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•LCH-hematological involvement (HI) is life-threatening, defined as hemoglobin ≤7 g/dL and platelets ≤20 G/L•LCH-HI severity, associated with BRAFV600Evariant and macrophage activation, may require early MAPK inhibitors

Introduction:Hematological involvement (HI) is a life-threatening involvement of Langerhans cell histiocytosis (LCH). Since 1975, its definition is based on the Lahey criteria: Anemia (Hb <10 g/dL and <9 g/dL in infants) and/or thrombocytopenia (platelet count <100x10 9/l).

An international phase 2 study combining cladribine and cytarabine (Ara-C) was initiated for patients with refractory, risk-organ–positive Langerhans cell histiocytosis (LCH) in 2005. The protocol, comprising at least two 5-day courses of Ara-C (1 g/m2 per day) plus cladribine (9 mg/m2 per day) followed by maintenance therapy, was administered to 27 patients (median age at diagnosis, 0.7 years; median follow-up, 5.3 years). At inclusion, all patients were refractory after at least 1 course of vinblastine (VBL) plus corticosteroid, all had liver and spleen involvement, and 25 patients had hematologic cytopenia. After 2 courses, disease status was nonactive (n = 2), better (n = 23), or stable (n = 2), with an overall response rate of 92%. Median disease activity scores decreased from 12 at the start of therapy to 3 after 2 courses (P < .0001). During maintenance therapy, 4 patients experienced reactivation in risk organs. There were 4 deaths; 2 were related to therapy toxicity and 2 were related to reactivation. All patients experienced severe toxicity, with World Health Organization grade 4 hematologic toxicity and 6 documented severe infections. The overall 5-year survival rate was 85% (95% confidence interval, 65.2%-94.2%). Thus, the combination of cladribine/Ara-C is effective therapy for refractory multisystem LCH but is associated with high toxicity.

SYNOPTIC ABSTRACTRecent progress in information technology brings new challenges in dealing with the dynamic vehicle routing problem with time windows (DVRPTW). However, few alternate methods to the well-known Tabu Search –based techniques have been proposed so far to solve the DVRPTW efficiently. In this paper, a new hybrid genetic approach (HGA-LCS) to address the DVRPTW is presented. The basic scheme consists in concurrently evolving two populations of solutions to minimize customer service denial, lateness or temporal constraint violation, and total traveled distance. Combining variations of key concepts inspired from routing techniques and search strategies to define new hybrid genetic operators, the proposed approach also exploits a least commitment routing policy in servicing scheduled customers to potentially improve solution quality. The strategy consists in delaying customer visits and therefore premature route construction as long as possible to deal with a larger number of customers all at once when building a solution. Comparative results from a computational experiment over a common set of benchmark problems show the proposed procedure to match or outperform some of the best heuristic routing methods while being fast and highly competitive.

Heterozygous mutations of the gene encoding neutrophil elastase (ELA2) have been associated with cyclic neutropenia (CN) and severe congenital neutropenia (SCN). To date, 30 different mutations have been reported, but no correlation has been found with the degree of neutropenia. To address this issue, we analyzed the clinical, hematologic, and molecular characteristics of 81 unrelated patients with SCN (n = 54) or CN (n = 27). We identified mutations in 31 patients, two thirds of whom had sporadic forms. Familial cases were consistent with dominant inheritance. Seventeen novel mutations were identified, showing that the mutational spectrum encompasses not only the region encoding the mature enzyme but also the prodomains and promoter region. Genotype-phenotype analysis strongly suggested that ELA2 mutations correlate with more severe expression of neutropenia, specifically in patients diagnosed with SCN. This study underlines the importance of ELA2 molecular screening to identify patients who may be at particular risk of severe bacterial infections and/or acute myeloid leukemia/myelodysplasia. By phenotypic analysis of affected relatives and carriers of the same ELA2 mutations, we showed that the expression of neutropenia in CN and SCN may be either homogeneous or variable according to the type of mutations, suggesting different pathogenetic mechanisms.

Heterozygous mutations of the gene encoding neutrophil elastase (ELA2)have been associated with cyclic neutropenia (CN) and severe congenital neutropenia (SCN). To date, 30 different mutations have been reported, but no correlation has been found with the degree of neutropenia. To address this issue, we analyzed the clinical, hematologic, and molecular characteristics of 81 unrelated patients with SCN (n = 54) or CN (n = 27). We identified mutations in 31 patients, two thirds of whom had sporadic forms. Familial cases were consistent with dominant inheritance. Seventeen novel mutations were identified, showing that the mutational spectrum encompasses not only the region encoding the mature enzyme but also the prodomains and promoter region. Genotype-phenotype analysis strongly suggested that ELA2mutations correlate with more severe expression of neutropenia, specifically in patients diagnosed with SCN. This study underlines the importance of ELA2molecular screening to identify patients who may be at particular risk of severe bacterial infections and/or acute myeloid leukemia/myelodysplasia. By phenotypic analysis of affected relatives and carriers of the same ELA2mutations, we showed that the expression of neutropenia in CN and SCN may be either homogeneous or variable according to the type of mutations, suggesting different pathogenetic mechanisms.