Nonchromosomal birth defects and risk of childhood acute leukemia: An assessment in 15 000 leukemia cases and 46 000 controls from the Childhood Cancer and Leukemia International Consortium.

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.

Cause specific mortality in an Italian pool of asbestos workers cohorts.

BACKGROUND: Asbestos is a known human carcinogen and is causally associated with malignant mesothelioma, lung, larynx and ovarian cancers. METHODS: Cancer risk was studied among a pool of formerly asbestos-exposed workers in Italy. Fifty-two Italian asbestos cohorts (asbestos-cement, rolling-stock, shipbuilding, and other) were pooled and their mortality follow-up was updated to 2018. Standardized mortality ratios (SMRs) were computed for major causes of death considering duration of exposure and time since first exposure (TSFE), using reference rates by region, age and calendar period. RESULTS: The study included 63,502 subjects (57,156 men and 6346 women): 40% who were alive, 58% who died (cause known for 92%), and 2% lost to follow-up. Mortality was increased for all causes (SMR: men = 1.04, 95% confidence interval [CI] 1.03-1.05; women = 1.15, 95% CI 1.11-1.18), all malignancies (SMR: men = 1.21, 95% CI 1.18-1.23; women = 1.29, 95% CI 1.22-1.37), pleural and peritoneal malignancies (men: SMR = 10.46, 95% CI 9.86-11.09 and 4.29, 95% CI 3.66-5.00; women: SMR = 27.13, 95% CI 23.29-31.42 and 7.51, 95% CI 5.52-9.98), lung (SMR: men = 1.28, 95% CI 1.24-1.32; women = 1.26, 95% CI 1.02-1.53), and ovarian cancer (SMR = 1.42, 95% CI 1.08-1.84). Pleural cancer mortality increased during the first 40 years of TSFE (latency), reaching a plateau thereafter. CONCLUSIONS: Analyses by time-dependent variables showed that the risk for pleural neoplasms increased with latency and no longer increases at long TSFE, consistent with with asbestos clearance from the lungs. Peritoneal neoplasm risk increased over all observation time.

Cholangiocarcinoma and Occupational Exposure to Asbestos: Insights From the Italian Pooled Cohort Study.

BACKGROUND: Recent studies supported the association between occupational exposure to asbestos and risk of cholangiocarcinoma (CC). Aim of the present study is to investigate this association using an update of mortality data from the Italian pooled asbestos cohort study and to test record linkage to Cancer Registries to distinguish between hepatocellular carcinoma (HCC) and intrahepatic/extrahepatic forms of CC. METHODS: The update of a large cohort study pooling 52 Italian industrial cohorts of workers formerly exposed to asbestos was carried out. Causes of death were coded according to ICD. Linkage was carried out for those subjects who died for liver or bile duct cancer with data on histological subtype provided by Cancer Registries. RESULTS: 47 cohorts took part in the study (57,227 subjects). We identified 639 causes of death for liver and bile duct cancer in the 44 cohorts covered by Cancer Registry. Of these 639, 240 cases were linked to Cancer Registry, namely 14 CC, 83 HCC, 117 cases with unspecified histology, 25 other carcinomas, and one case of cirrhosis (likely precancerous condition). Of the 14 CC, 12 occurred in 2010-2019, two in 2000-2009, and none before 2000. CONCLUSION: Further studies are needed to explore the association between occupational exposure to asbestos and CC. Record linkage was hampered due to incomplete coverage of the study areas and periods by Cancer Registries. The identification of CC among unspecific histology cases is fundamental to establish more effective and targeted liver cancer screening strategies.

Rate advancement measurement for lung cancer and pleural mesothelioma in asbestos-exposed workers.

