Residential proximity to croplands at birth and childhood leukaemia.

BACKGROUND: Domestic and parental occupational pesticide exposures are suspected of involvement in the occurrence of childhood acute leukaemia (AL), but the role of exposure to agricultural activities is little known. In a previous ecological study conducted in France, we observed an increase in acute lymphoblastic leukaemia (ALL) incidence rate with increasing viticulture density in the municipalities of residence at diagnosis. OBJECTIVES: This study aimed to test the hypothesis that residential proximity to croplands at birth increases the risk of childhood AL, with a particular focus on vineyards. METHODS: We identified all the primary AL cases diagnosed before the age of 15 years in the cohorts of children born in the French municipalities between 1990 and 2015. We estimated crop densities in each municipality of residence at birth using agricultural census data, for ten crop types. Variations in standardized incidence ratios (SIR) were evaluated with Poisson regression models, for all AL, ALL and acute myeloid leukaemia (AML), separately. RESULTS: Among the 19,809,700 children born and residing in mainland France at birth in 1990-2015, 8,747 AL cases (7,236 ALL and 1,335 AML) were diagnosed over the period. We did not evidence any statistically significant positive association between total crop density or any specific crop density in the municipality of residence at birth and all AL, ALL or AML. Interestingly, we observed a higher ALL incidence rate in the municipalities with the highest viticulture densities (SIR = 1.25 95%CI [1.01-1.54]). Adjusting for the main potential confounders did not change the results. CONCLUSION: Our study does not support the hypothesis that residential proximity to croplands, particularly vineyards, around birth plays a role in childhood leukaemia. The slightly higher ALL incidence rate in children born in the municipalities with the highest viticulture densities may reflect the previously-observed association at diagnosis.

Seasonal variations in childhood leukaemia incidence in France, 1990-2014.

BACKGROUND: Several studies have addressed the potential seasonality of childhood acute leukaemia (AL) without conclusive results. Using data from the National Registry of Childhood Cancers over 1990-2014 in mainland France, we investigated the seasonal variations in childhood AL taken together, and lymphoblastic (ALL) and myeloid (AML) leukaemia separately. METHODS: Assuming constant variations over 1990-2014, we used a Poisson regression model to evaluate variations in standardized incidence ratios (SIRs) by month of birth or diagnosis. A scan method for temporal cluster detection was used to identify windows of several consecutive months with high or low SIR. The yearly reproducibility of the observed monthly variations was then evaluated. RESULTS: We included 11,528 AL, of which 9493 ALL and 1,843 AML. No seasonal variation was detected for ALL. With a clear seasonal pattern, differences in AML incidence rates were evidenced between January-April and May-December birth periods (SIR = 0.85, 95% CI 0.77-0.94 and SIR = 1.07, 95% CI 1.01-1.14, respectively). AML incidence variations by month of diagnosis were less clear-cut. CONCLUSION: Based on a large number of cases from a high-quality registry, we did not evidence any seasonality in ALL incidence rates but evidenced seasonal variations in AML incidence rates by month of birth.

Agricultural crop density in the municipalities of France and incidence of childhood leukemia: An ecological study.

BACKGROUND: Pesticide exposure is suspected to play a role in the etiology of childhood leukemia (AL). Various sources of exposure have been explored, but few studies have investigated the risk of childhood AL in relation to residential exposure to agricultural pesticides. Since around 50% of France is agricultural land, with marked pesticide use, France is a suitable location to investigate for an association. We aimed to analyze the association between the agricultural crop density in the municipalities of France and the incidence of childhood AL between 1990 and 2014. METHODS: 11,487 cases of AL diagnosed in children aged 0-14 years were registered by the French National Registry of Childhood Hematological Malignancies over 1990-2014. National agricultural census data for 1990, 2000 and 2010 were used to estimate the densities of the most common crops in France. The incidence of AL was estimated in the 35,512 municipalities, by age and gender, and 3 observation periods, and expressed as the standardized incidence ratio (SIR). RESULTS: We observed a moderate log-linear association between viticulture density and the incidence of AL, with a 3% increase in SIR for a 10% increase in viticulture density (SIRR = 1.03; 95%CI [1.00-1.06]). The association remained for lymphoblastic AL but not for myeloid AL. The association was stable after stratification by geographic area, age and period, and after adjustment on UV radiation and a French deprivation index. No consistent association was observed for other crop types. DISCUSSION: This nationwide study shows a moderate increase in incidence of childhood AL in municipalities where viticulture is common. Future individual studies are needed to know whether this observation is confirmed and related to particular use of pesticides.

