Germline Elongator mutations in Sonic Hedgehog medulloblastoma.

Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children1,2, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma3. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype4 and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U34) position5,6. Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems7-9. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.

Early mortality in children with cancer in Denmark and Sweden: The role of social background in a setting with universal healthcare.

Socioeconomic differences in overall survival from childhood cancer have been shown previously, but the underlying mechanisms remain unclear. We aimed to investigate if social inequalities were seen already for early mortality in settings with universal healthcare. From national registers, all children diagnosed with cancer at ages 0-19 years, during 1991-2014, in Sweden and Denmark, were identified, and information on parental social characteristics was collected. We estimated odds ratios (OR) and 95% confidence intervals (CI) of early mortality (death within 90 days after cancer diagnosis) by parental education, income, employment, cohabitation, and country of birth using logistic regression. For children with acute lymphoblastic leukaemia (ALL), clinical characteristics were obtained. Among 13,926 included children, 355 (2.5%) died within 90 days after diagnosis. Indications of higher early mortality were seen among the disadvantaged groups, with the most pronounced associations observed for maternal education (ORadj_Low_vs_High 1.65 [95% CI 1.22-2.23]) and income (ORadj_Q1(lowest)_vs_Q4(highest) 1.77 [1.25-2.49]). We found attenuated or null associations between social characteristics and later mortality (deaths occurring 1-5 years after cancer diagnosis). In children with ALL, the associations between social factors and early mortality remained unchanged when adjusting for potential mediation by clinical characteristics. In conclusion, this population-based cohort study indicated differences in early mortality after childhood cancer by social background, also in countries with universal healthcare. Social differences occurring this early in the disease course requires further investigation, also regarding the timing of diagnosis.

Suicide attempt and death by suicide among parents of young individuals with cancer: A population-based study in Denmark and Sweden.

BACKGROUND: The psychological toll on parents of a child receiving a cancer diagnosis is known to be high, but there is a knowledge gap regarding suicidal behavior among these parents. The aim of this study was to investigate the risk of suicide attempt and death by suicide in relation to having a child with cancer. METHODS AND FINDINGS: We performed a binational population-based and sibling-controlled cohort study, including all parents with a child diagnosed with cancer in Denmark (1978 to 2016) or Sweden (1973 to 2014), 10 matched unexposed parents per exposed parent (population comparison), and unaffected full siblings of the exposed parents (sibling comparison). Suicide attempt was identified through the Patient Register and the Psychiatric Central Register in Denmark and the Patient Register in Sweden, whereas death by suicide was identified through the Danish Causes of Death Register and the Swedish Causes of Death Register. In population comparison, we used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of suicide attempt and death by suicide associated with cancer diagnosis of a child, adjusting for sex, age, country of residence, calendar year, marital status, highest attained educational level, household income, history of cancer, history of psychiatric disorder, and family history of psychiatric disorder. The sibling comparison was performed to assess the role of familial confounding in the studied associations. The population comparison consisted of 106,005 exposed parents and 1,060,050 matched unexposed parents, with a median age of 56 at cohort entry and 46.9% male. During the median follow-up of 7.3 and 7.2 years, we observed 613 (incidence rate [IR], 58.8 per 100,000 person-years) and 5,888 (IR, 57.1 per 100,000 person-years) cases of first-onset suicide attempt among the exposed and unexposed parents, respectively. There was an increased risk of parental suicide attempt during the first years after a child's cancer diagnosis (HR, 1.15; 95% CI, [1.03, 1.28]; p = 0.01), particularly when the child was 18 or younger at diagnosis (HR, 1.25; 95% CI, [1.08, 1.46]; p = 0.004), when the child was diagnosed with a highly aggressive cancer (HR, 1.60; 95% CI, [1.05, 2.43]; p = 0.03), or when the child died due to cancer (HR, 1.63; 95% CI, [1.29, 2.06]; p < 0.001). The increased risk did not, however, maintain thereafter (HR, 0.86; 95% CI: [0.75, 0.98]; p = 0.03), and there was no altered risk of parental death by suicide any time after the child's cancer diagnosis. Sibling comparison corroborated these findings. The main limitation of the study is the potential residual confounding by factors not shared between full siblings. CONCLUSIONS: In this study, we observed an increased risk of parental suicide attempt during the first years after a child's cancer diagnosis, especially when the child was diagnosed during childhood, or with an aggressive or fatal form of cancer. There was, however, no altered risk of parental death by suicide at any time after a child's cancer diagnosis. Our findings suggest extended clinical awareness of suicide attempt among parents of children with cancer, especially during the first few years after cancer diagnosis.