INTRODUCTION: Exposure to asbestos increases the risk of lung cancer and mesothelioma. Few studies quantified the premature occurrence of these diseases in asbestos-exposed workers. Focus on premature disease onset (rate advancement or acceleration) can be useful in risk communication and for the evaluation of exposure impact. We estimated rate advancement for total mortality, lung cancer and pleural mesothelioma deaths, by classes of cumulative asbestos exposure in a pooled cohort of asbestos cement (AC) workers in Italy. METHOD: The cohort study included 12 578 workers from 21 cohorts, with 6626 deaths in total, 858 deaths from lung cancer and 394 from pleural malignant neoplasm (MN). Rate advancement was estimated by fitting a competitive mortality Weibull model to the hazard of death over time since first exposure (TSFE). RESULT: Acceleration time (AT) was estimated at different TSFE values. The highest level of cumulative exposure compared with the lowest, for pleural MN AT was 16.9 (95% CI 14.9 to 19.2) and 33.8 (95% CI 29.8 to 38.4) years at TSFE of 20 and 40 years, respectively. For lung cancer, it was 13.3 (95% CI 12.0 to 14.7) and 26.6 (95% CI 23.9 to 29.4) years, respectively. As for total mortality, AT was 3.35 (95% CI 2.98 to 3.71) years at 20 years TSFE, and 6.70 (95% CI 5.95 to 7.41) at 40 years TSFE. CONCLUSION: The current study observed marked rate advancement after asbestos exposure for lung cancer and pleural mesothelioma, as well as for total mortality.

Infant feeding practices and childhood acute leukemia: Findings from the Childhood Cancer & Leukemia International Consortium.

Increasing evidence suggests that breastfeeding may protect from childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). However, most studies have limited their analyses to any breastfeeding, and only a few data have examined exclusive breastfeeding, or other exposures such as formula milk. We performed pooled analyses and individual participant data metaanalyses of data from 16 studies (N = 17 189 controls; N = 10 782 ALL and N = 1690 AML cases) from the Childhood Leukemia International Consortium (CLIC) to characterize the associations of breastfeeding duration with ALL and AML, as well as exclusive breastfeeding duration and age at introduction to formula with ALL. In unconditional multivariable logistic regression analyses of pooled data, we observed decreased odds of ALL among children breastfed 4 to 6 months (0.88, 95% CI 0.81-0.96) or 7 to 12 months (OR 0.85, 0.79-0.92). We observed a similar inverse association between breastfeeding ≥4 months and AML (0.82, 95% CI 0.71-0.95). Odds of ALL were reduced among children exclusively breastfed 4 to 6 months (OR 0.73, 95% CI 0.63-0.85) or 7 to 12 months (OR 0.70, 95% CI 0.53-0.92). Random effects metaanalyses produced similar estimates, and findings were unchanged in sensitivity analyses adjusted for race/ethnicity or mode of delivery, restricted to children diagnosed ≥1 year of age or diagnosed with B-ALL. Our pooled analyses indicate that longer breastfeeding is associated with decreased odds of ALL and AML. Few risk factors for ALL and AML have been described, therefore our findings highlight the need to promote breastfeeding for leukemia prevention.

Night shift work and lymphoma: results from an Italian multicentre case-control study.

BACKGROUND: Night shift work can disrupt circadian rhythm and cause chronic sleep deprivation, which might increase the risk of lymphoma through immunosuppression and oxidative stress. MATERIAL AND METHODS: We investigated the association between night shift work and risk of lymphoma subtypes in 867 incident cases and 774 controls, who participated in a multicentre Italian study between 2011 and 2017. Based on questionnaire information, occupational experts assessed the lifetime probability of night shift work, the total number of night shifts and years of night shift work among study participants. OR and 95% CI for lymphoma and its major subtypes associated with night shift work was calculated with logistic regression, adjusting by age, gender, education, study area, marital status and family history of haemolymphatic cancer. RESULTS: Ever working night shifts was associated with an increase in the risk of chronic lymphocytic leukaemia (CLL) (OR 1.9, 95% CI 1.14 to 3.32), which was highest after a 15-34 years latency. However, there was not a linear increase in risk by probability of exposure, years of night shift work, nor lifetime number of night shifts whether under rotating or permanent work schedules. Risk of lymphoma overall, B cell lymphoma (BCL), its major subtypes other than CLL, and other less prevalent BCL subtypes combined did not show an association. CONCLUSIONS: We found conflicting evidence of an association between night shift work and the risk of CLL. We did not observe an association with other lymphoma subtypes.

Pooled analysis of recent studies of magnetic fields and childhood leukemia.

