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Trust is a major factor in effective public dissemination and use of relevant health information to guide important health decisions. To examine mass media as a communication channel for delivering cancer information among Japanese adults, we identified the level of trust in various types of mass media as sources of cancer information, and examined factors associated with trust, including exposure to mass media, sociodemographic factors, and cancer history. Data were analyzed for 3,109 Japanese adults who responded to a nationally representative cross-sectional mail survey. Data included trust in cancer information sources, sociodemographic variables, cancer history, and exposure to mass media. Logistic regression analysis was used. The prevalence of high trust in cancer information sources was highest for physicians (94.7%). Among mass media, Internet (47.2%) was the most trusted source of cancer-related information, followed by television (44.3%), newspapers/magazines (42.7%), and radio (32.7%). The high-exposure group for newspapers (AOR = 1.28, 95%CI = 1.07–1.54) was more likely to trust newspapers. Similarly, high-exposure groups for radio (1.22, 1.02–1.45), Internet (1.21, 1.01–1.45), and television (1.30, 1.10–1.53) were positively associated with trust in each media type. Although trust in mass media was lower than trust in physicians, the study found that a large group of respondents had high levels of trust in mass media sources. Trust in cancer information from each mass media type was mainly related to the level of exposure to each mass media type. Developing health communication strategies using mass media may be effective for disseminating relevant cancer information in Japan. [ABSTRACT FROM AUTHOR]

Background: Health literacy (HL) has gained increasing attention as a factor related to health behaviors and outcomes. This study aimed to investigate geographic differences in HL levels and effect modification by geographic area on their relationship with self-rated health in the Japanese population using a nationwide sample. Methods: Data for this study were derived from a nationally representative cross-sectional survey on health information access for consumers in Japan using a mailed self-administered questionnaire in 2020 (INFORM Study 2020). Valid responses from 3,511 survey participants, selected using two-stage stratified random sampling, were analyzed in this study. HL was measured using the Communicative and Critical Health Literacy Scale (CCHL). Multiple regression and logistic regression analyses were conducted to examine the associations between geographic characteristics and HL and effect modification on the association between HL and self-rated health by geographic area, controlling for sociodemographic characteristics. Results: The mean HL score was 3.45 (SD = 0.78), somewhat lower compared with previous studies on the Japanese general population. HL was higher in Kanto area than in Chubu area, after controlling for sociodemographic factors and municipality size. Furthermore, HL was positively associated with self-rated health after controlling for sociodemographic and geographic factors; however, this association was more evident in eastern areas than in western areas. Conclusion: The findings indicate geographic differences in HL levels and effect modification by geographic area on the relationship between HL and self-rated health in the general Japanese population. HL was more strongly associated with self-rated health in eastern areas than in western areas. Further investigation is needed to explore the moderating effects of areal features, including the distribution of primary care physicians and social capital, when formulating strategies to improve HL in different contexts. [ABSTRACT FROM AUTHOR]

Sarcoma is a rare cancer, and little is known about the etiology, lifestyle epidemiology, and actual circumstances of treatment in hospitals in Japan. Understanding these issues is essential for the effective prevention and treatment of sarcoma. We therefore investigated the incidence of a personal and family cancer history in a total of 1320 sarcoma patients at the National Cancer Center Hospital. In addition, obesity, hypertension, dyslipidemia, diabetes mellitus, drinking, smoking, age and sex were compared in a descriptive study of 1159 of these sarcoma patients who were ≥ 20 years of age, and 7738 controls derived from the National Health and Nutrition Examination Survey in Japan. A total of 8% of sarcoma patients had a personal history of another cancer, and 30% of soft tissue sarcoma patients had a family cancer history in a first-degree relative (malignant peripheral nerve sheath tumor, 52%; leiomyosarcoma, 46%). A smoking habit was associated with the development of sarcoma (odds ratio [OR], 2.05; 95% confidence interval, 1.78–2.37; p < 0.01). According to the histology, the ORs for undifferentiated pleomorphic sarcoma (UPS) of bone, UPS of soft tissue, and liposarcoma were 5.71, 3.04, and 2.92, respectively. A family cancer history may be associated with certain soft tissue sarcomas, and a smoking habit was significantly associated with the development of sarcomas; however, further studies are necessary. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to examine whether cardiorespiratory fitness and leg strength can be estimated based on their relationship with physical performance tests in Japanese breast cancer survivors. Methods: Participants were 50 sedentary women aged 20 to 59 years who have received breast surgery in the past 2 to 13 months after diagnosis of invasive breast cancer (stage I-IIa). Cardiorespiratory fitness and leg strength were measured by peak oxygen consumption (VO2peak), and one-repetition maximum for leg press (leg press 1RM). Physical performance tests were performed 6-min walk test, chair stand test, and grip strength. Using multiple regression analysis, we developed prediction equations for VO2peak and leg strength based on their associations with the physical performance tests. The validity of the estimation equations was assessed using Bland–Altman plots. Results: Mean age, VO2peak, and leg press 1RM were 48 ± 6 years, 25.0 ± 3.6 mL/kg/min, and 95 ± 32 kg, respectively. Multiple regression analysis yielded 6-min walk test distance, age, height, and body weight as predictors of VO2peak. Measured VO2peak and predicted VO2peak showed a moderate positive correlation (r = 0.463, p < 0.001). Chair stand test, grip strength, age, height, and body weight were selected as predictors of leg press 1RM. There was a strong positive correlation between predicted and measured leg press 1RM (r = 0.754, p < 0.001). Conclusion: The results suggest that leg strength can be predicted using physical performance tests. However, further examination may be needed to determine whether cardiorespiratory fitness can be predicted based on 6-min walk test. [ABSTRACT FROM AUTHOR]

