Partial substitution of red meat or processed meat with plant-based foods and the risk of colorectal cancer.

OBJECTIVES: Shifting from animal-based to plant-based diets could reduce colorectal cancer (CRC) incidence. Currently, the impacts of these dietary shifts on CRC risk are ill-defined. Therefore, we examined partial substitutions of red or processed meat with whole grains, vegetables, fruits or a combination of these in relation to CRC risk in Finnish adults. METHODS: We pooled five Finnish cohorts, resulting in 43 788 participants aged ≥ 25 years (79% men). Diet was assessed by validated food frequency questionnaires at study enrolment. We modelled partial substitutions of red (100 g/week) or processed meat (50 g/week) with corresponding amounts of plant-based foods. Cohort-specific hazard ratios (HR) for CRC were calculated using Cox proportional hazards models and pooled together using random-effects models. Adjustments included age, sex, energy intake and other relevant confounders. RESULTS: During the median follow-up of 28.8 years, 1124 CRCs were diagnosed. We observed small risk reductions when red meat was substituted with vegetables (HR 0.97, 95% CI 0.95 - 0.99), fruits (0.97, 0.94 - 0.99), or whole grains, vegetables and fruits combined (0.97, 0.95 - 0.99). For processed meat, these substitutions yielded 1% risk reductions. Substituting red or processed meat with whole grains was associated with a decreased CRC risk only in participants with < median whole grain intake (0.92, 0.86 - 0.98; 0.96, 0.93 - 0.99, respectively; pinteraction=0.001). CONCLUSIONS: Even small, easily implemented substitutions of red or processed meat with whole grains, vegetables or fruits could lower CRC risk in a population with high meat consumption. These findings broaden our insight into dietary modifications that could foster CRC primary prevention.

The burden of colon cancer attributable to modifiable factors-The Norwegian Women and Cancer Study.

Colon cancer is the second most frequently diagnosed cancer in women in Norway, where incidence rates of colon cancer increased 3-fold between 1955 and 2014, for unknown reasons. We aimed to assess the burden of colon cancer attributable to modifiable risk factors in Norwegian women using the data from the Norwegian Women and Cancer (NOWAC) study. Self-reported information from 35 525 women from the NOWAC study were available. These included the following exposures: smoking status, alcohol consumption, body mass index, physical activity, intake of calcium, fibers, and red and processed meat. Colon cancer cases were identified from the Cancer Registry of Norway. A parametric piecewise constant hazards model was used to estimate the strength of exposure-cancer associations. Population attributable fractions with 95% confidence intervals (CIs) were calculated considering competing risk of death. The fraction of incident colon cancer attributable to ever smoking was 18.7% (95% CI 4.7%-30.6%), low physical activity 10.8% (95% CI -0.7% to 21.0%), alcohol consumption 14.5% (95% CI -2.8% to 28.9%), and low intake of calcium 10.0% (95% CI -7.8% to 24.8%). A small proportion of colon cancer cases was attributable to combined intake of red and processed meat over 500 g/week, overweight/obesity, and low intake of fibers. Jointly, these seven risk factors could explain 46.0% (95% CI 23.0%-62.4%) of the colon cancer incidence burden. Between 23% and 62% of the colon cancer burden among women in Norway was attributable to modifiable risk factors, indicating an important preventive potential of a healthy lifestyle.

The future burden of oesophageal and stomach cancers attributable to modifiable behaviours in Australia: a pooled cohort study.