Regression calibration of self-reported mobile phone use to optimize quantitative risk estimation in the COSMOS study.

The Cohort Study of Mobile Phone Use and Health (COSMOS) has repeatedly collected self-reported and operator-recorded data on mobile phone use. Assessing health effects using self-reported information is prone to measurement error, but operator data were available prospectively for only part of the study population and did not cover past mobile phone use. To optimize the available data and reduce bias, we evaluated different statistical approaches for constructing mobile phone exposure histories within COSMOS. We evaluated and compared the performance of four regression calibration (RC) methods (simple, direct, inverse, and generalized additive model for location, shape, and scale), complete-case (CC) analysis and multiple imputation (MI) in a simulation study with a binary health outcome. We used self-reported and operator-recorded mobile phone call data collected at baseline (2007-2012) from participants in Denmark, Finland, the Netherlands, Sweden, and the UK. Parameter estimates obtained using simple, direct, and inverse RC methods were associated with less bias and lower mean squared error than those obtained with CC analysis or MI. We showed that RC methods resulted in more accurate estimation of the relation between mobile phone use and health outcomes, by combining self-reported data with objective operator-recorded data available for a subset of participants.

Educational attainment in survivors of childhood cancer in Denmark, Finland, and Sweden.

BACKGROUND: Survivors of childhood cancer may face difficulties at school. We investigated whether childhood cancer affects attainment of upper secondary education, in a register-based cohort study from Denmark, Finland, and Sweden, where we limit bias from selection and participation. METHODS: From the national cancer registers, we identified all long-term survivors of childhood cancer diagnosed aged 0-14 years in 1971-2005 (n = 7629), compared them to matched population comparisons (n = 35,411) and siblings (n = 6114), using odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Overall, 6127 survivors (80%) had attained upper secondary education by age 25, compared to 84% among comparison groups. Elevated OR for not attaining this level were mainly confined to survivors of central nervous system (CNS) tumours (ORSurv_PopComp2.05, 95%CI: 1.83-2.29). Other risk groups were survivors who had spent more time in hospital around cancer diagnosis and those who had hospital contacts in early adulthood, particularly psychiatric. Survivors of all cancer types were less likely to have attained upper secondary education without delay. CONCLUSIONS: Although survivors of childhood cancer experienced delays in their education, many had caught up by age 25. Except for survivors of CNS tumours, survivors attained upper secondary education to almost the same extent as their peers.

Effects of Recall and Selection Biases on Modeling Cancer Risk From Mobile Phone Use: Results From a Case-Control Simulation Study.

BACKGROUND: The largest case-control study (Interphone study) investigating glioma risk related to mobile phone use showed a J-shaped relationship with reduced relative risks for moderate use and a 40% increased relative risk among the 10% heaviest regular mobile phone users, using a categorical risk model based on deciles of lifetime duration of use among ever regular users. METHODS: We conducted Monte Carlo simulations examining whether the reported estimates are compatible with an assumption of no effect of mobile phone use on glioma risk when the various forms of biases present in the Interphone study are accounted for. Four scenarios of sources of error in self-reported mobile phone use were considered, along with selection bias. Input parameters used for simulations were those obtained from Interphone validation studies on reporting accuracy and from using a nonresponse questionnaire. RESULTS: We found that the scenario simultaneously modeling systematic and random reporting errors produced a J-shaped relationship perfectly compatible with the observed relationship from the main Interphone study with a simulated spurious increased relative risk among heaviest users (odds ratio = 1.91) compared with never regular users. The main determinant for producing this J shape was higher reporting error variance in cases compared with controls, as observed in the validation studies. Selection bias contributed to the reduced risks as well. CONCLUSIONS: Some uncertainty remains, but the evidence from the present simulation study shifts the overall assessment to making it less likely that heavy mobile phone use is causally related to an increased glioma risk.

Headache in the international cohort study of mobile phone use and health (COSMOS) in the Netherlands and the United Kingdom.