Residential exposure to ultraviolet light and risk of precursor B-cell acute lymphoblastic leukemia: assessing the role of individual risk factors, the ESCALE and ESTELLE studies.

BACKGROUND: In a previous nationwide ecological study based on 20 years of registration and 7,443 cases of acute lymphoblastic leukemia (ALL), we reported a positive association between residential solar ultraviolet (UV) light at diagnosis and childhood precursor B-cell acute lymphoblastic leukemia (PBC-ALL). OBJECTIVE: The present study investigated the influence of suspected individual risk factors for ALL on the association between UV and PBC-ALL, and evaluated this association at the residence at birth. METHODS: Individual data collected by interviews in the ESCALE (2003-2004) and ESTELLE (2010-2011) nationwide case-control studies, which included 1,511 cases of leukemia aged less than 15 years and 3,102 population controls, were analyzed. Municipalities of residences at birth and at diagnosis/interview were extracted and assigned UV radiation exposure from the EUROSUN database. The potential confounders or effect modifiers considered were strongly suspected risk factors for ALL that were available in the ESCALE and ESTELLE studies. RESULTS: UV exposure at diagnosis was associated with PBC-ALL (OR = 1.27 [1.08-1.48]) for UV > 105.5 J/cm2 compared to UV ≤ 105.5 J/cm2. Considering exposure to UV at birth rather than at diagnosis/inclusion yielded almost identical results as both variables were strongly correlated. Taking into account the suspected ALL risk factors did not affect this association in the pooled study. CONCLUSION: Our findings suggest that our previous observation of an ecological association between residential UV radiation exposure at diagnosis and PBC-ALL was not confounded or modified by individual risk factors, and that the critical exposure time window may be prenatal.

Risk of Childhood Cancer and Socio-economic Disparities: Results of the French Nationwide Study Geocap 2002-2010.

BACKGROUND: Socio-economic status is related to many life style and environmental factors, some of which have been suggested to influence the risk of childhood cancer. Studies requiring subject participation are usually hampered by selection of more educated parents. To prevent such bias, we used unselected nationwide Geographical Information System (GIS)-based registry data, to investigate the influence of socio-economic disparities on the risk of childhood cancer. METHODS: The Geocap study included all French residents diagnosed with cancer aged up to 15 years over the period 2002-2010 (15 111 cases) and 45 000 contemporaneous controls representative of the childhood population. Area socio-economic characteristics used to calculate the European Deprivation Index (EDI) were based on census data collected on the fine scale of the Merged Islet for Statistical Information (IRIS). RESULTS: Overall, the risk of acute lymphoblastic leukaemia (ALL) was lower in the most deprived quintile than in the other quintiles of EDI (ORQ5vs

Residential Proximity to Heavy-Traffic Roads, Benzene Exposure, and Childhood Leukemia-The GEOCAP Study, 2002-2007.

Childhood leukemia may be associated with traffic-related environmental exposure to benzene, and additional data are needed. The Géolocalisation des Cancers Pédiatriques (GEOCAP) Study, a nationwide French case-control study, was designed to avoid selection bias due to differential participation and misclassification. The study compared the 2,760 childhood leukemia cases diagnosed in France between 2002 and 2007 (including 2,275 cases of acute lymphoblastic leukemia (ALL) and 418 cases of acute myeloblastic leukemia (AML)) with 30,000 contemporaneous child population controls. The residence addresses were precisely geocoded, and 3 indicators of residential proximity to traffic were considered. Estimates of benzene concentrations were also available for the Île-de-France region (including Paris). A 300-m increase in major road length within 150 m of the geocoded address was significantly associated with AML (odds ratio = 1.2, 95% confidence interval: 1.0, 1.4) but not with ALL (odds ratio = 1.0, 95% confidence interval: 0.9, 1.1), and the association was reinforced in the Île-de-France region when this indicator was combined with benzene estimates. These results, which were free from any participation bias and based on objectively determined indices of exposure, showed an increased incidence of AML associated with heavy-traffic road density near a child's home. The results support a role for traffic-related benzene exposure in the etiology of childhood AML.