BACKGROUND: We quantified the individual and joint contribution of contemporaneous causal behavioural exposures on the future burden of oesophageal and stomach cancers and their subtypes and assessed whether these burdens differ between population groups in Australia, as such estimates are currently lacking. METHODS: We combined hazard ratios from seven pooled Australian cohorts (N = 367,058) linked to national cancer and death registries with exposure prevalence from the 2017-2018 National Health Survey to estimate Population Attributable Fractions (PAFs) with 95% confidence intervals (CIs), accounting for competing risk of death. RESULTS: Current and past smoking explain 35.2% (95% CI = 11.7-52.4%), current alcohol consumption exceeding three drinks/day 15.7% (95% CI = 0.9-28.4%), and these exposures jointly 41.4% (95% CI = 19.8-57.3%) of oesophageal squamous cell carcinomas in Australia. Current and past smoking contribute 38.2% (95% CI = 9.4-57.9%), obesity 27.0% (95% CI = 0.6-46.4%), and these exposures jointly 54.4% (95% CI = 25.3-72.1%) of oesophageal adenocarcinomas. Overweight and obesity explain 36.1% (95% CI = 9.1-55.1%), current and past smoking 24.2% (95% CI = 4.2-40.0%), and these exposures jointly 51.2% (95% CI = 26.3-67.8%) of stomach cardia cancers. Several population groups had a significantly higher smoking-attributable oesophageal cancer burden, including men and those consuming excessive alcohol. CONCLUSIONS: Smoking is the leading preventable behavioural cause of oesophageal cancers and overweight/obesity of stomach cancers.

Thyroid cancers potentially preventable by reducing overweight and obesity in Australia: A pooled cohort study.

Thyroid cancer incidence and the prevalence of overweight and obesity are increasing, but the future thyroid cancer burden attributable to contemporary levels of overweight and obesity has not been evaluated before. We quantified this burden in Australia, and assessed whether the overweight/obesity-attributable burden differed by sex or other population subgroupings. We estimated the strength of the associations of overweight and obesity with thyroid cancer with adjusted proportional hazards models using pooled data from seven Australian cohorts (N = 367 058) with 431 thyroid cancer cases ascertained from linked national cancer registry data during a maximum 22-year follow-up. We combined these estimates with nationally representative 2017 to 2018 estimates of overweight and obesity prevalence to estimate population attributable fractions (PAFs) of future thyroid cancers attributable to overweight and obesity, accounting for competing risk of death, and compared PAFs for population subgroups. Contemporary levels of overweight and obesity explain 18.6% (95% confidence interval [CI] = 5.2%-30.2%), and obesity alone 13.7% (95% CI: 5.2%-21.4%), of the future thyroid cancer burden. The obesity-attributable thyroid cancer burden is 21.4% (95% CI: 2.8%-36.5%) for men and 10.1% (95% CI: 0.8%-18.6%) for women. Were the currently obese overweight instead, 9.9% (95% CI: 1.0%-18.1%) of thyroid cancers could be avoided. The relative overweight/obesity-attributable burden is higher for those consuming on average more than two alcoholic drinks per day (63.4%) and for those who are not married/co-habiting (33.2%). In conclusion, avoiding excess weight, especially obesity, should be a priority for thyroid cancer prevention. Further studies, with findings stratified by tumour size, may reveal the potential role of overdiagnosis in our results.

Incidence trends and risk factors of lung cancer in never smokers: Pooled analyses of seven cohorts.

The trends in incidence of lung cancer in never smokers are unclear as well as the significance of risk factors. We studied time trends in the incidence and risk factors of lung cancer in never smokers in Finland in a large, pooled cohort. We pooled data from seven Finnish health cohorts from the period between 1972 and 2015 with 106 193 never smokers. The harmonised risk factors included education, alcohol consumption, physical activity, height and BMI. We retrieved incident lung cancers from the nation-wide Finnish Cancer Registry. We estimated average annual percent change (AAPC) and the effects of risk factors on cause-specific hazard ratios (HRs) of lung cancer using Poisson regression. We detected 47 lung cancers in never smoking men (n = 31 859) and 155 in never smoking women (n = 74 334). The AAPC of lung cancer incidence was -3.30% (95% confidence interval [CI]: -5.68% to -0.88%, P = .009) in never smoking men and 0.00% (95% CI: -1.57% to 1.60%, P = .996) in never smoking women. Of the five studied risk factors only greater height in women had a statistically significant increased risk of lung cancer (multivariate HR = 1.84, 95%CI: 1.08 to 3.12). It is plausible that tobacco control measures focused on working places have reduced passive smoking among men more than among women, which could explain the declining trend in lung cancer incidence in never smoker men but not in never smoker women. As tobacco control measures have not been targeted to domestic environments, it is likely that women's exposure to passive smoking has continued longer.

Cancer incidence and cancer death in relation to tobacco smoking in a population-based Australian cohort study.