BACKGROUND: Over forty epidemiologic studies have addressed an association between measured or calculated extremely-low-frequency magnetic fields (MF) and childhood leukemia. These studies have been aggregated in a series of pooled analyses, but it has been 10 years since the last such. METHODS: We present a pooled analysis combining individual-level data (24,994 cases, 30,769 controls) from four recent studies on MF and childhood leukemia. RESULTS: Unlike previous pooled analyses, we found no increased risk of leukemia among children exposed to greater MF: odds ratio (OR) = 1.01, for exposure ≥0.4 µT (µT) compared with exposures <0.1 µT. Similarly, no association was observed in the subset of acute lymphoblastic leukemia, birth homes, studies using calculated fields, or when geocoding accuracy was ignored. In these studies, there is a decline in risk over time, also evident when we compare three pooled analyses. A meta-analysis of the three pooled analyses overall presents an OR of 1.45 (95% CI: 0.95-2.20) for exposures ≥0.4 µT. CONCLUSIONS: Our results are not in line with previous pooled analysis and show a decrease in effect to no association between MF and childhood leukemia. This could be due to methodological issues, random chance, or a true finding of disappearing effect.

Pleural mesothelioma risk by industry and occupation: results from the Multicentre Italian Study on the Etiology of Mesothelioma (MISEM).

BACKGROUND: The Italian mesothelioma registry (ReNaM) estimates mesothelioma incidence and addresses its etiology by assessing cases' exposures but cannot provide relative risk estimates. OBJECTIVES: i) To estimate pleural mesothelioma relative risk by industry and occupation and by ReNaM categories of asbestos exposure; and ii) to provide quantitative estimates of the exposure-response relationship. METHODS: A population-based mesothelioma case-control study was conducted in 2012-2014 in five Italian regions. Cases and age and gender frequency-matched controls were interviewed using a standard ReNaM questionnaire. Experts coded work histories according to international standard classifications of industries/occupations and assigned asbestos exposure according to ReNaM categories. Job codes were further linked to SYN-JEM, a quantitative job-exposure matrix. Cumulative exposure (CE, f/mL-years) was computed by summing individual exposures over lifetime work history. Unconditional logistic regression analyses adjusted by gender, centre and age were fitted to calculate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Among men we observed increased risks of mesothelioma in many industries and associated occupations, including: asbestos-cement (OR = 3.43), manufacture of railroad equipment (OR = 8.07), shipbuilding and repairing (OR = 2.34), iron and steel mills (OR = 2.15), and construction (OR = 1.94). ORs by ReNaM exposure categories were as follows: definite/probable occupational exposure (OR = 15.8, men; OR = 8.80, women), possible occupational (OR = 2.82, men; OR = 3.70, women), sharing home with an exposed worker (OR = 2.55, men; OR = 10.3, women), residential (OR = 2.14, men; OR = 3.24, women). Based on SYN-JEM, mesothelioma risk increased by almost 30% per f/mL-year (OR = 1.28, CI 1.16-1.42). CONCLUSIONS: Out study involved five regions with historically different types and levels of industrial development, encompassing one third of the Italian population and half of Italian mesothelioma cases. As expected, we found increased pleural mesothelioma risk in the asbestos industry and in trades with large consumption of asbestos materials. Clear associations were found using both qualitative (ReNaM classifications) and quantitative estimates (using SYN-JEM) of past asbestos exposure, with clear evidence of an exposure-response relationship.

Occupational exposure to glyphosate and risk of lymphoma:results of an Italian multicenter case-control study.

BACKGROUND: The International Agency for Research on Cancer (IARC) recently classified glyphosate, the most used herbicide worldwide, as a probable human carcinogen. We inquired into the association between occupational exposure to glyphosate and risk of lymphoma subtypes in a multicenter case-control study conducted in Italy. METHODS: The Italian Gene-Environment Interactions in Lymphoma Etiology (ItGxE) study took place in 2011-17 in six Italian centres. Overall, 867 incident lymphoma cases and 774 controls participated in the study. Based on detailed questionnaire information, occupational experts classified duration, confidence, frequency, and intensity of exposure to glyphosate for each study subject. Using unconditional regression analysis, we modelled risk of major lymphoma subtypes associated with exposure to glyphosate adjusted by age, gender, education, and study centre. RESULTS: Very few study subjects (2.2%) were classified as ever exposed to glyphosate. Risk of follicular lymphoma (FL) was elevated 7-fold in subjects classified as ever exposed to glyphosate with medium-high confidence, 4.5-fold in association with medium-high cumulative exposure level, 12-fold with medium-high exposure intensity, and 6-fold with exposure for 10 days or more per year. Significant upward trends were detected with all the exposure metrics, but duration. The overall p-value for an upward trend with four independent metrics was 1.88 × 10- 4. There was no association with risk of lymphoma (any subtype), Non Hodgkin Lymphoma, B-cell lymphoma, or the major lymphoma subtypes other than FL. CONCLUSIONS: Our findings provide limited support to the IARC decision to classify glyphosate as Group 2A human carcinogen.

