Search

Osteonecrosis (ON) is a known complication of acute leukemia (AL) management, affecting 1%–10% of young patients and resulting in long-term morbidity. Widespread access to MRI over the past decade has allowed earlier detection and more accurate assessment. This study investigated clinical and MRI features of the 129 (2.5%) patients with symptomatic ON retrospectively recruited from the French LEA (Leucémies de l'Enfant et de l'Adolescent, or child and adolescent leukemias) cohort (n = 4,973). We analyzed data concerning ON risk factors, multifocal involvement, severe lesions detected by MRI, and patient quality of life (QoL). ON patients tended to be >10 years old at the time of AL diagnosis (odds ratio [OR]: 22.46; p < 10−6), female (OR: 1.8; p = 0.002), or treated for relapse (OR: 1.81; p = 0.041). They more frequently suffered from other sequelae (p < 10−6). Most necroses involved weight-bearing joints, and they were multifocal in 69% of cases. Double-blinded review of MRIs for 39 patients identified severe lesions in 14, usually in the hips. QoL of adolescents and adults was poor and permanently impacted after onset of ON. In conclusion, age >10 at time of AL diagnosis, female sex, and relapse occurrence were risk factors for multifocal ON; MRI revealed severe ON in a third of the patients considered; and ON was associated with persistently poor QoL affecting multiple domains. Future studies should include prospective data addressing ON management and seek to identify genetic markers for targeted screening enabling early ON detection and treatment. [ABSTRACT FROM AUTHOR]

Résumé: Les cellules T à récepteur antigénique chimérique (CAR-T) sont une innovation thérapeutique majeure en hématologie pédiatrique, susceptible d'avoir des effets durables sur les stratégies futures de prise en charge des patients. L'expérience acquise dans les leucémies aiguës lymphoblastiques CD19+ de l'enfant, de l'adolescent et de l'adulte jeune en rechute ou réfractaire est maintenant suffisante pour faire les conclusions suivantes. La rémission complète est obtenue dans environ 80 % des cas avec le plus souvent une maladie résiduelle indétectable. Les principales toxicités observées sont une aplasie des lymphocytes B, conséquence directe de l'activité anti-CD19 du médicament, le syndrome de relargage cytokinique et la neurotoxicité liée aux cellules effectrices de l'immunité. Le domaine de costimulation CD28 est associé à une expansion plus rapide et plus forte des CAR-T mais à une persistance beaucoup plus brève que celle associée au CD137 (4-1BB). Les rechutes peuvent être liées soit à la perte d'expression de CD19 à la surface des cellules leucémiques ou à la perte des CAR-T, souvent annoncée par la réapparition de lymphocytes B normaux CD19+. Les défis pour l'avenir sont nombreux. Le positionnement des CAR-T à des phases plus précoces pour les formes les plus graves de la maladie est à l'étude, avant une allogreffe pour en améliorer l'efficacité ou en remplacement de celle-ci. D'autres travaux sont en cours pour prévenir l'évolution clonale CD19 négative en ciblant plusieurs antigènes, produire de CAR-T pour d'autres hémopathies malignes ou encore mettre au point des CAR-T allogéniques issus de donneurs sains et donc immédiatement disponibles. CAR T-cells constitute a major innovation in the field of pediatric haematology and will probably deeply influence our therapeutic strategies in the future. Several clinical trials in children, adolescent and young adults with relapsed or refractory CD19+ acute lymphoblastic leukemia have consistently drawn the following conclusions. Complete remission is achieved in about 80 % of infused patients, most of them with undetectable residual disease. Adverse effects include B-cell aplasia as a direct consequence of CD19 targeting, the cytokine release syndrome (CRS) and immune effector-cell associated neurotoxicity (ICANS). The CD28 costimulation domain is associated with more vigorous expansion but less persistence than the CD137 (4-1BB) one. Post-CAR T-cells relapses can be due to acquired loss of expression of CD19 molecules on leukemic cells or to lack of persistence of CAR T-cells, often preceded by reappearance of normal B lymphocytes. Many challenges remain to improve CAR T cell therapy. Using CAR T-cells during early phase of very high risk CD19+ acute lymphoblastic leukemia is under investigation, either as a bridge to hematopoietic stem cell transplantation or to avoid transplantation. Other ongoing studies include prevention of CD19- clonal evolution by targeting 2 antigens or more, development of off-the-shelf "universal" allogeneic CAR T-cells and identification of suitable targets for CD19- hematological malignancies. [ABSTRACT FROM AUTHOR]

Résumé: Les cellules T à récepteur antigénique chimérique (CAR-T) sont une innovation thérapeutique majeure en hématologie pédiatrique, susceptible d'avoir des effets durables sur les stratégies futures de prise en charge des patients. L'expérience acquise dans les leucémies aiguës lymphoblastiques CD19+ de l'enfant, de l'adolescent et de l'adulte jeune en rechute ou réfractaire est maintenant suffisante pour faire les conclusions suivantes. La rémission complète est obtenue dans environ 80 % des cas avec le plus souvent une maladie résiduelle indétectable. Les principales toxicités observées sont une aplasie des lymphocytes B, conséquence directe de l'activité anti-CD19 du médicament, le syndrome de relargage cytokinique et la neurotoxicité liée aux cellules effectrices de l'immunité. Le domaine de costimulation CD28 est associé à une expansion plus rapide et plus forte des CAR-T mais à une persistance beaucoup plus brève que celle associée au CD137 (4-1BB). Les rechutes peuvent être liées soit à la perte d'expression de CD19 à la surface des cellules leucémiques ou à la perte des CAR-T, souvent annoncée par la réapparition de lymphocytes B normaux CD19+. Les défis pour l'avenir sont nombreux. Le positionnement des CAR-T à des phases plus précoces pour les formes les plus graves de la maladie est à l'étude, avant une allogreffe pour en améliorer l'efficacité ou en remplacement de celle-ci. D'autres travaux sont en cours pour prévenir l'évolution clonale CD19 négative en ciblant plusieurs antigènes, produire de CAR-T pour d'autres hémopathies malignes ou encore mettre au point des CAR-T allogéniques issus de donneurs sains et donc immédiatement disponibles. CAR T-cells constitute a major innovation in the field of pediatric haematology and will probably deeply influence our therapeutic strategies in the future. Several clinical trials in children, adolescent and young adults with relapsed or refractory CD19+ acute lymphoblastic leukemia have consistently drawn the following conclusions. Complete remission is achieved in about 80 % of infused patients, most of them with undetectable residual disease. Adverse effects include B-cell aplasia as a direct consequence of CD19 targeting, the cytokine release syndrome (CRS) and immune effector-cell associated neurotoxicity (ICANS). The CD28 costimulation domain is associated with more vigorous expansion but less persistence than the CD137 (4-1BB) one. Post-CAR T-cells relapses can be due to acquired loss of expression of CD19 molecules on leukemic cells or to lack of persistence of CAR T-cells, often preceded by reappearance of normal B lymphocytes. Many challenges remain to improve CAR T cell therapy. Using CAR T-cells during early phase of very high risk CD19+ acute lymphoblastic leukemia is under investigation, either as a bridge to hematopoietic stem cell transplantation or to avoid transplantation. Other ongoing studies include prevention of CD19- clonal evolution by targeting 2 antigens or more, development of off-the-shelf "universal" allogeneic CAR T-cells and identification of suitable targets for CD19- hematological malignancies. [ABSTRACT FROM AUTHOR]

The number of childhood leukemia survivors increases. Many of them do not have any late effects and enjoy normal life. Others suffer from physical late complications or psychological, social and professional difficulties. The most common therapeutic risk factors for physical late effects are anthracycline, high-dose alkylating agents, brain irradiation and hematopoietic stem cell transplantation, notably after a total body irradiation-containing conditioning regimen. Inter-individual variability of late effects occurrence suggests that genetic susceptibility may play a role. The main late effects after leukemia treatment are endocrine (growth, gonadal function, fertility, and thyroid), nutritional (metabolic syndrome), cardiac, bone disorders and second malignancies. Interaction between physical late effects and quality of life are complex. [ABSTRACT FROM AUTHOR]

