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Survival and cure rates for childhood cancers in Europe have greatly improved over the past 40 years and are mostly good, although not in all European countries. The EUROCARE-5 survival study estimates survival of children diagnosed with cancer between 2000 and 2007, assesses whether survival differences among European countries have changed, and investigates changes from 1999 to 2007. We analysed survival data for 157 499 children (age 0–14 years) diagnosed between Jan 1, 1978 and Dec 31, 2007. They came from 74 population-based cancer registries in 29 countries. We calculated observed, country-weighted 1-year, 3-year, and 5-year survival for major cancers and all cancers combined. For comparison between countries, we used the corrected group prognosis method to provide survival probabilities adjusted for multiple confounders (sex, age, period of diagnosis, and, for all cancers combined without CNS cancers, casemix). Age-adjusted survival differences by area and calendar period were calculated with period analysis and were given for all cancers combined and the major cancers. We analysed 59 579 cases. For all cancers combined for children diagnosed in 2000–07, 1-year survival was 90·6% (95% CI 90·2–90·9), 3-year survival was 81·0 % (95% CI 80·5–81·4), and 5-year survival was 77·9% (95% CI 77·4–78·3). For all cancers combined, 5-year survival rose from 76·1% (74·4–77·7) for 1999–2001, to 79·1% (77·3–80·7) for 2005–07 (hazard ratio 0·973, 95% CI 0·965–0·982, p<0·0001). The greatest improvements were in eastern Europe, where 5-year survival rose from 65·2% (95% CI 63·1–67·3) in 1999–2001, to 70·2% (67·9–72·3) in 2005–07. Europe-wide average yearly change in mortality (hazard ratio) was 0·939 (95% CI 0·919–0·960) for acute lymphoid leukaemia, 0·959 (0·933–0·986) for acute myeloid leukaemia, and 0·940 (0·897–0·984) for non-Hodgkin lymphoma. Mortality for all of Europe did not change significantly for Hodgkin's lymphoma, Burkitt's lymphoma, CNS tumours, neuroblastoma, Wilms' tumour, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. Disparities for 5-year survival persisted between countries and regions, ranging from 70% to 82% (for 2005–07). Several reasons might explain persisting inequalities. The lack of health-care resources is probably most important, especially in some eastern European countries with limited drug supply, lack of specialised centres with multidisciplinary teams, delayed diagnosis and treatment, poor management of treatment, and drug toxicity. In the short term, cross-border care and collaborative programmes could help to narrow the survival gaps in Europe. Italian Ministry of Health, European Commission, Compagnia di San Paolo Foundation.

Background Air pollution, in particular due to traffic, is suspected of increasing the risk of childhood acute leukemia (AL), most of the evidence coming from epidemiological studies and literature reviews that focused on the time around diagnosis. Using data on the national scale, we tested the hypothesis that prenatal exposure to traffic-related air pollution increases the risk of childhood AL. Methods This case–control study included 581 cases of acute lymphoblastic leukemia (ALL) and 136 cases of acute myeloid leukemia (AML), registered in the French national registry of childhood cancer and born and diagnosed between 2010 and 2015, and 11,908 controls. Exposure indicators were evaluated at the addresses at birth and included major road length in 500 m buffers, and modeled exposures of nitrogen dioxide (NO 2 ), fine particulate matter (PM 2.5 ) and black carbon (BC). Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models. Exposures were considered in categories using tertiles’ cut offs or continuously for increments of ½ interquartile range. Results Both ALL and AML risks increased with PM 2.5 exposure (OR ALL = 1.14, 95%CI = 1.08–1.20 and OR AML = 1.12, 95%CI = 1.00–1.25 for an increment of 2 µg/m 3 , respectively). The risk of ALL was associated with BC exposure in urban units of < 5,000 inhabitants and of 5,000–99,999 inhabitants (OR = 1.90, 95%CI = 1.22–2.97 and OR = 1.58, 95%CI = 1.16–2.17 for an increment of 0.5 10 –5 /m, respectively), and not in more urban municipalities. An elevated OR for AML was observed for NO 2 exposure (OR = 1.4, 95%CI = 0.9–2.1 for the highest versus lowest category). There was no association with the length of major roads. Conclusion The results support a role of exposure to air pollution at time of birth in the risk of childhood AL.