Malignant mesothelioma: Ongoing controversies about its etiology in females.

Malignant mesothelioma (MM) is one of the most aggressive cancers with the poorest of outcomes. There is no doubt that mesothelioma in males is related to asbestos exposure, but some authors suggest that most of the cases diagnosed in females are "idiopathic." In our assessment of the science, the "low risk" of mesothelioma in females is because of the nonsystematic recording of exposure histories among females. Indeed, asbestos exposure is mentioned in only some of the studies that include females. We estimate the risk of MM among females to be close to that in males. The absence of detailed exposure histories should be rectified in future studies involving ​women. As a matter of social justice, the ongoing failure to recognize asbestos as the cause of a majority of cases of MM in females does them, and their kin, a profound disservice.

L'impatto dell'esposizione occupazionale ad amianto sul tumore del polmone in Italia.

OBJECTIVES: to perform a meta-analysis of cohort studies on lung cancer mortality in occupational sectors exposed to asbestos, particularly in the construction sector, and to use data from Italian cohorts exposed to asbestos to estimate the number of lung cancer cases attributable to asbestos in Italy. METHODS: systematic literature review and estimation of lung cancer deaths and cases attributable to asbestos in Italian cohorts and from the Italian National Register of Malignant Mesothelioma (ReNaM). SETTING AND PARTICIPANTS: the literature search was conducted in Medline and Embase (Ovid), including papers published from 1999 to May 2019. The following sectors were considered most exposed to asbestos: asbestos-cement, rolling-stock, shipyards, dockyards, glass workers, insulators, asphalt roll production workers, industrial ovens, miners. Moreover, the construction sector was included. MAIN OUTCOME MEASURES: the standardized mortality ratio (SMR) was estimated from the meta-analysis of the literature review. The ratio lung cancer to mesothelioma attributable cases was estimated by occupational sector from the Italian cohorts. For the construction sector, the ratio lung cancer to mesothelioma cases was estimated within the exposed workers estimated by CAREX (1990-1993). The ratios were applied to the mesothelioma cases registered at the ReNaM for the 2010-2015 period, to obtain a national estimate of lung cancer cases attributable to occupational exposure to asbestos. RESULTS: the meta-analytical SMR for lung cancer in men varied between 1.05 (asphalt roll) and 2.36 (insulation). The mean risk for all sectors was 1.37 in men and 1.60 in women. It increased in cohorts with latency higher than 20 years. Significant risks were observed in asbestos-cement (both genders), construction, and mining sectors. There was a mean of 1.1, 2.7, and 2.8 lung cancer deaths per mesothelioma death in the cement-asbestos, harbour, and construction sectors, respectively. The impact in terms of lung cancer cases estimated at the national level was equal to 3,814 cases between 2010 and 2015. CONCLUSIONS: to provide an overall assessment of the impact of the occupational asbestos exposure, it is important to consider lung cancer cases, in addition to malignant mesotheliomas. This study was able to estimate the impact of asbestos on lung cancer in Italy 25 years after the ban of this occupational carcinogen, with the largest contribution in terms of attributable cases coming from the construction sector. It is urgent to implement adequate information and prevention strategies, health surveillance of workers, and the appropriate legal framework for insurance purposes.

Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes.

Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

Mortality and mesothelioma incidence among chrysotile asbestos miners in Balangero, Italy: A cohort study.

