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International audience; 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.

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).

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; Ptrend = 0.048). After we corrected for multiple comparisons, none of the examined biomarkers were associated with pancreatic cancer risk at P-value 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.

The association between alcohol intake and stomach cancer risk remains controversial. We undertook a pooled analysis of data from six large‐scale Japanese cohort studies with 256 478 participants on this topic. Alcohol intake as ethanol was estimated using a validated questionnaire. The participants were followed for incidence of stomach cancer. We calculated study‐specific hazard ratios (HRs) and 95% confidence intervals (CIs) for stomach cancer according to alcohol intake using a Cox regression model. Summary HRs were estimated by pooling the study‐specific HRs using a random‐effects model. During 4 265 551 person‐years of follow‐up, 8586 stomach cancer cases were identified. In men, the multivariate‐adjusted HRs (95% CIs) of stomach cancer were 1.00 (0.87‐1.15) for occasional drinkers, and 1.00 (0.91‐1.11) for, Alcohol intake increased stomach cancer risk in men, and heavy drinkers showed a greater point estimate of risk for proximal cancer than for distal cancer.

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.

Evidence is limited regarding the association between low-carbohydrate diet (LCD) score and mortality among Asians, a population that consumes a large amount of carbohydrates.The present study examined the association between low-carbohydrate diet (LCD) score (based on percentage of energy as carbohydrate, fat, and protein) and the risk of total and cause-specific mortality among Asians.This study was a prospective cohort study in Japan with follow-up for a median of 16.9 years involving 43008 men and 50646 women aged 45-75 years. Association of LCD score, LCD score based on animal sources of protein and fat, and LCD score based on plant sources of protein and fat with risk of mortality was assessed using Cox proportional hazards model.A U-shaped association was observed between LCD score and total mortality: the multivariable-adjusted hazard ratios (HRs) (95% CI) of total mortality for lowest through highest scores were 1.00, 0.95 (0.91, 1.01), 0.93 (0.88, 0.98), 0.93 (0.88, 0.98), and 1.01 (0.95, 1.07) (P-non-linearity0.01). A similar association was found for mortality from cardiovascular disease (CVD) and heart disease. LCD score based on carbohydrate, animal protein, and animal fat also showed a U-shaped association for total mortality (P-non-linearity0.01). In contrast, LCD score based on carbohydrate, plant protein, and plant fat was linearly associated with lower total (HR, 0.89; 95% CI: 0.83, 0.94 for highest versus lowest quintile), CVD [0.82 (0.73, 0.92)], heart disease [0.83 (0.71, 0.98)], and cerebrovascular disease [0.75 (0.62, 0.91) mortality.Both LCD with high animal protein and fat and high-carbohydrate diet with low animal protein and fat were associated with higher risk of mortality. Meanwhile, LCD high in plant-based sources of protein and fat was associated with a lower risk of total and CVD mortality.

Summary 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.

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 (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.

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: 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/m2 compared with average BMI less than or equal to 22.5 kg/m2, 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.

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. 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. 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. Intake of fermented soy products such as natto was inversely associated with the risk of CVD in women.

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.

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.

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/m2 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.

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

We evaluated the association between total soy, soy product (natto, miso and tofu) and isoflavone intake and incident disabling dementia in a Japanese population.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.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.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.

Background With the recent advances in genomic medicine, the unmet needs of cancer patients (unmet needs) may be changing. A large-scale unmet needs survey was launched in 2021 with the aim of understanding the latest unmet needs and sharing information with healthcare professionals and patients, thereby contributing to the improvement of cancer treatment in Japan. The Rare Cancer Patients' Network (RCJ) is conducting this survey in collaboration with the National Cancer Centre and the National Federation of Cancer Patients' Associations (Zenganren). This presentation will report on progress since the JSNO2021 publication. Methods A total of 38 questions were asked in six categories: (1) detection and diagnosis; (2) treatment; (3) genomic medicine (access to genetic mutation testing); (4) clinical trials; (5) necessary information, medical care and support systems; and (6) quality of life. A combination of free-text and multiple-choice questions were asked on these, with approval obtained from the Ethics Review Committee of the National Cancer Centre at the end of October 2021 to conduct the survey online via the RCJ and the All Cancer Federation network (response deadline: 08/2022). Results The survey is scheduled to complete response collection and final analysis in August 2022. The results of the interim analysis will be presented at the poster session. Conclusions Depending on the final response collection, it may be possible to make comparisons between cancer types and identify specific patient needs in individual cancer types, such as brain tumours. At JSNO2022, we will present the results of each of the 38 questions and discuss the unmet needs of brain tumour patients with healthcare professionals, hoping that results and discussions will improve healthcare with a focus on brain tumour patients.

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.

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., A significant positive additive interaction between cigarette smoking and alcohol drinking for the risk of esophageal cancer was found, although significant interaction on a multiplicative scale was not observed. Population attributable fraction suggest that either quitting smoking or drinking alone might make a major contribution to esophageal cancer prevention.

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.

Background: Circulating inflammation proteins may be important mediators or markers of carcinogenic mechanisms. There have been few studies with limited numbers of analytes in patients with upper gastrointestinal (GI) tract tumors. We therefore evaluated risk associations of gastric and esophageal cancers with prediagnostic levels of a wide range of these molecules. Methods: We performed a case–cohort analysis within the Japan Public Health Center–Based Prospective Study Cohort II, including incident cases of gastric (n = 446) and esophageal (n = 68) cancers and a random subcohort (n = 774). A total of 64 biomarkers were measured in baseline plasma using Luminex bead-based assays. The median time between blood collection and diagnosis was 8.1 years for gastric cancer and 9.4 years for esophageal cancer. HRs for association with each marker were adjusted for potential confounders using Cox regression. Results: In separate models, sEGFR and TSLP were nominally associated with gastric cancer risk, and CRP, CXCL11/ITAC, and CCL15/MIP1D were associated with esophageal cancer. However, no association satisfied statistical significance after FDR correction. Associations did not differ by time from blood collection to cancer ( Conclusions: Our study failed to identify associations of circulating inflammation markers with risk of upper GI tract tumors. Impact: To date, this is the largest assessment of inflammation-related proteins with gastric and esophageal cancer risks. However, the evaluated molecules may not fully represent the complex inflammation processes preceding malignant transformation. Further investigation of other markers in prospective studies is warranted, as demonstration of associations may have important implications for prevention and treatment of these cancers.