Transplantation of 2 unrelated cord blood (UCB) units instead of 1 has been proposed to increase the cell dose. We report a prospective randomized study, designed to compare single- vs double-UCB transplantation in children and young adults with acute leukemia in remission or myelodysplasia. Eligible patients had at least two 4-6 HLA-identical UCBs with >3×107 nucleated cells/kg for the first and>1.5×107 for the second. The primary end point was the 2-year cumulative incidence of transplantation strategy failure, a composite end point including transplant-related mortality (TRM), engraftment failure, and autologous recovery. Randomized patients who did not proceed to transplantation due to refractory disease were considered transplantation failures. A total of 151 patients were randomized and included in the intent-to-treat analysis; 137 were transplanted. Double-UCB transplantation did not decrease transplantation strategy failure (23.4% ± 4.9% vs 14.9%±4.2%). Two-year posttransplant survival, disease-free survival, and TRM were 68.8%±6.0%, 67.6%±6.0%, and 5.9%±2.9% after single-unit transplantation compared with 74.8%±5.5%, 68.1%±6.0%, and 11.6% ± 3.9% after double-unit transplantation. The final relapse risk did not significantly differ, but relapses were delayed after double-unit transplantation. Overall incidences of graft-versus-host disease (GVHD) were similar, but chronic GVHD was more frequently extensive after double-UCB transplantation (31.9%±5.7% vs 14.7%±4.3%, P=.02). In an exploratory subgroup analysis, we found a significantly lower relapse risk after double-unit transplantation in patients receiving total body irradiation without antithymocyte globulin (ATG), whereas the relapse risk was similar in the group treated with busulfan, cyclophosphamide, and ATG. Single-UCB transplantation with adequate cell dose remains the standard of care and leads to low TRM. Double-unit transplantation should be reserved for patients who lack such units. This trial was registered at www.clinicaltrials.gov as #NCT01067300. [ABSTRACT FROM AUTHOR]

The main aim of the Leucémies de l’Enfant et l’Adolescent (LEA) project (Childhood and Adolescent Leukaemia) is to study the determinants (medical, socioeconomic, behavioural and environmental) of medium- and long-term outcomes of patients treated for childhood acute leukaemia (AL). The LEA study began in 2004 and is based on a French multicentric prospective cohort. Included are children treated for AL since January 1980 (incident and prevalent cases), surviving at month 24 for myeloblastic AL and lymphoblastic AL grafted in first complete remission or at month 48 for lymphoblastic AL not grafted in first complete remission. Information is collected during specific medical visits and notably includes the following data: socioeconomic data, AL history, physical late effects (such as fertility, cardiac function and metabolic syndrome) and quality of life. Data are collected every 2 years until the patient is 20 years old and has had a 10-year follow-up duration from diagnosis or last relapse. Thereafter, assessments are planned every 4 years. In active centres in 2013, eligible patients number more than 3000. The cohort has already included 2385 survivors, with rate of exhaustiveness of almost 80%. Data access can be requested from principal coordinators and must be approved by the steering committee. [ABSTRACT FROM PUBLISHER]

Abstract: The 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. [Copyright &y& Elsevier]

Pseudomonas aeruginosa is an opportunistic pathogen involved in several diseases, including cystic fibrosis and nosocomial infections. Although the behavior of this bacterium at 37°C has been intensively studied, little is known about its capacity to adapt and survive at suboptimal temperatures, such as those encountered in hospitals. In this work, transcriptomic and proteomic analyses were used to identify factors that allow P. aeruginosa to become established at room temperature (close to 25°C) and thus facilitate host infections. Since the virulence of this pathogen is multifactorial and dependent on the extracellular release of toxins and degradative enzymes targeted to the host by several secretory systems, the study focused on genes activated at 25°C, namely, those encoding either components of the secretory machinery or secreted proteins. These observations were enhanced by 2D-PAGE analyses, which showed that the production of effectors from type I and type II secretion systems (respectively, proteases AprA and PrpL) and of a hemolysin co-regulated protein (Hcp) related to the type VI secretion system was specifically stimulated when the growth temperature was lowered from 37 to 25°C. The results provide a fundamental basis for investigating the processes that allow P. aeruginosa to adapt to suboptimal growth temperatures and which thereby promote nosocomial infection. [ABSTRACT FROM AUTHOR]

Abstract: This study focuses on composite multi-girder railway bridges of moderate span for high-speed trains. In this type of bridge the concrete deck is the primary element of transverse rigidity, so the real impact of cross beams is unknown. These cross beams increase the cost of this type of bridge, because they require handling and welding on site. This research studies the impact of a diaphragm in a typical multi-girder railway bridge used in France. The first objective is to develop appropriate modelling techniques that can be used to evaluate the function and effectiveness of a diaphragm in the transverse distribution of traffic loads. The second objective is to know if a diaphragm is really necessary. To answer this question, a three-dimensional model and nonlinear material constitutive equations are considered. Different static loading conditions (self-weight, UIC load, and TGV) are studied and the bridge deck responses to them with and without transverse diaphragm are analyzed. The TGV is modelled with moving loads in order to take into account the dynamic behaviour of the bridge deck. Several critical speeds of train corresponding to natural frequencies are then studied in dynamic analysis. Our static and dynamic analyses concluded that the diaphragm does not seem to be necessary, except for an accidental lateral load. Therefore, it may be possible to not install diaphragms on these bridges. [Copyright &y& Elsevier]

Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen equipped with multiple secretion systems. The type II secretion machinery (Xcp secreton) is involved in the release of toxins and enzymes. The Xcp secreton is a multiprotein complex, and most of its components share homology with proteins involved in type IV pili biogenesis. Among them, the XcpT-X pseudopilins possess characteristics of the major constituent of the type IV pili, the pilin PilA. We have shown previously that XcpT can be assembled in a multifibrillar structure that was called the pseudopilus. By using two different microscopic approaches, we show here that the pseudopili are preferentially isolated fibers rather than tight bundles. Moreover, none of the other four pseudopilins are able to form a pseudopilus, suggesting that the assembly of such a structure is a unique property of XcpT. Moreover, we show that 5 of the 12 Xcp proteins are not required for pseudopilus biogenesis, whereas they are for type II secretion. Most interestingly, we showed that one pseudopilin, XcpX, controls the assembly of XcpT into a pseudopilus. Indeed, when the number of XcpX subunits increases, the length of the pseudopilus decreases. Conversely, in the absence of XcpX, the pseudopilus length is abnormally long. Our results indicate that XcpT and XcpX directly interact with each other. Furthermore, this interaction induces a clear destabilization of XcpT. The interaction between XcpT and XcpX could be part of the molecular mechanism underlying the dynamic control of pseudopilus elongation, which could be crucial for type II-dependent protein secretion. [ABSTRACT FROM AUTHOR]

Background: To investigate the educational outcomes of siblings of childhood leukemia survivors, explore determinants of school difficulties, and compare the rates of repeating grades between siblings and the general population. Methods: A cross‐sectional study of childhood leukemia survivors' siblings recruited through the Leucémies de l'Enfant et de l'Adolescent cohort, a French long‐term follow‐up program, was conducted, and education‐related data were obtained via self‐report questionnaires. Adjusted logistic regression models were used to identify variables associated with school difficulties and time since diagnosis. Rates of repeating a grade in middle school were compared between siblings and the general population of the same generation. Results: A total of 564 siblings with a mean time from diagnosis of 14.1 ± 6.4 years were included, among whom 139 (24.6%) repeated a grade, at an average of 6.4 ± 4.5 years after diagnosis. In multivariate analysis, the risk factors for repeating a grade were older siblings (odds ratio [OR] 2.3, p = 0.006), family financial difficulties (OR 2.8, p = 0.008), and history of repetition in survivors (OR, 2.5, p = 0.001). Sibling hematopoietic stem cell donors were at greater risk of repeating a grade long‐term after diagnosis (p = 0.018). Overall, siblings did not have a higher risk of educational delays at the end of middle school than the general population. Conclusion: Although the results are reassuring, socioeconomic and cancer‐related factors may have an impact on siblings' schooling long after diagnosis. Paying attention to siblings contributes to identifying the most vulnerable families, allowing more attention and appropriate resources to avoid long‐term repercussions. Additionally, supportive and targeted interventions can be developed to improve the organization of education and the health care system. [ABSTRACT FROM AUTHOR]

