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Objectives: The public does not always understand key information conveyed by epidemiologists and statisticians. The purpose of this study was to understand the level of public access to, trust in, and comprehension of, cancer statistics through a population-based survey in Japan., Methods: We used an online research method, requesting online responses to a 15-question questionnaire. The survey was sent to males and females aged 20 years and older, selected by sex, age and prefecture to match the national population proportions shown in the latest census. The final number of valid responses was 10 477. The statistical analyses mainly used χ2 testing., Results: Respondents were not frequently exposed to cancer statistics regardless of sex or age group, nor did they necessarily have confidence in the statistics. The increase of collected information and trust in cancer statistics was aligned with increasing age and cancer exposure. Respondents found Relative Risk and Relative Survival Rate easier to understand and more useful than the Standardized Incidence Ratio. In addition, those with cancer experience, higher income and were elderly gave more accurate responses when asked questions related to cancer incidence and probability of getting cancer., Conclusions: Our respondents showed limited familiarity with cancer statistical indicators. Enhanced awareness of indicators such as infographics and visual tools has the potential to enhance cancer visibility, thereby promoting public prevention and early detection efforts. Educating cancer patients about pertinent indicators can boost their confidence in managing their condition. Conversely, the introduction of indicators unrelated to the public should be discouraged., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

An East Asian-specific variant on aldehyde dehydrogenase 2 ( ALDH2 rs671, G>A) is the major genetic determinant of alcohol consumption. We performed an rs671 genotype-stratified genome-wide association study meta-analysis of alcohol consumption in 175,672 Japanese individuals to explore gene-gene interactions with rs671 behind drinking behavior. The analysis identified three genome-wide significant loci ( GCKR , KLB , and ADH1B ) in wild-type homozygotes and six ( GCKR , ADH1B , ALDH1B1 , ALDH1A1 , ALDH2 , and GOT2 ) in heterozygotes, with five showing genome-wide significant interaction with rs671. Genetic correlation analyses revealed ancestry-specific genetic architecture in heterozygotes. Of the discovered loci, four ( GCKR , ADH1B , ALDH1A1 , and ALDH2 ) were suggested to interact with rs671 in the risk of esophageal cancer, a representative alcohol-related disease. Our results identify the genotype-specific genetic architecture of alcohol consumption and reveal its potential impact on alcohol-related disease risk.

Cancer registry data provide a very important source of information for improving our understanding of the epidemiology of various cancers. In this work, we estimated the 5-year crude probabilities of death from cancer and from other causes for five common cancers, namely stomach, lung, colon-rectum, prostate and breast, in Japan, using population-based registry data. Based on data on 344 676 patients diagnosed with one of these cancers between 2006 and 2008 in 21 prefectures participating in the Monitoring of Cancer Incidence in Japan (MCIJ) and followed-up for at least 5 years, we used a flexible excess hazard model to compute the crude probabilities of death for different combinations of sex, age and stage at diagnosis. For tumours diagnosed at the distant stage, as well as for regional lung tumours, the vast majority of deaths at 5 years in cancer patients were attributable to the disease itself (although this proportion was only around 60% in older prostate cancer patients). For localised and most regional tumours, the impact of other causes of death on the total mortality increased with age at diagnosis, especially for localised breast, colorectal and gastric cancer. By allowing the partition of the mortality experience of cancer patients into a cancer- and an other-cause-specific component, crude probability of death estimates provide insight into how the impact of cancer on mortality might differ among populations with different background mortality risks. This might be useful for informing discussions between clinicians and patients about treatment options., (© 2023 UICC.)

Background: The head and neck cancers (HNCs) incidence differs between Europe and East Asia. Our objective was to determine whether survival of HNC also differs between European and Asian countries., Methods: We used population-based cancer registry data to calculate 5-year relative survival (RS) for the oral cavity, hypopharynx, larynx, nasal cavity, and major salivary gland in Europe, Taiwan, and Japan. We modeled RS with a generalized linear model adjusting for time since diagnosis, sex, age, subsite, and histological grouping. Analyses were performed using federated learning, which enables analyses without sharing sensitive data., Findings: Five-year RS for HNC varied between geographical areas. For each HNC site, Europe had a lower RS than both Japan and Taiwan. HNC subsites and histologies distribution and survival differed between the three areas. Differences between Europe and both Asian countries persisted even after adjustments for all HNC sites but nasal cavity and paranasal sinuses, when comparing Europe and Taiwan., Interpretation: Survival differences can be attributed to different factors including different period of diagnosis, more advanced stage at diagnosis, or different availability/access of treatment. Cancer registries did not have stage and treatment information to further explore the reasons of the observed survival differences. Our analyses have confirmed federated learning as a feasible approach for data analyses that addresses the challenges of data sharing and urge for further collaborative studies including relevant prognostic factors., Competing Interests: LL declares research funds to the institute for clinical studies from Astrazeneca, BMS, Boehringer Ingelheim, Celgene International, Eisai, Exelixis, Debiopharm International SA, Hoffmann-La Roche ltd, IRX Therapeutics, Medpace, Merck-Serono, MSD, Novartis, Pfizer, Roche, Buran, Alentis; occasional fees for participation as a speaker at conferences/congresses or as a scientific consultant for advisory boards from Astrazeneca, Bayer, MSD, Merck-Serono, AccMed, Neutron Therapeutics, Inc. GGe received grants or contracts from Astra-Zeneca, Janssen, Roche, Health~Holland TKI; KWF Dutch Cancer Society and European Commission. AG received grants or contracts from KWF Dutch Cancer Society and European Commission. AG and GGe have patents assigned to Royal Philips. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Botta, Matsuda, Charvat, Chiang, Lee, van Gestel, Martin, Geleijnse, Cellamare, Bonfarnuzzo, Marcos-Gragera, Guevara, Mousavi, Craig, Rodrigues, Rubió-Casadevall, Licitra, Cavalieri, Resteghini, Gatta, Trama and the RARECAREnet working group.)