To elucidate the individual impacts of insulin and blood glucose on cancer risk, we investigated the association of plasma C-peptide, a surrogated marker of insulin and glycated albumin (GA), a more stable marker of blood glucose, with all-site and site-specific cancer risk by mutually accounting for their confounding effects. The study was prospectively conducted with nearly 4,000 cancer cases arising in our population-based cohort of 33,736 subjects who answered the baseline questionnaire and supplied blood samples. After exclusion of subjects with apparent DM, analysis was done in 3,036 cancer cases and 3,667 subcohort subjects. Among men and women combined, highest levels of C-peptide were statistically significantly associated with an increased risk of all-site [Hazard ratio (HR): 1.21; 95% confidence interval: 1.02-1.42], colon [1.73; 1.20-2.47], liver [3.23; 1.76-5.91], kidney, renal pelvis and ureter cancers [2.47; 1.07-5.69], compared to the respective lowest levels, after adjustment for GA levels. Among these C-peptide-related cancers, colon and liver cancers also showed an increased risk associated with elevated GA levels independently of C-peptide levels. The corresponding HRs for colon and liver cancers compared to the highest and lowest GA levels were 1.43 [1.02-2.00] and 2.02 [1.15-3.55], respectively. Effect modification by gender was only evident for the association between C-peptide and colon cancer (p for interaction = 0.04). Higher insulin levels, independently of higher blood glucose levels, may be relevant to DM-related carcinogenesis for several cancer sites. Examination of circulating insulin levels is a plausible option in evaluating cancer risk even in individuals who have not developed DM.

Blood levels of inflammation-related markers may reveal molecular pathways contributing to carcinogenesis. To date, prospective associations with colorectal cancer (CRC) risk have been based on few studies with limited sets of analytes. We conducted a case-cohort study within the Japan Public Health Center-based Prospective Study Cohort II, comparing 457 incident CRC cases during median 18 years follow-up with a random subcohort of 774 individuals. Baseline plasma levels of 62 cytokines, soluble receptors, acute-phase proteins, and growth factor markers were measured using Luminex bead-based assays. We estimated hazard ratios (HRs) associating each marker with CRC risk by Cox proportional hazards models adjusted for potential confounders. Subanalyses compared cases by years after blood draw (

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 (Ptrends

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.

We present mexhaz, an R package for fitting flexible hazard-based regression models with the possibility to add time-dependent effects of covariates and to account for a two-level hierarchical structure in the data through the inclusion of a normally distributed random intercept (i.e., a log-normally distributed shared frailty). Moreover, mexhaz-based models can be fitted within the excess hazard setting by allowing the specification of an expected hazard in the model. These models are of common use in the context of the analysis of population-based cancer registry data. Follow-up time can be entered in the right-censored or counting process input style, the latter allowing models with delayed entries. The logarithm of the baseline hazard can be flexibly modeled with B-splines or restricted cubic splines of time. Parameters estimation is based on likelihood maximization: in deriving the contribution of each observation to the cluster-specific conditional likelihood, Gauss-Legendre quadrature is used to calculate the cumulative hazard; the cluster-specific marginal likelihoods are then obtained by in-tegrating over the random effects distribution, using adaptive Gauss-Hermite quadrature. Functions to compute and plot the predicted (excess) hazard and (net) survival (possibly with cluster-specific predictions in the case of random effect models) are provided. We illustrate the use of the different options of the mexhaz package and compare the results obtained with those of other available R packages.

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.

The associations of daily total physical activity and total moderate to vigorous physical activity (MVPA) with dementia are still unclear.To investigate the association between daily total physical activity and subsequent risk of disabling dementia in large-scale, extended follow-up prospective study.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.Daily total physical activity, total MVPA, and leisure-time MVPA.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).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).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.

ObjectiveWe 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 hospitalization data.DesignWe included new colon cancer cases diagnosed between 1 January 2006 and 31 July 2017, followed up to 31 December 2019. We linked these cases to hospitalisation data for the five years before the cancer diagnosis. We modelled the effect of age at diagnosis, sex, deprivation, comorbidity, and route to diagnosis on colon cancer survival by stage at diagnosis (localized, regional, distant, missing).ResultsNet survival decreased as the age at diagnosis increased, notably in advanced stages and missing stage. The excess mortality in older patients was minimal for localised cancers, maximal during the first six months for regional cancers, the first 18 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, the route to diagnosis for regional and distant cancers, and comorbidity for cancer with missing stages.ConclusionThe present population-based study shows that factors reflecting timeliness of cancer diagnosis most affected the difference in survival between middle-aged and older patients, 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.

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.

Highlights • We propose an update of a global standard for cancer survival comparisons entitled the World Cancer Patient Population (WCPP), constructed from the current global age distributions of cancer patients. • From an analysis of the 36 major cancer types, three standards of age-specific weights are derived to enable age-adjusted comparisons of cancer-specific survival. • Around two-thirds of cancer sites were described by one standard, representing the majority of epithelial cancers more often diagnosed at older age groups. • The two other standards represent a number of non-epithelial cancers that are more common among younger and older age groups, respectively., 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.

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.