Tobacco smoke is a known carcinogen, but the magnitude of smoking-related cancer risk depends on country-specific, generational smoking patterns. We quantified cancer risk in relation to smoking in a population-based cohort, the 45 and Up Study (2006-2009) in New South Wales, Australia. Cox proportional hazards regressions estimated adjusted hazard ratios (HR) by self-reported smoking history at baseline (2006-2009) for incident, primary cancers via linkage to cancer registry data to 2013 and cancer death data to 2015. Among 229 028 participants aged ≥45 years, 18 475 cancers and 5382 cancer deaths occurred. Current-smokers had increased risks of all cancers combined (HR = 1.42, 95% confidence interval [CI], 1.34-1.51), cancers of the lung (HR = 17.66, 95%CI, 14.65-21.29), larynx (HR = 11.29, 95%CI, 5.49-23.20), head-and-neck (HR = 2.53, 95%CI, 1.87-3.41), oesophagus (HR = 3.84, 95%CI, 2.33-6.35), liver (HR = 4.07, 95%CI, 2.55-6.51), bladder (HR = 3.08, 95%CI, 2.00-4.73), pancreas (HR = 2.68, 95%CI, 1.93-3.71), colorectum (HR = 1.31, 95%CI, 1.09-1.57) and unknown primary site (HR = 3.26, 95%CI, 2.19-4.84) versus never-smokers. Hazards increased with increasing smoking intensity; compared to never-smokers, lung cancer HR = 9.22 (95%CI, 5.14-16.55) for 1-5 cigarettes/day and 38.61 (95%CI, 25.65-58.13) for >35 cigarettes/day. Lung cancer risk was lower with quitting at any age but remained higher than never-smokers for quitters aged >25y. By age 80y, an estimated 48.3% of current-smokers (41.1% never-smokers) will develop cancer, and 14% will develop lung cancer, including 7.7% currently smoking 1-5 cigarettes/day and 26.4% for >35 cigarettes/day (1.0% never-smokers). Cancer risk for Australian smokers is significant, even for 'light' smokers. These contemporary estimates underpin the need for continued investment in strategies to prevent smoking uptake and facilitate cessation, which remain key to reducing cancer morbidity and mortality worldwide.

The future burden of kidney and bladder cancers preventable by behavior modification in Australia: A pooled cohort study.

Substantial changes in the prevalence of the principal kidney and bladder cancer risk factors, smoking (both cancers) and body fatness (kidney cancer), have occurred but the contemporary cancer burden attributable to these factors has not been evaluated. We quantified the kidney and bladder cancer burden attributable to individual and joint exposures and assessed whether these burdens differ between population subgroups. We linked pooled data from seven Australian cohorts (N = 367,058) to national cancer and death registries and estimated the strength of the associations between exposures and cancer using adjusted proportional hazards models. We estimated exposure prevalence from representative contemporaneous health surveys. We combined these estimates to calculate population attributable fractions (PAFs) with 95% confidence intervals (CIs), accounting for competing risk of death, and compared PAFs for population subgroups. During the first 10-year follow-up, 550 kidney and 530 bladder cancers were diagnosed and over 21,000 people died from any cause. Current levels of overweight and obesity explain 28.8% (CI = 17.3-38.7%), current or past smoking 15.5% (CI = 6.0-24.1%) and these exposures jointly 39.6% (CI = 27.5-49.7%) of the kidney cancer burden. Current or past smoking explains 44.4% (CI = 35.4-52.1%) of the bladder cancer burden, with 24.4% attributable to current smoking. Ever smoking explains more than half (53.4%) of the bladder cancer burden in men, and the burden potentially preventable by quitting smoking is highest in men (30.4%), those aged <65 years (28.0%) and those consuming >2 standard alcoholic drinks/day (41.2%). In conclusion, large fractions of kidney and bladder cancers in Australia are preventable by behavior change.

The preventable burden of breast cancers for premenopausal and postmenopausal women in Australia: A pooled cohort study.

