NAP1L1-MLLT10 is a rare recurrent translocation that is associated with HOXA activation and poor treatment response in T-cell acute lymphoblastic leukaemia

International audienceno abstrac

A French Cohort of Childhood Leukemia Survivors: Impact of Hematopoietic Stem Cell Transplantation on Health Status and Quality of Life

AbstractThe late effects and quality of life (QoL) in childhood acute leukemia survivors were compared between hematopoietic stem cell transplantation (HSCT) recipients and patients who underwent conventional therapy. The study included 943 patients, 256 of whom underwent HSCT (27.1%). Medical visits were conducted to detect the occurrence of physical late effects. Based on patient age, different questionnaires were used to assess QoL. To evaluate the association between HSCT and each type of late effect or QoL dimension, the appropriate multivariate regressions were performed. QoL mean scores were compared with those obtained for age- and sex-matched French control subjects. Of all the survivors, 674 (71.5%) had at least 1 late effect, with the risk being 5.0 CI95 (3.0-8.6) times higher for transplantation survivors. For child survivors, scoring of QoL showed no significant differences between the treatment groups. The adult HSCT survivors reported lower physical dimension QoL scores than chemotherapy survivors. Compared with French norms, the survivor group reported a significantly lower mental composite score; however, the physical composite score showed no significant difference. Thus, transplanted survivors have a high risk of developing late effects, resulting in a decreased physical well-being in adulthood. However, long after treatment completion, childhood leukemia survivors report that effects on psychological well-being are more important than they are in physical QoL dimensions

Rôle du type de décontamination digestive sur la survenue d'épisodes fébriles au cours du traitement d'induction des leucémies aiguës (étude rétrospective à propos de 145 cas)

Notre étude a pour but de mettre en évidence l'évolution de la flore fécale et des épisodes infectieux, notamment à point de départ digestif, dans une population d'enfants recevant la phase d'induction thérapeutique d'une leucémie aiguë dans le service d'onco-hématologie du CHU de Nancy de janvier 1995 à mai 2005. Elle a été motivée par le fait du changement des mesures de prévention vis-à-vis des infections réalisé depuis le mois de mai 2004, pour la population des leucémies aiguës lymphoblastiques : une décontamination digestive partielle par gentamicine et amphotéricine B orales, associée à un isolement protecteur et une alimentation pauvre en germes, a remplacé la décontamination digestive totale associée à un isolement et une alimentation " stériles ". Le but de ce changement était de restreindre le coût de la prise en charge de la séquence la plus onéreuse : le traitement d'induction. Le taux de décontamination sous DDT est de 99% et sous DDP de 82% (respectivement pour les germes bactériens et les bacilles à Gram négatif (BGN)). Dans les deux modes de prise en charge, la mortalité d'origine infectieuse est nulle et aucune translocation de BGN n'a été constatée. Une translocation de levures a été observée dans le groupe de la DDP.L'émergence d'un germe résistant à la gentamicine dans le groupe de la DDP nous incite à la plus grande prudence et entraîne la nécessité d'un suivi bactériologique hebdomadaire des selles pour surveiller l'efficacité de la prophylaxie et permettre une adaptation de celle-ci à l'antibiogramme des BGN identifiés.NANCY1-SCD Medecine (545472101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Morphine-induced analgesic tolerance, locomotor sensitization and physical dependence do not require modification of micro opioid receptor, cdk5 and adenylate cyclase activity.

Acute morphine administration produces analgesia and reward, but prolonged use may lead to analgesic tolerance in patients chronically treated for pain and to compulsive intake in opioid addicts. Moreover, long-term exposure may induce physical dependence, manifested as somatic withdrawal symptoms in the absence of the drug. We set up three behavioral paradigms to model these adaptations in mice, using distinct regimens of repeated morphine injections to induce either analgesic tolerance, locomotor sensitization or physical dependence. Interestingly, mice tolerant to analgesia were not sensitized to hyperlocomotion, whereas sensitized mice displayed some analgesic tolerance. We then examined candidate molecular modifications that could underlie the development of each behavioral adaptation. First, analgesic tolerance was not accompanied by mu opioid receptor desensitization in the periaqueductal gray. Second, cdk5 and p35 protein levels were unchanged in caudate-putamen, nucleus accumbens and prefrontal cortex of mice displaying locomotor sensitization. Finally, naloxone-precipitated morphine withdrawal did not enhance basal or forskolin-stimulated adenylate cyclase activity in nucleus accumbens, prefrontal cortex, amygdala, bed nucleus of stria terminalis or periaqueductal gray. Therefore, the expression of behavioral adaptations to chronic morphine treatment was not associated with the regulation of micro opioid receptor, cdk5 or adenylate cyclase activity in relevant brain areas. Although we cannot exclude that these modifications were not detected under our experimental conditions, another hypothesis is that alternative molecular mechanisms, yet to be discovered, underlie analgesic tolerance, locomotor sensitization and physical dependence induced by chronic morphine administration

