ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome

Neuroblastic tumours may occur in a predisposition context. Two main genes are involved: PHOX2B, observed in familial cases and frequently associated with other neurocristopathies (Ondine's and Hirschsprung's disease); and ALK, mostly in familial tumours. We have assessed the frequency of mutations of these two genes in patients with a presumable higher risk of predisposition. We sequenced both genes in 26 perinatal cases (prebirth and o1 month of age, among which 10 were multifocal), 16 multifocal postnatal (41 month) cases, 3 pairs of affected relatives and 8 patients with multiple malignancies. The whole coding sequences of the two genes were analysed in tumour and/or constitutional DNAs. We found three ALK germline mutations, all in a context of multifocal tumours. Two mutations (T1151R and R1192P) were inherited and shared by several unaffected patients, thus illustrating an incomplete penetrance. Younger age at tumour onset did not seem to offer a relevant selection criterion for ALK analyses. Conversely, multifocal tumours might be the most to benefit from the genetic screening. Finally, no PHOX2B germline mutation was found in this series. In conclusion, ALK deleterious mutations are rare events in patients with a high probability of predisposition. Other predisposing genes remain to be discovered

Complications ostéo-articulaires au cours du traitement par le protocole Fralle 2000 des leucémies aiguës lymphoblastiques de l enfant (expérience de l unité d hémato-pédiatrie du CHU d Angers)

L'augmentation de l'espérance de vie des enfants atteints de leucémie aigue lymphoblastique s'accompagne de complications peu décrites sur le plan ostéoarticulaire. L'objectif principal de cette étude était de déterminer la fréquence de ces dernières et d'envisager les éléments de surveillance susceptibles de prévenir leur survenue. Il s'agit d'un travail rétrospectif portant sur 37 enfants admis entre 2000 et 2006 et traités selon le protocole FRALLE 2000. Nous avons recueilli les caractéristiques des complications ostéo-articulaires définies comme l'ensemble des fractures, entorses, luxations, ostéonécroses et douleurs musculo-squelettiques survenant au cours du traitement et pendant la phase post-thérapeutique. Ces complications ont été dans un second temps analysées en fonction de critères susceptibles de favoriser leur survenue. Dans cette série, la fréquence des complications ostéo-articulaires toutes confondues est importante, environ 70 %, et plus forte que celle généralement relevée dans la littérature, mais ces complications ostéo-articulaires incluent les douleurs musculo-squelettiques (65 % des patients) généralement non rapportées dans les autres études. Seul le sexe masculin a pu être individualisé en tant que facteur associé à la survenue de l'ensemble de ces complications. Une surveillance particulière de ces enfants semble requise. Dans ce cadre, la densitométrie osseuse paraît constituer un examen de choix pour apprécier l'état de minéralisation osseuse et définir un éventuel risque de fracture ou d'ostéonécrose. D'autres travaux rétrospectifs, et surtout prospectifs, seraient néanmoins nécessaires pour définir au mieux des stratégies préventives.ANGERS-BU Médecine-Pharmacie (490072105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Complications postopératoires des tumeurs cérébrales de l enfant (expérience du service de réanimation polyvalente de l enfant du CHU d Angers)

Introduction: La neurochirurgie constitue l élément essentiel de la prise en charge des tumeurs cérébrales de l enfant avant un éventuel traitement complémentaire (chimio et/ou radiothérapie). En période postopératoire, les patients requièrent une surveillance étroite dans un service de réanimation afin de détecter et de prendre en charge rapidement les éventuelles complications liées à l acte opératoire. Le but de cette étude était de recenser l incidence et les caractéristiques de ces complications ainsi que l évolution neurologique des enfants en période postopératoire.Patients et méthodes: Notre étude rétrospective portait sur les patients hospitalisés entre le 1er janvier 2002 et le 31 décembre 2008 dans l unité de Réanimation Polyvalente de l Enfant du CHU d Angers après exérèse d une tumeur cérébrale. Les détails de la population, les données opératoires et post chirurgicales ont été recensées.Résultats: Nous rapportons 117 interventions. Les complications métaboliques (30%) ainsi que les hémorragies (6%) survenaient précocement (avant 48 heures). Les complications infectieuses (20,5%) étaient plus tardives. Une amélioration neurologique était constatée dans les 2 premiers jours en particulier chez les enfants présentant un syndrome cérébelleux, des convulsions ou un déficit endocrinien préexistants. Un seul patient est décédé après la chirurgie.Conclusion: Toutes ces complications et leurs facteurs de risque doivent être systématiquement recherchés afin de diminuer la morbidité post opératoire des tumeurs cérébrales de l enfant. Elles justifient d une équipe chirurgicale et d une équipe d anesthésie réanimation particulièrement habituées à ce type de pathologie.ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Long-term visual acuity in patients with optic pathway glioma treated during childhood with up-front BB-SFOP chemotherapy-Analysis of a French pediatric historical cohort.

