Lifestyle and Subsequent Malignant Neoplasms in Childhood Cancer Survivors: A Report from the St. Jude Lifetime Cohort Study.

INTRODUCTION: This study aimed to assess longitudinal associations between lifestyle and subsequent malignant neoplasms (SMNs) in young adult childhood cancer survivors. METHODS: Members of the St. Jude Lifetime Cohort (SJLIFE) aged ≥18 years and surviving ≥5 years after childhood cancer diagnosis were queried and evaluated for physical activity, cardiorespiratory fitness (CRF), muscle strength, body mass index (BMI), smoking, risky drinking, and a combined lifestyle score. Time to first SMN, excluding nonmalignant neoplasms and nonmelanoma skin cancer, was the outcome of longitudinal analysis. RESULTS: Survivors (n = 4072, 47% female, 29% smokers, 37% risky drinkers, 34% obese, and 48% physically inactive) had a mean (SD) time between baseline evaluation and follow-up of 7.0 (3.3) years, an age of 8.7 (5.7) years at diagnosis, and an age of 30 (8.4) years at baseline lifestyle assessment. Neither individual lifestyle factors nor a healthy lifestyle score (RR 0.8, 0.4-1.3, p = 0.36) were associated with the risk of developing an SMN. CONCLUSIONS: We did not identify any association between lifestyle factors and the risk of SMN in young adult childhood cancer survivors.

Associations between BMI in youth and site-specific cancer in men-A cohort study with register linkage.

OBJECTIVE: This study examined BMI in young men and incident site-specific cancer to estimate population attributable fractions due to BMI based on projected obesity prevalence. METHODS: A population-based cohort study with measured height and weight at age 18. Cox regression models assessed linear associations for BMI and included age, year, and site of conscription as well as parental level of education as covariates. RESULTS: Primary analyses were performed in 1,489,115 men, of whom 78,217 subsequently developed cancer during a mean follow-up of 31 years. BMI was linearly associated with risk of developing all 18 site-specific cancers assessed (malignant melanoma; leukemia; myeloma; Hodgkin lymphoma; non-Hodgkin lymphoma; and cancer in the lungs, head and neck, central nervous system, thyroid, esophagus, stomach, pancreas, liver and gallbladder, colon, rectum, kidney, and bladder), in some instances evident at BMI levels usually defined as normal (20-25 kg/m2 ). Higher BMI was associated with lower risk of prostate cancer. The highest hazard ratios and population attributable fractions were seen for some gastrointestinal cancers. CONCLUSIONS: This study reports linear associations between BMI at age 18 and subsequent site-specific cancers, calling for rapid action to stem the obesity epidemic and to prepare the health care system for steep increases in cancer cases.

Cardiorespiratory fitness and BMI measured in youth and 5-year mortality after site-specific cancer diagnoses in men-A population-based cohort study with register linkage.

BACKGROUND: Our aim was to assess associations between cardiorespiratory fitness (CRF) and body mass index (BMI) in youth and 5-year mortality after site-specific cancer diagnoses in men. METHODS: Men with cancer from a population who underwent military conscription at ages 16-25 during 1968-2005 in Sweden were included. CRF was assessed as maximal aerobic workload on a cycle ergometer test and was classified as low, moderate, or high. BMI (kg/m2 ) was classified as underweight (<18.5), normal weight (18.5-24.9), overweight (25-29.9), or obesity (>30). Conscription data were linked with register data on cancer diagnosis and mortality. Analyses included CRF, BMI, date of diagnosis, and age, year, and center for conscription. RESULTS: A total of 84,621 cancer cases were included. Mean age at diagnosis was 52 years. Follow-up data were available during a mean of 6.5 years. There were linear protective associations between CRF and mortality after any cancer diagnosis (hazard ratio [HR] for high vs. low CRF 0.70), malignant skin cancer (HR 0.80), non-Hodgkin lymphoma (HR 0.78), and cancer in the lungs (HR 0.80), head and neck (HR 0.68), pancreas (HR 0.83), stomach (HR 0.78), liver (HR 0.84), rectum (HR 0.79), and bladder (HR 0.71). Overweight and/or obesity were associated with increased mortality after any cancer (HR for obesity vs. normal weight 1.89), malignant skin cancer (HR 2.03), Hodgkin lymphoma (HR 2.86) and cancer in the head and neck (HR 1.38), thyroid (HR 3.04), rectum (HR 1.53), kidney (HR 1.90), bladder (HR 2.10), and prostate (HR 2.44). CONCLUSION: We report dose-dependent associations between CRF and BMI in youth and mortality after site-specific cancer diagnoses in men. The associations with mortality could be due to both cancer inhibition and an improved tolerance to withstand cancer treatment. These results strengthen the incentive for public health efforts aimed at establishing a high CRF and normal weight in youth.