Background: Gastric cancer risk can be accurately predicted by measuring the methylation level of a single marker gene in gastric mucosa. However, the mechanism is still uncertain. We hypothesized that the methylation level measured reflects methylation alterations in the entire genome (methylation burden), induced by Helicobacter pylori (H. pylori) infection, and thus cancer risk., Methods: Gastric mucosa of 15 healthy volunteers without H. pylori infection (G1), 98 people with atrophic gastritis (G2), and 133 patients with gastric cancer (G3) after H. pylori eradication were collected. Methylation burden of an individual was obtained by microarray analysis as an inverse of the correlation coefficient between the methylation levels of 265,552 genomic regions in the person's gastric mucosa and those in an entirely healthy mucosa., Results: The methylation burden significantly increased in the order of G1 (n = 4), G2 (n = 18), and G3 (n = 19) and was well correlated with the methylation level of a single marker gene (r = 0.91 for miR124a-3). The average methylation levels of nine driver genes tended to increase according to the risk levels (P = 0.08 between G2 vs G3) and was also correlated with the methylation level of a single marker gene (r = 0.94). Analysis of more samples (14 G1, 97 G2, and 131 G3 samples) yielded significant increases of the average methylation levels between risk groups., Conclusions: The methylation level of a single marker gene reflects the methylation burden, which includes driver gene methylation, and thus accurately predicts cancer risk., (© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: Population-based cancer registry (PBCR) data provide crucial information for evaluating the effectiveness of cancer services and reflect prospects for cure by estimating population-based cancer survival. This study provides long-term trends in survival among patients diagnosed with cancer in the Barretos region (São Paulo State, Brazil)., Methods: In this population-based study, we estimated the one- and five-year age-standardized net survival rates of 13,246 patients diagnosed with 24 different cancer types in Barretos region between 2000 and 2018. The results were presented by sex, time since diagnosis, disease stage, and period of diagnosis., Results: Marked differences in the one- and five-year age-standardized net survival rates were observed across the cancer sites. Pancreatic cancer had the lowest 5-year net survival (5.5 %, 95 %CI: 2.9-9.4) followed by oesophageal cancer (5.6 %, 95 %CI: 3.0-9.4), while prostate cancer ranked the best (92.1 %, 95 %CI: 87.8-94.9), followed by thyroid cancer (87.4 %, 95 %CI: 69.9-95.1) and female breast cancer (78.3 %, 95 %CI: 74.5-81.6). The survival rates differed substantially according to sex and clinical stage. Comparing the first (2000-2005) and last (2012-2018) periods, cancer survival improved, especially for thyroid, leukemia, and pharyngeal cancers, with differences of 34.4 %, 29.0 %, and 28.7 %, respectively., Conclusion: To our knowledge, this is the first study to evaluate long-term cancer survival in the Barretos region, showing an overall improvement over the last two decades. Survival varied by site, indicating the need for multiple cancer control actions in the future with a lower burden of cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests related to the study “Cancer survival in the northwestern of São Paulo state, Brazil: a population-based study”., (Copyright © 2023. Published by Elsevier Ltd.)

In the presence of competing causes of event occurrence (e.g., death), the interest might not only be in the overall survival but also in the so-called net survival, that is, the hypothetical survival that would be observed if the disease under study were the only possible cause of death. Net survival estimation is commonly based on the excess hazard approach in which the hazard rate of individuals is assumed to be the sum of a disease-specific and expected hazard rate, supposed to be correctly approximated by the mortality rates obtained from general population life tables. However, this assumption might not be realistic if the study participants are not comparable with the general population. Also, the hierarchical structure of the data can induces a correlation between the outcomes of individuals coming from the same clusters (e.g., hospital, registry). We proposed an excess hazard model that corrects simultaneously for these two sources of bias, instead of dealing with them independently as before. We assessed the performance of this new model and compared it with three similar models, using extensive simulation study, as well as an application to breast cancer data from a multicenter clinical trial. The new model performed better than the others in terms of bias, root mean square error, and empirical coverage rate. The proposed approach might be useful to account simultaneously for the hierarchical structure of the data and the non-comparability bias in studies such as long-term multicenter clinical trials, when there is interest in the estimation of net survival., (© 2023 The Authors. Biometrical Journal published by Wiley-VCH GmbH.)

Background: Over the last 50 years, occupational exposure to carcinogenic agents has been widely regulated in France., Objective: Report population-attributable fraction (PAF) and number of attributable cancer cases linked to occupational exposure in France based on an updated method to estimate lifetime occupational exposure prevalence., Methods: Population-level prevalence of lifetime exposure to ten carcinogenic agents (asbestos, benzene, chromium VI, diesel engine exhaust, formaldehyde, nickel compounds, polycyclic aromatic hydrocarbons, silica dust, trichloroethylene, wood dust) and two occupational circumstances (painters and rubber industry workers) were estimated using the French Census linked with MATGÉNÉ job-exposure matrices and French occupational surveys. PAF and number of attributable cancer cases were calculated using the estimated prevalence, relative risks from systematic review and national estimates of cancer incidence in 2017., Results: The lifetime occupational exposure prevalences were much higher in men than in women ranging from 0.2% (workers in the rubber industry) to 10.2% in men (silica), and from 0.10% (benzene, PAH and workers in the rubber industry) to 5.7% in women (formaldehyde). In total, 4,818 cancer cases (men: 4,223; women: 595) were attributable to the ten studied carcinogens and two occupational circumstances, representing 5.2% of cases among the studied cancer sites (M: 7.0%; W: 1.9%). In both sexes, mesothelioma (M: 689 cases; W: 160) and lung cancer (M: 3,032; W: 308) were the largest cancer sites impacted by the studied occupational agents and circumstances., Significance: A moderate proportion of the cancer cases in France is linked to carcinogens in occupational settings. Our method provides more precise estimates of attributable cancer taking into account evolution of exposure to occupational agents by sex, age and time. This methodology can be easily replicated using cross-sectional occupational data to aid priority making and implementation of prevention strategies in the workplace., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: We evaluated the association between total soy, soy product (natto, miso and tofu) and isoflavone intake and incident disabling dementia in a Japanese population., Methods: We conducted a population-based prospective study in 18,991 men and 22,456 women. Intake of soy products and isoflavone was calculated using a validated food frequency questionnaire when participants were 45-74 years old (1995 and 1998). Incident disabling dementia was defined by the daily living disability status related to dementia in the long-term care insurance program of Japan from 2006 to 2016. Multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) of disabling dementia were calculated by quintiles of total soy, individual soy product and isoflavone intake, using Cox proportional hazard regression models., Results: Total soy product intake was not associated with disabling dementia risk in both men and women. By individual soy products, natto intake was marginally inversely associated with disabling dementia in women (trend P = 0.050). When we stratified by age, this inverse association was clearer in women aged under 60 years (multivariate HR for the highest versus lowest quintile was 0.78, 95% CI 0.59-1.04, trend P = 0.020 for those aged under 60 years and 0.90, 95% CI 0.77-1.05, trend P = 0.23 for those aged 60 years and older, respectively). Any soy product or isoflavone intake was not associated with disabling dementia risk in men., Conclusions: Although total soy product intake was not associated with disabling dementia risk, natto intake may contribute to reducing the risk of disabling dementia in women, especially in those aged under 60 years., (© 2022. The Author(s).)