The opportunistic human pathogen bacterium Pseudomonas aeruginosa secretes various exoproteins in its surrounding environment. Protein secretion involves different secretory systems, including the type II secretion system, or T2SS, that is one of the most efficient secretory pathways of P. aeruginosa. There are two T2SS in this bacterium, the quorum-sensing-regulated Xcp system and the Hxc system, which is only present under phosphate-limiting conditions. Like T2SS of other bacteria, the Xcp T2SS is species specific, and this specificity mainly involves two proteins, XcpP (GspC family) and the secretin XcpQ (GspD family), which are the gatekeepers of the system. Interestingly, an orphan secretin, XqhA, was previously reported as being able to functionally replace the XcpQ secretin. In this study, we identified another gene, which we named xphA (xcpP homologue A), which is located next to xqhA. We showed that deletion of the xphA gene in an xcpP mutant caused the disappearance of the residual secretion observed in this mutant strain, indicating that the protein XphA plays a role in the secretion process. Our results also revealed that complementation of an xcpP/xcpQ mutant can be obtained with the gene couple xphA/xqhA. The XphA and XqhA proteins (the PAQA subunit) could thus form, together with XcpR-Z, a functional hybrid T2SS. A two-dimensional polyacrylamide gel electrophoresis analysis showed that except for the aminopeptidase PaAP, for which secretion is not restored by the PAQA subunit in the xcpP/xcpQ deletion mutant, each major Xcp-dependent exoprotein is secreted by the new hybrid machinery. Our work supports the idea that components of the GspC/GspD families, such as XphA/XqhA or XcpP/XcpQ, are assembled as a specific tandem within the T2SS. Each of these pairs may thus confer a different level of secretion specificity, as is the case with respect to PaAP. Finally, using a chromosomal xphA-lacZ fusion, we showed that the xphA-xqhA genes are transcribed from an early stage of bacterial growth. We thus suggest that the PAQA subunit might be involved in the secretion process at a different growth stage than XcpP/XcpQ. [ABSTRACT FROM AUTHOR]

Purpose: In the acute lymphoblastic leukemia (ALL) landscape, adolescents and young adults (AYA) often present high-risk diseases and increased chemotherapy-related toxicity. Studies analyzing the outcomes of AYA after hematopoietic stem cell transplantation (HSCT) are scarce. Our study aimed to compare the outcomes of children and AYA with ALL after HSCT and to determine the factors influencing potential differences. Method: 891 patients, from the SFGM-TC registry, aged between 1 and 25 years who received HSCT between 2005 and 2012 were included. The outcomes of AYA were compared to the ones of their younger counterparts. Results: Five-year OS and GRFS were lower in AYA: 53.1% versus 64% and 36% versus 47% (p = 0.0012 and p = 0.007, respectively). WhileCIR was similar in both groups, 5 year-treatment related mortality was higher in AYA: 19% versus 13% (p = 0.04). The lower GRFS in AYA was mainly explained by a higher chronic graft versus host disease (cGvHD) incidence: 32% versus 19% (p < 0.001). Use of peripheral blood stem cells and use of anti-thymoglobulin appeared to be the main factors impacting cGvHD occurrence in AYA. Conclusion: AYA have worse outcomes than children after HSCT for ALL because of a greater risk of TRM due to cGvHD. HSCT practices should be questioned in this population. [ABSTRACT FROM AUTHOR]

Background: Although survival from childhood cancer has increased, little is known on the long-term impact of treatment late effects on occupational attainment or work ability.Methods: A total of 3512 five-year survivors treated before the age of 19 years in 10 French cancer centres between 1948 and 2000 were identified. Educational level, employment status and occupational class of survivors were assessed by a self-reported questionnaire. These outcome measures were compared with sex-age rates recorded in the French population, using indirect standardisation. Paternal occupational class was also considered to control for the role of survivors' socioeconomic background on their achievement. Multivariable analyses were conducted to explore clinical characteristics associated with the outcomes.Results: A total of 2406 survivors responded to the questionnaire and survivors aged below 25 years were included in the current analysis. Compared with national statistics adjusted on age and sex, male survivors were more likely to be college graduates (39.2% vs 30.9% expected; P<0.001). This higher achievement was not observed either for leukaemia or central nervous system (CNS) tumour survivors. Health-related unemployment was higher for survivors of CNS tumour (28.1% vs 4.3%; P<0.001) but not for survivors of other diagnoses. Survivors of non-CNS childhood cancer had a similar or a higher occupational class than expected.Conclusions: Survivors treated for CNS tumour or leukaemia, especially when treatment included cranial irradiation, might need support throughout their lifespan. [ABSTRACT FROM AUTHOR]

Background: Childhood cancer confront the whole family with a traumatic event. Because brothers and sisters may encounter emotional problems that can remain for a long time and that only few studies have assessed their long‐term outcome, our present objectives were to describe the long‐term quality of life (QoL) of childhood leukemia survivors' siblings and to explore its determinant. Methods: Brothers and sisters (from 8‐year‐old) of survivors included in the French LEA Cohort completed a QoL questionnaire (according to their age). Scores were compared with those reported by age‐ and gender‐matched French general population and by survivors. Using a clustering method, siblings were categorized into 3 groups depending on their level of QoL's scores and factors likely to be linked with these clusters were explored with multivariate analyses. Results: We included 689 brothers and sisters (313 minors, 376 adults) and the mean time from diagnosis was 13.2 ± 6.6 years. Minor siblings reported higher QoL scores than general population (p < 0.001), but a lower score for relationship with family than survivors (p < 0.001). In adult siblings, Mental Component Summary score was lower than general population (p < 0.001). Level of siblings' QoL was linked with female gender, but no association was found with cancer‐related factors. Conclusion: Brothers and sisters expressed a divergent perception of their long‐term QoL depending on their age. To minimize the impact from childhood to adulthood, long‐term attention should also be paid to siblings, often referred as "forgotten children". [ABSTRACT FROM AUTHOR]

Relapse after transplantation is a major cause of treatment failure in paediatric acute lymphoblastic leukaemia ( ALL). Here, we report the findings of a prospective national study designed to investigate the feasibility of immune intervention in children in first or subsequent remission following myeloablative conditioning. This study included 133 children who received a transplant for ALL between 2005 and 2008. Minimal Residual Disease ( MRD) based on T cell receptor/immunoglobulin gene rearrangements was measured on days −30, 30, 90 and 150 post-transplantation. Ciclosporin treatment was rapidly discontinued and donor lymphocyte infusions ( DLI) were programmed for patients with a pre- or post-transplant MRD status ≥10−3. Only nine patients received DLI. Pre- and post-transplant MRD status, and the duration of ciclosporin were independently associated with 5-year overall survival ( OS), which was 62·07% for the whole cohort. OS was substantially higher in patients cleared of MRD than in those with persistent MRD (52·3% vs. 14·3%, respectively). Only pre-transplant MRD status (Hazard Ratio 2·57, P = 0·04) and duration of ciclosporin treatment ( P < 0·001) were independently associated with relapse. The kinetics of chimerism were not useful for predicting relapse, whereas MRD monitoring up to 90 d post-transplantation was a valuable prognostic tool to guide therapeutic intervention. [ABSTRACT FROM AUTHOR]

Background: There are currently few data on the outcome of acute myeloid leukemia (AML) in adolescents after allogeneic HSCT. The aim of this study is to describe the outcome and its specific risk factors for children, adolescents and young adults after a first allogeneic HSCT for AML. Methods: In this retrospective study, we compared the outcome of AML patients receiving a first allogeneic HSCT between 2005 and 2017 according to their age at transplantation's time: children (< 15 years, n = 564), adolescent and post-adolescent (APA) patients (15–25 years, n = 647) and young adults (26–40 years; n = 1434). Results: With a median follow-up of 4.37 years (min–max 0.18–14.73 years), the probability of 2-year overall survival (OS) was 71.4% in children, 61.1% in APA patients and 62.9% in young adults (p = 0.0009 for intergroup difference). Both relapse and non-relapse mortality (NRM) Cumulative Incidence (CI) estimated at 2 years were different between the age groups (30.8% for children, 35.2% for APA patients and 29.4% for young adults—p = 0.0254, and 7.0% for children, 10.6% for APA patients and 14.2% for young adults, p < 0.0001; respectively). Whilst there was no difference between the three groups for grade I to IV acute GVHD CI at 3 months, the chronic GVHD CI at 2 years was higher in APA patients and young adults (31.4% and 36.4%, respectively) in comparison to the children (17.5%) (p < 0.0001). In multivariable analysis, factors associated with death were AML cytogenetics (HR1.73 [1.29–2.32] for intermediate risk 1, HR 1.50 [1.13–2.01] for intermediate risk 2, HR 2.22 [1.70–2.89] for high cytogenetics risk compared to low risk), use of TBI ≥ 8 Grays (HR 1.33 [1.09–1.61]), disease status at transplant (HR 1.40 [1.10–1.78] for second Complete Remission (CR), HR 2.26 [1.02–4.98] for third CR and HR 3.07 [2.44–3.85] for active disease, compared to first CR), graft source (HR 1.26 [1.05–1.50] for Peripheral Blood Stem Cells compared to Bone Marrow) and donor age (HR 1.01 (1–1.02] by increase of 1 year). Conclusion: Age is an independent risk factor for NRM and extensive chronic GVHD. This study suggests that APA patients with AML could be beneficially treated with a chemotherapy-based MAC regimen and bone marrow as a stem cells source. [ABSTRACT FROM AUTHOR]