Estimates of the future breast cancer burden preventable through modifications to current behaviours are lacking. We assessed the effect of individual and joint behaviour modifications on breast cancer burden for premenopausal and postmenopausal Australian women, and whether effects differed between population subgroups. We linked pooled data from six Australian cohort studies (n = 214,536) to national cancer and death registries, and estimated the strength of the associations between behaviours causally related to cancer incidence and death using adjusted proportional hazards models. We estimated exposure prevalence from representative health surveys. We combined these estimates to calculate Population Attributable Fractions (PAFs) with 95% confidence intervals (CIs), and compared PAFs for population subgroups. During the first 10 years follow-up, there were 640 incident breast cancers for premenopausal women, 2,632 for postmenopausal women, and 8,761 deaths from any cause. Of future breast cancers for premenopausal women, any regular alcohol consumption explains 12.6% (CI = 4.3-20.2%), current use of oral contraceptives for ≥5 years 7.1% (CI = 0.3-13.5%), and these factors combined 18.8% (CI = 9.1-27.4%). Of future breast cancers for postmenopausal women, overweight or obesity (BMI ≥25 kg/m2 ) explains 12.8% (CI = 7.8-17.5%), current use of menopausal hormone therapy (MHT) 6.9% (CI = 4.8-8.9%), any regular alcohol consumption 6.6% (CI = 1.5-11.4%), and these factors combined 24.2% (CI = 17.6-30.3%). The MHT-related postmenopausal breast cancer burden varied by body fatness, alcohol consumption and socio-economic status, the body fatness-related postmenopausal breast cancer burden by alcohol consumption and educational attainment, and the alcohol-related postmenopausal breast cancer burden by breast feeding history. Our results provide evidence to support targeted and population-level cancer control activities.

The preventable burden of endometrial and ovarian cancers in Australia: A pooled cohort study.

OBJECTIVE: Evidence on the endometrial and ovarian cancer burden preventable through modifications to current causal behavioural and hormonal exposures is limited. Whether the burden differs by population subgroup is unknown. METHODS: We linked pooled data from six Australian cohort studies to national cancer and death registries, and quantified exposure-cancer associations using adjusted proportional hazards models. We estimated exposure prevalence from representative health surveys. We then calculated Population Attributable Fractions (PAFs) with 95% confidence intervals (CIs), accounting for competing risk of death, and compared PAFs for population subgroups. RESULTS: During a median 4.9 years follow-up, 510 incident endometrial and 303 ovarian cancers were diagnosed. Overweight and obesity explained 41.9% (95% CI 32.3-50.1) of the endometrial cancer burden and obesity alone 34.5% (95% CI 27.5-40.9). This translates to 12,800 and 10,500 endometrial cancers in Australia in the next 10 years, respectively. The body fatness-related endometrial cancer burden was highest (49-87%) among women with diabetes, living remotely, of older age, lower socio-economic status or educational attainment and born in Australia. Never use of oral contraceptives (OCs) explained 8.1% (95% CI 1.8-14.1) or 2500 endometrial cancers. A higher BMI and current long-term MHT use increased, and long-term OC use decreased, the risk of ovarian cancer, but the burden attributable to overweight, obesity or exogenous hormonal factors was not statistically significant. CONCLUSIONS: Excess body fatness, a trait that is of high and increasing prevalence globally, is responsible for a large proportion of the endometrial cancer burden, indicating the need for effective strategies to reduce adiposity.

Longitudinal immunosuppression data can minimize misclassification bias in solid organ transplantation cohorts.

BACKGROUND: Most cohort studies investigating the effect of immunosuppression on transplant outcomes use drugs at first hospital discharge. We evaluated the extent of drug exposure misclassification and its impact on outcome prediction. METHODS: We retrospectively collected longitudinal immunosuppression data, at discharge and at 1, 5, 10, and 15 years after transplantation, and outcomes for solid organ transplant recipients 1984-2006 (n = 3133). We compared the risk of death from exposure to individual immunosuppressive drugs (cyclosporine, tacrolimus, azathioprine, and mycophenolate) and dual therapies, as defined by discharge only vs longitudinal immunosuppression data, using adjusted Cox proportional hazards models. RESULTS: During a median follow-up of 5.2 years, immunosuppressive drugs were altered for 947 (30%) recipients and 955 recipients died. Longitudinal receipt of cyclosporine and azathioprine were associated with an increased risk (HR 1.41, 95% CI 1.07-1.89, and HR 1.34, 95% CI 1.00-1.80), and mycophenolate with a reduced risk (HR 0.35, 0.16-0.78), of death. Recipients on mycophenolate and tacrolimus dual therapy had a lower risk of death compared to those on azathioprine and cyclosporine dual therapy (HR 0.30, 0.10-0.93). The increased risk of death associated with the receipt of cyclosporine or azathioprine was not shown in the analyses based on drugs allocated at discharge, and all of the associations between immunosuppressive regimens and death were strengthened in the analyses based on longitudinal immunosuppression data. CONCLUSIONS: Cohort findings based on immunosuppressive drugs allocated at discharge should be interpreted with caution due to potential exposure misclassification. The use of granular, longitudinal data on immunosuppressive regimens could improve prediction.