Background: Reducing socioeconomic inequalities in cancer is a priority for the public health agenda. A systematic assessment and benchmarking of socioeconomic inequalities in cancer across many countries and over time in Europe is not yet available., Methods: Census-linked, whole-of-population cancer-specific mortality data by socioeconomic position, as measured by education level, and sex were collected, harmonized, analysed, and compared across 18 countries during 1990-2015, in adults aged 40-79. We computed absolute and relative educational inequalities; temporal trends using estimated-annual-percentage-changes; the share of cancer mortality linked to educational inequalities., Findings: Everywhere in Europe, lower-educated individuals have higher mortality rates for nearly all cancer-types relative to their more highly-educated counterparts, particularly for tobacco/infection-related cancers [relative risk of lung cancer mortality for lower- versus higher-educated = 2.4 (95% confidence intervals: 2.1-2.8) among men; = 1.8 (95% confidence intervals: 1.5-2.1) among women]. However, the magnitude of inequalities varies greatly by country and over time, predominantly due to differences in cancer mortality among lower-educated groups, as for many cancer-types higher-educated have more similar (and lower) rates, irrespective of the country. Inequalities were generally greater in Baltic/Central/East-Europe and smaller in South-Europe, although among women large and rising inequalities were found in North-Europe (relative risk of all cancer mortality for lower- versus higher-educated ≥1.4 in Denmark, Norway, Sweden, Finland and the England/Wales). Among men, rate differences (per 100,000 person-years) in total-cancer mortality for lower-vs-higher-educated groups ranged from 110 (Sweden) to 559 (Czech Republic); among women from approximately null (Slovenia, Italy, Spain) to 176 (Denmark). Lung cancer was the largest contributor to inequalities in total-cancer mortality (between-country range: men, 29-61%; women, 10-56%). 32% of cancer deaths in men and 16% in women (but up to 46% and 24%, respectively in Baltic/Central/East-Europe) were associated with educational inequalities., Interpretation: Cancer mortality in Europe is largely driven by levels and trends of cancer mortality rates in lower-education groups. Even Nordic-countries, with a long-established tradition of equitable welfare and social justice policies, witness increases in cancer inequalities among women. These results call for a systematic measurement, monitoring and action upon the remarkable socioeconomic inequalities in cancer existing in Europe., Funding: This study was done as part of the LIFEPATH project, which has received financial support from the European Commission (Horizon 2020 grant number 633666), and the DEMETRIQ project, which received support from the European Commission (grant numbers FP7-CP-FP and 278511). SV and WN were supported by the French Institut National du Cancer (INCa) (Grant number 2018-116). PM was supported by the Academy of Finland (#308247, # 345219) and the European Research Council under the European Union's Horizon 2020 research and innovation programme (grant agreement No 101019329). The work by Mall Leinsalu was supported by the Estonian Research Council (grant PRG722)., Competing Interests: We declare no competing interests., (© 2022 Published by Elsevier Ltd.)

We aimed to explore the underlying reasons that estimates of overdiagnosis vary across and within low-dose computed tomography (LDCT) lung cancer screening trials. We conducted a systematic review to identify estimates of overdiagnosis from randomised controlled trials of LDCT screening. We then analysed the association of Ps (the excess incidence of lung cancer as a proportion of screen-detected cases) with postscreening follow-up time using a linear random effects meta-regression model. Separately, we analysed annual Ps estimates from the US National Lung Screening Trial (NLST) and German Lung Cancer Screening Intervention Trial (LUSI) using exponential decay models with asymptotes. We conducted stratified analyses to investigate participant characteristics associated with Ps using the extended follow-up data from NLST. Among 12 overdiagnosis estimates from 8 trials, the postscreening follow-up ranged from 3.8 to 9.3 years, and Ps ranged from -27.0% (ITALUNG, 8.3 years follow-up) to 67.2% (DLCST, 5.0 years follow-up). Across trials, 39.1% of the variation in Ps was explained by postscreening follow-up time. The annual changes in Ps were -3.5% and -3.9% in the NLST and LUSI trials, respectively. Ps was predicted to plateau at 2.2% for NLST and 9.2% for LUSI with hypothetical infinite follow-up. In NLST, Ps increased with age from -14.9% (55-59 years) to 21.7% (70-74 years), and time trends in Ps varied by histological type. The findings suggest that differences in postscreening follow-up time partially explain variation in overdiagnosis estimates across lung cancer screening trials. Estimates of overdiagnosis should be interpreted in the context of postscreening follow-up and population characteristics., (© 2022 The World Health Organization. The World Health Organization retains copyright and all other rights in the manuscript of this article as submitted for publication.)

Epstein-Barr virus (EBV) is one of the risk factors of nasopharyngeal carcinoma (NPC), and understanding the modifiable risk factors of EBV activation is crucial in the prevention of NPC. In this study, we aimed to investigate the association between solid fuel use and EBV seropositivity in a high-risk area of NPC. Our study was based on the baseline findings from an ongoing population-based prospective cohort in Sihui county in Southern China. We explored the association between current use of solid fuel in cooking and EBV seropositivity, and NPC-related EBV activation, using logistic regression models. Stratification analyses were further conducted to assess potential effect modifiers. We also examined the impact of frequency and duration of solid fuel use, and switch in fuel types, on EBV seropositivity among ever users. Of the 12,579 participants included in our analysis, 4088 (32.5%) were EBV seropositive and 421 (3.3%) were high risk for NPC-related EBV activation. Solid fuel use was associated with a higher risk of EBV seropositivity and NPC-related EBV activation, with odds ratios (ORs) of 1.33 (95%CI: 1.01, 1.76) and 1.81 (95%CI: 1.03, 3.18), respectively. Higher risk of EBV seropositivity was observed for those who did not use ventilation apparatus and those who consumed salted food. Among ever users, OR was highest for participants with more than 40 years of solid fuel exposure (1.17, 95%CI: 1.00-1.37) and who have been constantly using solid fuel (1.30, 95%CI: 0.96-1.75). We did not find a statistically significant impact of cooking frequency on EBV seropositivity. The identification of solid fuel as a risk factor for EBV activation is of great value for understanding the etiology of NPC. Our findings also have important public health implications given the fact that a third of the global population still lack access to clean cooking, especially in low resource settings., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Body mass index (BMI) and cardiometabolic comorbidities such as cardiovascular disease and type 2 diabetes have been studied as negative prognostic factors in cancer survival, but possible dependencies in the mechanisms underlying these associations remain largely unexplored. We analysed these associations in colorectal and breast cancer patients., Methods: Based on repeated BMI assessments of cancer-free participants from four European countries in the European Prospective Investigation into Cancer and nutrition (EPIC) study, individual BMI-trajectories reflecting predicted mean BMI between ages 20 to 50 years were estimated using a growth curve model. Participants with incident colorectal or breast cancer after the age of 50 years were included in the survival analysis to study the prognostic effect of mean BMI and cardiometabolic diseases (CMD) prior to cancer. CMD were defined as one or more chronic conditions among stroke, myocardial infarction, and type 2 diabetes. Hazard ratios (HRs) and confidence intervals (CIs) of mean BMI and CMD were derived using multivariable-adjusted Cox proportional hazard regression for mean BMI and CMD separately and both exposures combined, in subgroups of localised and advanced disease., Results: In the total cohort of 159,045 participants, there were 1,045 and 1,620 eligible patients of colorectal and breast cancer. In colorectal cancer patients, a higher BMI (by 1 kg/m2) was associated with a 6% increase in risk of death (95% CI of HR: 1.02-1.10). The HR for CMD was 1.25 (95% CI: 0.97-1.61). The associations for both exposures were stronger in patients with localised colorectal cancer. In breast cancer patients, a higher BMI was associated with a 4% increase in risk of death (95% CI: 1.00-1.08). CMDs were associated with a 46% increase in risk of death (95% CI: 1.01-2.09). The estimates and CIs for BMI remained similar after adjustment for CMD and vice versa., Conclusions: Our results suggest that cumulative exposure to higher BMI during early to mid-adulthood was associated with poorer survival in patients with breast and colorectal cancer, independent of CMD prior to cancer diagnosis. The association between a CMD diagnosis prior to cancer and survival in patients with breast and colorectal cancer was independent of BMI., (© 2022. The Author(s).)

