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.

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.

Disease incidence and not case fatality drives the rural disadvantage in myocardial-infarction-related mortality in Germany.

OBJECTIVE: Demographic and infrastructural developments might compromise medical care provision in rural regions, particularly for acute health conditions. Studying the case of myocardial infarction (MI), we investigated how MI-related mortality at ages 65+ varies between rural and urban regions in Germany and to what extent differences are driven by varying case fatality and disease incidence. METHODS: The study relies on data containing all hospitalizations, cause-specific deaths and population counts for the total German population between years 2012-2018 and ages 65+. MI-related mortality, MI incidence and case fatality are compared between urban and rural regions in a population-wide analysis. The impacts of changing incidence and case fatality on rural-urban MI-related mortality differences are assessed using a counterfactual approach. RESULTS: Rural regions in Germany show systematically higher MI-related death rates and MI incidence at ages 65+ compared to urban regions. Higher mortality is primarily the result of higher MI incidence in rural regions, while case fatality is largely similar. The rural excess in MI-related death rates would be nullified and 1 out of 6 MI-related deaths in rural regions could be prevented if rural regions in Germany would have at least the median MI incidence of urban regions. CONCLUSIONS: MI incidence and not case fatality drives the rural disadvantage in MI-related mortality in Germany. Higher MI incidence points towards potential regional variation in the effectiveness of disease prevention. The findings highlight that improving disease prevention at the patient level carries larger opportunities for reducing regional MI-related mortality inequalities in Germany.

Parental occupational exposure to metals and risk of cancer in the offspring: A register-based case-control study from Sweden.

BACKGROUND: Cancer risks in the offspring of mothers and fathers exposed to metals are unknown. We estimated the relative risks of childhood cancer, overall and by type, associated with parental occupational exposure to arsenic, cadmium, chromium, nickel, and lead. METHODS: We conducted a nested case-control study (1960-2015) of children born in Sweden aged 0-19 years diagnosed with cancer (National Cancer Register) matched 25:1 to controls on birth year and sex. We obtained parental occupational data around their birth from censuses and a nationwide register and identified exposure to each metal (yes/no, or higher/lower/no exposure) using the Swedish job-exposure matrix (SWEJEM). Adjusted odds ratios (OR) and 95% confidence intervals (CIs) were estimated separately for maternal and paternal exposures using conditional logistic regression. RESULTS: We compared 9653 cases to 1,72,194 controls in maternal and 12,521 cases to 2,74,434 controls in paternal analyses, respectively. We found a 38% increased risk of cancer associated with maternal occupational exposure to arsenic (OR 1.38 [95% CI 1.06, 1.82]), likely driven by higher risks for lymphoma (OR 1.52 [0.73, 3.15]), central nervous system (CNS) (OR 1.49 [0.88, 2.54]) and other solid malignancies (OR 1.74 [1.14, 2.65]). There were also indications of higher risks of lymphoma in children of mothers exposed to nickel and iron, and of CNS tumours due to chromium exposure. No associations were observed from paternal occupational exposure to any of the metals. CONCLUSIONS: We found evidence of increased risks of cancer in children of mothers but not fathers occupationally exposed to arsenic and potentially other metals.

Income disparities between adult childhood cancer survivors and their peers-A register-based cohort study from the SALiCCS research programme.

BACKGROUND: Childhood cancer survivors face various adverse consequences. This Nordic register-based cohort study aimed to assess whether survivors of childhood cancer are more likely to have low income than their peers. METHODS: We identified 17,392 childhood cancer survivors diagnosed at ages 0 to 19 between 1971 and 2009 with 83,221 age-, sex-, and country-matched population comparisons. Annual disposable income at ages 20 to 50 years was retrieved from statistical offices (for 1990-2017) and categorized into low income and middle/high income. The number of transitions between income categories were assessed using binomial regression analyses. RESULTS: The prevalence of annual low income among childhood cancer survivors was 18.1% and 15.6% among population comparisons (risk ratio [RR] 1.17; 95% confidence interval [CI] 1.16-1.18). Compared to population comparisons, childhood cancer survivors were 10% (95% CI 8%-11%) less likely to transition from low to middle/high income and 12% (10%-15%) more likely to transition from middle/high to low income during follow-up. Among those initially in the low income category, survivors were 7% (95% CI 3%-11%) more likely to remain in the low income category. If the initial category was middle/high income, childhood cancer survivors were 10% (95% CI 8%-11%) less likely to remain in the middle/high income and 45% (37%-53%) more likely to transition to the low income category permanently. CONCLUSIONS: Childhood cancer survivors are at higher risk for low income in adulthood than their peers. These disparities might be reduced by continued career counseling along with support in managing within the social security system.

