CHU Necker

Paris, France

CHU Necker

Paris, France
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Coyaud E.,French Institute of Health and Medical Research | Coyaud E.,University Paul Sabatier | Struski S.,Toulouse University Hospital Center | Prade N.,French Institute of Health and Medical Research | And 30 more authors.
Blood | Year: 2010

PAX5 is the main target of somatic mutations in acute B lymphoblastic leukemia (B-ALL). We analyzed 153 adult and child B-ALL harboring karyotypic abnormalities at chromosome 9p, to determine the frequency and the nature of PAX5 alterations. We found PAX5 internal rearrangements in 21% of the cases. To isolate fusion partners, we used classic and innovative techniques (rolling circle amplification-rapid amplification of cDNA ends) and single nucleotide polymorphism-comparative genomic hybridization arrays. Recurrent and novel fusion partners were identified, including NCoR1, DACH2, GOLGA6, and TAOK1 genes showing the high variability of the partners. We noted that half the fusion genes can give rise to truncated PAX5 proteins. Furthermore, malignant cells carrying PAX5 fusion genes displayed a simple karyotype. These data strongly suggest that PAX5 fusion genes are early players in leukemogenesis. In addition, PAX5 deletion was observed in 60% of B-ALL with 9p alterations. Contrary to cases with PAX5 fusions, deletions were associated with complex karyotypes and commonrecurrent translocations. This supports the hypothesis of the secondary nature of the deletion. Our data shed more light on the high variability of PAX5 alterations in B-ALL. Therefore, it is probable that gene fusions occur early, whereas deletions should be regarded as a late/secondary event. © 2010 by The American Society of Hematology.

Legriel S.,Center Hospitalier Of Versailles Andre Mignot Hospital | Azoulay E.,CHU Saint Louis | Resche-Rigon M.,CHU Saint Louis | Lemiale V.,CHU Saint Louis | And 14 more authors.
Critical Care Medicine | Year: 2010

Objectives: Few outcome data are available about convulsive status epilepticus managed in the intensive care unit. We studied 90-day functional outcomes and their determinants in patients with convulsive status epilepticus. Design: Two hundred forty-eight convulsive status epilepticus patients admitted to 18 intensive care units in 2005-2007 were included in a prospective observational cohort study. The main outcome measure was a Glasgow Outcome Scale score of 5 (good recovery) on day 90. Main results: Convulsive status epilepticus occurred out of hospital in 177 (67%) patients, and all but 15 patients were still seizing at medical team arrival. The median time from convulsive status epilepticus onset to anticonvulsant drug initiation was 40 mins (interquartile range, 5-80). Total seizure duration was 85 mins (interquartile range, 46.5-180). Convulsive status epilepticus was refractory in 49 (20%) patients. The most common causes of convulsive status epilepticus were anticonvulsive agent withdrawal (36.4%) in patients with previous epilepsy and stroke (27.7%) in inaugural convulsive status epilepticus. Mechanical ventilation was needed in 210 (85%) patients. On day 90, 42 (18.8%) patients were dead, 87 (38.8%) had marked functional impairments (Glasgow Outcome Scale score, 2-4), and 95 (42.4%) had a good recovery (Glasgow Outcome Scale score, 5). Factors showing independent positive associations with poor outcome (Glasgow Outcome Scale score, <5) were older age (odds ratio, 1.04/year; 95% confidence interval, 1.02-1.05; p = .0005), cerebral insult (odds ratio, 2.70; 95% confidence interval, 1.37-5.26; p = .007), longer seizure duration (odds ratio, 1.72/120 min; 95% confidence interval, 1.05-2.86; p = .03), on-scene focal neurologic signs (odds ratio, 2.08; 95% confidence interval, 1.03-4.16; p = .04), and refractory convulsive status epilepticus (odds ratio, 2.70; 95% confidence interval, 1.02-7.14; p = .045). Conclusions: Ninety days after intensive care unit admission for convulsive status epilepticus, half the survivors had severe functional impairments. Longer seizure duration, cerebral insult, and refractory convulsive status epilepticus were strongly associated with poor outcomes, suggesting a role for early neuroprotective strategies. © 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

Acute renal failure (ARF) in critically ill patients is currently very frequent and requires renal replacement therapy (RRT) in many patients. During the last 15years, several studies have considered important issues regarding the use of RRT in ARF, like the time to initiate the therapy, the dialysis dose, the types of catheter, the choice of technique, and anticoagulation. However, despite an abundant literature, conflicting results do not provide evidence on RRT implementation. We present herein recommendations for the use of RRT in adult and pediatric intensive care developed with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system by an expert group of French Intensive Care Society (SRLF), with the participation of the French Society of Anesthesia and Intensive Care (SFAR), the French Group for Pediatric Intensive Care and Emergencies (GFRUP), and the French Dialysis Society (SFD). The recommendations cover 4 fields: criteria for RRT initiation, technical aspects (access routes, membranes, anticoagulation, reverse osmosis water), practical aspects (choice of the method, peritoneal dialysis, dialysis dose, adjustments), and safety (procedures and training, dialysis catheter management, extracorporeal circuit set-up). These recommendations have been designed on a practical point of view to provide guidance for intensivists in their daily practice.