Residential exposure to solar ultraviolet radiation and incidence of childhood hematological malignancies in France.

PURPOSE: Few studies have investigated the relationship between solar ultraviolet radiation (UV) and childhood hematological malignancies (CHM). This study addresses the associations between residential UV exposure at diagnosis and the incidence of types and subtypes of CHM, by age and gender, in France, over a long period, on the fine scale of the 36,326 Communes that constitute mainland France. METHODS: The 9,082 cases of acute leukemia and 3,563 cases of lymphoma diagnosed before the age of 15 years from 1990 to 2009 were provided by the French National Registry of Childhood Hematological Malignancies. The incidence of CHM was calculated by Commune, year, age and gender and expressed as the standardized incidence ratio (SIR). UV data from 1988 to 2007 were extracted from the EUROSUN database. RESULTS: The annual daily average UV exposure of the children ranged from 85.5 to 137.8 J/cm(2). For each additional 25 J/cm(2), there was a significant increase in precursor B-cell acute lymphoblastic leukemia (PBC-ALL) in children aged less than 5 years (SIR 1.18; 95% CI 1.10-1.27). Further analysis of PBC-ALL in the young children suggested a better fit of models with a threshold, with the risk increasing above 100 J/cm(2), for which the SIR was 1.24 (95% CI 1.14-1.36) for a 25 J/cm(2) increase. The results remained stable in analyses stratifying by deprivation index or degree of urbanization of the Communes. CONCLUSION: The study suggests that higher residential UV exposure may be positively associated with a higher incidence of PBC-ALL in early childhood.

Association between Residential Proximity to Viticultural Areas and Childhood Acute Leukemia Risk in Mainland France: GEOCAP Case-Control Study, 2006-2013.

BACKGROUND: Pesticide exposures are suspected of being a risk factor for several childhood cancers, particularly acute leukemia (AL). Most of the evidence is based on self-reported parental domestic use of pesticides, but some studies have also addressed associations with agricultural use of pesticides near the place of residence. OBJECTIVES: The objective of the study was to evaluate the risk of AL in children living close to vines, a crop subject to intensive pesticide use. METHODS: Data were drawn from the national registry-based GEOCAP study. We included all of the AL cases under the age of 15 years diagnosed in 2006-2013 (n=3,711) and 40,196 contemporary controls representative of the childhood population in France. The proximity of the vines (probability of presence within 200, 500, and 1,000m) and the viticulture density (area devoted to vines within 1,000m) were evaluated around the geocoded addresses in a geographic information system combining three national land use maps. Logistic regression models were used to estimate odds ratios (ORs) for all AL and for the lymphoblastic (ALL) and myeloid (AML) subtypes. Heterogeneity between regions was studied by stratified analyses. Sensitivity analyses were carried out to take into account, in particular, geocoding uncertainty, density of other crops and potential demographic and environmental confounders. RESULTS: In all, about 10% of the controls lived within 1km of vines. While no evidence of association between proximity to vines and AL was found, viticulture density was positively associated with ALL [OR=1.05 (1.00-1.09) for a 10% increase in density], with a statistically significant heterogeneity across regions. No association with AML was observed. The results remained stable in all the sensitivity analyses. CONCLUSION: We evidenced a slight increase in the risk of ALL in children living in areas with high viticulture density. This finding supports the hypothesis that environmental exposure to pesticides may be associated with childhood ALL. https://doi.org/10.1289/EHP12634.

Seasonality of main childhood embryonal tumours and rhabdomyosarcoma, France, 2000-2015.