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.

Improved prediction of 10-year risk of severe liver disease in the general population using commonly available biomarkers.

BACKGROUND: Estimating the risk for cirrhosis in the general population is complex. Existing prediction tools are in general unsatisfactory. AIMS: To explore if using commonly available biomarkers can improve the commonly used FIB-4 score in the identification of subgroups at risk of cirrhosis. METHODS: We used laboratory and clinical data on 126,925 individuals aged 35-79 years in Stockholm, Sweden, undergoing health examinations from 1985 to 1996. We used Swedish nationwide registries to ascertain 10-year cumulative incidence of severe liver disease, a composite of diagnoses corresponding to cirrhosis and its complications. We considered combinations of biomarkers associated with severe liver disease to identify subgroups with different risk profiles. RESULTS: During an average follow-up of 9.3 years, we ascertained 630 incident cases of severe liver disease (0.5%). Age, the FIB-4 score, diabetes or impaired glucose and gamma-glutamyl transferase (gGT) were the most relevant characteristics for classifying risk profiles. Using these factors, we identified 24 groups with a cumulative incidence of severe liver disease at 10 years ranging from 0.2% (age 35-65, low FIB-4, no diabetes or impaired glucose and normal gGT) to 32.1% (age 35-65, high FIB-4, diabetes or impaired glucose and high gGT). CONCLUSIONS: Identification of subjects at increased risk of severe liver disease in the general population using the FIB-4 score can be substantially improved by adding age and specific biomarkers commonly available in the primary care setting. These parameters should be considered for inclusion in the development of future risk prediction models.

Trends in Frailty Between 1990 and 2020 in Sweden Among 75-, 85-, and 95-Year-Old Women and Men: A Nationwide Study from Sweden.

BACKGROUND: Aging is the primary risk factor for frailty, which is defined as an inability to respond to acute or chronic stressors. Individuals are living longer with greater multimorbidity, but there is a paucity of evidence examining frailty across birth cohorts and ages. METHODS: We investigated frailty prevalence and its association with mortality at ages 75, 85, and 95 in the 1895-1945 birth cohorts in Sweden with data from population registries. Frailty was assessed with the Hospital Frailty Risk Score (HFRS). RESULTS: We observed that frailty increased with increasing age and that it has become more common in more recent birth cohorts. At age 75, the percent frail in the Total Population Register increased from 1.1% to 4.6% from birth cohorts 1915-1945, corresponding to calendar years 1990-2020. At age 85, the percentage of frail increased from 3.5% to 11.5% from birth cohorts 1905-1935, and at age 95 from birth cohorts 1895-1925, from 4.7% to 18.7%. Our results show that the increase was primarily driven by an increase in the distribution of individuals with scores in the highest quartile of HFRS, while the bottom 3 quartiles remained relatively stable across birth cohorts. Women accounted for a greater distribution of the overall population and frail population, though these disparities decreased over time. Despite increasing levels of frailty, the relationship between frailty and mortality did not change over time, nor did it differ by sex. CONCLUSION: Increased frailty with improved survival points to a chronic condition that could be intervened upon.

Heritability of nervous system tumors: a sibling-based design.

Background: The contribution of genetic and environmental factors to susceptibility to nervous system tumors remains unclear. We performed a quantitative genetic study using a sibling design to estimate the heritability of nervous system tumors, as well as the proportion of the risk of these tumors, which is attributable to environmental factors. Methods: We conducted a population-based cohort study using Swedish National Register data. All individuals born in Sweden during 1950-2010 with available information on both biological parents were included. A Multi-Generation Register was used to identify family clusters, including both full- and half-siblings. Initially, one index person was randomly selected from each cluster containing only full siblings and one sibling was randomly assigned to this index person. Subsequently, within each of the remaining clusters of full- and half-siblings, an index person was randomly selected, and a half-sibling was randomly assigned to this index person. Among the randomly selected siblings, cases of nervous system tumors were identified using the cancer registry. Quantitative genetic models were used to estimate the proportion of the variance in nervous system tumors attributable to additive genetic factors, shared environment, and individual-specific environment. Results: The heritability of nervous system tumors was estimated to be 29% (95% confidence interval (CI) = 19%-39%), while the contribution of the non-shared environment to the variance of nervous system tumors was estimated to be 71% (95% CI = 61%-81%). The shared environmental parameter was estimated as zero in the full model. Conclusion: The variation in susceptibility to nervous system tumors is predominantly attributable to non-shared environmental factors, followed by genetic factors.