Background Epidemiological studies have shown a small but significantly increased risk of leukemia in children conceived by in vitro fertilization. Atypical DNA methylation patterns observed in pediatric cancers are suspected to occur in utero, and it is known that periconceptional conditions linked to assisted reproductive technologies (ART) are responsible for DNA methylation modifications. Results Using databases and systematic literature screens, we derived a list of cancer/leukemia genes ( n  = 1246 and n  = 532 genes, respectively, corresponding to 1466 individual genes) and of differentially methylated genes (DMG) in leukemia ( n  = 2642) and pre-leukemia ( n  = 381). These lists were cross-referenced with DMG ( n  = 93) curated from 18 ART Epigenome-Wide Association Studies (EWAS) (2369 samples). Among the ART DMG, more than one-third ( n  = 33) were leukemia, and six were pre-leukemia DMG, all representing a significant enrichment. Seven of the enriched genes ( NTM , PRSS16 , SCAND3 , SYCP1 , TP73 , ZNF184 , and ISL1-DT ) showed concordant methylation between ART and leukemia/pre-leukemia. Moreover, five of the ART DMG are known targets for somatic/germline alterations in leukemia: ATP10A , CHD2 , FBRSL1 , FGFR2 , and SORCS1 . The ART DMG were not significantly enriched in cancer genes, supporting the hypothesis that ART may not link broadly to any cancer type but rather to leukemia. Conclusion This study indicates that relatively few genes that are known targets for somatic/germline mutation in cancer experience DNA methylation changes in individuals conceived through ART. By contrast, DNA methylation disturbances reported in leukemia represent more than one-third of those associated with ART conception, thus raising the question of their role in leukemia risk in ART-conceived individuals. Among them, a few critical genes such as TP73 , a tumor suppressor, were shown to be targeted for hypermethylation, both in ART and leukemia, warranting further investigation.

Paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common cancer of childhood, yet little is known about BCP-ALL predisposition. In this study, in 2,187 cases of European ancestry and 5,543 controls, we discover and replicate a locus indexed by rs77728904 at 9p21.3 associated with BCP-ALL susceptibility ( P combined =3.32 × 10 −15 , OR=1.72) and independent from rs3731217, the previously reported ALL-associated variant in this region. Of correlated SNPs tagged by this locus, only rs662463 is significant in African Americans, suggesting it is a plausible causative variant. Functional analysis shows that rs662463 is a cis -eQTL for CDKN2B , with the risk allele associated with lower expression, and suggests that rs662463 influences BCP-ALL risk by regulating CDKN2B expression through CEBPB signalling. Functional analysis of rs3731217 suggests it is associated with BCP-ALL by acting within a splicing regulatory element determining CDKN2A exon 3 usage ( P =0.01). These findings provide new insights into the critical role of the CDKN2 locus in BCP-ALL aetiology. A risk variant located at 9p21.3 is associated with cancer risk in pediatric B-cell precursor acute lymphoblastic leukaemia. Here, the authors show that this variant affects the gene expression of the tumour suppressor gene Cdkn2b .

ObjectivesTo investigate the association between occupational exposure to aromatic hydrocarbon solvents and risk of multiple myeloma (MM) in a large, consortium-based study.MethodsWe pooled data on 2854 cases and 10 743 controls from nine studies participating in the InterLymph consortium. Occupational exposures to benzene, toluene and xylene were assigned by a job–exposure matrix, coupled with ‘correction’ of exposure probability by self-reported or expert-assessed exposure from the individual studies. Cumulative intensity was calculated as the job-specific exposure intensity multiplied by job duration, summed across jobs. Associations were estimated using logistic regression, with inclusion of covariates for study matching factors and other potential confounders. We repeated our main analysis using random-effects meta-analysis to evaluate heterogeneity of effect.ResultsBenzene, toluene and xylene were each associated with MM. For the three solvents, the highest quartile of high-probability cumulative intensity exposure (vs unexposed) was associated with 42% to 63% increased risks of MM. Associations with toluene and xylene exposures were fairly consistent and robust to sensitivity analyses. The estimated effect for benzene was moderately heterogeneous between the studies. Each solvent’s association with MM was stronger for exposure occurring within 20 years of diagnosis than with exposure lagged by more than 20 years.ConclusionsOur study adds important evidence for a role of aromatic hydrocarbon solvents in causation of MM. The difficulty in disentangling individual compounds in this group and a lack of data on potential carcinogenicity of toluene and xylene, in widespread current use, underscore a need for further epidemiological evaluation.

Genome wide association studies (GWAS) have established association of ARID5B and IKZF1 variants with childhood acute lymphoblastic leukemia (ALL). Epidemiological studies suggest that environmental factors alone appear to make a relatively minor contribution to disease risk. The polygenic nature of childhood ALL predisposition together with the timing of environmental triggers may hold vital clues for disease etiology. This study presents results from an Australian GWAS of childhood ALL cases (n = 358) and population controls (n = 1192). Furthermore, we utilised family trio (n = 204) genotypes to extend our investigation to gene-environment interaction of significant loci with parental exposures before conception, and child's sex and age. Thirteen SNPs achieved genome wide significance in the population based case/control analysis; ten annotated to ARID5B and three to IKZF1. The most significant SNPs in these regions were ARID5B rs4245595 (OR 1.63, CI 1.38-1.93, P = 2.13×10(-9)), and IKZF1 rs1110701 (OR 1.69, CI 1.42-2.02, p = 7.26×10(-9)). There was evidence of gene-environment interaction for risk genotype at IKZF1, whereby an apparently stronger genetic effect was observed if the mother took folic acid or if the father did not smoke prior to pregnancy (respective interaction P-values: 0.04, 0.05). There were no interactions of risk genotypes with age or sex (P-values >0.2). Our results evidence that interaction of genetic variants and environmental exposures may further alter risk of childhood ALL however, investigation in a larger population is required. If interaction of folic acid supplementation and IKZF1 variants holds, it may be useful to quantify folate levels prior to initiating use of folic acid supplements.