Headache is a common condition with a substantial burden of disease worldwide. Concerns have been raised over the potential impact of long-term mobile phone use on headache due to radiofrequency electromagnetic fields (RF-EMFs). We explored prospectively the association between mobile phone use at baseline (2009-2012) and headache at follow-up (2015-2018) by analysing pooled data consisting of the Dutch and UK cohorts of the Cohort Study of Mobile Phone Use and Health (COSMOS) (N = 78,437). Frequency of headache, migraine, and information on mobile phone use, including use of hands-free devices and frequency of texting, were self-reported. We collected objective operator data to obtain regression calibrated estimates of voice call duration. In the model mutually adjusted for call-time and text messaging, participants in the high category of call-time showed an adjusted odds ratio (OR) of 1.04 (95 % CI: 0.94-1.15), with no clear trend of reporting headache with increasing call-time. However, we found an increased risk of weekly headache (OR = 1.40, 95 % CI: 1.25-1.56) in the high category of text messaging, with a clear increase in reporting headache with increasing texting. Due to the negligible exposure to RF-EMFs from texting, our results suggest that mechanisms other than RF-EMFs are responsible for the increased risk of headache that we found among mobile phone users.

Frailty Among Breast Cancer Survivors: Evidence From Swedish Population Data.

Incidence and survival of breast cancer, the most common cancer among women, have been increasing, leaving survivors at risk of aging-related health conditions. In this matched cohort study, we examined frailty risk with the Hospital Frailty Risk Score among breast cancer survivors (n = 34,900) and age-matched comparison subjects (n = 290,063). Women born in 1935-1975, registered in the Swedish Total Population Register (1991-2015), were eligible for inclusion. Survivors had a first breast cancer diagnosis in 1991-2005 and survived ≥5 years after initial diagnosis. Death date was determined by linkage to the National Cause of Death Registry (through 2015). Cancer survivorship was weakly associated with frailty (subdistribution hazard ratio (SHR) = 1.04, 95% confidence interval (CI): 1.00, 1.07). In age-stratified models, those diagnosed at younger ages (<50 years) had higher risk of frailty (SHR = 1.12, 95% CI: 1.00, 1.24) than those diagnosed at ages 50-65 (SHR = 1.03, 95% CI: 0.98, 1.07) or >65 (SHR = 1.09, 95% CI: 1.02, 1.17) years. Additionally, there was increased risk of frailty for diagnoses in 2000 or later (SHR = 1.15, 95% CI: 1.09, 1.21) compared with before 2000 (SHR = 0.97, 95% CI: 0.93, 1.17). This supports work from smaller samples showing that breast cancer survivors have increased frailty risk, particularly when diagnosed at younger ages.

The relationship between congenital heart disease and cancer in Swedish children: A population-based cohort study.

BACKGROUND: Birth defects have been consistently associated with elevated childhood cancer risks; however, the relationship between congenital heart disease (CHD) and childhood cancer remains conflicting. Considering the increasing patient population with CHD after improvements in their life expectancies, insights into this relationship are particularly compelling. Thus, we aimed to determine the relationship between CHD and cancer in Swedish children. METHODS AND FINDINGS: All individuals registered in the Swedish Medical Birth Register (MBR) between 1973 and 2014 were included in this population-based cohort study (n = 4,178,722). Individuals with CHD (n = 66,892) were identified from the MBR and National Patient Register, whereas cancer diagnoses were retrieved from the Swedish Cancer Register. The relationship between CHD and childhood cancer (<20 years at diagnosis) was evaluated using Cox proportional hazards regression models. We observed increased risks of cancer overall, leukemia, lymphoma, and hepatoblastoma in children with CHD, but after adjustment for Down syndrome, only the increased lymphoma (hazard ratio (HR) = 1.64, 95% confidence interval (CI) 1.11 to 2.44) and hepatoblastoma (HR = 3.94, 95% CI 1.83 to 8.47) risk remained. However, when restricting to CHD diagnoses from the MBR only, i.e., those diagnosed around birth, the risk for childhood cancer overall (HR = 1.45, 95% CI 1.23 to 1.71) and leukemia (HR = 1.41, 95% CI 1.08 to 1.84) was more pronounced, even after controlling for Down syndrome. Finally, a substantially elevated lymphoma risk (HR = 8.13, 95% CI 4.06 to 16.30) was observed in children with complex CHD. Limitations of the study include the National Patient Register not being nationwide until 1987, in addition to the rareness of the conditions under study providing limited power for analyses on the rarer cancer subtypes. CONCLUSIONS: We found associations between CHD and childhood lymphomas and hepatoblastomas not explained by a diagnosis of Down syndrome. Stronger associations were observed in complex CHD.