Abstract: In Gram-negative bacteria, most of the sec-dependent exoproteins are secreted via the type II secretion system (T2SS or secreton). In Pseudomonas aeruginosa, T2SS consists of 12 Xcp proteins (XcpA and XcpP to XcpZ) organized as a multiproteic complex within the envelope. In this study, by a co-purification approach using a His-tagged XcpZ as a bait, XcpY and XcpZ were found associated together to constitute the most stable functional unit so far isolated from the P. aeruginosa secreton. This subcomplex was also found to interact with XcpR and XcpS to form a XcpRSYZ complex which was isolated under native conditions. Another component, XcpP was not found to be associated to the complex but the results suggest that it can transiently interact with the XcpYZ subcomplex in vivo. [Copyright &y& Elsevier]

Abstract: In Gram-negative bacteria, most signal-peptide-dependent exoproteins are secreted via the type II secretion system (T2SS or secreton). In Pseudomonas aeruginosa, T2SS consists of twelve Xcp proteins (XcpA and XcpP to XcpZ) thought to be organized as a multiproteic complex within the envelope. Although well conserved, T2SS are known to be species-specific, namely for distant organisms, and this characteristic was thought to involve XcpP. To check which domain of XcpP could be involved in the species specificity, hybrid proteins were generated using protein domain swapping between P. aeruginosa XcpP and homolog proteins of either Erwinia chrysanthemi or Pseudomonas alcaligenes. The results obtained with hybrid proteins constructed by exchanging the C-terminal domains of P. aeruginosa and E. chrysanthemi suggested that XcpP interacts with XcpQ, probably via its C-terminal domain. More interestingly, the data obtained with a hybrid protein containing the C-terminal part of the P. alcaligenes XcpP homolog, showed that the wild-type C-terminal end plays a very important role in the function of the protein and is required both for a correct interaction with XcpQ and for modulating the opening of the secreton channel. [Copyright &y& Elsevier]

The xcp gene products in Pseudomonas aeruginosa are required for the secretion of proteins across the outer membrane. Four of the Xcp proteins, XcpT, U, V and W, present sequence homology to the subunits of type IV pili at their N-termini, and they were therefore designated pseudopilins. In this study, we characterized the xcpX gene product, a bitopic cytoplasmic membrane protein. Remarkably, amino acid sequence comparisons also suggested that the XcpX protein resembles the pilins and pseudopilins at the N-terminus. We show that XcpX could be processed by the prepilin peptidase, PilD/XcpA, and that the highly conserved glycine residue preceding the hydrophobic segment could not be mutated without loss of the XcpX function. We, therefore, classified XcpX (GspK) as the fifth pseudopilin of the system. [ABSTRACT FROM AUTHOR]

Summary: Childhood chronic immune thrombocytopenic purpura (cITP) is a rare disease. In severe cases, there is no evidence for the optimal therapeutic strategy. Our aim was to describe the real‐life management of non‐selected children with cITP at diagnosis. Since 2004, patients less than 18 years old with cITP have been enrolled in the national prospective cohort, OBS'CEREVANCE. From 1990 to 2014, in 29 centres, 392 children were diagnosed with cITP. With a median follow‐up of six years (2·0–25), 45% did not need second‐line therapy, and 55% (n = 217) received one or more second lines, mainly splenectomy (n = 108), hydroxychloroquine (n = 61), rituximab (n = 61) or azathioprine (n = 40). The overall five‐year further second‐line treatment‐free survival was 56% [95% CI 49·5–64.1]. The use of splenectomy significantly decreased over time. Hydroxychloroquine was administered to children with positive antinuclear antibodies, more frequently older and girls, and reached 55% efficacy. None of the patients died. Ten years after the initial diagnosis, 55% of the 56 followed children had achieved complete remission. Children with cITP do not need second‐line treatments in 45% of cases. Basing the treatment decision on the pathophysiological pathways is challenging, as illustrated by ITP patients with positive antinuclear antibodies treated with hydroxychloroquine. [ABSTRACT FROM AUTHOR]

Background: Efforts to improve the quality of end-of-life (EOL) care depend on better knowledge of the care that children, adolescents, and young adults with cancer receive, including high-intensity EOL (HI-EOL) care. The objective was to assess the rates of HI-EOL care in this population and to determine patient- and hospital-related predictors of HI-EOL from the French national hospital database.Methods: This was a population-based, retrospective study of a cohort of patients aged 0 to 25 years at the time of death who died at hospital as a result of cancer in France between 2014 and 2016. The primary outcome was HI-EOL care, defined as the occurrence of ≥1 chemotherapy session <14 days from death, receiving care in an intensive care unit ≥1 time, >1 emergency room admission, and >1 hospitalization in an acute care unit in the last 30 days of life.Results: The study included 1899 individuals from 345 hospitals; 61.4% experienced HI-EOL care. HI-EOL was increased with social disadvantage (adjusted odds ratio [AOR], 1.30; 95% confidence interval [CI], 1.03-1.65; P = .028), hematological malignancies (AOR, 2.09; 95% CI, 1.57-2.77; P < .001), complex chronic conditions (AOR, 1.60; 95% CI, 1.23-2.09; P = .001) and care delivered in a specialty center (AOR, 1.70; 95% CI, 1.22-2.36; P = .001). HI-EOL was reduced in cases of palliative care (AOR, 0.31; 95% CI, 0.24-0.41; P < .001).Conclusion: A majority of children, adolescents, and young adults experience HI-EOL care. Several features (eg, social disadvantage, cancer diagnosis, complex chronic conditions, and specialty center care) were associated with HI-EOL care. These findings should now be discussed with patients, families, and professionals to define the optimal EOL. [ABSTRACT FROM AUTHOR]

Highlights • Hematopoietic stem cell transplantation (HSCT) significantly improves survival in patients with cerebral adrenoleukodystrophy. • When performed early in the course of disease, HSCT improves major functional disability-free survival ABSTRACT Cerebral adrenoleukodystrophy (CALD) is a rapidly progressing, often fatal neurodegenerative disease caused by mutations in the ABCD1 gene, resulting in deficiency of ALD protein. Clinical benefit has been reported following allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a large multicenter retrospective chart review to characterize the natural history of CALD, to describe outcomes after HSCT, and to identify predictors of treatment outcomes. Major functional disabilities (MFDs) were identified as having the most significant impact on patients' abilities to function independently and were used to assess HSCT outcome. Neurologic function score (NFS) and Loes magnetic resonance imaging score were assessed. Data were collected on 72 patients with CALD who did not undergo HSCT (untreated cohort) and on 65 patients who underwent transplantation (HSCT cohort) at 5 clinical sites. Kaplan-Meier (KM) estimates of 5-year overall survival (OS) from the time of CALD diagnosis were 55% (95% confidence interval [CI], 42.2% to 65.7%) for the untreated cohort and 78% (95% CI, 64% to 86.6%) for the HSCT cohort overall (P =.01). KM estimates of 2-year MFD-free survival for patients with gadolinium-enhanced lesions (GdE+) were 29% (95% CI, 11.7% to 48.2%) for untreated patients (n = 21). For patients who underwent HSCT with GdE+ at baseline, with an NFS ≤1 and Loes score of 0.5 to ≤9 (n = 27), the 2-year MFD-free survival was 84% (95% CI, 62.3% to 93.6%). Mortality rates post-HSCT were 8% (5 of 65) at 100days and 18% (12 of 65) at 1 year, with disease progression (44%; 7 of 16) and infection (31%; 5 of 16) listed as the most common causes of death. Adverse events post-HSCT included infection (29%; 19 of 65), acute grade II-IV graft-versus-host disease (GVHD) (31%; 18 of 58), and chronic GVHD (7%; 4 of 58). Eighteen percent of the patients (12 of 65) experienced engraftment failure after their first HSCT. Positive predictors of OS in the HSCT cohort may include donor-recipient HLA matching and lack of GVHD, and early disease treatment was predictive of MFD-free survival. GdE+ status is a strong predictor of disease progression in untreated patients.‎ This study confirms HSCT as an effective treatment for CALD when performed early. We propose survival without MFDs as a relevant treatment goal, rather than solely assessing OS as an indicator of treatment success. [ABSTRACT FROM AUTHOR]