BackgroundVisual outcome is one of the main issues in the treatment of optic pathway glioma in childhood. Although the prognostic factors of low vision have been discussed extensively, no reliable indicators for visual loss exist. Therefore, we aimed to define initial and evolving factors associated with long-term vision loss.MethodsWe conducted a multicenter historical cohort study of children treated in France with up-front BB-SFOP chemotherapy between 1990 and 2004. Visual acuity performed at the long-term follow-up visit or within 6 months prior was analyzed. Logistic regression analysis was used to estimate the effects of clinical and radiological factors on long-term visual outcome.FindingsOf the 180 patients in the cohort, long-term visual acuity data were available for 132 (73.3%) patients (median follow-up: 14.2 years; range: 6.1-25.6). At the last follow-up, 61/132 patients (46.2%) had impaired vision, and 35 of these patients (57.3%) were partially sighted or blind. Multivariate analysis showed that factors associated with a worse prognosis for long-term visual acuity were an age at diagnosis of InterpretationOur study confirms that a large proportion of children with optic pathway glioma have poor long-term outcomes of visual acuity. These data suggest new prognostic factors for visual acuity, but these results need to be confirmed further by large- and international-scale studies

Mechanisms involved in lipid accumulation and apoptosis induced by 1-nitropyrene in Hepa1c1c7 cells.

International audience1-Nitropyrene (1-NP) is a nitro-polycyclic aromatic hydrocarbon (nitro-PAH) present in diesel exhaust and bound to particular matter in urban air. We show that 1-NP and the referent PAH benzo(a)pyrene (BP) induce apoptosis and a lipid accumulation dependent on cytochrome P450 1A1-metabolites in mouse hepatoma cells, whereas 1-amino-pyrene had no effect. The caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethyl ketone (Z-VAD-fmk), inhibits 1-NP-induced apoptosis, but failed to alter 1-NP-triggered lipid accumulation determined by Nile red staining. We further show that cholesterol and fatty acid contents are modified after nitro-PAH exposure and that 1-NP-induced cholesterol level is partially involved in related apoptosis. In parallel, the activity of the stearoyl-CoA desaturase 1 (SCD1), determined by fatty acid analysis, and its expression are reduced by 1-NP. The role of SCD1 in 1-NP-induced apoptosis is demonstrated in cells down-expressing SCD1, in which an increased apoptosis is observed, whereas the SCD1 overexpression elicits the opposite effects. In contrast, changes in SCD1 gene expression have no effect on the induced lipid accumulation. Moreover, 1-NP increases the activity of the AMP-dependent protein kinase (AMPK) leading to a caspase-independent apoptosis. Overall, our study demonstrates that the 1-NP-induced apoptosis is caspase- and AMPK-dependent, and is associated to a decrease of SCD1 expression which results in an alteration of lipid homeostasis

Selective IgG subclass deficiency in children with recurrent infections : clinical, biological and therapeutic relevance

Date du colloque&nbsp;: 10/2008</p

Mortality in Children with Optic Pathway Glioma Treated with Up-Front BB-SFOP Chemotherapy.

In terms of overall survival (OS), limited data are available for the very long-term outcomes of children treated for optic pathway glioma (OPG) with up-front chemotherapy. Therefore, we undertook this study with the aim of clarifying long-term OS and causes of death in these patients.We initiated and analyzed a historical cohort study of 180 children with OPG treated in France with BB-SFOP chemotherapy between 1990 and 2004. The survival distributions were estimated using Kaplan-Meier method. The effect of potential risk factors on the risk of death was described using Cox regression analysis.The OS was 95% [95% CI: 90.6-97.3] 5 years after diagnosis and significantly decreased over time without ever stabilizing: 91.6% at 10 years [95% CI: 86.5-94.8], 80.7% at 15 years [95% CI: 72.7-86.8] and 75.5% [95% CI: 65.6-83] at 18 years. Tumor progression was the most common cause of death (65%). Age and intracranial hypertension at diagnosis were significantly associated with a worse prognosis. Risk of death was increased by 3.1[95% CI: 1.5-6.2] (p=0.002) for patients less than 1 year old at diagnosis and by 5.2[95% CI: 1.5-17.6] (p=0.007) for patients with initial intracranial hypertension. Boys without diencephalic syndrome had a better prognosis (HR: 0.3 [95% CI: 0.1-0.8], p=0.007).This study shows that i) in children with OPG, OS is not as favorable as previously described and ii) patients can be classified into 2 groups depending on risk factors (age, intracranial hypertension, sex and diencephalic syndrome) with an OS rate of 50.4% at 18 years [95% CI: 31.4-66.6] in children with the worst prognosis. These findings could justify, depending on the initial risk, a different therapeutic approach to this tumor with more aggressive treatment (especially chemotherapy) in patients with high risk factors

Parental smoking, maternal alcohol, coffee and tea consumption during pregnancy and childhood malignant central nervous system tumours: the ESCALE study (SFCE).