Purpose: A known barrier to getting breast cancer survivors (BCSs) to engage in habitual exercise is a lack of information on recommended physical activity levels provided to them by oncology care providers (OCPs). However, the actual situation in Japan remains unclear. This study sought to clarify OCPs' awareness and practice related to Japan's physical activity recommendation for BCSs and to ascertain barriers to routine information provision. Methods: We conducted a web-based survey involving members of the Japanese Breast Cancer Society (JBCS) and the Japanese Association of Cancer Rehabilitation between Dec. 2018 and Feb. 2019. Results: Of 10,830 members, 1,029 (9.5%) responded. Only 19.1% were aware of the details of the JBCS physical activity recommendation, and only 21.2% routinely provided physical activity information to BCSs. Factors related to being aware of the recommendation details were 1) availability of the guidelines, 2) experience reading relevant parts of the guidelines, and 3) involvement in multidisciplinary team case meetings. Barriers to routine information provision were 1) absence of perceived work responsibility, 2) underestimation of survivors' needs, 3) lack of resources, 4) lack of self-efficacy about the recommendation, and 5) poor knowledge of the recommendation. Conclusions: Only one fifth of the OCPs routinely provided physical activity information. Barriers to provision were poor awareness, self-efficacy, and attitudes and unavailable resources. The physical activity recommendation needs to be disseminated to all OCPs and an information delivery system needs to be established for BCSs to receive appropriate information and support to promote their engagement in habitual physical activity. [ABSTRACT FROM AUTHOR]

Pancreatic cancer shows very poor prognosis and is the fifth leading cause of cancer death in Japan. Previous studies indicated some genetic factors contributing to the development and progression of pancreatic cancer; however, there are limited reports for common genetic variants to be associated with this disease, especially in the Asian population. We have conducted a genome-wide association study (GWAS) using 991 invasive pancreatic ductal adenocarcinoma cases and 5,209 controls, and identified three loci showing significant association (P-value<5×10-7) with susceptibility to pancreatic cancer. The SNPs that showed significant association carried estimated odds ratios of 1.29, 1.32, and 3.73 with 95% confidence intervals of 1.17-1.43, 1.19-1.47, and 2.24-6.21; P-value of 3.30×10-7, 3.30×10-7, and 4.41×10-7; located on chromosomes 6p25.3, 12p11.21 and 7q36.2, respectively. These associated SNPs are located within linkage disequilibrium blocks containing genes that have been implicated some roles in the oncogenesis of pancreatic cancer. [ABSTRACT FROM AUTHOR]

The Japanese government's 2013 suspension of its proactive recommendation for Human papillomavirus (HPV) vaccination resulted in low HPV vaccination coverage and was unique. However, data on awareness and knowledge of HPV vaccines in the general population was limited. Here, to investigate more recent awareness and knowledge of HPV vaccines by age, gender, and socioeconomic status, we used data from the INFORM Study 2020, a nationally representative cross-sectional survey of self-administered questionnaires with 1,998 Japanese individuals aged 20 to 59 years. We found that 47.5% of females and 21.0% of males had heard of HPV, and 33.6% of females and 16.8% of males had knowledge of HPV vaccine efficacy. After adjusting for potential confounders, females aged 50–54 years were more likely to be aware of HPV than females aged 20–24 (AOR, 2.02, 95%CI: 1.12–3.65). Females (AOR, 2.13, 95%CI: 1.48–3.07) and males (AOR, 1.64, 95%CI: 1.03–2.59) with higher education had more awareness than those with less education. Females with higher education had more knowledge about HPV vaccine efficacy than those with less education (AOR, 1.70; 95%CI: 1.16–2.50). We found a generally low level of awareness and knowledge about HPV vaccines in Japan, which might be attributable to the suspension of proactive recommendations. Additionally, we identified disparities in awareness and knowledge by age, gender, socioeconomic status, and health literacy. Enhancing HPV awareness and understanding of HPV vaccines and implementing targeted efforts for specific subpopulations within Japan after the resumption of proactive recommendation for HPV vaccines, are imperative. [ABSTRACT FROM AUTHOR]