Benchmarking Observational Analyses Before Using Them to Address Questions Trials Do Not Answer: An Application to Coronary Thrombus Aspiration.

To increase confidence in the use of observational analyses when addressing effectiveness questions beyond those addressed by randomized trials, one can first benchmark the observational analyses against existing trial results. We used Swedish registry data to emulate a target trial similar to the Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTE) randomized trial, which found no difference in the risk of death or myocardial infarction by 1 year with or without thrombus aspiration among individuals with ST-elevation myocardial infarction. We benchmarked the emulation against the trial at 1 year and then extended the emulation's follow-up to 3 years and estimated effects in subpopulations underrepresented in the trial. As in the TASTE trial, the observational analysis found no differences in risk of outcomes by 1 year between groups (risk difference = 0.7 (confidence interval, -0.7, 2.0) and -0.2 (confidence interval, -1.3, 1.0) for death and myocardial infarction, respectively), so benchmarking was considered successful. We additionally showed no difference in risk of death or myocardial infarction by 3 years, or within subpopulations by 1 year. Benchmarking against an index trial before using observational analyses to answer questions beyond those the trial could address allowed us to explore whether the observational data can be trusted to deliver valid estimates of treatment effects.

Childhood cancer risk in offspring of parents occupationally exposed to dusts: A register-based nested case-control study from Sweden of 5 decades.

BACKGROUND: Some largely inconsistent associations between parental occupational dust exposure and childhood cancer have been reported, with maternal exposures inadequately studied. The authors examined whether maternal or paternal occupational exposure to animal, wood, textile, or paper dust around a child's birth was associated with an increased risk of childhood cancer, both overall and by type (leukemias, lymphomas, central nervous system tumors, and other cancers). METHODS: In this nationwide, register-based, case-control study, children who were diagnosed with cancer from 1960 to 2015 were compared with up to 25 matched controls regarding maternal and paternal occupational dust exposure (9653 cases in maternal analyses and 12,521 cases in paternal analyses). Exposures were assessed using a job-exposure matrix and occupational information from census and register data. By using conditional logistic regression models, adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. RESULTS: Neither maternal nor paternal occupational exposure to animal, wood, textile, or paper dust was associated with childhood cancer overall, leukemias, or central nervous system tumors. Maternal, but not paternal, wood dust exposure was associated with an increased risk of lymphoma (OR, 1.42; 95% CI, 1.10-1.84), particularly non-Hodgkin lymphoma (OR, 2.03; 95% CI, 1.21-3.40). CONCLUSIONS: The current study did not confirm the associations reported previously but is the first to suggest a link between maternal occupational exposure to wood dust around pregnancy and lymphoma in the offspring.

Maternal smoking during pregnancy and type 1 diabetes in the offspring: a nationwide register-based study with family-based designs.

BACKGROUND: Maternal smoking during pregnancy was reported to be associated with a reduced risk of type 1 diabetes in the offspring. We investigated whether this association is consistent with a causal interpretation by accounting for familial (shared genetic and environmental) factors using family-based, quasi-experimental designs. METHODS: We included 2,995,321 children born in Sweden between 1983 and 2014 and followed them for a diagnosis of type 1 diabetes until 2020 through the National Patient, Diabetes and Prescribed Drug Registers. Apart from conducting a traditional cohort study, we performed a nested case-control study (quasi-experiment) comparing children with type 1 diabetes to their age-matched siblings (or cousins). Information on maternal smoking during pregnancy was retrieved from the Swedish Medical Birth Register. Multivariable adjusted Cox proportional hazards regression and conditional logistic regression were used. RESULTS: A total of 18,617 children developed type 1 diabetes, with a median age at diagnosis of 9.4 years. The sibling and cousin comparison design included 14,284 and 7988 of these children, respectively. Maternal smoking during pregnancy was associated with a 22% lower risk of offspring type 1 diabetes in the full cohort (hazard ratio 0.78, 95% confidence interval [CI] 0.75-0.82). The corresponding odds ratio was 0.78 (95% CI 0.69-0.88) in the sibling and 0.72 (95% CI 0.66-0.79) in the cousin comparison analysis. CONCLUSIONS: This nationwide, family-based study provides support for a protective effect of maternal smoking on offspring type 1 diabetes. Mechanistic studies are needed to elucidate the underlying pathways behind this link.