Background: Many epidemiological studies have reported the association between exposure to particulate matter and mortality, but long-term prospective studies from Asian populations are sparse. Furthermore, associations at low levels of air pollution are not well clarified. Here, we evaluated associations between long-term exposure to particulate matter <2.5 µg/m 3 (PM 2.5 ) and mortality in a Japanese cohort with a relatively low exposure level., Methods: The Japan Public Health Center-based Prospective Study (JPHC Study) is a prospective cohort study of men and women aged 40-69 years in 1990 who were followed up through 2013 for mortality. In this cohort of 87,385 subjects who did not move residence during follow-up, average PM 2.5 levels from 1998 to 2013 by linkage with 1-km 2 grids of PM 2.5 concentration were assigned to the residential addresses of all participants. To avoid exposure misclassification, we additionally evaluated the association between 5-year (1998-2002) cumulative exposure level and mortality during the follow-up period from 2003 to 2013 in 79,078 subjects. Cox proportional hazards models were used to calculate the association of long-term exposure to PM 2.5 on mortality, with adjustment for several individual confounding factors., Results: Average PM 2.5 was 11.6 µg/m 3 . Average PM 2.5 exposure was not associated with all-cause mortality or cancer and respiratory disease mortality. However, average PM 2.5 was positively associated with mortality from cardiovascular disease (hazard ratio (HR) of 1.23 (95%CI=1.08-1.40) per 1-µg/m 3 increase; in particular, HR in mortality from cerebrovascular disease was 1.34 (95%CI=1.11-1.61) per 1-µg/m 3 increase. Additionally, these results using cumulative 5-year PM 2.5 data were similar to those using average PM 2.5 over 15 years., Conclusions: We found evidence for a positive association between PM 2.5 exposure and mortality from cardiovascular disease in a Japanese population, even in an area with relatively low-level air pollution., (© 2022. The Author(s).)

Importance: The associations of daily total physical activity and total moderate to vigorous physical activity (MVPA) with dementia are still unclear., Objective: To investigate the association between daily total physical activity and subsequent risk of disabling dementia in large-scale, extended follow-up prospective study., Design, Setting, and Participants: This prospective cohort study used data from questionnaires collected between 2000 and 2003 from 8 areas from the Japan Public Health Center-based Prospective Disabling Dementia Study. Participants included adults aged 50 to 79 years in with available follow-up data on disabling dementia. Data analysis was performed from February 1, 2019, to July 31, 2021., Exposures: Daily total physical activity, total MVPA, and leisure-time MVPA., Main Outcomes and Measures: The main outcome was incidence of disabling dementia during the dementia ascertainment period between 2006 and 2016, based on the national long-term care insurance system. Risks of dementia in association with daily total physical activity, total MVPA, and leisure time MVPA were calculated using multivariable adjusted hazard ratios (aHRs)., Results: Among 43 896 participants (mean [SD] age, 61.0 [7.5] years; 23 659 [53.9%] women), 5010 participants were newly diagnosed with disabling dementia during a mean (SD) of 9.5 (2.8) years in the dementia ascertainment period. In the highest daily total physical activity group, compared with the lowest activity group, risk of dementia was lower in men (aHR, 0.75 [95% CI, 0.66-0.85]; P for trend < .001) and women (aHR, 0.75 [95% CI, 0.67-0.84]; P for trend < .001). Similar inverse associations were observed in men and women for total MVPA (men: aHR, 0.74 [95% CI, 0.65-0.84]; P for trend < .001; women: aHR, 0.74 [95% CI, 0.66-0.83]; P for trend < .001) and leisure-time MVPA (men: aHR, 0.59 [95% CI, 0.53-0.67]; P for trend < .001; women: aHR, 0.70 [95% CI, 0.63-0.78]; P for trend < .001). However, these inverse associations disappeared when participants diagnosed with disabling dementia within 7 years of the starting point were excluded in men (aHR, 0.93 [95%CI, 0.77-1.12]) and within 8 years were excluded in women (aHR, 0.86 [95%CI, 0.71-1.04]). The association remained significant among men in the highest vs lowest group of leisure-time MVPA, after excluding participants diagnosed within the first 9 years (aHR, 0.72 [95% CI, 0.56-0.92]; P for trend = .004)., Conclusions and Relevance: This cohort study examined associations of daily total physical activity and total MVPA with risk of disabling dementia. The findings suggest that a high level of leisure-time MVPA was associated with decreased risk of disabling dementia in men.

Background: Here, we explore the association between excess weight during early to mid-adulthood and survival in patients diagnosed with breast and colorectal cancer, using a pooled analysis of five cohort studies and study participants from 11 countries., Methods: Participant-level body mass index (BMI) trajectories were estimated by fitting a growth curve model using over 2 million repeated BMI measurements from close to 600,000 cohort participants. Cumulative measures of excess weight were derived. Data from over 23,000 patients with breast and colorectal cancer were subsequently analyzed using time-to-event models for death with the date of diagnosis as start of follow-up. Study-specific results were combined through a random effect meta-analysis., Results: We found a significant dose-response relationship ( P trend = 0.013) between the average BMI during early and mid-adulthood and death from breast cancer, with a pooled HR of 1.31 (1.07-1.60) and the time to death shortened by 16% for average BMI above 25 kg/m 2 compared with average BMI less than or equal to 22.5 kg/m 2 , respectively. Similar results were found for categories of cumulative time spent with excess weight. There was no association between excess body fatness during early to mid-adulthood and death in patients with colorectal cancer., Conclusions: Excess body fatness during early to mid-adulthood is associated not only with an increased risk of developing cancer, but also with a lower survival in patients with breast cancer., Impact: Our results emphasize the importance of public health policies aimed at reducing overweight during adulthood and inform future studies on the relationship between excess weight and cancer outcomes., (©2021 American Association for Cancer Research.)

Background: Previous prospective studies of associations between circulating inflammation-related molecules and pancreatic cancer risk have included limited numbers of markers., Methods: We conducted a case-cohort study nested within the Japan Public Health Center-based Prospective Study Cohort II. We selected a random subcohort ( n = 774) from a total of 23,335 participants aged 40 to 69 years who returned a questionnaire and provided blood samples at baseline. During the follow-up period from 1993 to 2010, we identified 111 newly diagnosed pancreatic cancer cases, including one case within the subcohort. Plasma concentrations of 62 inflammatory markers of chemokines, cytokines, and growth factors were measured by a Luminex fluorescent bead-based assay. Cox regression models were applied to estimate HR and 95% confidence intervals (CI) for pancreatic cancer risk for quartiles of marker levels adjusted for potential confounders., Results: The HR (95% CI) for the highest versus the lowest category of C-C motif ligand chemokine 8/monocyte chemoattractant protein 2 (CCL8/MCP2) was 2.03 (1.05-3.93; P trend = 0.048). After we corrected for multiple comparisons, none of the examined biomarkers were associated with pancreatic cancer risk at P -value <0.05., Conclusions: We found no significant associations between 62 inflammatory markers and pancreatic cancer risk., Impact: The suggestive association with circulating levels of leukocyte recruiting cytokine CCL8/MCP2 may warrant further investigation., (©2021 American Association for Cancer Research.)

