Some previous epidemiological studies have suggested that pesticide exposure during pregnancy may have a possible role in the development of childhood brain tumors (CBT). We pooled data from two ...French national population‐based, case–control studies to investigate the association between maternal residential use of pesticides during pregnancy and the risk of CBT. The mothers of 437 CBT cases and 3,102 controls aged under 15 years who resided in France at diagnosis/interview, frequency‐matched by age and gender, answered a structured telephone interview conducted by trained interviewers. Unconditional logistic regression was used to estimate pooled odds ratio (OR) and 95% confidence intervals (95% CI). CBT was significantly associated with the maternal home use of pesticides during pregnancy (OR 1.4, 95% CI 1.2–1.8) and, more specifically, with insecticide (OR 1.4, 1.2–1.8). We could not draw any conclusions about herbicides and/or fungicides because few women used them during pregnancy and most of these mothers also used insecticides. Although potential recall bias cannot be excluded, our findings of this pooled analysis support the hypothesis that residential maternal use of pesticides during pregnancy and particularly insecticides may increase the risk of CBT. Future investigations to verify these findings and to explore for CBT subtypes and dose–response are necessary to have a better understanding of the possible role of pesticides in etiology of CBT.
What's new?
The etiology of childhood brain tumor (CBT) remains unknown. Several perinatal factors are suspected to increase CBT risk, including maternal exposure to pesticides. In our study of malignant CBT, the authors found a positive association between maternal residential pesticide use (particularly of insecticides) during pregnancy, and malignant CBT. These results further implicate pesticides in the development of these cancers in children.
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.
Aim
To assess objective response after two cycles of temozolomide and topotecan (TOTEM) in children with refractory or relapsed miscellaneous extracranial solid and central nervous system (CNS) ...tumors, including medulloblastoma and primitive neuroectodermal tumors (PNET).
Procedure
Multicenter, nonrandomized, phase 2 basket trial including children with solid tumors, completed by a one‐stage design confirmatory cohort for medulloblastoma, and an exploratory cohort for PNET. Main eligibility criteria were refractory/relapsed measurable disease and no more than two prior treatment lines. Temozolomide was administered orally at 150 mg/m2/day followed by topotecan at 0.75 mg/m2/day intravenously for five consecutive days every 28 days. Tumor response was assessed every two cycles according to WHO criteria and reviewed independently.
Results
Thirty‐two patients were enrolled and treated in the miscellaneous solid tumor and 33 in the CNS strata; 20 patients with medulloblastoma and six with PNET were included in the expansion cohorts. The median age at inclusion was 10.0 years (range, 0.9‐20.9). In the basket cohorts, confirmed complete and partial responses were observed in one glioma, four medulloblastoma, and one PNET, leading to the extension. The overall objective response rate (ORR) in medulloblastoma was 28% (95% CI, 12.7‐47.2) with 1/29 complete and 7/29 partial responses, those for PNET 10% (95% CI, 0.3‐44.5). Post hoc Bayesian analysis estimates that the true ORR in medulloblastoma is probably between 20% and 30% and below 20% in PNET. The most common treatment‐related toxicities of the combination therapy were hematologic.
Conclusions
Temozolomide‐topotecan results in significant ORR in children with recurrent and refractory medulloblastoma with a favorable toxicity profile.
This study investigates invasive fungal infections (IFIs) in patients with acute myelogenous leukemia who were included in the Enfant Leucemie Aigue 02 protocol between 2005 and 2011. Among 387 ...patients, 15 had aspergillosis, 9 had candidiasis, and 2 had mucormycosis. The most frequent localization of IFIs was in the lungs. It was found that after a median of 34 months, 2 deaths were attributable to IFI without any difference in survival between the groups with and without IFI.