Purpose: Immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) are associated in the definition of Evans syndrome (ES). The occurrence of neurological involvement in this population is poorly described and suggests an underlying primary immunodeficiency (PID). We aimed to describe the clinical manifestations, evolution, and PID profiles of these patients. Methods: OBS'CEREVANCE is a French, nationwide prospective cohort that includes children with chronic ITP, AIHA, and ES. Patients with a neurological involvement were described. Centralized radiological and pathological reviews and genetic analyses were performed. Results: On October 2016, eight patients (7/181 ES, 1/371 AIHA, and 0/615 ITP) were identified, all male, with a median age (range) at cytopenia onset of 11.5 years (1.6–15.8). Neurological symptoms appeared with a median delay of 6 years (2.5–18) after cytopenia and were polymorphic: seizures (n = 4), cranial nerve palsy (n = 2), Brown-Sequard syndrome (n = 2), intracranial pressure (n = 2), vertigo (n = 1), and/or sensory neuropathy (n = 1). Magnetic resonance imaging (MRI) showed inflammatory lesions, confirmed by pathology for five patients with macrophagic or lymphoplasmocytic infiltrates. All patients had other relevant immunopathological manifestations: pulmonary nodules (n = 6), lymphoproliferation (n = 4), abnormal immunophenotype (n = 8), and hypogammaglobulinemia (n = 7). Treatment consisted of steroids that improved symptomatology and MRI. Five patients relapsed and three had an asymptomatic radiological progression. A PID was identified in 3/8 patients: 22q11.2 microdeletion (n = 1) and CTLA deficiency (n = 2). Conclusion: Neurological involvement is a rare and severe late event in the course of childhood ES, which can reveal an underlying PID. Imaging and pathology examination highlight a causative immune dysregulation that may guide targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

Evans syndrome (ES) is defined by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. Clinical presentation includes manifestations of immune dysregulation, found in primary immune deficiencies, autoimmune lymphoproliferative syndrome with FAS (ALPS-FAS), Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and Lipopolysaccharide-Responsive vesicle trafficking Beige-like and Anchor protein (LRBA) defects. We report the clinical history and genetic results of 18 children with ES after excluding ALPS-FAS. Thirteen had organomegaly, five lymphocytic infiltration of non-lymphoid organs, nine hypogammaglobulinemia and fifteen anomalies in lymphocyte phenotyping. Seven patients had genetic defects: three CTLA4 mutations (c.151C > T; c.109 + 1092_568-512del; c.110-2A > G) identified by Sanger sequencing and four revealed by Next Generation Sequencing: LRBA (c.2450 + 1C > T), STAT3 gain-of-function (c.2147C > T; c.2144C > T) and KRAS (c.37G > T). No feature emerged to distinguish patients with or without genetic diagnosis. Our data on pediatric-onset ES should prompt physicians to perform extensive screening for mutations in the growing pool of genes involved in primary immune deficiencies with autoimmunity. [ABSTRACT FROM AUTHOR]

ETV6 is a target of recurrent aberrations in sporadic and familial acute lymphoblastic leukemia ( ALL). Here, we report on a new pedigree with a germline ETV6 mutation in which the index patient and his father developed high hyperdiploid (HeH) ALL and polycythemia vera at age 13 and 51, respectively. The index patient achieved durable complete remission without transplantation but had persistent moderate thrombocytopenia without bleeding tendency. To determine the prevalence of ETV6 alterations in HeH- ALL, we screened 81 unrelated subjects with HeH- ALL by single nucleotide polymorphism array and high-throughput sequencing for the ETV6 gene. Overall, ETV6 microdeletions and mutations were identified in 9% of cases, all of which were somatic and considered as secondary events. Apart from the index patient, no germline ETV6 aberration was identified. Finally, we reviewed the literature for ETV6 germline aberrations and predispositions to ALL. [ABSTRACT FROM AUTHOR]

Background: Survival of childhood, adolescent and young adult (CAYA) cancers has increased with progress in the management of the treatments and has reached more than 80% at 5 years. Nevertheless, these survivors are at great risk of second cancers and non-malignant co-morbidities in later life. DeNaCaPST is a non-interventional study whose aim is to organize a national screening for thyroid cancer and breast cancer in survivors of CAYA cancers. It will study the compliance with international recommendations, with the aim, regarding a breast screening programme, of offering for every woman living in France, at equal risk, an equal screening.Method: DeNaCaPST trial is coordinated by the INSERM 1018 unit in cooperation with the LEA (French Childhood Cancer Survivor Study for Leukaemia) study's coordinators, the long term follow up committee and the paediatric radiation committee of the SFCE (French Society of Childhood Cancers). A total of 35 centres spread across metropolitan France and la Reunion will participate. FCCSS (French Childhood Cancer Survivor Study), LEA and central registry will be interrogated to identify eligible patients. To participate, centers agreed to perform a complete "long-term follow-up consultations" according to good clinical practice and the guidelines of the SFCE (French Society of Children Cancers).Discussion: As survival has greatly improved in childhood cancers, detection of therapy-related malignancies has become a priority even if new radiation techniques will lead to better protection for organs at risk. International guidelines have been put in place because of the evidence for increased lifetime risk of breast and thyroid cancer. DeNaCaPST is based on these international recommendations but it is important to recognize that they are based on expert consensus opinion and are supported by neither nonrandomized observational studies nor prospective randomized trials in this specific population. Over-diagnosis is a phenomenon inherent in any screening program and therefore such programs must be evaluated. [ABSTRACT FROM AUTHOR]

BACKGROUND: According to the World Health Organization (WHO), recurrent cytogenetic abnormalities define many specific groups of hematopoietic tumors of acute myeloid and lymphoblastic leukemia, and these abnormalities are often strongly associated with prognosis and sometimes require specific treatments. These rearrangements are commonly detected by conventional and molecular cytogenetic techniques. OBJECTIVE: Using an alternative method, we sought to highlight the presence of chromosomal rearrangements. METHODS: We applied molecular combing to detect and directly visualize gene fusions associated with balanced translocations found in acute leukemia. RESULTS: In patients harboring t(12;21)(p13;q22), we demonstrated the presence of the fusion using specific probes covering the ETV6 and RUNX1 genes, with a positive result occurring due to the hybridization of the two probes to the same DNA fiber. Thanks to molecular combing, we also showed the presence of different breakpoints using these same probes. CONCLUSIONS: Using several probes that are specific to the most common genes involved in acute leukemia, molecular combing could be an interesting additional tool in acute leukemia diagnosis. [ABSTRACT FROM AUTHOR]

Aim of the study: To evaluate the feasibility and to measure the effects of a six-week-long adapted physical activity programme (APAP), including 5 days of intense dog sledding, on the physical and psychological health of children and adolescents treated for cancer. Methods: Eleven children and teenagers (4 girls, 7 boys; mean age 14.3 ' 2.9 years) participated in this monocentric pilot programme of adapted physical activities from February 2013 to March 2013. Seven were still on treatment. The programme lasted 6 weeks. A series of physical tests and psychological questionnaires were carried out before and after the programme. Results: All children and teenagers completed the full programme. An improvement in all physical and psychological parameters was observed. Statistically significant differences were observed for global self-esteem (6.2 ' 2.1 to 7.7 ' 1.8; p = 0.02), perceived sport competence (5.3 ' 3.2 to 7.4 ' 2; p = 0.02) and perceived physical strength (5.6 ' 2.5 to 7.1 ' 1.8; p = 0.001). Regarding physical tests, the physical training led to statistically significant improvement for sit-ups (13.8 ' 2.6 to 21.75 ' 5.4; p = 0.01), muscle tone (76 ' 23.7 to 100 ' 22.9; p = 0.01), and resting heart rate (96.1 ' 3.2 to 91.6 ' 4.5; p = 0.03). Conclusion: This programme is feasible in children and adolescents even during their oncologic treatment. During the 6-week programme, children and adolescents improved their physical and psychological health, and the putative benefits of the APAP are discussed. A larger randomised trial started in 2014. [ABSTRACT FROM AUTHOR]

Patients with Langerhans cell histiocytosis ( LCH) refractory to conventional chemotherapy have a poor outcome. There are currently two promising treatment strategies for high-risk patients: the first involves the combination of 2-chlorodeoxyadenosine and cytarabine; the other approach is allogeneic haematopoietic stem cell transplantation ( HSCT). Here we evaluated 87 patients with high-risk LCH who were transplanted between 1990 and 2013. Prior to the year 2000, most patients underwent HSCT following myeloablative conditioning ( MAC): only 5 of 20 patients (25%) survived with a high rate (55%) of transplant-related mortality ( TRM). After the year 2000 an increasing number of patients underwent HSCT with reduced intensity conditioning ( RIC): 49/67 (73%) patients survived, however, the improved survival was not overtly achieved by the introduction of RIC regimens with similar 3-year probability of survival after MAC (77%) and RIC transplantation (71%). There was no significant difference in TRM by conditioning regimen intensity but relapse rates were higher after RIC compared to MAC regimens (28% vs. 8%, P = 0·02), although most patients relapsing after RIC transplantation could be salvaged with further chemotherapy. HSCT may be a curative approach in 3 out of 4 patients with high risk LCH refractory to chemotherapy: the optimal choice of HSCT conditioning remains uncertain. [ABSTRACT FROM AUTHOR]