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.

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.

Risk of Cancer in Children of Parents Occupationally Exposed to Hydrocarbon Solvents and Engine Exhaust Fumes: A Register-Based Nested Case-Control Study from Sweden (1960-2015).

BACKGROUND: It remains unclear whether parental occupational exposure to hydrocarbon solvents (HCS) or engine exhaust fumes (EEF) is associated with higher risks of cancer in the offspring. OBJECTIVES: Our aim was to estimate relative risks of childhood cancers associated with maternal or paternal exposure to aliphatic/alicyclic, aromatic, or chlorinated HCS or gasoline/diesel EEF. METHODS: We conducted a case-control study in which individuals <20y old, born 1960-2014, were identified from the Swedish National Cancer Register (1960-2015) at first cancer diagnosis and matched to population controls (1 case:25 controls) on birth year and sex. Maternal and paternal occupation around the child's birth was retrieved for 9,653 cases and 172,194 controls and 12,521 cases and 274,434 controls, respectively, using information from six censuses and a nationwide register. Using the Swedish job-exposure matrix (SWEJEM), we assessed exposure to HCS and EEF (any or higher/lower). Odds ratios (ORs) and 95% confidence intervals (CIs) of 15 childhood cancer subtypes were estimated using conditional logistic regression models adjusted for several confounders. RESULTS: Maternal exposure to aromatic HCS was associated with non-Hodgkin lymphoma (OR=1.64; 95% CI: 1.05, 2.58), aliphatic/alicyclic HCS with germ cell tumors (OR=1.52; 95% CI: 0.89, 2.59), and gasoline/diesel EEF with astrocytoma (OR=1.40; 95% CI: 1.04, 1.88), myeloid leukemia (OR=1.53; 95% CI: 0.84, 2.81), lymphomas (OR=1.60; 95% CI: 0.85, 3.02 for Hodgkin; OR=1.44; 95% CI: 0.71, 2.91 for non-Hodgkin), and epithelial tumors (OR=1.51; 95% CI: 0.93, 2.44). Paternal exposure to gasoline EEF was associated with Hodgkin lymphoma (OR=1.21; 95% CI: 1.01, 1.44) and soft tissue sarcomas (OR=1.22; 95% CI: 1.00, 1.48). No notable difference was observed between higher and lower exposure. DISCUSSION: Our findings suggest that occupational exposure to HCS or EEF, especially in the mother, may increase the risk of some childhood cancers. They add to the growing literature on adverse effects from HCS and EEF in the child, but replication of these associations in other populations is warranted. https://doi.org/10.1289/EHP11035.

Long-Term Risk of Hospitalization for Somatic Diseases Among Survivors of Childhood Acute Lymphoblastic Leukemia.

BACKGROUND: Survivors of childhood acute lymphoblastic leukemia (ALL) may be at increased long-term risk of hospitalization for somatic diseases. However, large population-based cohort studies with risk estimates for survivors successfully cured without experiencing a relapse or requiring hematopoietic stem cell transplantation (HSCT) are lacking. METHODS: Danish and Swedish patients diagnosed with ALL before age 20 years in 1982-2008 were identified in the national cancer registries. Five-year survivors and matched population comparisons without childhood cancer were followed for hospitalization for 120 somatic disease categories in the national hospital registries from 5 years postdiagnosis until 2017, and disease-specific hospitalization rate ratios (RR) were calculated. The mean cumulative count method was used to estimate the mean number of multiple and recurrent disease-specific hospitalizations per individual. RESULTS: A total of 2024 5-year survivors and 9797 population comparisons were included. The overall hospitalization rate was more than twice as high compared with comparisons (RR = 2.30, 95% confidence interval [CI] = 2.09 to 2.52). At 30 years postdiagnosis, the mean cumulative hospitalization count was 1.69 (95% CI = 1.47 to 1.90) per survivor and 0.80 (95% CI = 0.73 to 0.86) per comparison. In the subcohort without relapse or HSCT (n = 1709), the RR was 1.41 (95% CI = 1.27 to 1.58). CONCLUSIONS: Survivors of childhood ALL were at increased long-term risk for disease-specific hospitalizations; however, in survivors without relapse or HSCT, the rate was only modestly higher than in population comparisons without a childhood cancer. The absolute mean numbers of multiple and recurrent hospitalizations were generally low.