Few studies have investigated the seasonal patterns of embryonal tumours. Based on data from the French National Registry of Childhood Cancers, the present study aimed to investigate seasonal variations in embryonal tumour incidence rates by month of birth and by month of diagnosis. The study included 6635 primary embryonal tumour cases diagnosed before the age of 15 years over the period 2000-2015 in mainland France. Assuming monthly variations in incidence rates were homogeneous over 2000-2015, we used a Poisson regression model to test for overall heterogeneity in standardised incidence ratios (SIRs) by month of birth or diagnosis. The seasonal scan statistic method was used to detect monthly excesses or deficits of embryonal tumour cases over the whole study period. The annual reproducibility of the observed monthly variations was formally tested. An overall heterogeneity in incidence rates by month of birth was observed for rhabdomyosarcoma in boys only. Based on the month of diagnosis, a seasonality was evidenced for unilateral retinoblastoma, with a lower incidence rate in the summer (SIRJul-Aug  = 0.68, 95% CI = 0.52-0.87), whilst the incidence rate of rhabdomyosarcoma tended to be lower in August (SIRAug  = 0.68, 95% CI = 0.52-0.89). No seasonality was detected for the other embryonal tumour groups by month of birth or month of diagnosis. This study is one of the largest to have investigated the seasonality of childhood embryonal tumours. The study showed a seasonal variation in the incidence rates by month of diagnosis for unilateral retinoblastoma and rhabdomyosarcoma. Our findings are likely to reflect a delay in consultation during the summer months. However, the role of seasonally varying environmental exposures cannot be ruled out.

Impact of age on survival according to molecular tumor findings in children and adolescents with soft-tissue and bone sarcoma: The BIOSCA project.

BACKGROUND: Adolescents (15-19 years) with sarcoma are known to have significantly worse survival than children (0-14 years). One possible reason may be that the adolescent sarcomas exhibit specific biological characteristics resulting in differences in clinical presentation and treatment resistance behaviors. The BIOSCA project aims to further explore these age-related differences in survival accounting for molecular tumor characteristic in children and adolescents with sarcoma. METHODS: A retrospective national population-based observational study with documented somatic genetic analyses was conducted between 2011 and 2016 of all patients aged from 0 to 17 years with a diagnosis of sarcoma using the National Registry of Childhood Cancers Database. RESULTS: A total of 1637 children (0-9years: 40%), preadolescents (10-14years: 35%) and adolescents (15-17 years: 25%) with a diagnosis of bone (N = 845) or soft-tissue (N = 792) sarcoma were included. Adolescents had significantly worse outcome for undifferentiated small round cell sarcoma (USRCS), alveolar rhabdomyosarcoma (ARMS), and epithelioid sarcoma. Five-year overall survivals were worse among CIC-rearranged USRCS cases (47% [95%CI:21-69]) as compared to other USRCS, and PAX3::FOXO1 ARMS patients (44% [95%CI:32-55]) as compared to other ARMS. Adjusting for stage and genomic-profiling status, adolescents with USRCS were 1.6-fold more likely to die than children (P = 0.05), while the difference in survival between age of ARMS patients was weaken. Indeed, the prevalence of PAX3::FOXO1 increased significantly with age. CONCLUSION: Age was an independent prognostic factor of outcome only in patients with USRCS, while the association between age and survival of patients with ARMS could be partly explained by differences in prevalence of PAX3::FOXO1.

Passive environmental residential exposure to agricultural pesticides and hematological malignancies in the general population: a systematic review.

Incidence rates of hematological malignancies have been constantly increasing over the past 40 years. In parallel, an expanding use of agricultural pesticides has been observed. Only a limited number of studies investigated the link between hematological malignancies risk and passive environmental residential exposure to agricultural pesticides in the general population. The purpose of our review was to summarize the current state of knowledge on that question. A systematic literature search was conducted using PubMed and Scopus databases. We built a scoring scale to appraise relevance of each selected articles. We included 23 publications: 13 ecological studies, 9 case-control studies and a cohort study. Positive associations were reported between hematological malignancies and individual pesticides, pesticide groups, all pesticides without distinction, or some crop types. Relevance score was highly various across studies regardless of their design. Children studies were the majority and had overall higher relevance scores. The effect of passive environmental residential exposure to agricultural pesticides on hematological malignancies risk is suggested by the literature. The main limitation of the literature available is the high heterogeneity across studies, especially in terms of exposure assessment approach. Further studies with high methodological relevance should be conducted.