Objective The objectives of this study are to assess the quality of life (QoL) of siblings of childhood leukemia survivors in comparison with population controls and to identify determinants of sibling's QoL. Methods The nearest-aged siblings (8-17 years) of minor CLS participating in the French LEA cohort (Childhood and Adolescent Leukemia), at the Marseilles center, were included. Siblings' QoL was self-reported using the 'Vécu et Santé Perçue de l'Adolescent et l'enfant' questionnaire. Results were compared with those obtained for age-matched and sex-matched French controls subjects. Characteristics likely to be associated with siblings' QoL (sibling's and survivor's sociodemographic and health-related and cancer-related characteristics) were explored through multivariate analysis. Results Fifty-one siblings participated (mean age 12.7 ± 2.8 years, mean follow-up duration from diagnosis to evaluation 8.8 ± 2.5 years). They reported a significantly higher perception of QoL compared with the general population regarding psychological domains, while reporting a lower perception regarding social domains. In multivariate analysis, older age at diagnosis for both siblings and survivors was risk factor for impaired psychological QoL. An elevated leukemia burden index was linked with lower scores in self-esteem dimension, whereas having at least one sequelae for the survivor was linked with better scores in psychological well-being dimension. Low or middle affluence and older sibling's age at diagnosis were risk factors for impaired social QoL. Maximal R2 was 30%. Conclusions Minor siblings of CLS reported a relatively good QoL, particularly in psychological domains. Given the low proportion of QoL variability explained, other contributing factors (e.g., family functioning) must be explored. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

With the advent of multimodality therapy, the overall five-year survival rate from childhood cancer has improved considerably now exceeding 80% in developed European countries. This growing cohort of survivors, with many years of life ahead of them, has raised the necessity for knowledge concerning the risks of adverse long-term sequelae of the life-saving treatments in order to provide optimal screening and care and to identify and provide adequate interventions. Childhood cancer survivor cohorts in Europe. Considerable advantages exist to study late effects in individuals treated for childhood cancer in a European context, including the complementary advantages of large population-based cancer registries and the unrivalled opportunities to study lifetime risks, together with rich and detailed hospital-based cohorts which fill many of the gaps left by the large-scale population-based studies, such as sparse treatment information. Several large national cohorts have been established within Europe to study late effects in individuals treated for childhood cancer including the Nordic Adult Life after Childhood Cancer in Scandinavia study (ALiCCS), the British Childhood Cancer Survivor Study (BCCSS), the Dutch Childhood Oncology Group (DCOG) LATER study, and the Swiss Childhood Cancer Survivor Study (SCCSS). Furthermore, there are other large cohorts, which may eventually become national in scope including the French Childhood Cancer Survivor Study (FCCSS), the French Childhood Cancer Survivor Study for Leukaemia (LEA), and the Italian Study on off-therapy Childhood Cancer Survivors (OTR). In recent years significant steps have been taken to extend these national studies into a larger pan-European context through the establishment of two large consortia - PanCareSurFup and PanCareLIFE. The purpose of this paper is to present an overview of the current large, national and pan-European studies of late effects after childhood cancer. This overview will highlight the strong cooperation across Europe, in particular the EU-funded collaborative research projects PanCareSurFup and PanCareLIFE. Overall goal. The overall goal of these large cohort studies is to provide every European childhood cancer survivor with better care and better long-term health so that they reach their full potential, and to the degree possible, enjoy the same quality of life and opportunities as their peers. [ABSTRACT FROM AUTHOR]

A prospective phase II multicenter trial was performed with the aim to obtain less than 25% nonrelapse mortality (NRM) after unrelated cord blood transplantation (UCBT) for adults with acute myeloid leukemia (AML) using a reduced-intensity conditioning regimen (RIC) consisting of total body irradiation (2 Gy), cyclophosphamide (50 mg/kg), and fludarabine (200 mg/m 2 ). From 2007 to 2009, 79 UCBT recipients were enrolled. Patients who underwent transplantation in first complete remission (CR1) (n = 48) had a higher frequency of unfavorable cytogenetics and secondary AML and required more induction courses of chemotherapy to achieve CR1 compared with the others. The median infused total nucleated cells (TNC) was 3.4 × 10 7 /kg, 60% received double UCBT, 77% were HLA mismatched (4/6), and 40% had major ABO incompatibility. Cumulative incidence of neutrophil recovery at day 60 was 87% and the cumulative incidence of 100-day acute graft-versus-host disease (II to IV) was 50%. At 2 years, the cumulative incidence of NRM and relapse was 20% and 46%, respectively. In multivariate analysis, major ABO incompatibility ( P = .001) and TNC (<3.4 × 10 7 /kg; P = .001) were associated with increased NRM, and use of 2 or more induction courses to obtain CR1 was associated with increased relapse incidence ( P = .04). Leukemia-free survival (LFS) at 2 years was 35%, and the only factor associated with decreased LFS was secondary AML ( P = .04). In conclusion, despite the decreased NRM observed, other RIC regimens with higher myelosuppression should be evaluated to decrease relapse in high-risk AML. (EUDRACT 2006-005901-67). [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have identified that frequent polymorphisms in ARID5B and IKZF1, two genes involved in lymphoid differentiation, increase the risk of childhood acute lymphoblastic leukemia (ALL). These findings markedly modified the current field of research on the etiology of ALL. In this new context, the present exploratory study investigated the possible interactions between these at-risk alleles and the non-genetic suspected ALL risk factors that were of sufficient prevalence in the French ESCALE study: maternal use of home insecticides during pregnancy, preconception paternal smoking, and some proxies for early immune modulation, i.e. breastfeeding, history of common infections before age one year, and birth order. The analyses were based on 434 ALL cases and 442 controls of European origin, drawn from the nationwide population-based case-control study ESCALE. Information on non-genetic factors was obtained by standardized telephone interview. Interactions between rs10740055 in ARID5B or rs4132601 in IKZF1 and each of the suspected non-genetic factors were tested, with the SNPs coded as counts of minor alleles (trend variable). Statistical interactions were observed between rs4132601 and maternal insecticide use (p = 0.012), breastfeeding p = 0.017) and repeated early common infections (p = 0.0070), with allelic odds ratios (OR) which were only increased among the children not exposed to insecticides (OR = 1.8, 95%CI: 1.3, 2.4), those who had been breastfed (OR = 1.8, 95%CI: 1.3, 2.5) and those who had had repeated early common infections (OR = 2.4, 95%CI: 1.5, 3.8). The allelic ORs were close to one among children exposed to insecticides, who had not been breastfed and who had had no or few common infections. Repeated early common infections interacted with rs10740055 (p = 0.018) in the case-only design. Further studies are needed to evaluate whether these observations of a modification of the effect of the at-risk alleles by non-genetic factors are chance findings or reflect true underlying mechanisms. [ABSTRACT FROM AUTHOR]

Cataract was prospectively assessed by serial slip lamp tests in 271 patients included in the Leucémie Enfants Adolescents ( LEA) programme, the French cohort of childhood leukaemia survivors. All had received haematopoietic stem cell transplantation ( HSCT) after total body irradiation ( TBI, n = 201) or busulfan-based ( n = 70) myeloablative conditioning regimen. TBI was fractionated in all but six patients. The mean duration of follow-up from HSCT was 10·3 years. Cataract was observed in 113/271 patients (41·7%); 9/113 (8·1%) needed surgery. Cumulative incidence after TBI increased over time from 30% at 5 years to 70·8% and 78% at 15 and 20 years, respectively, without any plateau thereafter. The 15-year cumulative incidence was 12·5% in the Busulfan group. A higher cumulative steroid dose appeared to be a cofactor of TBI for cataract risk, in both univariate and multivariate Cox analysis. In the multivariate analysis, cataract had an impact in two quality of life domains: 'the role limitation due to physical problems' and 'the role limitation due to emotional problems'. These data suggest that with increasing follow-up, nearly all patients who receive TBI, even when fractionated, will suffer from cataract that can impact on their quality of life and that high cumulative steroid dose is a cofactor. [ABSTRACT FROM AUTHOR]