Associations between cardiorespiratory fitness in youth and the incidence of site-specific cancer in men: a cohort study with register linkage.

OBJECTIVES: To assess the associations between cardiorespiratory fitness (CRF) in young men and the incidence of site-specific cancer. METHODS: A Swedish population-based cohort study with register linkage of men who underwent military conscription in 1968-2005 was undertaken. CRF was assessed by maximal aerobic workload cycle test at conscription. Cox regression models assessed linear associations and included CRF, age, year and site of conscription, body mass index and parental level of education. CRF was also categorised into low, moderate and high for facilitated interpretation and results comparing high and low CRF are reported. RESULTS: Primary analyses were performed in 1 078 000 men, of whom 84 117 subsequently developed cancer in at least one site during a mean follow-up of 33 years. Higher CRF was linearly associated with a lower hazard ratio (HR) of developing cancer in the head and neck (n=2738, HR 0.81, 95% CI 0.74 to 0.90), oesophagus (n=689, HR 0.61, 95% CI 0.50 to 0.74), stomach (n=902, HR 0.79, 95% CI 0.67 to 0.94), pancreas (n=1280, HR 0.88, 95% CI 0.76 to 1.01), liver (n=1111, HR 0.60, 95% CI 0.51 to 0.71), colon (n=3222, HR 0.82, 95% CI 0.75 to 0.90), rectum (n=2337, HR 0.95, 95% CI 0.85 to 1.05), kidney (n=1753, HR 0.80, 95% CI 0.70 to 0.90) and lung (n=1635, HR 0.58, 95% CI 0.51 to 0.66). However, higher CRF predicted a higher hazard of being diagnosed with prostate cancer (n=14 232, HR 1.07, 95% CI 1.03 to 1.12) and malignant skin cancer (n=23 064, HR 1.31, 95% CI 1.27 to 1.36). CONCLUSION: We report a number of protective associations between higher CRF in healthy young men and the subsequent hazard of site-specific cancers. These results have implications for public health policymaking, strengthening the incentive to promote health through improving CRF in youth.

Occupational risks associated with severe COVID-19 disease and SARS-CoV-2 infection - a Swedish national case-control study conducted from October 2020 to December 2021.

OBJECTIVE: This study aimed to investigate whether workplace factors and occupations are associated with SARS-CoV-2 infection or severe COVID-19 in the later waves of the pandemic. METHODS: We studied 552 562 cases with a positive test for SARS-CoV-2 in the Swedish registry of communicable diseases, and 5985 cases with severe COVID-19 based on hospital admissions from October 2020 to December 2021. Four population controls were assigned the index dates of their corresponding cases. We linked job histories to job-exposure matrices to assess the odds for different transmission dimensions and different occupations. We used adjusted conditional logistic analyses to estimate odds ratios (OR) for severe COVID-19 and SARS-CoV-2 with 95% confidence intervals (CI). RESULTS: The highest OR for severe COVID-19 were for: regular contact with infected patients, (OR 1.37, 95% CI 1.23-1.54), close physical proximity (OR 1.47, 95% CI 1.34-1.61), and high exposure to diseases or infections (OR 1.72, 95% CI 1.52-1.96). Mostly working outside had lower OR (OR 0.77, 95% CI 0.57-1.06). The odds for SARS-CoV-2 when mostly working outside were similar (OR 0.83, 95% CI 0.80-0.86). The occupation with the highest OR for severe COVID-19 (compared with low-exposure occupations) was certified specialist physician (OR 2.05, 95% CI 1.31-3.21) among women and bus and tram drivers (OR 2.04, 95% CI 1.49-2.79) among men. CONCLUSIONS: Contact with infected patients, close proximity and crowded workplaces increase the risks for severe COVID-19 and SARS-CoV-2 infection. Outdoor work is associated with decreased odds for SARS-CoV-2 infection and severe COVID-19.

Age and sex differences in cause-specific excess mortality and years of life lost associated with COVID-19 infection in the Swedish population.