Late mortality among survivors of childhood acute lymphoblastic leukemia diagnosed during 1971-2008 in Denmark, Finland, and Sweden: A population-based cohort study.

OBJECTIVE: Investigate all-cause and cause-specific late mortality after childhood acute lymphoblastic leukemia (ALL) in a population-based Nordic cohort. METHODS: From the cancer registries of Denmark, Finland, and Sweden, we identified 3765 five-year survivors of ALL, diagnosed before age 20 during 1971-2008. For each survivor, up to five matched comparison subjects were randomly selected from the general population (n = 18,323). Causes of death were classified as relapse related, health related, and external. Late mortality was evaluated by cumulative incidences of death from 5-year survival date. Mortality hazard ratios (HR) were evaluated with Cox proportional models. RESULTS: Among the survivors, 315 deaths occurred during a median follow-up of 16 years from 5-year survival date (range 0-42). The majority were attributable to relapse (n = 224), followed by second neoplasm (n = 45). Cumulative incidence of all-cause late mortality at 15 years from diagnosis decreased gradually over treatment decades, from 14.4% (95% confidence interval [CI]: 11.6-17.2) for survivors diagnosed during 1971-1981, to 2.5% (95% CI: 1.3-3.7) for those diagnosed during 2002-2008. This was mainly attributable to a reduction in relapse-related deaths decreasing from 13.4% (95% CI: 10.7-16.1) for survivors diagnosed during 1971-1981 to 1.9% (95% CI: 0.9-2.8) for those diagnosed during 2002-2008. Health-related late mortality was low and did not change substantially across treatment decades. Compared to comparison subjects, all-cause mortality HR was 40 (95% CI: 26-61) 5-9 years from diagnosis, and 4.4 (95% CI: 3.4-5.6) ≥10 years from diagnosis. CONCLUSIONS: Survivors of ALL have higher late mortality than population comparison subjects. Among the survivors, there was a temporal reduction in risk of death from relapse, without increments in health-related death.

COVID-19 related outcomes among individuals with neurodegenerative diseases: a cohort analysis in the UK biobank.

BACKGROUND: An increased susceptibility to COVID-19 has been suggested for individuals with neurodegenerative diseases, but data are scarce from longitudinal studies. METHODS: In this community-based cohort study, we included 96,275 participants of the UK Biobank who had available SARS-CoV-2 test results in Public Health England. Of these, 2617 had a clinical diagnosis of neurodegenerative diseases in the UK Biobank inpatient hospital data before the outbreak of COVID-19 (defined as January 31st, 2020), while the remaining participants constituted the reference group. We then followed both groups from January 31st, 2020 to June 14th, 2021 for ascertainment of COVID-19 outcomes, including any COVID-19, inpatient care for COVID-19, and COVID-19 related death. Logistic regression was applied to estimate the association between neurogenerative disease and risks of COVID-19 outcomes, adjusted for multiple confounders and somatic comorbidities. RESULTS: We observed an elevated risk of COVID-19 outcomes among individuals with a neurodegenerative disease compared with the reference group, corresponding to a fully adjusted odds ratio of 2.47 (95%CI 2.25-2.71) for any COVID-19, 2.18 (95%CI 1.94-2.45) for inpatient COVID-19, and 3.67 (95%CI 3.11-4.34) for COVID-19 related death. Among individuals with a positive test result for SARS-CoV-2, individuals with neurodegenerative diseases had also a higher risk of COVID-19 related death than others (fully adjusted odds ratio 2.08; 95%CI 1.71-2.53). CONCLUSION: Among UK Biobank participants who received at least one test for SARS-CoV-2, a pre-existing diagnosis of neurodegenerative disease was associated with a subsequently increased risk of COVID-19, especially COVID-19 related death.