This study aimed to describe kinetics of complete donor chimerism occurrence ( cDC, >99·9% donor) after unrelated cord blood transplantation ( UCBT), to identify its predictive factors and its impact on post-transplant outcome. Ninety-four children who received single UCBT after a myeloablative conditioning regimen had blood chimerism evaluation at predefined post-transplant dates, using a real-time polymerase chain reaction method with 0·1% sensitivity. Cumulative incidence of cDC at 1 year post-transplantation was 61·8%. Three predictive factors were identified in multivariate analysis: history of malignant disease ( P = 0·03), older age (above 2·16 years, the first quartile of age, P = 0·0055) and higher level of cord/recipient human leucocyte antigen mismatch (4/6 vs. 5-6/6, P < 0·001) increased the probability of post-transplant cDC. Although graft cell dose had a strong impact on haematological recovery, it did not apparently influence cDC occurrence. Early cDC (i.e. more than 99·9% donor chimerism on days 15-30 post-transplant) appeared useful to predict engraftment ( P = 0·003) as well as acute and chronic graft-versus-host disease (GvHD). Severe acute or chronic GvHD never occurred in patients with DC ≤99·9%, suggesting than even minimal residual host haematopoiesis is associated with a very low risk of GvHD after UCBT. [ABSTRACT FROM AUTHOR]

Minimal residual disease ( MRD) is a major predictive factor of the cure rate of acute lymphoblastic leukaemia ( ALL). Haematopoietic cell transplantation is a treatment option for patients at high risk of relapse. Between 2005 and 2008, we conducted a prospective study evaluating the feasibility and efficacy of the reduction of immunosuppressive medication shortly after a non- ex vivo T depleted myeloablative transplantation. Immunoglobulin (Ig)H/T-cell receptor MRD 30 d before transplant could be obtained in 122 of the 133 cases of high-risk paediatric ALL enrolled. There were no significant demographic differences except remission status (first or second complete remission) between the 95 children with MRD <10−3 and the 27 with MRD ≥10−3. Multivariate analysis identified sex match and MRD as being significantly associated with 5-year survival. MRD ≥10−3 compromised the 5-year cumulative incidence of relapse (43·6 vs. 16·7%). Complete remission status and stem cell source did not modify the relationship between MRD and prognosis. Thus, pre-transplant MRD is still a major predictor of outcome for ALL. The MRD-guided strategy resulted in survival for 72·3% of patients with MRD<10−3 and 40·4% of those with MRD ≥10−3. [ABSTRACT FROM AUTHOR]

Corticosteroid and central nervous system ( CNS) irradiation can induce cataract in childhood lymphoblastic leukaemia survivors. Few prospective studies with systematic ophthalmological evaluation have been published. Cataract was prospectively assessed by serial slip lamp tests in 517 patients. All had acute lymphoblastic leukaemia, all had been treated by chemotherapy with or without CNS irradiation, and none had received haematopoietic stem cell transplantation. Median ages at last evaluation and follow-up duration from leukaemia diagnosis were 16·8 and 10·9 years, respectively. Cataract was observed in 21/517 patients (4·1%). Cumulative incidence was 4·5 ± 1·2% at 15 years and reached 26 ± 8·1% at 25 years. CNS irradiation was the only risk factor: prevalence was 11·1% in patients who had received irradiation and 2·8% in those who did not. We did not detect any steroid dose effect: cumulative dose was 5133 and 5190 mg/m2 in patients with and without cataract, respectively. Cataract occurrence did not significantly impact quality of life. We conclude that, in the range of steroid dose reported here, the cataract risk proves very low 15 years after treatment without CNS irradiation but an even more prolonged follow-up is required because of potential very late occurrence. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell (HSC) transplantation is a curative treatment for many hematologic malignancies for which umbilical cord blood (UCB) represents an alternative source of HSCs. To overcome the low cellularity of one UCB unit, double UCB transplantation (dUCBT) has been developed in adults. We have analyzed the outcome of 136 patients who underwent dUCBT reported to the SFGM-TC registry between 2005 and 2007. Forty-six patients received myeloablative regimens, and 90 patients received reduced-intensity conditioning regimens. There were 84 cases of leukemia, 17 cases of non-Hodgkin lymphoma, 11 cases of myeloma, and 24 other hematologic malignancies. At transplantation, 40 (29%) patients were in complete remission. At day 60 after transplantation, the cumulative incidence of neutrophil recovery was 91%. We observed one UCB unit domination in 88% of cases. The cumulative incidence of day 100 acute graft-versus-host disease, chronic graft-versus-host disease, transplant-related mortality, and relapse at 2 years were 36%, 23%, 27%, and 28% respectively. After a median follow-up of 49.5 months, the 3-year probabilities of overall and progression-free survival were 41% and 35%, respectively, with a significant overall survival advantage when male cord engrafted male recipients. We obtained a long-term plateau among patients in complete remission, which makes dUCBT a promising treatment strategy for these patients. [Copyright &y& Elsevier]

Abstract: Although hematopoietic stem cell transplantation (HSCT) offers curative potential for beta-thalassemia major (beta-TM), it is associated with a variable but significant incidence of graft rejection. We studied the French national experience for improvement over time and the potential benefit of antithymocyte globulin (ATG). Between December 1985 and December 2007, 108 patients with beta-TM underwent HSCT in 21 different French transplantation centers. The majority of patients received a matched sibling transplant (n = 96) and a busulfan- and cyclophosphamide-based conditioning regimen (n = 95), also with ATG in 57 cases. Ninety-five of the 108 patients survived, with a median follow-up of 12 years. Probabilities of 15-year survival and thalassemia-free survival after first HSCT were 86.8% and 69.4%, respectively. Graft failure occurred in 24 patients, 11 of whom underwent a second HSCT. The use of ATG was associated with a decrease in rejection rate from 35% to 10%. Thalassemia-free survival improved significantly with time, reaching 83% in the 54 patients undergoing HSCT after 1994 (median time of HSCT). In view of the increased risk of graft rejection after matched sibling HSCT, current French national guidelines recommend, for all children at risk for beta-TM, the systematic addition of ATG to the myeloablative conditioning regimen and special attention to optimize transfusion and chelation therapy in the pretransplantation period. [Copyright &y& Elsevier]

Chronic granulomatous disease is an inherited disorder in which phagocytes lack a functional NADPH oxidase and cannot produce superoxide anions. The most common form is caused by mutations in CYBB encoding gp91 phox. We investigated 24 CGD patients and their families. Twenty-one mutations in CYBB were classified as X91, X91 or X91 variants according to cytochrome b expression. Point mutations in encoding regions represented 50 % of the mutations found in CYBB, splice site mutations 27 %, deletions and insertions 23 %. Eight mutations in CYBB were novel leading to X91CGD cases. Two of these were point mutations: c493G>T and a double mutation c625C>G in exon 6 and c1510C>T in exon 12 leading to a premature stop codon at Gly165 in gp91 phox and missense mutations His209Arg/Thr503Ile respectively. Two novel splice mutations in 5′intronic regions of introns 1 and 6 were found. A novel deletion/insertion c1024_1026delCTG/insT results in a frameshift introducing a stop codon at position 346 in gp91 phox. The last novel mutation was the insertion of a T at c1373 leading to a frameshift and a premature stop codon at position 484 in gp91 phox. For the first time the precise size of two large mutations in CYBB was determined by array-comparative genomic hybridization and carriers' status were evaluated by multiplex ligation-dependent probe amplification assay. No clear correlation between clinical severity and CYBB mutations could be established. Of three mutations in CYBA, NCF1 and NCF2 leading to rare autosomal recessive CGD, one nonsense mutation c29G>A in exon 1 of NCF2 was new. [ABSTRACT FROM AUTHOR]

There is little data available regarding children and adolescents with Hodgkin lymphoma (HL) who relapse after combined-modality treatment, even though they have a substantial chance of cure. The purpose of this national retrospective study was to evaluate the outcome of patients with recurrent/refractory HL and determine adverse prognostic factors. From 1990 to 2006, 70 patients (median age 13·9 years) with refractory ( n = 31) or first relapse ( n = 39) HL were identified. Median time from end of treatment to relapse was 6 months (3-56). Relapses occurred in irradiated areas in 43/70 patients. Salvage therapy consisted of chemotherapy and 50 patients received high-dose chemotherapy with autologous stem cell transplantation. Radiotherapy was performed in 29 cases, tandem autologous transplantation in five and allograft in three. With a median follow-up of 40 months (2-140), significant prognostic factors were time to progression/relapse and response to therapy before autograft. Event-free survival and overall survival in patients with refractory disease, early relapse and late relapse were 35 ± 9%, 67 ± 11%, 76 ± 10% and 48 ± 11%, 89 ± 7% and 80 ± 10%, respectively. As progression <3 months was a major adverse prognostic factor, novel therapeutic approaches are needed for this group of patients. By contrast, patients have substantial chance of long term second remission in case of relapse >3 months. [ABSTRACT FROM AUTHOR]

