International audiencePurpose Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAFV600E mutation occurs frequently, but clinical significance remains to be determined. Patients and Methods BRAFV600E mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae. Results Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAFV600E mutation. Patients with BRAFV600E manifested more severe disease than did those with wild-type BRAF. Patients with BRAFV600E comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P , .001). BRAFV600E mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAFV600E more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001). Conclusion In children with LCH, BRAFV600E mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy. © 2016 by American Society of Clinical Oncology

Analysis of patients with severe congenital neutropenia (SCN) may shed light on the delicate balance of factors controlling differentiation, maintenance, and decay of neutrophils. We identify 9 distinct homozygous mutations in the gene encoding Jagunal homolog 1 (JAGN1) in 14 SCN patients. JAGN1-mutant granulocytes are characterized by ultrastructural defects, paucity of granules, aberrant N-glycosylation of multiple proteins, and increased apoptosis. JAGN1 participates in the secretory pathway and is required for granulocyte-colony stimulating factor receptor-mediated signaling. JAGN1 emerges as a factor necessary in differentiation and survival of neutrophils.

Our results suggest an association with maternal alcohol and coffee drinking during pregnancy and call for further investigations. Besides, the present study does not support the hypothesis of an increase in the risk of childhood leukemia related to parental smoking.

Metabolic polymorphisms may influence the risk of childhood leukaemia related to maternal tobacco, coffee or alcohol consumption. The data were extracted from a case-control study including 280 cases of acute leukaemia and 288 controls. Blood sampling was obtained for a representative subset of 219 cases and 105 controls. Gene-environment interactions were estimated using both case-control and case-only analyses. The polymorphisms of CYP1A1, GSTM1, GSTP1, GSTT1 and NQO1 were not associated with the risk of leukaemia. The slow EPHX1 allele was negatively associated with childhood leukaemia while an inverse non-significant association was observed with the fast EPHX1 allele. Maternal smoking during pregnancy was not related to leukaemia, but an interaction was observed in the case-only analysis with CYP1A1*2A variant allele (odds ratio (OR) 2.2 [1.0-4.9]) and with GSTM1 deletion (OR 2.3 [1.2-4.4]). Conversely, coffee drinking interacted negatively with NQO1 polymorphism in the case-only analysis (OR 0.6 [0.3-1.2] and 0.4 [0.1-1.0] for light and heavy coffee consumptions, respectively). This study suggests that maternal smoking may be a risk factor for leukaemia in children who carry CYP1A1 or GSTM1 genotypes, which might increase reactive metabolites of polycyclic aromatic hydrocarbons.

ABSTRACT. Objectives. Abnormalities in bone mineral density (BMD), body composition, and bone metabolism have been reported in children who were treated for acute lymphoblastic leukemia (ALL) during and after completion of therapy. However, these studies are crosssectional, and no longitudinal data are available in a large group of patients after completion of therapy. In the present study, 1-year longitudinal changes in BMD, body composition, and bone metabolism were evaluated in children with ALL during the first 3 years after completion of therapy without cranial irradiation.Methods. BMD of total body (TB; g/cm 2 ), areal and apparent volumetric lumbar spine (L2-L4), lean body mass, and percentage of body fat were measured by dual-energy x-ray absorptiometry in 37 children (median age: 7.9 years; range: 4.7-20.6 years) who were treated for ALL at a median age of 3.3 years (range: 1.1-16.6 years), after a median time of 2.2 years after the completion of treatment, and after a 1-year follow-up period. Two control subjects (n ‫؍‬ 74) who were matched for gender, age, and pubertal stage were also longitudinally investigated for body composition for 1 year. Usual serum biochemical markers of calcium metabolism and bone turnover were measured in patients during the study period.Results. A slight decrease in TB BMD was found after a median time of 2.2 years after the completion of therapy for ALL in childhood. Patients showed a significantly lower median TB BMD when evaluated <1.5 years as compared with those at >1.5 years since completion of therapy. At the time of first evaluation, the percentage of body fat mass was significantly higher and patients were physically less active than their matched control subjects. Although, as expected, during the 1 year of follow-up both groups showed an annual increment in their BMD measurements, a significantly higher increase in TB BMD was observed in patients in comparison with control subjects. During this same period, the increase in the percentage of body fat mass was slightly lower in ALL patients as compared with control subjects. At the end of the follow-up year, BMD, body-composition parameters, and physical activity of ALL patients were similar to those observed in matched control subjects. Serum biochemical markers of bone turnover were normal at both evaluations.Conclusions. A significant increase in TB BMD and a tendency to a lesser increase in percentage of body fat mass were observed during the study period in ALL patients as compared with chronological age-, gender-, and pubertal stage-matched control subjects. These findings suggest a positive effect of long-term completion therapy and increase in physical activity on BMD, body composition, and bone metabolism in patients who have been treated for ALL. A cute lymphoblastic leukemia (ALL) is the most common childhood malignancy, and 80% of children with standard-risk disease can now expect to be cured. 1,2 Children with ALL have reduced bone formation 3-10 and bone mineral density (BMD) 3,9,10 at diagnosis. Seve...