
Tabrizi R.,University Hospital |
And 18 more authors.
Blood | Year: 2015
Because a pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol yielded a markedly improved outcome in adults with Philadelphia chromosome-negative ALL, we aimed to reassess the role of allogeneic stem cell transplantation (SCT) in patients treated in the GRAALL-2003 and GRAALL-2005 trials. In all, 522 patients age 15 to 55 years old and presenting with at least 1 conventional high-risk factor were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission. At 3 years, posttransplant cumulative incidences of relapse, nonrelapse mortality, and relapse-free survival (RFS) were estimated at 19.5%, 15.5%,and64.7%, respectively. Time-dependent analysis did not reveal a significant difference in RFS between SCT and no-SCT cohorts. However, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD)≥10-3 (hazard ratio, 0.40) but not in good MRD responders. In B-cell precursor ALL, SCT also benefitted patients with focal IKZF1 gene deletion (hazard ratio, 0.42). This article shows that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patientswhomay benefit from allogeneic SCT in the context of intensified adult ALL therapy. Trial GRAALL-2003 was registered at www.clinicaltrials.gov as #NCT00222027; GRAALL-2005 was registered as #NCT00327678. © 2015 by The American Society of Hematology.
Duron J.-J.,University Hospital Pitie Salpetriere |
Duron J.-J.,University Pierre and Marie Curie |
Duron E.,University Hospital Broca |
Duron E.,University of Paris Descartes |
And 11 more authors.
Annals of Surgery | Year: 2011
Objective: To identify the mortality risk factors of elderly patients (≥65 years old) during major digestive surgery, as defined according to the complexity of the operation. Background: In the aging populations of developed countries, the incidence rate of major digestive surgery is currently on the rise and is associated with a high mortality rate. Consequently, validated indicators must be developed to improve elderly patients' surgical care and outcomes. Methods: We acquired data from a multicenter prospective cohort that included 3322 consecutive patients undergoing major digestive surgery across 47 different facilities. We assessed 27 pre-, intra-, and postoperative demographic and clinical variables. A multivariate analysis was used to identify the independent risk factors of mortality in elderly patients (n = 1796). Young patients were used as a control group, and the end-point was defined as 30-day postoperative mortality. Results: In the entire cohort, postoperative mortality increased significantly among patients aged 65-74 years, and an age ≥65 years was by itself an independent risk factor for mortality (odds ratio [OR], 2.21; 95% confidence interval [CI], 1.36-3.59; P = 0.001). The mortality rate among elderly patients was 10.6%. Six independent risk factors of mortality were characteristic of the elderly patients: age ≥85 years (OR, 2.62; 95% CI, 1.08-6.31; P = 0.032), emergency (OR, 3.42; 95% CI, 1.67-6.99; P = 0.001), anemia (OR, 1.80; 95% CI, 1.02-3.17; P = 0.041), white cell count > 10,000/mm (OR, 1.90; 95% CI, 1.08-3.35; P = 0.024), ASA class IV (OR, 9.86; 95% CI, 1.77-54.7; P = 0.009) and a palliative cancer operation (OR, 4.03; 95% CI, 1.99-8.19; P < 0.001). Conclusion: Characterization of independent validated risk indicators for mortality in elderly patients undergoing major digestive surgery is essential and may lead to an efficient specific workup, which constitutes a necessary step to developing a dedicated score for elderly patients. Copyright © 2011 by Lippincott Williams & Wilkins.
Loncar G.,Institut Universitaire de France |
Payot L.,Institut Universitaire de France |
Dubois M.,University Hospital Pitie Salpetriere
Echocardiography | Year: 2015
Platypnea-orthodeoxia syndrome (POS) is a rare clinical disorder characterized by dyspnea caused by the upright position and relieved at recumbent position. Few cases of POS and stroke were reported in literature, and the association between stroke and POS with evidence of patent foramen ovale (PFO) is rare. Stroke may occur in patients with cardiac shunt who undergo contrast echocardiography. We present a patient with POS who experienced transitory ischemic attack (TIA) most likely caused by injection of agitated saline microbubbles during screen for PFO. No case report of TIA/stroke during contrast echocardiography in patients with POS has previously been published. © 2015, Wiley Periodicals, Inc.
Beldjord K.,University Paris Diderot |
Chevret S.,University Paris Diderot |
Asnafi V.,University of Paris Descartes |
Huguet F.,University Hospital Purpan |
And 21 more authors.
Blood | Year: 2014
With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by immunoglobulin/T-cell receptor minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome-negative ALL in first remission (265 B-cell precursor [BCP] and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as the primary end point. In addition to conventional risk factors, the most frequent currently available genetic alterations were included in the analysis. A higher specific hazard of relapse was independently associated with postinduction MRD level ≥10-4 and unfavorable genetic characteristics (ie, MLL gene rearrangement or focal IKZF1 gene deletion in BCP-ALL and no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN gene alteration in T-cell ALL). These 2 factors allowed definition of a new risk classification that is strongly associated with higher CIR and shorter relapse-free and overall survival. These results indicate that genetic abnormalities are important predictors of outcomein adult ALL not fully recapitulated by early response to therapy. Patients included in this study were treated in the multicenter GRAALL-2003 and GRAALL-2005 trials. Both trials were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively. © 2014 by The American Society of Hematology.