BACKGROUND: We studied cancer mortality and mesothelioma incidence in 974 male workers employed at least 6 months at the Balangero mine (Italy), the largest chrysotile mine in Western Europe, active from 1917 to 1985. METHODS: Vital status as of 31 May 2013, causes of deaths and mesothelioma incidence from 1990 were ascertained. Past exposure to asbestos by working area and calendar period was estimated, based on historical data of fibers concentrations. Individual cumulative exposure was assessed by applying estimates to the job history of cohort members. Standardized mortality ratios (SMRs) for selected causes and standardized incidence ratios for malignant mesothelioma (MM) were calculated based on regional reference rates. Poisson regression analysis was used to study MM and lung cancer risk by latency, duration, and cumulative exposure. RESULTS: Mortality was increased for all causes (SMR = 1.28; 95% confidence interval [CI] = 1.17-1.40), pleural cancer (SMR = 4.30; 95% CI = 1.58-9.37), asbestosis (SMR = 375.06; 95% CI = 262.68-519.23). An increase was also found for lung cancer (SMR = 1.14; 95% CI = 0.81-1.55) and peritoneal cancer (SMR = 3.25; 95% CI = 0.39-11.75). The risk of both pleural and peritoneal cancer mortality and of mesothelioma incidence increased with increasing cumulative exposure, duration, and latency. Poisson regression analyses showed an increase in mesothelioma risk with cumulative asbestos exposure and suggest a similar trend for lung cancer. Asbestosis mortality also increased with cumulative exposure. CONCLUSIONS: Among Balangero chrysotile miners and millers, the occurrence of malignant and nonmalignant asbestos-related diseases was increased by exposure, with dose-response relation. The study confirms the carcinogenicity of chrysotile asbestos, in particular for pleural mesothelioma.

[Gender and age factors affecting the mortality during the COVID-19 epidemic in Italy]. / Effetti del genere e dell'età sugli eccessi di mortalità durante l'epidemia di COVID-19 in Italia.

BACKGROUND: the COVID-19 epidemic severely affected Italy among European countries causing a considerable number of deaths across the country, especially in Northern Italy, leading also to serious problems to the Italian healthcare system, in particular the overcrowding of Intensive Care Units (ICU). In literature, the debate on the overall mortality during the COVID-19 epidemic, directly and indirectly, associated with the disease, is still open. OBJECTIVES: to describe the time trend of the mortality in Italy during the COVID-19 pandemic accounting for age, gender, and geographical areas. DESIGN: analysis of mortality trend, by region, age, and gender. SETTING AND PARTICIPANTS: the Italian mortality data, released by the Italian National Institute of Statistics (Istat), have been considered for the analyses. The data refer to the first four months of 2015-2019 and 2020, involving 7,270 municipalities, corresponding to 93% of the Italian population. MAIN OUTCOME MEASURES: the mortality rates in the first four months of 2015-2019 and 2020, age-adjusted, have been calculated together with the percent variation. The data were analysed by gender, age class (<65; >=65 years), Region, and geographical areas (Northern versus Central-Southern Italy). The overall daily mortality series have been represented as rates over 100,000 resident population. RESULTS: in addition to the geographical location, the age component was a major determinant of the mortality pattern. The greater increase in the overall mortality was evidenced among elderly subjects in the Northern Italian Regions most affected by the epidemic. In these areas, also gender component played an important role in determining the mortality excess: higher mortality rates in the first four months of 2020 are observed for males in comparison to female populations. CONCLUSIONS: this research reveals that the population components are an important issue in determining the COVID-19 mortality excess. For this reason, it is of primary importance to monitor mortality (overall and by COVID-19) by age and gender and to consider these components and the related factors (comorbidity, exposures affecting the lung) in the public prevention policies towards the protection of the most fragile population groups.

[Effects of Asbestos on Human Health. Document of the Italian Epidemiological Association (AIE)]. / Effetti dell'amianto sulla salute. Documento dell'Associazione Italiana di Epiemiologia (AIE).

OBJECTIVES: the Italian Epidemiological Association (AIE) intends to formulate assessments and recommendations on the most relevant and critical aspects in the preparation, conduct, and interpretation of epidemiological investigations on the health effects of exposure to asbestos and asbestos-like fibres. DESIGN, SETTING, AND PARTICIPANTS: the document was prepared by a working group of AIE associates, with a broad curriculum of epidemiological investigations, starting from the evaluation of scientific evidence, and was subsequently evaluated by the AIE governing body. RESULTS: the topics covered included: • consumption and presence of asbestos; • association between asbestos exposure and disease; • epidemiological surveillance of asbestos related diseases in Italy; • risk function for asbestos related diseases; • increased risk and anticipation of the disease; • interaction between asbestos and other carcinogens; • diagnosis in epidemiological studies; • assessment of exposure to asbestos; • epidemiological evidence on asbestos related diseases. CONCLUSIONS: the document ends with a summary of the conclusions of scientific research shared by AIE, with reflection on the methodology to be followed for the application at individual level of the results of epidemiological studies, and the proposal of themes on which to direct research.