Little is known of the causes of childhood brain tumors (CBT). The aims of this study were to investigate whether extremes of birth weight were associated with increased risk of CBT and whether ...maternal preconceptional folic acid supplementation or breastfeeding reduced the risk. In addition, other maternal characteristics and birth related factors were also investigated. We pooled data from two French national population‐based case‐control studies with similar designs conducted in 2003–2004 and 2010–2011. The mothers of 510 CBT cases (directly recruited from the national childhood cancer register) and 3,102 controls aged under 15 years, frequency matched by age and gender did a telephone interview, which focussed on demographic and perinatal characteristics, and maternal life style habits and reproductive history. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression, adjusted for age, sex, study of origin and relevant confounders. No association was found between CBT and birth weight or fetal growth. The use of preconceptional folic acid supplementation was rare (5.3% in cases and 7.8% in controls) and the OR was 0.8 (95% CI 0.5, 1.4). There was no association with breastfeeding, even prolonged (six months or more; OR 1.0, 95% CI 0.8, 1.4). Neither was there any association between CBT and other investigated factors (maternal body mass index, gestational weight gain, congenital abnormality, maternal reproductive history or use of fertility treatments. Although large, this study was underpowered for subtype analyses. Pooling data with other population‐based studies may provide further insight into findings by CBT subtypes.
What's new?
In the search for causes of childhood brain tumors (CBTs), birth weight, fetal growth and maternal behaviors have attracted significant interest. Despite extensive study, however, associations between those factors and CBTs remain unclear. This investigation of 510 CBT cases and over 3,000 controls from two French studies yields no evidence of an association between fetal growth and CBT risk. There also was little indication that maternal preconceptional folic acid supplementation or breastfeeding protect against CBTs. The findings highlight the importance of replicating analyses in different populations and the need for international consortiums to make full use of available data.
Refractory chronic immune thrombocytopenia (r‐cITP) is one of the most challenging situations in chronic immune thrombocytopenia (cITP). Pediatric r‐cITP is inconsistently defined in literature, ...contributing to the scarcity of data. Moreover, no evidence is available to guide the choice of treatment. We compared seven definitions of r‐cITP including five pediatric definitions in 886 patients with cITP (median min‐max follow‐up 5.3 1.0–29.3 years). The pediatric definitions identified overlapping groups of various sizes (4%–20%) but with similar characteristics (higher proportion of immunopathological manifestations IM and systemic lupus erythematosus SLE), suggesting that they adequately captured the population of interest. Based on the 79 patients with r‐cITP (median follow‐up 3.1 0–18.2 years) according to the CEREVANCE definition (≥3 second‐line treatments), we showed that r‐cITP occurred at a rate of 1.15% new patients per year and did not plateau over time. In multivariate analysis, older age was associated with r‐cITP. One patient (1%) experienced two grade five bleeding events after meeting r‐cITP criteria and while not receiving second‐line treatment. The cumulative incidence of continuous complete remission (CCR) at 2 years after r‐cITP diagnosis was 9%. In this analysis, splenectomy was associated with a higher cumulative incidence of CCR (hazard ratio: 5.43, 95% confidence interval: 1.48–19.84, p = 7.8 × 10−4). In sum, children with cITP may be diagnosed with r‐cITP at any time point of the follow‐up and are at increased risk of IM and SLE. Second‐line treatments seem to be effective for preventing grade 5 bleeding. Splenectomy may be considered to achieve CCR.
Neuroblastoma (NB), an embryonic tumour arising from neural crest cells, is the most common malignancy among infants. The aetiology of NB is largely unknown. We conducted a pooled analysis to explore ...whether there is an association between NB and preconception and perinatal factors using data from two French national population‐based case‐control studies. The mothers of 357 NB cases and 1783 controls younger than 6 years, frequency‐matched by age and gender, responded to a telephone interview that focused on demographic, socioeconomic and perinatal characteristics, childhood environment, life‐style and maternal reproductive history. Unconditional logistic regression was used to estimate pooled odds ratios and 95% confidence intervals. After controlling for matching variables, study of origin and potential confounders, being born either small (OR 1.4 95% CI 1.0‐2.0) or large (OR 1.5 95% CI 1.1–2.2) for gestational age and, among children younger than 18 months, having congenital malformations (OR 3.6 95% CI 1.3–8.9), were significantly associated with NB. Inverse associations were observed with breastfeeding (OR 0.7 95% CI 0.5–1.0) and maternal use of any supplements containing folic acid, vitamins or minerals (OR 0.5 95% CI 0.3–0.9) during the preconception period. Our findings reinforce the hypothesis that fetal growth anomalies and congenital malformations may be associated with an increased risk of NB. Further investigations are needed in order to clarify the role of folic acid supplementation and breastfeeding, given their potential importance in NB prevention.