To describe patients' perceptions of the patient-centeredness of their communication with healthcare providers in Japan, and to examine factors associated with these perceptions. We analyzed the cross-sectional data from the INFORM Study 2020, which is a nationwide survey on health information access in Japan. A total of 3605 respondents completed the survey. Our primary outcome was the nine elements of the patient-centered communication scale (PCCS), which was compiled from 2703 respondents (75.0%) reporting at least one provider visit within 12 months. It was rated on a four-point Likert scale: always, usually, sometimes, and never. We used binary logistic regression to examine the association between sociodemographic and health-related variables, and each element of the PCCS. For all elements, the percentage of respondents who agreed that their healthcare providers always communicated in a patient-centered way was low (17–31%). Patients with higher age, higher education, poorer general health status and a larger number of visits to providers in the previous 12 months were more likely to have positive perception. Patient-centered communication as reported in a national sample in Japan was low. Efforts are needed to improve the patient-centeredness of patient-provider communication in Japan to optimize health outcomes. • Patient-centered communication, as reported in a national sample in Japan, was low. • Age, education, health status and number of visits were associated with perception. • To improve communication, it is necessary to approach both providers and patients. [ABSTRACT FROM AUTHOR]

Background: Thymic carcinoma is a rare malignant disease and standard treatment for advanced or metastatic thymic carcinoma previously treated with platinum-based chemotherapy has not been established. Lenvatinib is a novel multi-targeted inhibitor of VEGFR, FGFR, RET, c-Kit, and other kinases. The aim of this trial was to assess the activity and safety of lenvatinib as a second-line treatment in thymic carcinoma.Methods: This single-arm, phase 2 trial done in eight institutions in Japan (five cancer centres, two medical university hospitals, and one public hospital) enrolled patients with pathologically confirmed unresectable advanced or metastatic thymic carcinoma that progressed following at least one platinum-based chemotherapy. Key inclusion criteria were age 20 years or older, at least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 24 mg of lenvatinib orally once daily in 4-week cycles until disease progression or occurrence of unacceptable adverse events. The primary endpoint was objective response rate evaluated at the data cutoff date (Feb 22, 2019), by independent central review in the intention-to-treat population. This trial is registered on JMACCT, JMA-IIA00285, and on UMIN-CTR, UMIN000026777.Findings: Between April 21, 2017, and Feb 22, 2018, 42 patients were enrolled and all patients were included in the activity and safety analysis. The median follow-up period was 15·5 months (IQR 13·1-17·5). The objective response rate was 38% (90% CI 25·6-52·0, p<0·0001). 16 (38%) of 42 patients had a partial response and 24 (57%) had stable disease. The most frequent grade 3 treatment-related adverse events were hypertension (27 [64%]) and palmar-plantar erythrodysaesthesia syndrome (three [7%]). No patient died from adverse events.Interpretation: The activity and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma was confirmed. These results suggest that lenvatinib could become a standard treatment option for patients with previously treated advanced or metastatic thymic carcinoma.Funding: Center for Clinical Trials, Japan Medical Association. [ABSTRACT FROM AUTHOR]