Association between maternal education and survival after childhood cancer.

BACKGROUND: Several nonbiological factors, including socioeconomic status indicators and other family characteristics, influence survival from childhood cancers. Our study explores the association between parental education and childhood cancer survival. METHODS: The specialized Childhood Cancer Registry of the Piedmont region in Italy provided data on all the cases (aged 0-14) diagnosed with cancer in the period 1976-2011 who resided in the city of Turin (capital of the Piedmont region) at least once since 1971. Information on parental education was extracted from the Turin Longitudinal Study by record linkage. The association between parental educational level and survival was estimated using Cox regression. RESULTS: The study included 949 children. We observed a disadvantage in the overall survival for children of less educated mothers. No such effect was observed for paternal education. The effect of maternal education was particularly strong for central nervous system tumors (hazard ratios, 2.9; 95% confidence interval, 1.1-8.0). A similar effect, though smaller in magnitude, was observed for leukemia and embryonal tumors, whereas the estimates for lymphoma were imprecise. CONCLUSIONS: Our study shows an association between maternal educational level and survival in children with central nervous system tumors, a diagnosis that often requires long-lasting treatment and special care. Giving support to the families of affected children to provide them the optimal care has the potential to improve children's cancer treatment outcomes.

Parental occupational exposure to low-frequency magnetic fields and risk of leukaemia in the offspring: findings from the Childhood Leukaemia International Consortium (CLIC).

OBJECTIVES: Previously published studies on parental occupational exposure to extremely low-frequency magnetic fields (ELF-MF) and risk of acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) in their offspring were inconsistent. We therefore evaluated this question within the Childhood Leukemia International Consortium. METHODS: We pooled 11 case-control studies including 9723 childhood leukaemia cases and 17 099 controls. Parental occupational ELF-MF exposure was estimated by linking jobs to an ELF-MF job-exposure matrix (JEM). Logistic regression models were used to estimate ORs and 95% CIs in pooled analyses and meta-analyses. RESULTS: ORs from pooled analyses for paternal ELF-MF exposure >0.2 microtesla (µT) at conception were 1.04 (95% CI 0.95 to 1.13) for ALL and 1.06 (95% CI 0.87 to 1.29) for AML, compared with ≤0.2 µT. Corresponding ORs for maternal ELF-MF exposure during pregnancy were 1.00 (95% CI 0.89 to 1.12) for ALL and 0.85 (95% CI 0.61 to 1.16) for AML. No trends of increasing ORs with increasing exposure level were evident. Furthermore, no associations were observed in the meta-analyses. CONCLUSIONS: In this large international dataset applying a comprehensive quantitative JEM, we did not find any associations between parental occupational ELF-MF exposure and childhood leukaemia.

Role of asbestos clearance in explaining long-term risk of pleural and peritoneal cancer: a pooled analysis of cohort studies.

OBJECTIVES: Models based on the multistage theory of cancer predict that rates of malignant mesothelioma continuously increase with time since first exposure (TSFE) to asbestos, even after the end of external exposure. However, recent epidemiological studies suggest that mesothelioma rates level off many years after first exposure to asbestos. A gradual clearance of asbestos from the lungs has been suggested as a possible explanation for this phenomenon. We analysed long-term trends of pleural and peritoneal cancer mortality in subjects exposed to asbestos to evaluate whether such trends were consistent with the clearance hypothesis. METHODS: We used data from a pool of 43 Italian asbestos cohorts (51 801 subjects). The role of asbestos clearance was explored using the traditional mesothelioma multistage model, generalised to include a term representing elimination of fibres over time. RESULTS: Rates of pleural cancer increased until 40 years of TSFE, but remained stable thereafter. On the other hand, we observed a monotonic increase of peritoneal cancer with TSFE. The model taking into account asbestos clearance fitted the data better than the traditional one for pleural (p=0.004) but not for peritoneal (p=0.09) cancer. CONCLUSIONS: Rates of pleural cancer do not increase indefinitely after the exposure to asbestos, but eventually reach a plateau. This trend is well described by a model accounting for a gradual elimination of the asbestos fibres. These results are relevant for the prediction of future rates of mesothelioma and in asbestos litigations.