Association of allergic diseases and epilepsy with risk of glioma, meningioma and acoustic neuroma: results from the INTERPHONE international case-control study.

We investigated the association of allergic diseases and epilepsy with risk of brain tumours, in Interphone, a 13-country case-control study. Data were obtained from 2693 glioma cases, 2396 meningioma cases, and 1102 acoustic neuroma cases and their 6321 controls. Conditional logistic regression models were used to estimate pooled odds ratios (ORs) and their respective 95% confidence intervals (CIs), adjusted for education and time at interview. Reduced ORs were observed for glioma in relation to physician-diagnosed asthma (OR = 0.73; CI 0.58-0.92), hay fever (OR 0.72; CI 0.61-0.86), and eczema (OR 0.78, CI 0.64-0.94), but not for meningioma or acoustic neuroma. Previous diagnosis of epilepsy was associated with an increased OR for glioma (2.94; CI 1.87-4.63) and for meningioma (2.12; CI 1.27-3.56), but not for acoustic neuroma. This large-scale case-control study adds to the growing evidence that people with allergies have a lower risk of developing glioma, but not meningioma or acoustic neuroma. It also supports clinical observations of epilepsy prior to the diagnosis of glioma and meningioma.

Occupational exposure to respirable crystalline silica and acute myocardial infarction among men and women in Sweden.

OBJECTIVES: Occupational exposure to respirable crystalline silica (RCS) is common. The study aimed to assess the risk for acute myocardial infarction (AMI) after long-term exposure to RCS and to explore differences in risk between men and women. METHODS: The cohort included all manual workers identified from the Swedish National Census in 1980 using data on job titles and demography altogether from five censuses from 1960 to 1990, in total 605 246 men and 480 607 women. Information on AMI was obtained from nationwide registers from 1992 to 2006. Exposure to RCS was assessed with a job-exposure matrix. HRs and 95% CIs were estimated by Cox regression, adjusted for age, socioeconomic status and urbanisation index. RESULTS: Among manual workers ever exposed to RCS, the adjusted risk of AMI was HR 1.29 (95% CI 1.15 to 1.46) in women, and HR 1.02 (95% CI 1.00 to 1.04) in men. In the highest quartile of cumulative exposure, the risk of AMI was HR 1.66 (95% CI 1.27 to 2.18) for women, and HR 1.06 (95% CI 1.03 to 1.10) for men, respectively. The risk of AMI increased with cumulative exposure to RCS both in women (p=0.001) and in men (p=0.016). An interaction analysis showed that the relative risk from exposure to RCS was statistically significantly lower in men than in women at similar exposure levels. CONCLUSIONS: Occupational exposure to RCS was related to the risk of AMI. Women were more sensitive to exposure to RCS than men.

Occupational exposure to pesticides in mothers and fathers and risk of cancer in the offspring: A register-based case-control study from Sweden (1960-2015).

Maternal and paternal occupational exposure to pesticides was linked to leukemia in the offspring in some previous studies. Risks for other cancers, particularly from maternal exposure, are largely unknown. We examined the association between maternal and paternal exposure to pesticides and childhood cancer in a Swedish register-based case-control study (1960-2015). Cancer cases <20 years old were identified from the Cancer Register (n = 17313) and matched to controls (1:25) on birth year and sex. Employment history of each biological parent around the child's birth was retrieved from six censuses and a nationwide register, and exposure to any of herbicides, insecticides, and fungicides was evaluated using the Swedish job-exposure matrix (SWEJEM) in 9653/172194 mothers and 12521/274434 fathers of cases/controls. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated from conditional logistic regression models for any cancer, leukemia, lymphoma, central nervous system [CNS], and other solid tumors. We found an OR of 1.42 (95% CI 0.78, 2.57; 12 exposed cases) for lymphoma and 1.30 (95% CI 0.88, 1.93; 27 exposed cases) for other solid tumors associated with maternal occupational exposure to pesticides. No associations were observed between maternal exposure and leukemia or CNS tumors, or paternal exposure and any of the cancers examined, except for a potential association between pesticides exposure and myeloid leukemia (OR 1.15 [95% CI 0.73, 1.79; 22 exposed cases]). Although these findings merit further investigation, they indicate that parental exposure to pesticides may lead to higher risks of childhood cancer even in settings of low exposure.