Carreras E.,Institute of Hematology Oncology | Cahn J.Y.,Joseph Fourier University | Puozzo C.,IRPF | Kroger N.,University of Hamburg | And 4 more authors.
Anticancer Research | Year: 2010

This study investigated the effect of seizure prophylaxis on busulfan (Bu) plasma exposure. Twenty-four adult patients received an intravenous Bu-cyclophoshamide conditioning regimen prior to bone marrow transplantation. Busilvex® (0.8 mg/kg) was administered every six hours during four consecutive days. Clonazepam (0.025 to 0.03 mglkglday as a continuous 12-h i.v. infusion) was administered at least 12 hours prior to i.v. Bu dosing and continued until 24 hours after the last dose. Pharmacokinetic (PK) data were compared with those previously collected in patients (n=127) treated with phenytoin for seizure prophylaxis. Through population PK analysis, a 10% average increase (coeffiecient of variation, RSE=5.35%) in total clearance of Bu was quantified when Bu was associated with clonazepam as compared to phenytoin, which was considered as not being clinically relevant. The suspected induction on Bu metabolism by phenytoin should have resulted in the opposite effect. The patient efficacy and safety profiles were comparable between the two cohorts.

Quelen C.,French Institute of Health and Medical Research | Quelen C.,Toulouse University Hospital Center | Lippert E.,Bordeaux University Hospital Center | Struski S.,Toulouse University Hospital Center | And 12 more authors.
Blood | Year: 2011

Acute basophilic leukemia (ABL) is a rare subtype of acute leukemia with clinical features and symptoms related to hyperhistaminemia because of excessive growth of basophils. No known recurrent cytogenetic abnormality is associated with this leukemia. Rare cases of t(X;6)(p11;q23) translocation have been described but these were sporadic. We report here 4 cases of ABL with a t(X;6)(p11;q23) translocation occurring in male infants. Because of its location on chromosome 6q23, MYB was a good candidate gene. Our molecular investigations, based on fluorescence in situ hybridization and rapid amplification of cDNA ends, revealed that the translocation generated a MYB-GATA1 fusion gene. Expression of MYB-GATA1 in mouse lineage-negative cells committed them to the granulocyte lineage and blocked at an early stage of differentiation. Taken together, these results establish, for the first time, a link between a recurrent chromosomal translocation and the development of this particular subtype of infant leukemia. © 2011 by The American Society of Hematology.

Khellaf M.,University Paris Est Creteil | Michel M.,University Paris Est Creteil | Quittet P.,Montpellier University Hospital Center | Viallard J.-F.,CHU Haut Leveque | And 21 more authors.
Blood | Year: 2011

Romiplostim, a thrombopoietic agent with demonstrated efficacy against immune thrombocytopenia (ITP) in prospective controlled studies, was recently licensed for adults with chronic ITP. Only France has allowed romiplostim compassionate use since January 2008. ITP patients could receive romiplostim when they failed to respond to successive corticosteroids, intravenous immunoglobulins, rituximab, and splenectomy, or when splenectomy was not indicated. We included the first 80 patients enrolled in this program with at least 2 years of follow-up. Primary platelet response (platelet count ≥ 50 × 10 9/L and double baseline) was observed in 74% of all patients. Long-term responses (2 years) were observed in 47 (65%) patients, 37 (79%) had sustained platelet responses with a median platelet count of 106 × 10 9/L (interquartile range, 75-167 × 10 9/L), and 10 (21%) were still taking romiplostim, despite a median platelet count of 38 × 10 9/L (interquartile range, 35-44 × 10 9/L), but with clinical benefit (lower dose and/or fewer concomitant treatment(s) and/or diminished bleeding signs). A high bleeding score and use of concomitant ITP therapy were baseline factors predicting romiplostim failure. The most frequently reported adverse events were: arthralgias (26%), fatigue (13%), and nausea (7%). Our results confirmed that romiplostim use in clinical practice is effective and safe for severe chronic ITP. This trial was registered at as #NCT01013181. © 2011 by The American Society of Hematology.

Ishida-Yamamoto A.,Asahikawa University | Furio L.,University of Paris Descartes | Igawa S.,Asahikawa University | Honma M.,Asahikawa University | And 4 more authors.
Experimental Dermatology | Year: 2014

Peeling skin syndrome (PSS) type B is a rare recessive genodermatosis characterized by lifelong widespread, reddish peeling of the skin with pruritus. The disease is caused by small-scale mutations in the Corneodesmosin gene (CDSN) leading to premature termination codons. We report for the first time a Japanese case resulting from complete deletion of CDSN. Corneodesmosin was undetectable in the epidermis, and CDSN was unamplifiable by PCR. QMPSF analysis demonstrated deletion of CDSN exons inherited from each parent. Deletion mapping using microsatellite haplotyping, CGH array and PCR analysis established that the genomic deletion spanned 49-72 kb between HCG22 and TCF19, removing CDSN as well as five other genes within the psoriasis susceptibility region 1 (PSORS1) on 6p21.33. This observation widens the spectrum of molecular defects underlying PSS type B and shows that loss of these five genes from the PSORS1 region does not result in an additional cutaneous phenotype. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pillebout E.,CHU St Louis | Alberti C.,University Paris Diderot | Guillevin L.,CHU Cochin | Ouslimani A.,Assistance Publique Hpitaux de Paris | Thervet E.,CHU Necker
Kidney International | Year: 2010