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.

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.

Psychiatric disorders in childhood cancer survivors in Denmark, Finland, and Sweden: a register-based cohort study from the SALiCCS research programme.

BACKGROUND: A childhood cancer diagnosis and treatment-induced somatic late effects can affect the long-term mental health of survivors. We aimed to explore whether childhood cancer survivors are at higher risk of psychiatric disorders later in life than their siblings and the general population. METHODS: In this register-based cohort study (part of the Socioeconomic Consequences in Adult Life after Childhood Cancer [SALiCCS] research programme), we included 5-year survivors of childhood cancer diagnosed before 20 years of age between Jan 1, 1974 and Dec 31, 2011, in Denmark, Finland, and Sweden. In Denmark and Sweden, 94·7% of individuals were born in a Nordic country (ie, Denmark, Finland, Iceland, Norway, or Sweden); similar information was not available in Finland. Data on ethnicity were not collected. Survivors were compared with their siblings and randomly selected individuals from the general population who were matched to the survivors by year of birth, sex, and geographical region. We followed up our study population from 5 years after the childhood cancer diagnosis or corresponding calendar date for matched individuals (the index date) until Aug 11, 2017, and assessed information on hospital contacts for any and specific psychiatric disorders. For siblings, the index date was defined as 5 years from the date on which they were of the same age as their sibling survivor when diagnosed with cancer. FINDINGS: The study population included 18 621 childhood cancer survivors (9934 [53·3%] males and 8687 [46·7%] females), 24 775 siblings (12 594 [50·8%] males and 12 181 [49·2%] females), and 88 630 matched individuals (47 300 [53·4%] males and 41 330 [46·6%] females). The cumulative incidence proportion of having had a psychiatric hospital contact by 30 years of age between Jan 1, 1979, and Aug 11, 2017, was 15·9% (95% CI 15·3-16·5) for childhood cancer survivors, 14·0% (13·5-14·5) for siblings, and 12·7% (12·4-12·9) for matched individuals. Despite a small absolute difference, survivors were at higher relative risk of any psychiatric hospital contact than their siblings (1·39, 1·31-1·48) and matched individuals (hazard ratio 1·34, 95% CI 1·28-1·39). The higher risk persisted at the age of 50 years. Survivors had a higher burden of recurrent psychiatric hospital contacts and had more hospital contacts for different psychiatric disorders than their siblings and the matched individuals. INTERPRETATION: Childhood cancer survivors are at higher long-term risk of psychiatric disorders than their siblings and matched individuals from the general population. To improve mental health and the overall quality of life after childhood cancer, survivorship care should include a focus on early signs of mental health problems, especially among high-risk groups of survivors. FUNDING: NordForsk, Aarhus University, Swedish Childhood Cancer Foundation, Danish Health Foundation, and Swiss National Science Foundation.

Employment status and occupational positions of childhood cancer survivors from Denmark, Finland and Sweden: A Nordic register-based cohort study from the SALiCCS research programme.

BACKGROUND: A childhood cancer diagnosis and late effects of treatment may affect survivors' possibilities of employment or highly skilled occupations later in life. In this study, we compared the employment and occupational status of childhood cancer survivors with population comparisons and siblings. METHODS: In a cohort study based on Nordic registers, we identified 10 461 survivors of childhood cancer diagnosed before age 20 years in Denmark, Finland and Sweden since 1971. Survivors were compared with 48 928 population comparisons matched to survivors by age, sex and geographical region and 12 605 siblings of survivors. Annual outcome information on employment, unemployment, health-related unemployment and occupational position was obtained from the statistical institutes between 1980-2017 and assessed in multivariate logistic regression analyses from age 30 onwards. FINDINGS: By 30 years of age, 9.2% (95% CI, 8.6-9.9%) of survivors were unemployed for health reasons. Childhood cancer survivors had considerably higher odds of health-related unemployment at ages 30, 40 and 50 than population comparisons (ORage30, 2.57; 95% CI, 2.35-2.81) and siblings (ORage30, 2.50; 95% CI, 2.15-2.90). We observed no large difference in unemployment unrelated to health or in occupational position. Health-related unemployment was particularly pronounced among survivors of central nervous system tumours and survivors diagnosed below 15 years of age. INTERPRETATION: Survivors at risk of health-related unemployment should be offered comprehensive survivorship care and interventions for obtaining and maintaining suitable employment. FUNDING: NordForsk [76111], the Danish Childhood Cancer Foundation [2016-0293], Aarhus University [43239402], the Swedish Childhood Cancer Foundation [PR2020-0130] and [OB2019-0003], Tømrermester Jørgen Holm og Hustru Elisa F. Hansens Mindelegat [20088] and the Swiss National Science Foundation to LM [P2LUP3_175288].