The burden of pancreatic cancer in Australia attributable to smoking.

OBJECTIVE: To estimate the burden of pancreatic cancer in Australia attributable to modifiable exposures, particularly smoking. DESIGN: Prospective pooled cohort study. SETTING, PARTICIPANTS: Seven prospective Australian study cohorts (total sample size, 365 084 adults); participant data linked to national registries to identify cases of pancreatic cancer and deaths. MAIN OUTCOME MEASURES: Associations between exposures and incidence of pancreatic cancer, estimated in a proportional hazards model, adjusted for age, sex, study, and other exposures; future burden of pancreatic cancer avoidable by changes in exposure estimated as population attributable fractions (PAFs) for whole population and for specific population subgroups with a method accounting for competing risk of death. RESULTS: There were 604 incident cases of pancreatic cancer during the first 10 years of follow-up. Current and recent smoking explained 21.7% (95% CI, 13.8-28.9%) and current smoking alone explained 15.3% (95% CI, 8.6-22.6%) of future pancreatic cancer burden. This proportion of the burden would be avoidable over 25 years were current smokers to quit and there were no new smokers. The burden attributable to current smoking is greater for men (23.9%; 95% CI, 13.3-33.3%) than for women (7.2%; 95% CI, -0.4% to 14.2%; P = 0.007) and for those under 65 (19.0%; 95% CI, 8.1-28.6%) than for older people (6.6%; 95% CI, 1.9-11.1%; P = 0.030). There were no independent relationships between body mass index or alcohol consumption and pancreatic cancer. CONCLUSIONS: Strategies that reduce the uptake of smoking and encourage current smokers to quit could substantially reduce the future incidence of pancreatic cancer in Australia, particularly among men.

FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals.

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.

Iatrogenic immunosuppression and risk of non-Hodgkin lymphoma in solid organ transplantation: A population-based cohort study in Australia.

Iatrogenic immunosuppression is a strong risk factor for non-Hodgkin lymphoma (NHL) but the dose-related association between individual immunosuppressive agents and NHL risk is unknown. We conducted a population-based cohort study of 4131 adult Australian liver, heart and lung transplant recipients (1984-2006). We ascertained NHL incidence by probabilistic record linkage between transplant registries and the Australian Cancer Database, and abstracted risk factor data at transplantation and at regular intervals thereafter from medical records. We estimated adjusted hazard ratios (HR) for early (<1 year after transplantation; n = 29) and late (≥1 year; n = 61) NHL using the Fine and Gray proportional subdistribution hazards model that accounted for death as a competing risk. After adjustment for immunosuppression, the risk of both early and late NHL did not significantly differ by organ type. In final models, higher mean daily doses of azathioprine were associated with increased risk of both early [HR 2·20, 95% confidence interval (CI): 1·21-4·01] and late NHL (HR 1·78, 95% CI: 1·12-2·84). There was no association between any other maintenance immunosuppressive agent and NHL risk. This study provides evidence that differences in immunosuppression may explain variation in NHL incidence by organ type, and high doses of azathioprine may independently predict NHL risk.

High azathioprine dose and lip cancer risk in liver, heart, and lung transplant recipients: A population-based cohort study.