What's New?
Neuroblastoma is the most common extracranial solid tumor in children, yet little is known about its etiology. The vast majority of neuroblastomas are not inherited, suggesting that neuroblastoma risk is influenced by other factors, particularly certain preconception or perinatal factors. Here, in a population'based case'control study of 357 neuroblastoma patients, congenital malformations and small or large size for gestational age were associated with increased neuroblastoma risk. By contrast, breastfeeding and preconception supplementation with vitamins or minerals were inversely associated with risk. The findings confirm previous links between neuroblastoma, abnormal fetal growth, and congenital malformations while highlighting potential protective factors.
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Despite major treatment improvements over the past decades, pediatric acute myeloid leukemia (AML) is still a life‐threatening malignancy with ...relapse rates up to 30% and survival rates below 75%. A better description of the pattern of molecular aberrations in childhood AML is needed to refine prognostication in such patients. We report here the comprehensive molecular landscape using both high‐throughput sequencing focused on 36 genes and ligation‐dependent RT‐PCR in 385 children with de novo AML enrolled in the prospective ELAM02 trial and we evaluated their prognostic significance. Seventy‐six percent of patients had at least 1 mutation among the genes we screened. The most common class of mutations involved genes that control kinase signaling (61%) followed by transcription factors (16%), tumor suppressors (14%), chromatin modifiers (9%), DNA methylation controllers (8%), cohesin genes (5%), and spliceosome (3%). Moreover, a recurrent transcript fusion was detected in about a half of pediatric patients. Overall, CBF rearrangements, NPM1 and double CEBPA mutations represented 37% of the cohort and defined a favorable molecular subgroup (3 years OS: 92.1%) while NUP98 fusions, WT1, RUNX1, and PHF6 mutations (15% of the cohort) segregated into a poor molecular subgroup (3 years OS: 46.1%). KMT2A‐rearrangements (21% of the cohort) were associated with an intermediate risk. Despite some overlaps, the spectrum of molecular aberrations and their prognostic significance differ between childhood and adult AML. These data have important implications to contribute in refining risk stratification of pediatric AML and show the need for further validations in independent pediatric cohorts.
Summary
Childhood autoimmune haemolytic anaemia (AIHA) requires second‐line immunosuppressive therapy in 30–50% of cases. It appears that rituximab is indicated in such circumstances. This ...prospective national study reports the practice, efficacy and tolerance of rituximab in children with isolated AIHA and AIHA in the setting of Evans syndrome (ES). Sixty‐one children were given rituximab between 2000 and 2014. The median interval from diagnosis to rituximab was 9·9 interquartile range (IQR) 1·6–28·5 months. Forty‐six patients responded (75%) and the 6‐year relapse‐free survival (RFS) was 48%. Twenty patients relapsed at a median interval of 10·8 (IQR 3·9–18·7) months, rituximab allowed steroid withdrawal in 44/61 (72%) of children. In isolated AIHA, complete response and 6‐year RFS were significantly higher than in ES (P < 0·05). Ten out of 61 patients were infants, seven of who responded with a 6‐year RFS of 71%. Among patients without immunoglobulin substitution before rituximab, 4 are still receiving substitutions. Five patients died, including one potentially attributable to rituximab. This large observational series of childhood AIHA established the rituximab benefit‐risk ratio, allowing steroid withdrawal, with 37% of long‐term responders, mainly in isolated AIHA. All subgroups of patients drew benefit. Our long‐term results indicate the baseline to be challenged by new treatment approaches.
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