Background: Country-specific evidence is needed to guide decisions regarding whether and how to implement lung cancer screening in different settings. For this study, we estimated the potential numbers of individuals screened and lung cancer deaths prevented in Brazil after applying different strategies to define screening eligibility., Methods: We applied the Lung Cancer Death Risk Assessment Tool (LCDRAT) to survey data on current and former smokers (ever-smokers) in 15 Brazilian state capital cities that comprise 18% of the Brazilian population. We evaluated three strategies to define eligibility for screening: (1) pack-years and cessation time (≥30 pack-years and <15 years since cessation); (2) the LCDRAT risk model with a fixed risk threshold; and (3) LCDRAT with age-specific risk thresholds., Findings: Among 2.3 million Brazilian ever-smokers aged 55-79 years, 21,459 (95%CI 20,532-22,387) lung cancer deaths were predicted over 5 years without screening. Applying the fixed risk-based eligibility definition would prevent more lung cancer deaths than the pack-years definition [2,939 (95%CI 2751-3127) vs. 2,500 (95%CI 2318-2681) lung cancer deaths], and with higher screening efficiency [NNS=177 (95%CI 170-183) vs. 205 (95%CI 194-216)], but would tend to screen older individuals [mean age 67.8 (95%CI 67.5-68.2) vs. 63.4 (95%CI 63.0-63.9) years]. Applying age-specific risk thresholds would allow younger ever-smokers to be screened, although these individuals would be at lower risk. The age-specific thresholds strategy would avert three-fifths (60.1%) of preventable lung cancer deaths [ N  = 2629 (95%CI 2448-2810)] by screening 21.9% of ever-smokers., Interpretation: The definition of eligibility impacts the efficiency of lung cancer screening and the mean age of the eligible population. As implementation of lung screening proceeds in different countries, our analytical framework can be used to guide similar analyses in other contexts. Due to limitations of our models, more research would be needed., Competing Interests: The authors declare no competing interests., (© 2021 Published by Elsevier Ltd.)

Objective: We described the role of patient-related and clinical factors on age disparities in colon cancer survival among patients aged 50-99 using New Zealand population-based cancer registry data linked to hospitalisation data., Method: We included 21,270 new colon cancer cases diagnosed between 1 January 2006 and 31 July 2017, followed up to end 2019. We modelled the effect of age at diagnosis, sex, ethnicity, deprivation, comorbidity, and emergency presentation on colon cancer survival by stage at diagnosis using flexible excess hazard regression models., Results: The excess mortality in older patients was minimal for localised cancers, maximal during the first six months for regional cancers, the first eighteen months for distant cancers, and over the three years for missing stages. The age pattern of the excess mortality hazard varied according to sex for distant cancers, emergency presentation for regional and distant cancers, and comorbidity for cancer with missing stages. Ethnicity and deprivation did not influence age disparities in colon cancer survival., Conclusion: Factors reflecting timeliness of cancer diagnosis most affected age-related disparities in colon cancer survival, probably by impacting treatment strategy. Because of the high risk of poor outcomes related to treatment in older patients, efforts made to improve earlier diagnosis in older patients are likely to help reduce age disparities in colon cancer survival in New Zealand., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Alcohol use is causally linked to multiple cancers. We present global, regional, and national estimates of alcohol-attributable cancer burden in 2020 to inform alcohol policy and cancer control across different settings globally., Methods: In this population-based study, population attributable fractions (PAFs) calculated using a theoretical minimum-risk exposure of lifetime abstention and 2010 alcohol consumption estimates from the Global Information System on Alcohol and Health (assuming a 10-year latency period between alcohol consumption and cancer diagnosis), combined with corresponding relative risk estimates from systematic literature reviews as part of the WCRF Continuous Update Project, were applied to cancer incidence data from GLOBOCAN 2020 to estimate new cancer cases attributable to alcohol. We also calculated the contribution of moderate (<20 g per day), risky (20-60 g per day), and heavy (>60 g per day) drinking to the total alcohol-attributable cancer burden, as well as the contribution by 10 g per day increment (up to a maximum of 150 g). 95% uncertainty intervals (UIs) were estimated using a Monte Carlo-like approach., Findings: Globally, an estimated 741 300 (95% UI 558 500-951 200), or 4·1% (3·1-5·3), of all new cases of cancer in 2020 were attributable to alcohol consumption. Males accounted for 568 700 (76·7%; 95% UI 422 500-731 100) of total alcohol-attributable cancer cases, and cancers of the oesophagus (189 700 cases [110 900-274 600]), liver (154 700 cases [43 700-281 500]), and breast (98 300 cases [68 200-130 500]) contributed the most cases. PAFs were lowest in northern Africa (0·3% [95% UI 0·1-3·3]) and western Asia (0·7% [0·5-1·2]), and highest in eastern Asia (5·7% [3·6-7·9]) and central and eastern Europe (5·6% [4·6-6·6]). The largest burden of alcohol-attributable cancers was represented by heavy drinking (346 400 [46·7%; 95% UI 227 900-489 400] cases) and risky drinking (291 800 [39·4%; 227 700-333 100] cases), whereas moderate drinking contributed 103 100 (13·9%; 82 600-207 200) cases, and drinking up to 10 g per day contributed 41 300 (35 400-145 800) cases., Interpretation: Our findings highlight the need for effective policy and interventions to increase awareness of cancer risks associated with alcohol use and decrease overall alcohol consumption to prevent the burden of alcohol-attributable cancers., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (© 2021 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY NC ND 3.0 IGO license which permits users to download and share the article for non-commercial purposes, so long as the article is reproduced in the whole without changes, and provided the original source is properly cited. This article shall not be used or reproduced in association with the promotion of commercial products, services or any entity. There should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Gastric cancer is preceded by a chronic inflammatory process. Circulating levels of inflammation-related markers may reveal molecular pathways contributing to cancer development. Our study evaluated risk associations of gastric cancer with a wide range of systemic soluble inflammation and immune-response proteins. We performed a case-cohort analysis within the JPHC Study II, including a subcohort of 410 participants selected randomly within defined age and sex groups, and 414 individuals with incident gastric cancer. Ninety-two biomarkers were measured in baseline plasma using proximity extension assays. Gastric cancer multivariable hazard ratios were calculated for two to four quantiles used as ordinal variables of each biomarker by Cox proportional hazards regression models with age as the time metric. Of 73 evaluable biomarkers, three (CCL11, CCL20 and IL17C) were associated with increased gastric cancer risk and two (CCL23 and MMP1) with reduced cancer risk (P trends  < 0.05). However, no association was statistically significant after a false discovery rate correction. This study largely expands the range of inflammation molecules evaluated for gastric cancer risk but failed to identify novel associations with this neoplasia., (Published by Elsevier Ltd.)