The delta agonists DPDPE and deltorphin II recruit predominantly mu receptors to produce thermal analgesia: a parallel study of mu, delta and combinatorial opioid receptor knockout mice

International audienceDelta-selective agonists have been developed to produce potent analgesic compounds with limited side-effects. DPDPE and deltorphin II are considered prototypes, but their delta-selectivity in vivo and the true ability of delta receptors to produce analgesia remain to be demonstrated. Here we have performed a parallel analysis of mu, delta and combinatorial opioid receptor knockout mice, in which we found no obvious alteration of G-protein coupling for remaining opioid receptors. We compared behavioural responses in two models of acute thermal pain following DPDPE and deltorphin II administration by intracerebroventricular route. In the tail-immersion test, both compounds were fully analgesic in delta knockout mice and totally inactive in mu knockout mice. In the hotplate test, the two compounds again produced full analgesia in delta knockout mice. In mu knockout mice, there was significant, although much lower, analgesia. Furthermore, DPDPE analgesia in the delta knockout mice was fully reversed by the mu selective antagonist CTOP in both tests. Together, this suggests that mu rather than delta receptors are recruited by the two agonists for the tail withdrawal and the hotplate responses. Finally, deltorphin II slightly prolonged jump latencies in double mu/kappa knockout mice (delta receptors only) and this response was abolished in the triple knockout mice, demonstrating that the activation of delta receptors alone can produce weak but significant mu-independent thermal antinociception

Prevalence and risk factors of the metabolic syndrome in adult survivors of childhood leukemia

International audienceWe evaluate the prevalence and risk factors of the metabolic syndrome (MS) in young adults surviving childhood leukemia. During the years 2007 to 2008, assessment of MS was proposed to all adults included in the Leucémie de l'Enfant et de l'Adolescent program, a French prospective multicentric cohort of leukemia survivors. Among 220 eligible patients, 184 (83.6%) had complete evaluation. Median age at evaluation and follow-up duration were 21.2 and 15.4 years. Overall prevalence of MS was 9.2% (95% confidence interval, 5.5-14.4). There was no association of MS with sex, age at diagnosis, leukemia subtype, steroid therapy, and central nervous system irradiation. Patients were stratified according to 4 therapeutic modalities: chemotherapy alone (n = 97), chemotherapy and central nervous system irradiation (n = 27), hematopoietic stem cell transplantation (HSCT) without (n = 17) or with (n = 43) total body irradiation (TBI). MS occurred in 5.2%, 11.1%, 5.9%, and 18.6% of them, respectively. The higher risk observed in the HSCT-TBI group was significant in univariate and in multivariate analysis (odds ratio [OR] = 3.9, P = .03). HSCT with TBI was associated with a higher rate of hypertriglyceridemia (OR = 4.5, P = .004), low level of high-density lipoprotein cholesterol (OR = 2.5, P = .02), and elevated fasting glucose (OR = 6.1, P = .04) So, TBI is a major risk factor for MS. Further studies are warranted to explain this feature

Health Status and Quality of Life of Long-term Survivors of Childhood Acute Leukemia

International audienceWe evaluated the impact of central nervous system irradiation (CNSI) on long-term health status and quality of life (QoL) of childhood lymphoblastic leukemia survivors included in the French L.E.A. (Childhood and Adolescent Leukemia) multicentric cohort. QoL was self-reported in adults and assessed by parents in children and adolescents, using adapted questionnaires. From 2004 to 2009, 630 nongrafted patients were assessed after 11.8±6.3 years from diagnosis. Patients receiving CNSI (18.6%) or chemotherapy alone (81.4%) were compared. The risk of having long-term physical effects was increased with CNSI (odds ratio=3.3; 95% confidence interval, 1.8-5.9), especially regarding growth failure, second tumor, cataract, and overweight. QoL did not differ significantly according to the treatment received, despite a tendency toward lower scores with CNSI in children and adolescents (summary score 63.6±13.3 vs. 71.7±12.4, P=0.14). Compared with French norms, adult survivors had an impaired QoL, especially in mental domains (mental composite score 45.2±9.8 vs. 47.9±2.1, P<0.001). In pediatric survivors, QoL was not impaired and even tended to be higher than population norms (summary score 71.7±12.4 vs. 70.0±4.2, P=0.054), mainly in social and relational domains. In conclusion, QoL seems to be impaired by the trauma of a life-threatening illness in childhood, as well as by the treatment received