Factors associated with 5- and 10-year survival among a recent cohort of childhood cancer survivors (France, 2000-2015).

BACKGROUND: Childhood cancer survival currently exceeds 80 % five years after diagnosis in high-income countries. In this study, we aimed to describe long-term trends and to investigate socioeconomic and spatial disparities in childhood cancer survival. METHODS: The study included 28,073 cases recorded in the French National Registry of Childhood Cancers from 2000 to 2015. Contextual census data (deprivation indices, population density, spatial accessibility to general practitioners) were allocated to each case based on the residence at diagnosis. Overall survival (OS) and conditional 10-year OS for 5-year survivors were estimated for all cancers combined and by diagnostic group and subgroup. Comparisons were conducted by sex, age at diagnosis, period of diagnosis, and contextual indicators. Hazard ratios for death were estimated using Cox models. RESULTS: All cancers combined, the OS reached 82.8 % [95 % CI: 82.4-83.3] at 5 years and 80.8 % [95 % CI: 80.3-81.3] at 10 years. Conditional 10-year OS of 5-year survivors reached 97.5 % [95 % CI: 97.3-97.7] and was higher than 95 % for all subgroups except osteosarcomas and most subgroups of the central nervous system. In addition to disparities by sex, age at diagnosis, and period of diagnosis, we observed a slight decrease in survival for cases living in the most deprived areas at diagnosis, not consistent across diagnostic groups. CONCLUSION: Our results confirm the high 5-year survival for childhood cancer and show an excellent 10-year conditional survival of 5-year survivors. Additional individual data are needed to clarify the factors underlying the slight decrease in childhood cancer survival observed in the most deprived areas.

Childhood head and neck cancer in France: Incidence, survival and trends from 2000 to 2015.

INTRODUCTION: Childhood head and neck cancers (HNC) are rare and represent a complex group of anatomical topographies. The aim of this study is to describe the distribution, the incidence and survival rates of children with malignant HNC in France. METHODS: A population-based study was conducted between 2000 and 2015 in children less than 15 years with a diagnosis of HNC using the French National Registry of Childhood Cancers database (RNCE). Age-standardized incidence rates (ASR) and survival analysis were performed. RESULTS: The 1623 included HNC represented 5.6% of all cancers included in the RNCE. The thyroid was the leading tumor site category (26.6%), followed by head and neck soft tissue location (15.4%) and the nasopharynx (10.8%). The most common cancers were thyroid gland carcinomas (26.1%), rhabdomyosarcomas (23.9%) and Burkitt Lymphomas (8.6%). Nasopharynx cancers and soft-tissue sarcomas were statistically more frequent in boys, while thyroid carcinomas were significantly more frequent in girls. The annual ASR was 8.6 new cancer cases per million children. For all HNC combined, the 5-year overall survival (OS) was 87.7% [95%CI: 85.9-89.2]. There was no statistically significant variation in 5-year OS between 2000-2007 and 2008-2015. CONCLUSIONS: Epidemiological data on HNC distribution, incidence and survival contributes to better understand these tumors by quantifying their impact on the French population and assessing their burden. Regarding the exclusion of topographies and some histological origins performed by some authors, this report proposes new recommendations to study HNC in a pediatric population.

Residential exposure to natural background radiation at birth and risk of childhood acute leukemia in France, 1990-2009.