BACKGROUND: Estimating excess mortality and years of life lost (YLL) attributed to coronavirus disease 19 (COVID-19) infection provides a comprehensive picture of the mortality burden on society. We aimed to estimate the impact of the COVID-19 pandemic on age- and sex-specific excess mortality and YLL in Sweden during the first 17 months of the pandemic. METHODS: In this population-based observational study, we calculated age- and sex-specific excess all-cause mortality and excess YLL during 2020 and the first 5 months of 2021 and cause-specific death [deaths from cardiovascular disease (CVD), cancer, other causes and deaths excluding COVID-19] in 2020 compared with an average baseline for 2017-19 in the whole Swedish population. RESULTS: COVID-19 deaths contributed 9.9% of total deaths (98 441 deaths, 960 305 YLL) in 2020, accounting for 75 151 YLL (7.7 YLL/death). There were 2672 (5.7%) and 1408 (3.0%) excess deaths, and 19 141 (3.8%) and 3596 (0.8%) excess YLL in men and women, respectively. Men aged 65-110 years and women aged 75-110 years were the greatest contributors. Fewer deaths and YLL from CVD, cancer and other causes were observed in 2020 compared with the baseline adjusted to the population size in 2020. CONCLUSIONS: Compared with the baseline, excess mortality and YLL from all causes were experienced in Sweden during 2020, with a higher excess observed in men than in women, indicating that more men died at a younger age while more women died at older ages than expected. A notable reduction in deaths and YLL due to CVD suggests a displacement effect from CVD to COVID-19.

Occupational outcomes after high-grade or low-grade brain tumors in childhood: A Swedish, nationwide, registry-based study.

BACKGROUND: Survivors of pediatric brain tumors are at high risk of late complications that may affect their daily life in both short- and long-term perspectives. METHODS: In this nationwide registry-based study we explored the occupational outcomes, including employment, sickness or activity compensation and parental leave, in 452 individuals in Sweden, born 1988-1996, and diagnosed with a brain tumor before their 15th birthday. Their results were compared with 2188 matched controls. RESULTS: There were significant differences between cases and controls for all assessed variables. The cases had benefitted from sickness or activity compensation 11 times more often than controls (CI 7.90-15.83; p < 0.001) between 2005 and 2016. Controls were almost three times more likely to have an employment (OR 0.36; CI 0.28-0.47; p < 0.001) and nearly twice as likely to have been on parental leave (OR 0.56; CI 0.39-0.80; p = 0.002). Although cases treated for high-grade tumors typically fared worse than those treated for low-grade tumors, significant differences for all assessed variables were also observed for cases treated for a low-grade tumor compared with controls. CONCLUSIONS: Our findings emphasize the need for follow-up programs for all brain tumor diagnoses, not only those known to be at most risk. This is evident, for example, from the high number of cases who received sickness or activity compensation.

Post-Compulsory Education in Teenagers and Young Adults Treated for Brain Tumors in Childhood: A Swedish Nationwide Registry-Based Study.

The risk of late complications after a brain tumor in childhood is high. Both the tumor itself and the treatments give rise to sequelae that affect daily life activities. In this registry study, we explored post-compulsory education, i.e., further education following the nine compulsory years in school, in 452 cases born 1988-1996 and diagnosed with a brain tumor before their fifteenth birthday. They were compared with 2188 individual controls who were not treated for cancer. Significantly fewer teenagers and young adults treated for brain tumors in childhood attended high school or university compared with controls, especially individuals treated for embryonal tumors or optic pathway gliomas. A significantly larger proportion of subjects treated for embryonal tumors and craniopharyngiomas attended folk high schools, a type of post-compulsory school with a more accessible learning environment. For both cases and controls, we observed a positive correlation between parental education levels and attendance in high school and university. In our previous studies we have shown that children treated for brain tumors, as a group, tend to perform worse during their last year of compulsory school compared with their peers, and the current study confirms that these differences remain over time.

High IQ in Early Adulthood Is Associated with Parkinson's Disease.

BACKGROUND: High education level and high occupational complexity have been implicated as risk factors for Parkinson's disease (PD). OBJECTIVE: The objective was to determine whether cognitive capacity, measured as IQ, in early adulthood is associated with the subsequent development of PD. METHOD: Data on IQ were retrieved from the Swedish Military Service Conscription Registry, comprising Swedish males who enlisted for military service in the period 1968-1993 (N = 1,319,235). After exclusion, 1,189,134 subjects in total were included in the present study. Individuals who later developed PD (N = 1,724) were identified using the Swedish National Patient Register and the Swedish Cause of Death Register. RESULTS: High education level was associated with PD. High IQ was associated with PD (p < 0.0001), both when analyzed as a continuous variable and when divided into three categories. The hazard ratio for the high IQ category compared to the low IQ category was 1.35 (95% confidence interval 1.17-1.55). Strong test results on the subtests, measuring verbal, logic, visuospatial and technical abilities, were also associated with PD. In a subgroup, smoking was inversely associated with PD, as well as with IQ. CONCLUSIONS: This study identifies high IQ to be a risk factor for PD.