Alterations in Biomarkers Related to Glycemia, Lipid Metabolism, and Inflammation up to 20 Years Before Diagnosis of Type 1 Diabetes in Adults: Findings From the AMORIS Cohort.

OBJECTIVE: Type 1 diabetes is described to have an acute onset, but autoantibodies can appear several years preceding diagnosis. This suggests a long preclinical phase, which may also include metabolic parameters. Here we assessed whether elevations in glycemic, lipid, and other metabolic biomarkers were associated with future type 1 diabetes risk in adults. RESEARCH DESIGN AND METHODS: We studied 591,239 individuals from the Swedish AMORIS cohort followed from 1985-1996 to 2012. Through linkage to national patient, diabetes, and prescription registers, we identified incident type 1 diabetes. Using Cox regression models, we estimated hazard ratios for biomarkers at baseline and incident type 1 diabetes. We additionally assessed trajectories of biomarkers during the 25 years before type 1 diabetes diagnosis in a nested case-control design. RESULTS: We identified 1,122 type 1 diabetes cases during follow-up (average age of patient at diagnosis: 53.3 years). The biomarkers glucose, fructosamine, triglycerides, the ratio of apolipoprotein (apo)B to apoA-I, uric acid, alkaline phosphatase, and BMI were positively associated with type 1 diabetes risk. Higher apoA-I was associated with lower type 1 diabetes incidence. Already 15 years before diagnosis, type 1 diabetes cases had higher mean glucose, fructosamine, triglycerides, and uric acid levels compared with control subjects. CONCLUSIONS: Alterations in biomarker levels related to glycemia, lipid metabolism, and inflammation are associated with clinically diagnosed type 1 diabetes risk, and these may be elevated many years preceding diagnosis.

Cohort Profile: The Socioeconomic Consequences in Adult Life After Childhood Cancer in Scandinavia (SALiCCS) Research Programme.

INTRODUCTION: The growing number of survivors of childhood cancer, with many years of life ahead, demonstrates the increasing clinical and public health relevance of investigating the risks of social and socioeconomic impairment after a childhood cancer diagnosis and the life-saving treatment. To enrich understanding of the mental, social and socioeconomic difficulties that childhood cancer survivors may face during their life-course, identify particularly vulnerable survivors and overcome the limitations of previous research, we initiated the Socioeconomic Consequences in Adult Life after Childhood Cancer in Scandinavia (SALiCCS) research programme. METHODS: This Nordic cross-border research programme is a collaboration between the Danish Cancer Society, the Finnish Cancer Registry and Karolinska Institutet to investigate a broad range of mental, social and socioeconomic conditions in long-term childhood cancer survivors in Denmark, Finland and Sweden. SALiCCS is based on a registry-based matched cohort design, comprising five-year survivors of cancer diagnosed at ages 0-19 years (1971-2008 in Denmark, 1971-2009 in Finland, 1971-2011 in Sweden), age-, sex- and country-matched population comparisons and sibling comparisons who were followed over time. Outcomes of interest included mental disorders, educational achievements, employment and profession, family life and the need of social security benefits. Individual-level data linkage among various national registries provided the data for the research programme. RESULTS: The SALiCCS core population comprises 21,292 five-year survivors, 103,303 population comparisons and 29,644 siblings as a second comparison group. The most common diagnoses in survivors were central nervous system tumours, leukaemias and lymphomas. DISCUSSION: SALiCCS is the largest, most comprehensive population-based research initiative in this field, based on high-quality registry data with minimal risk of bias. The findings will be informative for evidence-based survivorship care targeting not only somatic late effects but also psychosocial impairments.