Objective: Age is an important prognostic factor for lung cancer. However, no studies have investigated the age difference in lung cancer survival per se. We, therefore, described the role of patient-related and clinical factors on the age pattern in lung cancer excess mortality hazard by stage at diagnosis in New Zealand., Materials and Methods: We extracted 22 487 new lung cancer cases aged 50-99 (median age = 71, 47.1 % females) diagnosed between 1 January 2006 and 31 July 2017 from the New Zealand population-based cancer registry and followed up to December 2019. We modelled the effect of age at diagnosis, sex, ethnicity, deprivation, comorbidity, and emergency presentation on the excess mortality hazard by stage at diagnosis, and we derived corresponding lung cancer net survival., Results: The age difference in net survival was particularly marked for localised and regional lung cancers, with a sharp decline in survival from the age of 70. No identified factors influenced age disparities in patients with localised cancer. However, for other stages, females had a greater difference in survival between middle-age and older-age than males. Comorbidity and emergency presentation played a minor role. Ethnicity and deprivation did not influence age disparities in lung cancer survival., Conclusion: Sex and stage at diagnosis were the most important factors of age disparities in lung cancer survival in New Zealand., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: WHO has launched an initiative aiming to eliminate cervical cancer as a public health problem. Elimination is a long-term target that needs long-lasting commitment. To support local authorities in implementing human papillomavirus (HPV) vaccination, we provide regional and country-specific estimates of cervical cancer burden and the projected impact of HPV vaccination among today's young girls who could develop cervical cancer if not vaccinated., Methods: The expected number of cervical cancer cases in the absence of vaccination among girls born between 2005 and 2014 was quantified by combining age-specific incidence rates from GLOBOCAN 2018 and cohort-specific mortality rates by age from UN demographic projections. Preventable cancers were estimated on the basis of HPV prevalence reduction attributable to vaccination and the relative contribution of each HPV type to cervical cancer incidence. We assessed the number of cervical cancer cases preventable through vaccines targeting HPV types 16 and 18, with and without cross-protection, and through vaccines targeting HPV types 16, 18, 31, 33, 45, 52, and 58., Findings: Globally, without vaccination, the burden of cervical cancer in these birth cohorts is expected to reach 11·6 million (95% uncertainty interval 11·4-12·0) cases by 2094. Approximately 75% of the burden will be concentrated in 25 countries mostly located in Africa and Asia, where the future number of cases is expected to increase manyfold, reaching 5·6 million (5·4-6·0) cases in Africa and 4·5 million (4·4-4·6) cases in Asia. Worldwide immunisation with an HPV vaccine targeted to HPV types 16 and 18, with cross-protection against HPV types 31, 33, and 45, could prevent about 8·7 million (8·5-9·0) cases., Interpretation: Detailed estimates of the increasing burden of cervical cancer and projected impact of HPV vaccination is of immediate relevance to public health decision makers. Shifting the focus of projections towards recently born girls who could develop cervical cancer if not vaccinated is fundamental to overcome stakeholders' hesitancy towards HPV vaccination., Funding: Bill & Melinda Gates Foundation, Canadian Institutes of Health Research., Competing Interests: Declaration of interests ELF has received grants to his university and personal fees from Merck, outside of the submitted work. ELF has a patent “Methylation markers in cervical cancer” pending to his university. The other authors declare no competing interests., (Copyright © 2021 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Background: Existing methods to estimate lifetime exposure to occupational carcinogenic agents could be improved., Objective: We propose a new method to estimate the lifetime prevalence of exposure to occupational carcinogens using the example of painters and workers of the rubber industry in France., Methods: From census, we calculated the proportion of painters and rubber industry workers using predefined occupational codes related to each occupation by sex and 10-year age group in 1982, 1990, 1999, 2007, and 2013. Using a beta-regression model, we obtained the yearly prevalence of exposure by 10-year age group over the period 1967-2007. We estimated the age- and sex-specific lifetime prevalence of exposure of the population in 2017 over 1967-2007, summing up the estimated prevalence of exposure for years 1967, 1977, 1987, 1997, and 2007 combined with a sex- and age-specific turnover factor. Corresponding population-attributable fractions were estimated for lung and bladder cancers in 2017., Results: In 2017, we estimated that 5.6 and 0.2% of men in France had ever worked as a painter or in the rubber industry, respectively, during their working time. The lifetime prevalence of ever having worked as a painter or in the rubber industry was much lower in women: 1.8% and 0.1%, respectively. We estimated that 950 lung cancer and 40 bladder cancer cases were attributable to these occupations in 2017., Significance: Based on accurate data and taking into account evolution of specific jobs over time, the proposed method provides good estimates of lifetime prevalence of exposure to occupational carcinogens. It could be applied in any other country with similar data.

Background/objectives: The association of fermented soy products, separately from total soy products, with cardiovascular disease (CVD) and total cancer has not been reported. We examined this association in a population-based prospective cohort study in Japan., Subjects/methods: We studied 79,648 participants (42,788 women; 36,860 men) aged 45-74 years without a history of cancer, myocardial infarction, or stroke. Participants completed a food frequency questionnaire (1995-1998) and were followed to 2009-2012. Cox proportional hazards regression analysis was used to calculate the hazard ratios (HR) and 95% confidence intervals (CI) of incidence of CVD and total cancer according to quartiles of total soy products, nonfermented soy products, fermented soy products, miso soup, natto, total isoflavones from soy products, isoflavones from nonfermented soy products, and isoflavones from fermented soy products., Results: In women, we observed a significant inverse association between fermented soy product intake and the risk of CVD (multivariate HR in the highest compared with the lowest quartile of fermented soy product intake: 0.80; 95% CI: 0.68, 0.95; P for trend = 0.010), and also found significant inverse associations for natto and isoflavones among fermented soy products. In site-specific analysis, we observed a similar, significant inverse association between fermented soy product intake and the risk of stroke in women. We found no significant association between any soy product and risk of CVD in men or total cancer in both sexes., Conclusions: Intake of fermented soy products such as natto was inversely associated with the risk of CVD in women.

We sought to understand the role of stage at diagnosis in observed age disparities in colon cancer survival among people aged 50 to 99 years using population-based cancer registry data from seven high-income countries: Australia, Canada, Denmark, Ireland, New Zealand, Norway and the United Kingdom. We used colon cancer incidence data for the period 2010 to 2014. We estimated the 3-year net survival, as well as the 3-year net survival conditional on surviving at least 6 months and 1 year after diagnosis, by country and stage at diagnosis (categorised as localised, regional or distant) using flexible parametric excess hazard regression models. In all countries, increasing age was associated with lower net survival. For example, 3-year net survival (95% confidence interval) was 81% (80-82) for 50 to 64 year olds and 58% (56-60) for 85 to 99 year olds in Australia, and 74% (73-74) and 39% (39-40) in the United Kingdom, respectively. Those with distant stage colon cancer had the largest difference in colon cancer survival between the youngest and the oldest patients. Excess mortality for the oldest patients with localised or regional cancers was observed during the first 6 months after diagnosis. Older patients diagnosed with localised (and in some countries regional) stage colon cancer who survived 6 months after diagnosis experienced the same survival as their younger counterparts. Further studies examining other prognostic clinical factors such as comorbidities and treatment, and socioeconomic factors are warranted to gain further understanding of the age disparities in colon cancer survival., (© 2020 Union for International Cancer Control.)