Parental occupational exposures in wood-related jobs and risk of testicular germ cell tumours in offspring in NORD-TEST a registry-based case-control study in Finland, Norway, and Sweden.

OBJECTIVE: We assessed the association between parental prenatal exposures in wood-related jobs and risk of testicular germ cell tumours (TGCT) in offspring. METHODS: NORD-TEST, a registry-based case-control study in Sweden, Finland and Norway, included 8112 TGCT cases diagnosed at ages 14-49 years between 1978 and 2012 with no history of prior cancer, and up to four controls matched to each case on year and country of birth. Parents of cases and controls were identified via linkages with the population registries and their occupational information was retrieved from censuses. The Nordic Occupational Cancer Study Job-Exposure Matrix was used to assign occupational exposures to each parent. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Maternal wood-related job was not associated with the risk of TGCT in offspring (OR 1.08, CI 0.55-2.14), while paternal wood-related job was associated with a decreased risk of TGCT in offspring (OR 0.85, CI 0.75-0.96). None of the specific wood-related jobs, such as upholsterers, sawyers, or construction carpenters, were significantly associated with a risk of TGCT. Only exception was observed in a sensitivity analysis which showed an increased risk in the small group of sons of fathers working as 'cabinetmakers and joiners' the year before conception (OR of 2.06, CI 1.00-4.25). CONCLUSION: This large-scale NORD-TEST analysis provided no evidence of an association between parental prenatal exposures in wood-related jobs and TGCT in sons.

Is the risk of childhood leukaemia associated with socioeconomic measures in Denmark? A nationwide register-based case-control study.

The aetiology of childhood leukaemia is poorly understood. Knowledge about differences in risk by socioeconomic status (SES) may enhance etiologic insights. We conducted a nationwide register-based case-control study to evaluate socioeconomic differences in the risk of childhood leukaemia in Denmark and to access whether associations varied by different measures of SES, time point of assessment, leukaemia type and age at diagnosis. We identified all cases of leukaemia in children aged 0 to 19 years, born and diagnosed between 1980 and 2013 from the Danish Cancer Registry (N = 1336) and sampled four individually matched controls per case (N = 5330). We used conditional logistic regression models for analysis. Medium and high level of parental education was associated with a higher risk of acute myeloid leukaemia (AML) in the offspring, mainly driven by children diagnosed at ages 0 to 4 years [odds ratio (OR) for high maternal education = 3.07; 95% confidence interval (CI): 1.44-6.55]. We also observed a modestly increased risk for lymphoid leukaemia (LL) in association with higher level of parental education, but only in children diagnosed at ages 5 to 19 years. Higher parental income was associated with an increased risk of LL but not AML among children aged 5 to 19 years at diagnosis (OR for high maternal income = 2.78; 95% CI: 1.32-5.89). Results for neighbourhood SES measures indicated null associations. Bias or under-ascertainment of cases among families with low income or basic education are unlikely to explain the observed socioeconomic differences. Future research addressing explicitly the underlying mechanisms of our results may help to enhance etiologic insights of the disease.

Number of siblings and survival from childhood leukaemia: a national register-based cohort study from Sweden.

BACKGROUND: Previous studies suggest worse leukaemia survival for children with siblings, but the evidence is sparse, inconsistent and does not consider clinical factors. We explored the associations between number of siblings in the household, birth order and survival from childhood acute lymphoid leukaemia (ALL) and acute myeloid leukaemia (AML). METHODS: In this nationwide register-based study we included all children aged 1-14, diagnosed with ALL and AML between 1991-mid-2015 in Sweden (n = 1692). Using Cox regression models, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) according to number of siblings and birth order, adjusting for known prognostic and sociodemographic factors. RESULTS: A tendency towards better ALL survival among children with one, or ≥2, siblings was observed, adjHRs (95% CI): 0.73 (0.49-1.10) and 0.63 (0.40-1.00), respectively. However, this was mainly limited to children with low risk profiles. An indication of better AML survival among children with siblings was seen, adjHRs (95% CI) 0.68 (0.36-1.29) and 0.71 (0.34-1.48) but diminished after adjusting for birth order. CONCLUSION: Our results do not support previous findings that a larger number of siblings is associated with poorer survival. Inconsistencies might be explained by underlying mechanisms that differ between settings, but chance cannot be ruled out.