BACKGROUND: The role of natural background radiation (NBR) in childhood acute leukemia (AL) remains unclear. Several large record based studies have recently reported heterogeneous results. Differences in exposure assessment timing may explain this heterogeneity. OBJECTIVES: In a previous ecological study we did not observe any association between childhood AL incidence in France and NBR exposure at the time of diagnosis. With the same methodology, the present study focused on NBR exposure at the time of birth. Based on data from the French national registry of childhood cancer, we analyzed all AL together, and lymphoblastic and myeloid AL, separately. METHODS: We included 6,059 childhood AL cases born and diagnosed in mainland France between 1990 and 2009. NBR levels in municipalities of residence at birth were estimated by cokriging models, using NBR measurements and precise geological data. The incidence rate ratio (IRR) per unit variation of exposure was estimated with Poisson regression models, with adjustment for socio-demographic indicators and ultraviolet radiation levels. NBR exposures were considered at the time of birth, and cumulatively from birth to diagnosis. We also estimated a total NBR dose to red-bone marrow (RBM). RESULTS: There was no evidence for an association between NBR exposure at birth and childhood AL incidence, neither overall (gamma radiation: IRR = 0.99 (0.94,1.05) per 50 nSv/h; radon: IRR = 0.97 (0.91,1.03) per 100 Bq/m3) nor for the main AL types. The conclusions were similar with the cumulative exposures, and the total RBM dose. CONCLUSIONS: The study was based on high quality incidence data, large numbers of AL cases, and validated models of NBR exposure assessment. In all, the results further support the hypothesis that NBR are not associated to childhood AL in France.

Ecological association between residential natural background radiation exposure and the incidence rate of childhood central nervous system tumors in France, 2000-2012.

BACKGROUND: High-dose ionizing radiation is an established risk factor for childhood central nervous system tumors (CNST) but the role of low doses remains debated. In particular, there are few studies of natural background radiation (NBR, gamma radiation and radon) and childhood CNST, and their results are inconclusive. OBJECTIVES: This study aimed to investigate the ecological association between NBR exposure and childhood CNST incidence in France, considering childhood CNST overall and by subgroups. METHODS: Incidence data were provided by the French national registry of childhood cancers, which has high completeness. We included 5471 childhood CNST cases registered over the period 2000-2012, and their municipality of residence at diagnosis was recorded. Municipality NBR exposures were estimated by cokriging models, using NBR measurements and additional geographic data. The incidence rate ratio (IRR) per unit variation of exposure was estimated with Poisson regression models. NBR exposures were considered at the time of diagnosis, and cumulatively from birth to diagnosis. In an exploratory analysis, the total brain dose due to NBR was used. RESULTS: Overall, there was no association between NBR exposure and childhood CNST incidence (IRR = 1.03 (0.98,1.09) per 50 nSv/h for gamma radiation, and IRR = 1.02 (0,96,1.07) per 100 Bq/m3 for radon). An association was suggested between pilocytic astrocytomas and gamma radiation (IRR = 1.12 (1.00,1.24) per 50 nSv/h) but not with radon (IRR = 1.07 (0.95,1.20) per 100 Bq/m3). Upward trends for this CNST subtype were also suggested with the cumulative exposures to gamma radiation and the total brain dose. NBR exposure was not associated with other CNST subgroups (ependymomas, embryonal tumors, and gliomas other than pilocytic astrocytomas). Adjustment for socio-demographic factors did not change the findings. CONCLUSIONS: Our study was based on high quality incidence data, large numbers of CNST cases, and validated models of NBR exposure assessment. Results suggest an association between gamma radiation, as a component of NBR, and pilocytic astrocytomas incidence in France.

Infant cancers in France: Incidence and survival (2000-2014).

BACKGROUND: On average 185 children are diagnosed each year in France with a cancer in their first year of life, representing 11 % of cancers diagnosed in children less than 15 years. METHODS: A retrospective population-based observational study was conducted between 2000 and 2014 of all infants with a diagnosis of cancer using the National Registry of Childhood Cancers Database. RESULTS: Out of 2760 cases of primary cancers in infancy, there were mainly neuroblastomas 30.1 %), central nervous system (CNS) tumors (16.1 %), leukemias (15.3 %), retinoblastomas (11.6 %), and Wilms tumors (6.9 %). Embryonal malignancies accounted for 55.2 % of cases. Most diagnoses showed a male excess, particularly for malignant gonadal germ-cell tumors (GCT) with a 17.5 sex-ratio. The annual incidence rate, 242.9 per million infants overall, was stable over the study period for all types of cancer. Most deaths occurred within the first month of life (70.8 % of deaths). The 5-year overall survival (5-y OS) was 81.0 % (95 %CI, 79.4-82.4) with large contrasts between diagnoses. The best 5-y OS (>85 %) were observed for retinoblastomas, carcinomas, nephroblastomas, GCT, neuroblastomas, and hepatoblastomas. Conversely, the lowest 5-y OS (<65 %) were observed for acute myeloid leukemias, CNS tumors, and lymphoid leukemias. We observed no substantial change over time (80.5 % [95 %CI, 77.7-82.9] in 2000-2004 and 82.6 % [95 %CI, 80.0-84.9] in 2010-2014) for all cancers combined. The same result has been found whatever the diagnostic group. CONCLUSION: Our results contribute to better understand these tumors by quantifying their impact on the French population and assessing the burden of some devastating infant cancers.