Purpose: This study addresses the need for a global cancer patient-based standard population that adjusts for the expected age structure of different cancers, thus aiding the comparison of survival estimates worldwide., Methods: Counts of age-specific incidence for 36 cancer sites in 185 countries for the year 2018 were extracted from IARC's GLOBOCAN database of national estimates. We used a multinomial mixture regression to identify clusters of cancer sites with similar age-specific profiles., Results: An updated standard entitled the World Cancer Patient Population (WCPP) is presented, derived from the current estimated global numbers of cancer patients that comprises three sets of age-specific weights. Around two-thirds of cancer sites were described by a unique standard, representing the majority of epithelial cancers more often diagnosed at older age groups. The two other standards represent a number of non-epithelial cancer types, and cancers common at younger and older age groups, respectively., Conclusion: The WCPP proposed here provides a contemporary and global means to estimate age-standardised survival for international benchmarking purposes., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Helicobacter pylori (H pylori) is a carcinogen that causes a huge burden of gastric cancer in China. We aimed to evaluate the temporal trends and other sources of variation of H pylori infection in adults from mainland China., Materials and Methods: For this systematic review and meta-analysis, we searched PubMed, Embase, China National Knowledge Infrastructure, and Wanfang databases for articles published from January 1983 to June 2020. We included studies reporting H pylori prevalence in adults and then applied random effect meta-analyses to obtain pooled prevalence estimates for all studies and subgroups. Sources of heterogeneity were investigated by moderator analysis, and time trends were assessed through random effect meta-regression., Results: Of the 2121 studies identified, 98 were eligible for inclusion. The pooled estimate of 670 572 participants from 26 provinces during 1983-2018 was 49.6% (95% CI: 46.9%, 52.4%). H pylori prevalence varied considerably, ranging from 20.6% to 81.8%. Periods, urban/rural status, detection method, and study design explained 18.8%, 24.0%, 17.8%, and 30.4% of the heterogeneity, respectively. Overall, H pylori prevalence declined by -0.9% (95% CI: -1.1%, -0.6%) annually. Consistent declines in prevalence were observed by sex, age, and study characteristics., Conclusions: Helicobacter pylori prevalence is slowly decreasing over time in mainland China, but the low declining speed is not enough to have a major impact on gastric cancer incidence for many years. The time trends and the large heterogeneity should be taken into account when conducting regional comparisons, disease burden estimations, and customized strategy making., (© 2020 John Wiley & Sons Ltd.)

Introduction: We recently developed a risk prediction model for gastric cancer which showed good performance in terms of discrimination. However, lack of external validation hampers the generalizability of our results., Methods: The study population consisted of 1292 individuals from JPHC cohort I (Omonogawa town, Akita prefecture). The previously developed model was used to predict survival for each individual at 10 years of follow-up., Results: Thirty-three cases of gastric cancer occurred during 17,246 person-years of follow-up (27 cases occurred during the first 10 years). The c-index was estimated at 0.798 at 10 years of follow-up. In terms of calibration, the Nam-d'Agostino test was non significant (p-value = 0.23)., Discussion: Our previously developed risk prediction model for gastric cancer showed good performance on an external population. This suggests it might be used for risk discrimination in the general Japanese population., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier Ltd.)

Esophageal squamous cell carcinoma (ESCC) is the predominant histologic subtype of esophageal cancer worldwide. Measurements of circulating inflammation-related biomarkers may inform etiology or provide noninvasive signatures for early diagnosis. We therefore examined levels of inflammation molecules for associations with ESCC risk. Using a case-cohort study designed within the Japan Public Health Center-based Prospective Study, we measured baseline plasma levels of 92 biomarkers using a multiplex assay in a subcohort of 410 randomly selected participants and 66 participants with incident ESCC (including four cases that occurred in the subcohort). ESCC hazard ratios (HRs) were calculated for 2-4 quantiles of each biomarker by Cox proportional hazards regression models with age as the time metric, adjusted for sex, smoking and alcohol use. Twenty analytes were undetectable in nearly all samples. Of the remaining 72, 12 biomarkers (FGF19, ST1A1, STAMBP, AXIN1, CASP8, NT3, CD6, CDCP1, CD5, SLAMF1, OPG and CSF1) were associated with increased ESCC risk (p trend  < 0.05) with HRs per quantile 1.28-1.65. Seven biomarkers (CXCL6, CCL23, CXCL5, TGFA, CXCL1, OSM and CCL4) were inversely associated with HRs 0.57-0.72. FGF19, CASP8, STAMBP, ST1A1 and CCL-4 met statistical significance with false discovery rate correction. Associations did not differ <5 vs. ≥5 years between blood collection and ESCC diagnosis. CASP8, STAMBP and ST1A1 were strongly correlated (p < 0.05). Our study expands the range of inflammation molecules associated with the development of this highly lethal neoplasia. Correlations among these novel biomarkers suggest a possible shared pathway. These findings need replication and could further delineate ESCCs molecular mechanisms of carcinogenesis., (© 2019 UICC.)

Obesity, often assessed at one point in time, is an established risk factor of several types of cancer, however, associations with cumulative exposure to obesity across the life course are not well understood. We investigated the relationship between combined measures of duration and intensity of premenopausal overweight and obesity and the incidence of postmenopausal breast, endometrial, and colorectal cancers in Icelandic women. Body mass index (BMI) trajectories between ages 20 and 50 of 88,809 women from the Cancer Detection Clinic Cohort were predicted using growth curve models. Indicators of overweight and obesity duration and intensity were computed and their association with risk of postmenopausal breast, endometrial, and colorectal cancers was examined using multivariate Cox models for subjects followed-up beyond the age of 50 (n = 67,488). During a mean follow-up of 17 years, incident events of 3,016 postmenopausal breast, 410 endometrial and 987 colorectal cancers were ascertained. Each 0.1 kg/m 2 per year increase in BMI between ages 20 and 50 was positively associated with risks of postmenopausal breast, endometrium and colorectal cancers with hazard ratios equal to 1.09 (95% Confidence Interval (CI):1.04-1.13), 1.31 (95% CI: 1.18-1.44) and 1.10 (95% CI: 1.00-1.21), respectively. Compared to women who were never obese, cumulative BMI × years of obesity were linearly positively associated with risk of endometrial cancer, whereas the association with breast cancer was initially positive, but leveled off with increasing cumulative BMI × years. Cumulative exposure to obesity may provide additional insights into the etiology of cancer and should be considered in future studies that assess obesity-cancer relationships., (© 2019 International Agency for Research on Cancer (IARC/WHO); licensed by UICC.)

Background: Metabolic syndrome (MetS) is a systemic inflammatory state. Low physical activity (PA) could modify this patho-physiology or act as an independent contributor to inflammation. Previous studies of both conditions have identified altered levels of inflammation- and immune-related proteins based on limited sets of candidate markers., Methods: We investigated associations of MetS and low PA with circulating inflammation markers in a stratified random sample of Japanese adults ( N = 774, mean age 60.7 years) within the Japan Public Health Center-based Prospective Study (JPHC) Cohort II. AHA/NHLBI criteria were used to define MetS (19%) and the bottom quartile of PA was considered low. 110 circulating biomarkers, including cytokines, chemokines, and soluble receptors were measured by multiplex bead-based and proximity-extension assays. Associations of MetS and low PA with marker quantiles were adjusted for each other and for age, sex, study site, cigarette smoking, alcohol consumption, and blood sample fasting state by ordinal logistic regression. P values were corrected for FDR., Results: MetS was significantly associated with levels of six markers: IL18R1 [odds ratio 2.37; 95% confidence interval (CI), 1.45-3.87], CRP (2.07; 95% CI, 1.48-2.90), SAP (2.08; 95% CI, 1.47-2.95), CCL19/MIP3β (2.06; 95% CI, 1.48-2.88), CXCL12/SDF1α+β (0.48; 95% CI, 0.32-0.65), and CCL28 (0.44; 95% CI, 0.27-0.71). Low PA had no significant marker associations., Conclusions: Positively associated markers with MetS are mostly Th1 immune response-related and acute phase proteins, whereas negatively associated markers are generally Th2-related., Impact: MetS is associated with a broad range of alterations in immune and inflammatory biomarkers that may contribute to risks of various chronic diseases, independent of low PA., (©2020 American Association for Cancer Research.)