This study describes patient adherence to leukemia maintenance therapy and the factors associated with nonadherence, with a particular focus on the different age groups concerned. Sixty-four in-depth interviews were performed in three centers among 31 parents of children, 12 parents of adolescents, 12 adolescents, and 9 adult patients. Adherence was determined through a multimethod approach based on patient and/or parent responses to three self-administered questions and patient and/or parent interviews. The results were compared with physician evaluation of adherence. Factors explaining nonadherence were investigated in the in-depth interviews and by statistical analysis of self-administered questionnaires. Intentional nonadherence occurred rarely (4/52 patients, 8%) following poor tolerance of the maintenance therapy. Despite a high motivation to follow the maintenance therapy, repeated forgetfulness (8/52, 15%) was not rare and rarely detected by physicians. Nonadherence increased with age, but also existed among children. Outings, the administration of therapy at bedtime, the lack of monitoring, a low socioeconomic status, and the hepatic side effects of the treatment were also associated with nonadherence. Declared nonadherence of leukemia maintenance therapy is not negligible and should be screened at follow-up consultations using three simple questions. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The study objective was to validate a specific quality of life (QoL) questionnaire for caregivers of cancer patients, the CareGiver Oncology Quality of Life questionnaire (CarGOQoL), based on the exclusive points of view of the caregivers. Materials and methods: A 75-item questionnaire generated from content analysis of interviews with caregivers was self-completed by 837 caregivers of cancer patients. In addition to sociodemographic data and patient characteristics, self-reported questionnaires assessing QoL, burden, coping and social support were collected. Psychometric properties combined methods relying on both classical test theory and item response theory. Results: The final 29 items selected assessed 10 dimensions: psychological well-being, burden, relationship with health care, administration and finances, coping, physical well-being, self-esteem, leisure time, social support and private life; they were isolated from principal component analysis explaining 73% of the total variance. The missing data and the floor effects were low. Some ceiling effects were found for B (34%). Cronbach’s alpha coefficients ranged from 0.72 to 0.89, except private life (PL) (0.55). Unidimensionality of the scales was confirmed by Rasch analyses. Correlations with other instruments confirmed the isolated content and significant links were found with respect to patient’s characteristics. Reproducibility and sensitivity to change were found satisfactory. Conclusion: The CarGOQoL could provide a reliable and valid measure of caregivers of cancer patients’ QoL which are key-actors in the provision of health care. [Copyright &y& Elsevier]

Since several years, the use of intravenous immunoglobulins (IVIg) has increased. This growth has encouraged some countries to publish guidelines. In parallel, some countries have conducted audits to know how IVIg are used in clinical practice in the light of the available guidelines. The objective of this study was to assess IVIg use in three French university hospitals in 2006. All IVIg administrations were evaluated during 6 months (12 September 2005-12 March 2006) in French university hospitals of Marseille. Different data were recorded for each administration: patient characteristics, indication, formulation and quantity. During the study period, 2802 administrations of IVIg (corresponding to a total quantity of 76 780 g) have been recorded. Four hundred and thirty-five patients received at least one of these administrations. The five most reported indications were multifocal motor neuropathy (11.0% of total quantity), chronic inflammatory demyelinating polyradiculoneuropathy (10.2%), corticoresistant dermatomyositis (10.2%), immune thrombocytopaenia (9.9%) and primary immune deficiency (9.1%). According to available French recommendations, 70% of the IVIg use was for 'acknowledged indications', 9% for 'indications to be assessed' and 18% for 'unwarranted indications'. The 10 most reported indications were 'acknowledged indications' according to available recommendations of the French expert group. Nevertheless, the two most reported indications were not approved by the French Health Products Agency (AFSSAPS) at the time of the study and were approved since. [ABSTRACT FROM AUTHOR]

Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder characterized by early-onset, chronic, nonmalignant lymphoproliferation, autoimmune manifestations, and susceptibility to lymphoma. The majority of ALPS patients carry heterozygous germline (ALPS-FAS) or somatic mutations (ALPS-sFAS) of the TNFRSF6 gene coding for FAS. Although the clinical features of ALPS have been described previously, long-term follow-up data on morbidity and mortality are scarce. We performed a retrospective analysis of clinical and genetic features of 90 ALPS-FAS and ALPS-sFAS patients monitored over a median period of 20.5 years. Heterozygous germline mutations of TNFRSF6 were identified in 83% of probands. Somatic TNFRSF6 mutations were found in 17% of index cases (all located within the intracellular domain of FAS). Sixty percent of the ALPS-FAS patients with mutations in the extracellular domain had a somatic mutation affecting the second allele of TNFRSF6; age at onset was later in these patients. No other genotype-phenotype correlations could be found. Long-term analysis confirmed a trend toward spontaneous remission of lymphoproliferation in adulthood but mixed outcomes for autoimmune manifestations. We observed significant and potentially life-threatening disease and treatment-related morbidity, including a high risk of sepsis after splenectomy that calls for careful long-term monitoring of ALPS patients. We also noted a significantly greater occurrence of disease-related symptoms in male than in female patients. [ABSTRACT FROM AUTHOR]

Abstract: To get precise material data for advanced numerical modelling of tube hydroforming process, the tube bulging test is recommended. Stresses and strains in the tube cannot be evaluated easily and several approaches have been proposed. A review is proposed and points out their advantages and drawbacks. A semi-analytical model is presented and experimental measures done on an original tube show the thickness scattering along a generating line of the tube. These observations justify the processing of a linear sensitivity analysis which reveals the most influencing parameters on the accuracy of the hardening curve and gives information to perform relevant experiments. [Copyright &y& Elsevier]

Femoral and lumbar bone mineral densities (BMDs) were measured in 159 adults enrolled in the Leucémies de l'Enfant et de l'Adolescent program, a French prospective multicentric cohort of childhood leukemia survivors. BMDs were expressed as Z-scores, and multivariate linear regression analyses were used to construct association models with potential risk factors. Mean age at evaluation and follow-up was 23 and 14.7 years, respectively. In the whole cohort, mean femoral Z-score was -0.19 ± 0.08. Two factors were associated with lower femoral BMD transplantation (-0.49 ± 0.15 vs -0.04 ± 0.10 in the chemotherapy group; P = .006) and female sex (-0.34 ± 0.10 vs -0.03 ± 0.13; P = .03). Among patients who received a transplant, the only significant risk factor was hypogonadism (-0.88 ± 0.16 vs -0.10 ± 0.23; P = .04). A slight reduction in lumbar BMD (mean Z-score, -0.37 ± 0.08) was detected in the whole cohort without difference between the transplantation and chemotherapy groups. Among patients who received a transplant, younger age at transplantation was correlated with a low lumbar BMD (P = .03). We conclude that adults who had received only chemotherapy for childhood leukemia have a slight reduction in their lumbar BMD and a normal femoral BMD. Patients who received a transplant with gonadal deficiency have a reduced femoral BMD which might increase the fracture risk later in life. [ABSTRACT FROM AUTHOR]

Cumulative evidence indicates that MYC, one of the major downstream effectors of NOTCH1, is a critical component of T-cell acute lymphoblastic leukemia (T-ALL) oncogenesis and a potential candidate for targeted therapy. However, MYC is a complex oncogene, involving both fine protein dosage and cell-context dependency, and detailed understanding of MYC-mediated oncogenesis in T-ALL is still lacking. To better understand how MYC is interspersed in the complex T-ALL oncogenic networks, we performed a thorough molecular and biochemical analysis of MYC activation in a comprehensive collection of primary adult and pediatric patient samples. We find that MYC expression is highly variable, and that high MYC expression levels can be generated in a large number of cases in absence of NOTCH1/FBXW7 mutations, suggesting the occurrence of multiple activation pathways in addition to NOTCH1. Furthermore, we show that posttranscriptional deregulation of MYC constitutes a major alternative pathway of MYC activation in T-ALL, operating partly via the PI3K/AKT axis through down-regulation of PTEN, and that NOTCH1m might play a dual transcriptional and posttranscriptional role in this process. Altogether, our data lend further support to the significance of therapeutic targeting of MYC and/or the PTEN/AKT pathways, both in GSI-resistant and identified NOTCH1-independent/MYC-mediated T-ALL patients. [ABSTRACT FROM AUTHOR]