Henoch Schönlein Purpura (HSP) is a common disease in children, usually associated with a good prognosis. In adults there are no prospective studies concerning its prognosis or treatment, especially in cases of severe visceral involvement. Here we compared steroid therapy without or with cyclophosphamide co-treatment in adults with severe HSP in a 12-month, multi-center, prospective, open-label trial that treated 54 adults with biopsy-proven HSP including proliferative glomerulonephritis and severe visceral manifestations. All received steroids; however, 25 were randomized to also receive cyclophosphamide. The primary endpoint that occurred in three patients in each group was complete disease remission defined as zero on the Birmingham Vasculitis Activity Score with no persistent or new clinical and/or biological vasculitis at 6 months. No patient had active visceral involvement. The secondary endpoints were renal outcome, deaths, and adverse events at 12 months. Renal function, proteinuria, safety data, incidence of diabetes, and severe infections were similar between the two groups. At the last follow-up, renal function remained stable. The small population size of our study does not permit definitive conclusions; however, we suggest that treatment of adults with severe HSP by adding cyclophosphamide provides no benefit compared with steroids alone. © 2010 International Society of Nephrology.

Courivaud C.,University of Franche Comte | Courivaud C.,Besancon University Hospital Center | Bamoulid J.,University of Franche Comte | Bamoulid J.,Besancon University Hospital Center | And 16 more authors.
Transplantation | Year: 2013

Background. Fractalkine (CX3CL1) and its receptor (CX3CR1) are involved in antitumor immunity. Two common single nucleotide polymorphisms of the CX3CR1 gene, V249I and T280M, have been associated with reduced fractalkine signaling characterized by decreased adhesive function, signaling, and chemotaxis of leukocytes. We hypothesized that a renal transplant recipient (RTR) carrying the homozygous I249M280 genotype could experience more cancer due to lower CX3CL1-dependent antitumorigenic effects. Methods. We studied the association between these polymorphisms and cancer incidence in two independent cohorts of RTR, including a total of 622 patients. Results. The median follow-up was 8.7 and 7.9 years for the first and second cohorts, respectively. Analysis of 622 patients identified 20 (3.2%) I249M280 homozygous patients, 321 (51.6%) V249T280 homozygous patients, and 281 (45.2%) heterozygous patients. I249M280 homozygotes have an independent increased risk of cancer (hazard ratio [95% confidence interval], 3.3 [1.04-10.52], P=0.043 for cohort 1 and 9.2 [1.67-50.91], P=0.011 for cohort 2) compared with other patients. Age and male gender were also risk factors for cancer occurrence. Conclusions. CX3CR1 gene polymorphism is associated with a higher rate of cancer in RTRs. Such findings may be used to influence immunosuppressive strategies and optimize patient management. Copyright © 2013 by Lippincott Williams & Wilkins.

Tillou X.,Caen University Hospital Center | Guleryuz K.,Caen University Hospital Center | Doerfler A.,Caen University Hospital Center | Bensadoun H.,Caen University Hospital Center | And 15 more authors.
American Journal of Transplantation | Year: 2014

Nephron sparing surgery (NSS) results in the transplanted population remain unknown because they are only presented in small series or case reports. Our objective was to study renal sparing surgery for kidney graft renal cell carcinomas (RCC) in a multicenter cohort. Data were collected from 32 French transplantation centers. Cases of renal graft de novo tumors treated as RCC since the beginning of their transplantation activity were included. Seventy-nine allograft kidney de novo tumors were diagnosed. Forty-three patients (54.4%) underwent renal sparing surgery. Mean age of grafted kidneys at the time of diagnosis was 47.5 years old (26.1-72.6). The mean time between transplantation and tumor diagnosis was 142.6 months (12.2-300). Fifteen tumors were clear cell carcinomas (34.9%), and 25 (58.1%) were papillary carcinomas. Respectively, 10 (24.4%), 24 (58.3%) and 8 (19.5%) tumors were Fuhrman grade 1, 2 and 3. Nine patients had postoperative complications (20.9%) including four requiring surgery (Clavien IIIb). At the last follow-up, 41 patients had a functional kidney graft, without dialysis and no long-term complications. NSS is safe and appropriate for all small tumors of transplanted kidneys with good long-term functional and oncological outcomes, which prevent patients from returning to dialysis. This study of 43 nephron sparing surgeries demonstrates a safe and appropriate indication for small tumors of transplanted kidneys, with very good long-term functional and oncological outcomes that prevent patients from returning to dialysis. © Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.

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