Intake of heterocyclic amines (HCAs) and other mutagenic compounds formed during cooking has been hypothesized to be responsible for the positive association observed between red meat and colorectal cancer. We evaluated whether well-done/very well-done preferences for various meat and fish items, higher intakes of meat and fish, and meat-derived and fish-derived HCA are associated with the risk of colorectal adenoma (CRA) in a Japanese-Brazilian population. We selected 302 patients with adenoma and 403 control individuals who underwent total colonoscopy between 2007 and 2013, and collected information on aspects of meat intake using a detailed questionnaire. We also estimated HCA intake of the study participants using an HCA database that matched the cooking methods of this population. Latent class analysis on the basis of response to doneness preferences for different cooking methods of commonly consumed meat and fish items identified four distinct subgroups. Compared with the subgroup characterized by a preference for rare/medium well-done cooking for most meat and fish items, the odds ratio of CRA for the well-done/very well-done preference subgroup was 1.19 (95% confidence interval: 0.51-2.75). High intake of mixed-meat dishes was suggestively associated inversely with CRA, whereas a high intake of poultry was associated positively with CRA. No clear association with intake of total or specific HCAs and no effect modification by N-acetyltransferase 2 acetylation genotype were observed. We found no statistically significant associations between meat and HCA intake and CRA. These findings do not support a positive association between meat and meat-derived HCA intake and the risk of CRA.

Importance: Epidemiological evidence regarding the long-term effects of higher dietary protein intake on mortality outcomes in the general population is not clear., Objective: To evaluate the associations between animal and plant protein intake and all-cause and cause-specific mortality., Design, Setting, and Participants: This prospective cohort study included 70 696 participants in the Japan Public Health Center-based Prospective Cohort who were aged 45 to 74 years and had no history of cancer, cerebrovascular disease, or ischemic heart disease at study baseline. Data were collected from January 1, 1995, through December 31, 1999, with follow-up completed December 31, 2016, during which 12 381 total deaths were documented. Dietary intake information was collected through a validated food frequency questionnaire and used to estimate protein intake in all participants. Participants were grouped into quintile categories based on their protein intake, expressed as a percentage of total energy. Data were analyzed from July 18, 2017, through April 10, 2019., Main Outcomes and Measures: Hazard ratios (HRs) and 95% CIs for all-cause and cause-specific mortality were estimated using Cox proportional hazards regression models with adjustment for potential confounding factors., Results: Among the 70 696 participants, 32 201 (45.5%) were men (mean [SD] age, 55.6 [7.6] years) and 38 495 (54.5%) were women (mean [SD] age, 55.8 [7.7] years). Intake of animal protein showed no clear association with total or cause-specific mortality. In contrast, intake of plant protein was associated with lower total mortality, with multivariable-adjusted HRs of 0.89 (95% CI, 0.83-0.95) for quintile 2; 0.88 (95% CI, 0.82-0.95) for quintile 3; 0.84 (95% CI, 0.77-0.92) for quintile 4; and 0.87 (95% CI, 0.78-0.96) for quintile 5, with quintile 1 as the reference category (P = .01 for trend). For cause-specific mortality, this association with plant protein intake was evident for cardiovascular disease (CVD)-related mortality (HRs, 0.84 [95% CI, 0.73-0.96] to 0.70 [95% CI, 0.59-0.83]; P = .002 for trend). Isocaloric substitution of 3% energy from plant protein for red meat protein was associated with lower total (HR, 0.66; 95% CI, 0.55-0.80), cancer-related (HR, 0.61; 95% CI, 0.45-0.82), and CVD-related (HR, 0.58; 95% CI, 0.39-0.86) mortality; substitution for processed meat protein was associated with lower total (HR, 0.54; 95% CI, 0.38-0.75) and cancer-related (HR, 0.50; 95% CI, 0.30-0.85) mortality., Conclusions and Relevance: In this large prospective study, higher plant protein intake was associated with lower total and CVD-related mortality. Although animal protein intake was not associated with mortality outcomes, replacement of red meat protein or processed meat protein with plant protein was associated with lower total, cancer-related, and CVD-related mortality.

Cigarette smoking and alcohol drinking are two major risk factors for esophageal cancer. Not all, but several of case-control studies have indicated interaction between the two factors; however, no prospective study has validated this phenomenon to date. Therefore, the interaction between smoking and alcohol drinking is still open-ended question. To answer this, we conducted a pooled analysis using large-scale population-based cohort studies in Japan. Male subjects from eight cohort studies were included. Cigarette smoking and alcohol drinking were both categorized categorically (never/ever), and in the three consumption levels of pack years and ethanol consumption/day. Effects of smoking and drinking in each study were estimated by Cox regression models. The study-specific results were combined through meta-analysis to obtain summary effects of hazard ratios (HRs) and measures of interactions at both additive and multiplicative scales. Population attributable fractions (PAFs) from smoking and drinking were obtained using distributions of exposures and fully adjusted HRs. In 162 826 male subjects, 954 esophageal cancer incidences were identified. HRs of ever smoking, ever drinking, and their combination were 2.92 (1.59-5.36), 2.73 (1.78-4.18), and 8.86 (4.82-16.30), respectively. Interaction between cigarette smoking and alcohol drinking was significantly positive on the additive scale, but not significant on the multiplicative scale. The joint effect of smoking and drinking in three levels of evaluation showed a similar significant super-additive interaction. PAFs from smoking, drinking, and their combination were 55.4%, 61.2%, and 81.4%, respectively. Cigarette smoking and alcohol drinking had a significant positive additive interaction for esophageal cancer risk., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

In competing risks setting, we account for death according to a specific cause and the quantities of interest are usually the cause-specific hazards (CSHs) and the cause-specific cumulative probabilities. A cause-specific cumulative probability can be obtained with a combination of the CSHs or via the subdistribution hazard. Here, we modeled the CSH with flexible hazard-based regression models using B-splines for the baseline hazard and time-dependent (TD) effects. We derived the variance of the cause-specific cumulative probabilities at the population level using the multivariate delta method and showed how we could easily quantify the impact of a covariate on the cumulative probability scale using covariate-adjusted cause-specific cumulative probabilities and their difference. We conducted a simulation study to evaluate the performance of this approach in its ability to estimate the cumulative probabilities using different functions for the cause-specific log baseline hazard and with or without a TD effect. In the scenario with TD effect, we tested both well-specified and misspecified models. We showed that the flexible regression models perform nearly as well as the nonparametric method, if we allow enough flexibility for the baseline hazards. Moreover, neglecting the TD effect hardly affects the cumulative probabilities estimates of the whole population but impacts them in the various subgroups. We illustrated our approach using data from people diagnosed with monoclonal gammopathy of undetermined significance and provided the R-code to derive those quantities, as an extension of the R-package mexhaz., (© 2019 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.)