Body Mass Index in Young Women and Risk of Cardiomyopathy: A Long-Term Follow-Up Study in Sweden.

BACKGROUND: Incidence rates of cardiomyopathies, which are a common cause of heart failure in young people, have increased during the last decades. An association between body weight in adolescence and future cardiomyopathy among men was recently identified. Whether or not this holds true also for women is unknown. The aim was therefore to determine whether for young women being overweight or obese is associated with a higher risk of developing cardiomyopathy. METHODS: This was a registry-based national prospective cohort study with data collected from the Swedish Medical Birth Register, 1982 to 2014, with up to 33 years of follow-up. Included women were of childbearing age (18-45 years) during the initial antenatal visit in their first or second pregnancy (n=1 393 346). We obtained baseline data on body mass index (BMI), smoking, education, and previous disorders. After exclusions, mainly because of previous disorders, the final sample was composed of 1 388 571 women. Cardiomyopathy cases were identified by linking the Medical Birth Register to the National Patient and Cause of Death registers. RESULTS: In total, we identified 1699 cases of cardiomyopathy (mean age at diagnosis, 46.2 [SD 9.1] years) during the follow-up with an incidence rate of 5.9 per 100 000 observation years. Of these, 481 were diagnosed with dilated cardiomyopathy, 246 had hypertrophic cardiomyopathy, 61 had alcohol/drug-induced cardiomyopathy, and 509 had other forms. The lowest risk for being diagnosed with a cardiomyopathy was detected at a BMI of 21 kg/m2, with a gradual increase in risk with higher BMI, particularly for dilated cardiomyopathy, where a hazard ratio of 4.71 (95% CI, 2.81-7.89) was found for severely obese subjects (BMI ≥35 kg/m2), as compared with BMI 20 to <22.5. CONCLUSIONS: Elevated BMI among young women was associated with an increased risk of being diagnosed with a subsequent cardiomyopathy, especially dilated cardiomyopathy, starting already at mildly elevated body weight, whereas severe obesity entailed an almost 5-fold increase in risk. With the increasing numbers of persons who are overweight or obese, higher rates of cardiomyopathy can be expected in the future, along with an altered disease burden related to adiposity.

No clinically relevant effect on cognitive outcomes after low-dose radiation to the infant brain: a population-based cohort study in Sweden.

UNLABELLED: While the detrimental effects of cranial radiotherapy on the developing brain are well known, the effects on cognitive performance of low doses of ionizing radiation is less studied. We performed a population-based cohort study to determine whether low doses of ionizing radiation to the brain in infancy affects cognitive function later in life. Further we hypothesized that the dose to the hippocampus predicts cognitive late side effects better than the anterior or the posterior brain doses. MATERIAL AND METHODS: During 1950-1960 3860 boys were treated with radiation in Sweden for cutaneous hemangiomas before the age of 18 months. Of these, 3030 were analyzed for military test scores at the age of 18 years and 2559 for the highest obtained educational level. RESULTS: Logical, spatial and technical test scores were not affected by increasing irradiation doses. The verbal test scores displayed a significant trend for decreasing scores with increasing doses to the hippocampus (p = 0.005). However, the absolute mean difference between the zero dose and the highest dose category (median 680 mGy) was very small, only 0.64 stanine points, and the significance was dependent on the highest dose category, containing few subjects. The educational level was not affected by brain irradiation. Overall, the hippocampal dose was a better predictor of late cognitive side effects than the doses to the anterior or the posterior brain. In conclusion, there was no decrease in logical, spatial and technical verbal or global test scores after ionizing radiation doses up to 250 mGy, but a subtle decrease in verbal test scores if the highest dose category was included (median 680 mGy). However, the clinical relevance of this decline in the highest dose group is questionable, since we could not find any effect on the highest obtained educational level.

Clinical evaluation of a resorbable wrap-around implant as an alternative to nerve repair: a prospective, assessor-blinded, randomised clinical study of sensory, motor and functional recovery after peripheral nerve repair.