Acute lymphoblastic leukemia in the context of RASopathies

International audienceNoonan syndrome is associated with a range of malignancies including acute lymphoblastic leukemia (ALL). However, little information is available regarding the frequency, natural history, characteristics and prognosis of ALL in Noonan syndrome or RASopathies in general. Cross-referencing data from a large prospective cohort of 1176 patients having a molecularly confirmed RASopathy with data from the French childhood cancer registry allowed us to identify ALL in 6 (0.5%) patients including 4/778 (0.5%) with a germline PTPN11 mutation and 2/94 (2.1%) with a germline SOS1 mutation. None of the patients of our series with CFC syndrome (with germline BRAF or MAP2K1/MAP2K2 mutation - n = 121) or Costello syndrome (with HRAS mutation - n = 35) had an ALL. A total of 19 Noonan-ALL were gathered by adding our patients to those of the International Berlin-Munster-Frankfurt (I-BFM) study group and previously reported patients. Strikingly, all Noonan-associated ALL were B-cell precursor ALL, and high hyperdiploidy with more than 50 chromosomes was found in the leukemia cells of 13/17 (76%) patients with available genetics data. Our data suggest that children with Noonan syndrome are at higher risk to develop ALL. Like what is observed for somatic PTPN11 mutations, NS is preferentially associated with the development of hyperdiploid ALL that will usually respond well to chemotherapy. However, Noonan syndrome patients seem to have a propensity to develop post therapy myelodysplasia that can eventually be fatal. Hence, one should be particularly cautious when treating these patients

Adolescence and Socioeconomic Factors: Key Factors in the Long-Term Impact of Leukemia on Scholastic Performance—A LEA Study

International audienceOBJECTIVE:To evaluate the association between medical and social environmental factors and the risk of repeating a grade in childhood leukemia survivors.STUDY DESIGN:A cross-sectional study of childhood leukemia survivors, recruited through the LEA cohort (Leucémie de l'Enfant et de l'Adolescent [French Childhood Cancer Survivor Study for Leukemia]) in 2014. An adjusted logistic regression model was used to identify variables linked to repeating a grade after the diagnosis among the survivors, and the rates of repeating a grade were compared between the survivors and their siblings using a multilevel logistic regression model.RESULTS:The mean age at inclusion of the 855 participants was 16.2 ± 7.0 years, and the mean duration of follow-up from diagnosis to evaluation was 10.2 ± 6.2 years. After disease onset, 244 patients (28.5%) repeated a grade, with a median interval of 4 years (IQR, 2-8 years). Independent factors associated with repeating a grade were male sex (OR, 1.78; 95% CI, 1.21-2.60), adolescence (OR, 2.70; 95% CI, 1.63-4.48), educational support during the treatment period (OR, 3.79; 95% CI, 2.45-5.88), low parental education level (OR, 2.493; 95% CI, 1.657-3.750), and household financial difficulties (OR, 2.62; 95% CI, 1.607-4.28). Compared with siblings, survivors were at greater risk of repeating a grade (OR, 1.87; 95% CI, 1.48-2.35).CONCLUSIONS:The most vulnerable patients seemed to be adolescents and those with parents of low socioeconomic status. Improving the schooling career of leukemia survivors will require that the medical community more carefully consider the social status of patients

Inotuzumab ozogamicin in infants and young children with relapsed or refractory acute lymphoblastic leukaemia: a case series

No data on inotuzumab ozogamicin (InO) in infant acute lymphoblastic leukaemia (ALL) have been published to date. We collected data internationally on infants/young children (<3 years) with ALL treated with InO. Fifteen patients (median 4.4 months at diagnosis) received InO due to relapsed or refractory (R/R) disease. Median percentage of CD22+ blasts was 72% (range 40–100%, n = 9). The median dose in the first course was 1.74 mg/m2 (fractionated). Seven patients (47%) achieved complete remission; one additional minimal residual disease (MRD)-positive patient became MRD-negative. Six-month overall survival was 47% (95% confidence interval [CI] 27–80%). Two patients developed veno-occlusive disease after transplant. Further evaluation of InO in this subgroup of ALL is justified