BACKGROUND: Iatrogenic immunosuppression is a risk factor for lip cancer but the determinants are unknown. OBJECTIVE: We sought to quantify the association between the type, dose, and duration of iatrogenic immunosuppression and lip cancer risk in solid organ transplant recipients. METHODS: We conducted a population-based cohort study of all adult Australian liver, heart, and lung transplant recipients from 1984 to 2006 (n = 4141). We abstracted longitudinal data from medical records and ascertained incident lip cancer (n = 58) and deaths (n = 1434) by linkage with national registries. We estimated multivariable hazard ratios (HR) for lip cancer using the Fine and Gray proportional subdistribution hazards model, accounting for death as a competing risk. RESULTS: Lip cancer risk (n = 58) increased with high mean daily dose of azathioprine (HR 2.28, 95% confidence interval [CI] 1.18-4.38), longer duration of immunosuppression (HR 9.86, 95% CI 2.10-46.3), increasing year of age at transplantation (HR 1.14, 95% CI 1.04-1.25), earlier transplantation era (HR 8.73, 95% CI 1.11-68.7), and history of smoking (HR 2.71, 95% CI 1.09-6.70). LIMITATIONS: Data on potential confounders such as personal solar ultraviolet radiation exposure were not available. CONCLUSION: Higher doses of azathioprine increase lip cancer risk, with implications for managing immunosuppressed populations and our understanding of the relationship between solar ultraviolet radiation and lip cancer.

Longitudinal dose and type of immunosuppression in a national cohort of Australian liver, heart, and lung transplant recipients, 1984-2006.

Unconfounded comparative data on the type and dose of immunosuppressive agents among solid organ transplant recipients are sparse, as are data on longitudinal immunosuppressive therapy since transplantation. We addressed this issue in a population-based cohort of Australian liver (n = 1895), heart (n = 1220), and lung (n = 1059) transplant recipients, 1984-2006. Data on immunosuppressive therapy were retrospectively collected at discharge, three months, and one, five, 10, and 15 yr after first transplant. We computed unadjusted and adjusted estimates for the association between the type and dose of immunosuppressive therapy and organ type. After adjustment for confounders, use of induction antibody and maintenance corticosteroids was more common in heart and lung compared to liver recipients (p < 0.001), and antibody therapy for rejection more common in liver recipients (p < 0.001). Liver recipients were more likely to receive calcineurin inhibitor monotherapy, with or without corticosteroids, compared to heart and lung recipients (p < 0.001). Liver recipients consistently received lower doses of azathioprine than heart and lung recipients (p < 0.001). These differences in immunosuppression may partly explain variations in immunosuppression-related morbidity by transplanted organ, for example, malignancy risk. Longitudinal changes in the type and the dose of immunosuppressive therapy over time since transplantation also demonstrate the need for time-dependent data in observational research.

Sensitivity and specificity of automated detection of early repolarization in standard 12-lead electrocardiography.

BACKGROUND: Early repolarization (ER) is defined as an elevation of the QRS-ST junction in at least two inferior or lateral leads of the standard 12-lead electrocardiogram (ECG). Our purpose was to create an algorithm for the automated detection and classification of ER. METHODS: A total of 6,047 electrocardiograms were manually graded for ER by two experienced readers. The automated detection of ER was based on quantification of the characteristic slurring or notching in ER-positive leads. The ER detection algorithm was tested and its results were compared with manual grading, which served as the reference. RESULTS: Readers graded 183 ECGs (3.0%) as ER positive, of which the algorithm detected 176 recordings, resulting in sensitivity of 96.2%. Of the 5,864 ER-negative recordings, the algorithm classified 5,281 as negative, resulting in 90.1% specificity. Positive and negative predictive values for the algorithm were 23.2% and 99.9%, respectively, and its accuracy was 90.2%. Inferior ER was correctly detected in 84.6% and lateral ER in 98.6% of the cases. CONCLUSIONS: As the automatic algorithm has high sensitivity, it could be used as a prescreening tool for ER; only the electrocardiograms graded positive by the algorithm would be reviewed manually. This would reduce the need for manual labor by 90%.

A metabolic shift favoring sphingosine 1-phosphate at the expense of ceramide controls glioblastoma angiogenesis.