Risk of cancer in children exposed to antiretroviral nucleoside analogues in utero: The french experience.

All nucleoside analogues for treating HIV infection, due to their capacity to integrate into and alter human DNA, are experimentally genotoxic to some extent. The long-term oncogenic risk after in utero exposure remains to be determined. Cancer incidence in uninfected children exposed to nucleos(t)ide reverse transcriptase inhibitors (NRTIs) was evaluated, by cross-checking against the National Cancer Registry, in the French perinatal study of children born to HIV+ mothers. Twenty-one cancers were identified in 15,163 children (median age: 9.9 years [interquartile range (IQR): 5.8-14.2]) exposed to at least one NRTI in utero between 1990 and 2014. Five of these children were exposed to zidovudine monotherapy, and 15 to various combinations, seven of which included didanosine. Overall, the total number of cases was not significantly different from that expected for the general population (SIR = 0.8[0.47-1.24]), but the number of cases after didanosine exposure was twice that expected (SIR = 2.5 [1.01-5.19]). Didanosine accounted for only 10% of prescriptions but was associated with one-third of cancers. In multivariate analysis, didanosine exposure was significantly associated with higher risk (HR = 3.0 [0.9-9.8]). This risk was specifically linked to first-trimester exposure (HR = 5.5 [2.1-14.4]). Three cases of pineoblastoma, a very rare cancer, were observed, whereas 0.03 were expected. Two were associated with didanosine exposure. Despite reassuring data overall, there is strong evidence to suggest that didanosine displays transplacental oncogenicity. These findings cannot be extrapolated to other NRTIs, but they highlight the need for comprehensive evaluations of the transplacental genotoxicity of this antiretroviral class. Environ. Mol. Mutagen., 60:404-409, 2019. © 2017 Wiley Periodicals, Inc.

Spatial and temporal variations of childhood cancers: Literature review and contribution of the French national registry.

BACKGROUND: Significant increases in childhood cancer incidence since the 1970s have been consistently reported worldwide, but the persistence of the increase on recent periods is discussed. No conclusion can be drawn concerning the spatial variations of childhood cancer, either. This study is an in-depth investigation of the spatial and temporal variations of childhood cancer in France. An extensive review of all the studies published since 2000 on those issues is provided. METHODS: The study included 25 877 cases of childhood cancer registered nationwide over 2000-2014. The spatial heterogeneity (overdispersion, autocorrelation, overall heterogeneity) was tested, on two geographic scales, and two spatial scan methods were used to detect clusters of cases. The annual average percent change (AAPC) in incidence rate was estimated with Poisson regression models, and joinpoint analyses were considered. RESULTS: Glioma and non-Hodgkin lymphoma cases exhibited some spatial heterogeneity and two large clusters were detected. Overall, the incidence rate of childhood cancer was stable over 2000-2014 (AAPC = -0.1% [-0.3%; 0.2%]). A log-linear positive trend was significantly evidenced for gliomas other than pilocytic astrocytomas (AAPC = 1.8% [0.9%; 2.7%]), with some suggestion of a leveling-off at the end of the period, while Burkitt lymphoma and germ cell tumor incidence rates decreased (AAPC = -2.2% [-3.8%; -0.5%] and AAPC = -1.9% [-3.4%; -0.3%], respectively). No spatial heterogeneity or significant time variation was evidenced for other cancers. CONCLUSION: Several types of childhood cancer displayed some spatial heterogeneity and two large clusters were detected, the origins of which are to be investigated and might include differences in case ascertainment. Overall, the results do not support a sustained increase in incidence rates of childhood cancer in recent years.