International audienceParental smoking and maternal alcohol and caffeinated beverage consumption are prevalent exposures which may play a role, either directly or through their influence on metabolism, in the aetiology of childhood malignant central nervous system (CNS) tumours. The hypothesis was investigated in the Epidemiological Study on childhood Cancer and Leukemia ESCALE study, a national population-based case-control study carried out in France in 2003-2004. The study included 209 incident cases of CNS tumours and 1681 population-based controls, frequency matched with the cases by age and sex. The data were collected through a standardized telephone interview of the biological mothers. No association between maternal smoking during pregnancy and CNS tumours [odds ratio (OR): 1.1 (0.8-1.6)] was observed. Paternal smoking during the year before birth was associated with CNS tumours (P for trend=0.04), particularly astrocytomas [OR: 3.1 (1.3-7.6)]. Maternal alcohol consumption during pregnancy was not associated with CNS tumours. Associations between ependymomas and the highest consumption of coffee [OR: 2.7 (0.9-8.1)] and tea [OR: 2.5 (1.1-5.9)] were observed. A strong association between CNS tumours and the highest maternal consumption of both coffee and tea during pregnancy was observed [OR: 4.4 (1.5-13)]. The results constitute additional evidence for a role of paternal smoking and suggest that maternal coffee and tea consumption during pregnancy may also increase the risk of CNS tumours. The study does not suggest an increased risk of CNS tumours related to alcohol consumption during pregnancy

Maternal reproductive history, fertility treatments and folic acid supplementation in the risk of childhood acute leukemia: the ESTELLE Study

International audiencePURPOSE: To investigate the potential involvement of fertility treatments and other conditions of becoming pregnant (infertility, getting pregnant on birth control, maternal history of fetal loss) and folic acid supplements in the etiology of childhood leukemia (CL). METHODS: The ESTELLE study included 747 cases of CL [636 cases of acute lymphoblastic leukemia (ALL) and 100 of acute myeloblastic leukemia (AML)] diagnosed in France in 2010-2011 and 1,421 population controls frequency-matched with the cases on age and gender. Data were obtained from structured telephone questionnaires administered to mothers. The odds ratios (OR) and their 95 % confidence intervals were estimated using unconditional regression models adjusted for potential confounders. RESULTS: CL was not associated with difficulty in becoming pregnant [OR 0.9 (0.7-1.2)], in vitro fertilisation [OR 0.6 (0.3-1.5)] or the use of any fertility treatment [OR 0.8 (0.5-1.1)] for the index pregnancy. CL was not significantly associated with becoming pregnant on contraception [OR 1.2 (0.8-1.8)], but a positive association was observed for third generation oral contraception [OR 4.3 (1.2-16.2)]; however, the result is based on small numbers. Folic acid supplementation during pregnancy was not associated with CL, but an inverse borderline association was observed for supplementation initiated in the 3 months preceding pregnancy [OR 0.7 (0.5-1.0)]. In addition, maternal histories of stillbirth and miscarriage were associated with ALL [OR 2.6 (1.1-5.9)] and AML [OR 1.8 (1.1-2.8)], respectively. CONCLUSIONS: The findings do not suggest that infertility and fertility treatments are risk factors for CL. They suggest that maternal histories of stillbirth and miscarriage may be more frequent among mothers of CL cases and that folic acid supplementation during preconception may reduce the risk of CL

Folic acid supplementation, MTHFR and MTRR polymorphisms, and the risk of childhood leukemia: the ESCALE study (SFCE)

International audiencePURPOSE: Fetal folate deficiency may increase the risk of subsequent childhood acute leukemia (AL), since folates are required for DNA methylation, synthesis, and repair, but the literature remains scarce. This study tested the hypothesis that maternal folic acid supplementation before or during pregnancy reduces AL risk, accounting for the SNPs rs1801133 (C677T) and rs1801131 (A1298C) in MTHFR and rs1801394 (A66G) and rs1532268 (C524T) in MTRR, assumed to modify folate metabolism. METHODS: The nationwide registry-based case-control study, ESCALE, carried out in 2003-2004, included 764 AL cases and 1,681 controls frequency matched with the cases on age and gender. Information on folic acid supplementation was obtained by standardized telephone interview. The genotypes were obtained using high-throughput platforms and imputation for untyped polymorphisms. Odds ratios (OR) were estimated using unconditional regression models adjusted for potential confounders. RESULTS: AL was significantly inversely associated with maternal folic acid supplementation before and during pregnancy (OR = 0.4; 95 % confidence interval: [0.3-0.6]). MTHFR and MTRR genetic polymorphisms were not associated with AL. However, AL was positively associated with homozygosity for any of the MTHFR polymorphisms and carriership of both MTRR variant alleles (OR = 1.6 [0.9-3.1]). No interaction was observed between MTHFR, MTRR, and maternal folate supplementation. CONCLUSION: The study findings support the hypothesis that maternal folic acid supplementation may reduce the risk of childhood AL. The findings also suggest that the genotype homozygous for any of the MTHFR variants and carrying both MTRR variants could be a risk factor for AL