The aim of the study was to identify the major heat waves (HW) that occurred in France from 1971 to 2003 and describe their impact on all-cause and cause-specific mortality. Heat waves were defined as periods of at least three consecutive days when the maximum and the minimum temperature, averaged over the whole France, were simultaneously greater than their respective 95th percentile. The underlying causes of death were regrouped into 18 categories. Heatstroke, hyperthermia and dehydration were assigned to the \"heat-related causes\" (HRC) category. The numbers of deaths observed (O) during the identified HW were compared to those expected (E) on the basis of the mortality rates reported for the three preceding years. Six HW were identified from the period 1971 to 2003. They were associated with great excess mortality (from 1,300 to 13,700 deaths). The observations are compatible with a moderate harvesting effect for four of the six HW. The mortality ratios increased with age for subjects aged over 55 years and were higher for women than for men over 75 years. For the six HW, the excess mortality was significant for almost all the causes of death: (1) the greatest excess mortality (O-E) were observed for cardiovascular diseases, neoplasms, respiratory system diseases, HRC, ill-defined conditions and injury and poisoning, and (2) the mortality ratios (O/E) were highest for HRC, respiratory diseases, nervous system diseases, mental disorders, infectious diseases, and endocrine and nutritional diseases. Heat waves associated with excess mortality are not rare events in this temperate-climate country. The excess mortality is much greater than HRC mortality. Some populations are particularly vulnerable to HW: the elderly, women and people with some specific diseases. However, no segment of the population may be considered protected from the risks associated with HW.

Background For many years, the detection of clusters has been of great public health interest. Several detection methods have been developed, the most famous of which is the circular scan method. The present study, which was conducted in the context of a rare disease distributed over a large territory (7675 cases registered over 17 years and located in 1895 units), aimed to evaluate the performance of several of the methods in realistic hot-spot cluster situations. Methods All the methods considered aim to identify the most likely cluster area, i.e. the zone that maximizes the likelihood ratio function, among a set of cluster candidates. The circular and elliptic scan methods were developed to detect regularly shaped clusters. Four other methods that focus on irregularly shaped clusters were also considered (the flexible scan method, the genetic algorithm method, and the double connected and maximum linkage spatial scan methods). The power of the methods was evaluated via Monte Carlo simulations under 27 alternative scenarios that corresponded to three cluster population sizes (20, 45 and 115 expected cases), three cluster shapes (linear, U-shaped and compact) and three relative risk values (1.5, 2.0 and 3.0). Results Three situations emerged from this power study. All the methods failed to detect the smallest clusters with a relative risk lower than 3.0. The power to detect the largest cluster with relative risk of 1.5 was markedly better for all methods, but, at most, half of the true cluster was captured. For other clusters, either large or with the highest relative risk, the standard elliptic scan method appeared to be the best method to detect linear clusters, while the flexible scan method localized the U-shaped clusters more precisely than other methods. Large compact clusters were detected well by all methods, with better results for the circular and elliptic scan methods. Conclusions The elliptic scan method and flexible scan method seemed the most able to detect clusters of a rare disease in a large territory. However, the probability of detecting small clusters with relative risk lower than 3.0 remained low with all the methods tested.

Epstein-Barr virus (EBV) is the major environmental factor associated with Hodgkin's lymphoma (HL), a common lymphoma in young adults. Natural killer (NK) cells are key actors of the innate immune response against viruses. The regulation of NK cell function involves activating and inhibitory Killer cell Immunoglobulin-like receptors (KIRs), which are expressed in variable numbers on NK cells. Various viral and virus-related malignant disorders have been associated with the presence/absence of certain KIR genes in case/control studies. We investigated the role of the KIR cluster in HL in a family-based association study. We included 90 families with 90 HL index cases (age 16-35 years) and 255 first-degree relatives (parents and siblings). We developed a procedure for reconstructing full genotypic information (number of gene copies) at each KIR locus from the standard KIR gene content. Out of the 90 collected families, 84 were informative and suitable for further analysis. An association study was then carried out with specific family-based analysis methods on these 84 families. Five KIR genes in strong linkage disequilibrium were found significantly associated with HL. Refined haplotype analysis showed that the association was supported by a dominant protective effect of KIR3DS1 and/or KIR2DS1, both of which are activating receptors. The odds ratios for developing HL in subjects with at least one copy of KIR3DS1 or KIR2DS1 with respect to subjects with neither of these genes were 0.44[95% confidence interval 0.23-0.85] and 0.42[0.21-0.85], respectively. No significant association was found in a tentative replication case/control study of 68 HL cases (age 18-71 years). In the familial study, the protective effect of KIR3DS1/KIR2DS1 tended to be stronger in HL patients with detectable EBV in blood or tumour cells. This work defines a template for family-based association studies based on full genotypic information for the KIR cluster, and provides the first evidence that activating KIRs can have a protective role in HL.