Studies in cell culture and mouse models of cancer have indicated that the soluble sphingolipid metabolite sphingosine 1-phosphate (S1P) promotes cancer cell proliferation, survival, invasiveness, and tumor angiogenesis. In contrast, its metabolic precursor ceramide is prodifferentiative and proapoptotic. To determine whether sphingolipid balance plays a significant role in glioma malignancy, we undertook a comprehensive analysis of sphingolipid metabolites in human glioma and normal gray matter tissue specimens. We demonstrate, for the first time, a systematic shift in sphingolipid metabolism favoring S1P over ceramide, which increases with increasing cancer grade. S1P content was, on average, 9-fold higher in glioblastoma tissues compared with normal gray matter, whereas the most abundant form of ceramide in the brain, C18 ceramide, was on average 5-fold lower. Increased S1P content in the tumors was significantly correlated with increased sphingosine kinase 1 (SPHK1) and decreased sphingosine phosphate phosphatase 2 (SGPP2) expression. Inhibition of S1P production by cultured glioblastoma cells, using a highly potent and selective SPHK1 inhibitor, blocked angiogenesis in cocultured endothelial cells without affecting VEGF secretion. Our findings validate the hypothesis that an altered ceramide/S1P balance is an important feature of human cancers and support the development of SPHK1 inhibitors as antiangiogenic agents for cancer therapy.

Pairwise association of key lifestyle factors and risk of solid cancers - A prospective pooled multi-cohort register study.

Smoking, alcohol consumption, obesity, and physical inactivity are key lifestyle risk factors for cancer. Previously these have been mostly examined singly or combined as an index, assuming independent and equivalent effects to cancer risk. The aim of our study was to systematically examine the joint pairwise and interactive effects of these lifestyle factors on the risk of a first solid primary cancer in a multi-cohort prospective setting. We used pooled data from seven Finnish health survey studies during 1972-2015, with 197,551 participants diagnosed with 16,373 solid malignant primary tumors during follow-up. Incidence of any cancer was analyzed separately without and with lung cancers using Poisson regression with main and interaction effects of key lifestyle factors. When excluding lung cancer, the highest risk of any cancer in men was observed for smokers with a BMI of ≥25 kg/m2 (HR 1.36, 95 % CI 1.25-1.48) and in women for smokers consuming alcohol (HR 1.22, 1.14-1.30). No statistically significant interactions between any studied risk factor pairs were observed. When including lung cancer, the highest HRs among men were observed for smokers who consume alcohol (HR 1.72, 1.57-1.89) and among women for smokers who were physically inactive (HR 1.38, 1.27-1.49). Smoking combined with other lifestyle factors at any exposure level resulted in highest pairwise risks, both in men and women. These results highlight the importance of smoking prevention, but also the importance of preventing obesity and reducing alcohol consumption.

Every tenth malignant solid tumor attributed to overweight and alcohol consumption: A population-based cohort study.

BACKGROUND: Recent studies have shown that some four in ten cancers are attributable to a few key risk factors. The aim of this study was to estimate cohort-based population attributable fractions (PAFs) in Finland for potentially modifiable cancer risk factors. METHODS: Data from eight health studies including 253,953 subjects with 29,802 incident malignant solid tumors were analysed using Bayesian multivariate regression model with multiplicative risk factor effects. We estimated the effects of smoking, excess body weight, alcohol consumption, physical activity, parity and education on cancer incidence and related PAFs by cancer site, accounting for competing mortality. RESULTS: PAF for all cancer sites and exposures combined was 34% (95% credible interval 29%-39%) in men and 24% (19%-28%) in women. In men, 23% (21%-27%) and in women 8% (6%-9%) of all cancers were attributed to smoking. PAF related to excess body weight was 4% (2%-6%) in men and 5% (2%-7%) in women, to alcohol 7% (3%-10%) in men and 4% (0%-7%) in women, and to excess body weight and alcohol combined 10% (6%-15%) in men and 9% (4%-13%) in women. CONCLUSION: Smoking was the most important factor contributing to cancer burden in Finnish men and women over the last 40 years. The contribution of excess body weight and alcohol consumption together outweighed the role of smoking in women. As the prevalence of overweight is expected to increase, more efficient public health measures supporting adherence to healthy weight are essential to reduce cancer burden.