Cumulative asbestos exposure and mortality from asbestos related diseases in a pooled analysis of 21 asbestos cement cohorts in Italy.

BACKGROUND: Despite the available information on cancer risk, asbestos is used in large areas in the world, mostly in the production of asbestos cement. Moreover, questions are raised regarding the shape of the dose response relation, the relation with time since exposure and the association with neoplasms in various organs. We conducted a study on the relationship between cumulative asbestos exposure and mortality from asbestos related diseases in a large Italian pool of 21 cohorts of asbestos-cement workers with protracted exposure to both chrysotile and amphibole asbestos. METHODS: The cohort included 13,076 workers, 81.9% men and 18.1% women, working in 21 Italian asbestos-cement factories, with over 40 years of observation. Exposure was estimated by plant and period, and weighted for the type of asbestos used. Data were analysed with consideration of cause of death, cumulative exposure and time since first exposure (TSFE), and by gender. SMRs were computed using reference rates by region, gender and calendar time. Poisson regression models including cubic splines were used to analyse the effect of cumulative exposure to asbestos and TSFE on mortality for asbestos-related diseases. 95% Confidence Intervals (CI) were computed according to the Poisson distribution. RESULTS: Mortality was significantly increased for 'All Causes' and 'All Malignant Neoplasm (MN)', in both genders. Considering asbestos related diseases (ARDs), statistically significant excesses were observed for MN of peritoneum (SMR: men 14.19; women 15.14), pleura (SMR: 22.35 and 48.10), lung (SMR: 1.67 and 1.67), ovary (in the highest exposure class SMR 2.45), and asbestosis (SMR: 507 and 1023). Mortality for ARDs, in particular pleural and peritoneal malignancies, lung cancer, ovarian cancer and asbestosis increased monotonically with cumulative exposure. Pleural MN mortality increased progressively in the first 40 years of TSFE, then reached a plateau, while peritoneal MN showed a continuous increase. The trend of lung cancer SMRs also showed a flattening after 40 years of TSFE. Attributable proportions for pleural, peritoneal, and lung MN were respectively 96, 93 and 40%. CONCLUSIONS: Mortality for ARDs was associated with cumulative exposure to asbestos. Risk of death from pleural MN did not increase indefinitely with TSFE but eventually reached a plateau, consistently with reports from other recent studies.

Sensitivity to asbestos is increased in patients with mesothelioma and pathogenic germline variants in BAP1 or other DNA repair genes.

Pathogenic germline variants in the BAP1 tumor suppressor gene can cause a cancer syndrome called BAP1 tumor predisposition syndrome (BAP1-TPDS), which is characterized by predisposition to mesothelioma, melanoma, renal cell carcinoma, basal cell carcinoma, and other tumors. Other genes that may predispose to mesothelioma are CDKN2A and DNA repair genes. Asbestos exposure has often been reported in patients with malignant pleural mesothelioma (MPM) and germline variants in BAP1, but this exposure has never been quantified. We aimed to search for germline variants in BAP1 among 25 new Italian probands with suspected BAP1-TPDS, summarize the prevalence of these variants in 39 Italian patients with familial MPM and other tumors recruited over a 5-year period, and compare cumulative asbestos exposure in 14 patients with MPM and pathogenic germline variants in BAP1, CDKN2A, or DNA repair genes with that of 67 patients without germline variants in 94 cancer-predisposing genes. We report here a new pathogenic germline variant in BAP1: c.783 + 2 T > C. The prevalence of pathogenic germline variants in BAP1 was 7.7% among patients with familial MPM (3/39). Patients with pathogenic germline variants in BAP1, CDKN2A, or DNA repair genes showed lower cumulative asbestos exposure than patients without germline variants in 94 cancer-predisposing genes (P = .00002). This suggests an interaction between genetic risk factors and asbestos in the development of mesothelioma.