Peripheral nerve injures are common and often result in impaired functional recovery. The majority of injuries involve the arm and/or the hand. The traditional treatment for peripheral nerve injuries is repair by using microsurgical techniques, either by primary nerve suture or nerve graft, but research to find more successful methods that could improve recovery is ongoing. Tubulisation has been investigated by several authors and is suggested as an alternative to microsurgical techniques. The resorbable poly[(R)-3-hydroxybutyrate] (PHB) is one of the materials that has been previously tested experimentally. In this prospective, randomised, assessor-blinded clinical study, PHB was investigated as an alternative to epineural suturing in the treatment of peripheral nerve injuries at the wrist/forearm level of the arm. Twelve patients, with a complete, common, sharp injury of the median and/or ulnar nerve at the wrist/forearm level, were treated by either using PHB or microsurgical epineural end-to-end suturing. All patients were assessed using a battery of tests, including evaluation of functional, sensory and motor recovery by means of clinical, neurophysiological, morphological and physiological evaluations at 2 weeks and 3, 6, 9, 12 and 18 months after surgery. No adverse events or complications considered as product related were reported, and thus PHB can be regarded as a safe alternative for microsurgical epineural suturing. The majority of the methods in the test battery showed no significant differences between the treatment groups, but one should consider that the study involved a limited number of patients and a high variability was reported for the evaluating techniques. However, sensory recovery, according to the British Medical Research Council score and parts of the manual muscle test, suggested that treating with PHB may be advantageous as compared to epineural suturing. This, however, should be confirmed by large-scale efficacy studies.

Proliferative and protective effects of growth hormone secretagogues on adult rat hippocampal progenitor cells.

Progenitor cells in the subgranular zone of the hippocampus may be of significance for functional recovery after various injuries because they have a regenerative potential to form new neuronal cells. The hippocampus has been shown to express the GH secretagogue (GHS) receptor 1a, and recent studies suggest GHS to both promote neurogenesis and have neuroprotective effects. The aim of the present study was to investigate whether GHS could stimulate cellular proliferation and exert cell protective effects in adult rat hippocampal progenitor (AHP) cells. Both hexarelin and ghrelin stimulated increased incorporation of (3)H-thymidine, indicating an increased cell proliferation. Furthermore, hexarelin, but not ghrelin, showed protection against growth factor deprivation-induced apoptosis, as measured by annexin V binding and caspase-3 activity and also against necrosis, as measured by lactate dehydrogenase release. Hexarelin activated the MAPK and the phosphatidylinositol 3-kinase/Akt pathways, whereas ghrelin activated only the MAPK pathway. AHP cells did not express the GHS receptor 1a, but binding studies could show specific binding of both hexarelin and ghrelin, suggesting effects to be mediated by an alternative GHS receptor subtype. In conclusion, our results suggest a differential effect of hexarelin and ghrelin in AHP cells. We have demonstrated stimulation of (3)H-thymidine incorporation with both hexarelin and ghrelin. Hexarelin, but not ghrelin, also showed a significant inhibition of apoptosis and necrosis. These results suggest a novel cell protective and proliferative role for GHS in the central nervous system.

Insulin-like growth factor-I and neurogenesis in the adult mammalian brain.

In most brain regions of highly developed mammals, the majority of neurogenesis is terminated soon after birth. However, new neurons are continually generated throughout life in the subventricular zone and the dentate gyrus of the hippocampus. Insulin-like growth factor-I (IGF-I) is a polypeptide hormone that has demonstrated effects on these progenitor cells. IGF-I induces proliferation of isolated progenitors in culture, as well as affecting various aspects of neuronal induction and maturation. Moreover, systemic infusion of IGF-I increases both proliferation and neurogenesis in the adult rat hippocampus, and uptake of serum IGF-I by the brain parenchyma mediates the increase in neurogenesis induced by exercise. Neurogenesis in the adult brain is regulated by many factors including aging, chronic stress, depression and brain injury. Aging is associated with reductions in both hippocampal neurogenesis and IGF-I levels, and administration of IGF-I to old rats increases neurogenesis and reverses cognitive impairments. Similarly, stress and depression also inhibit neurogenesis, possibly via the associated reductions in serotonin or increases in circulating glucocorticoids. As both of these changes have the potential to down regulate IGF-I production by neural cells, stress may inhibit neurogenesis indirectly via downregulation of IGF-I. In contrast, brain injury stimulates neurogenesis, and is associated with upregulation of IGF-I in the brain. Thus, there is a tight correlation between IGF-I and neurogenesis in the adult brain under different conditions. Further studies are needed to clarify whether IGF-I does indeed mediate neurogenesis in these situations.