Background: The diversification of information sources and changes in social structures necessitates updates on the state of public awareness of palliative care. Therefore, we clarified the status and determinants of awareness, information sources, and beliefs, regarding palliative care in Japan., Methods: This nationwide cross-sectional survey included 10 000 participants aged ≥20 years enrolled through random sampling using a two-stage stratification in 2023. We used a mailed self-administered questionnaire (INFORM Study 2023). The questionnaire items were selected (partially modified) from the Health Information National Trends Survey (USA) to ensure comparability, included palliative care awareness, information sources, and beliefs. Weighted logistic regression was conducted to explore the determinants of awareness., Results: Of the 3452 participants that responded (response rate: 35.3%), 65.2% had palliative care awareness. The weighted logistic regression analysis revealed that respondents less likely to have any palliative care awareness were younger, were male, had limited education history, had lower household income, and were non-Internet users. Of these, sex had the clear association (adjusted odds ratio for female vs. male: 3.20 [95% CI: 2.66-3.85]). Across all age groups, healthcare professionals (58.5%) and the Internet (30.5%) were the most trusted source of information. Younger participants frequently received information online. Most participants believed that palliative care was beneficial, although 82.0% associated it with death., Conclusions: The Japanese population had a relatively high palliative care awareness, with the majority trusting information from healthcare professionals rather than the Internet. Further efforts are warranted to address barriers to receiving trustworthy palliative care information., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: In Japan, heated tobacco products (HTPs) are promoted by the tobacco industry as reduced-risk tobacco products despite the lack of evidence for this claim. This study determined the distribution of HTP-harmfulness perception and identified the explanatory factors associated with the perception of HTP as less harmful than conventional cigarettes., Methods: A nationwide cross-sectional survey was conducted with Japanese people aged 20 years or older (INFORM Study 2020) using a self-administered questionnaire. We performed descriptive analysis and weighted logistic regression analysis to examine the relationship between explanatory factors (eg, individual characteristics, socioeconomic status, and trusted sources of cancer information) and the perception of HTPs as less harmful., Results: Among 3,420 participants, the proportions of those who perceived HTPs as less harmful were 40.3% and 18.3% for users and non-users of tobacco, respectively. For participants aged 20-39 years, the proportions were 49.9% and 30.4%, respectively. Among 1,160 tobacco non-users who were familiar with HTPs, male, aged under 39 years, and having lower education were associated with the perception of HTPs as less harmful. Trusted sources of cancer information were not associated with the perception of HTPs as less harmful., Conclusion: This study showed that, among tobacco non-users, being male, aged under 39 years, and having lower education were associated with a perception of HTPs as less harmful. Public health stakeholders should provide the latest evidence about HTP harmfulness in their daily practice and strengthen the regulations on HTP marketing directed at both tobacco- and tobacco non-users.

Background: Colorectal Cancer (CRC) has been molecularly classified into several subtypes according to tumor, stromal, and immune components. Here, we investigated whether the preventive effect of vitamin D on CRC varies with subtypes defined by Vitamin D receptor (VDR) expression in tumors and their surrounding stroma, along with the association of somatic mutations in CRC., Methods: In a population-based prospective study of 22,743 Japanese participants, VDR expression levels in tumors and their surrounding stroma were defined in 507 cases of newly diagnosed CRC using immunohistochemistry. Hazard ratios of CRC and its subtypes according to dietary vitamin D intake were estimated using multivariable Cox proportional hazards models., Results: Dietary vitamin D intake was not associated with CRC or its subtypes defined by VDR expression in tumors. However, an inverse association was observed for CRC with high VDR expression in the stroma (the highest tertile vs the lowest tertile: 0.46 [0.23-0.94], P trend  = 0.03), but not for CRC with low VDR expression in the stroma (P heterogeneity  = 0.02). Furthermore, CRC with high VDR expression in the stroma had more somatic TP53 and BRAF mutations and fewer APC mutations than those with low VDR expression in the stroma., Conclusions: This study provides the first evidence that the preventive effect of vitamin D on CRC depends on VDR expression in the stroma rather than in the tumors. CRC with high VDR expression in the stroma is likely to develop through a part of the serrated polyp pathway, which tends to occur with BRAF but not with APC mutations., (© 2024. Japanese Society of Gastroenterology.)

Background: High lipoprotein (a) level is an established cardiovascular risk, but its association with non-cardiovascular diseases, especially cancer, is controversial. Serum lipoprotein (a) levels vary widely by genetic backgrounds and are largely determined by the genetic variations of apolipoprotein (a) gene, LPA. In this study, we investigate the association between SNPs in LPA region and cancer incidence and mortality in Japanese., Methods: A genetic cohort study was conducted utilizing the data from 9923 participants in the Japan Public Health Center-based Prospective Study (JPHC Study). Twenty-five SNPs in the LPAL2-LPA region were selected from the genome-wide genotyped data. Cox regression analysis adjusted for the covariates and competing risks of death from other causes, were used to estimate the relative risk (hazard ratios (HR) with 95% confidence intervals (CI)) of overall and site-specific cancer incidence and mortality, for each SNP., Results: No significant association was found between SNPs in the LPAL2-LPA region and cancer incidence or mortality (overall/site-specific cancer). In men, however, HRs for stomach cancer incidence of 18SNPs were estimated higher than 1.5 (e.g., 2.15 for rs13202636, model free, 95%CI: 1.28-3.62) and those for stomach cancer mortality of 2SNPs (rs9365171, rs1367211) were estimated 2.13 (recessive, 95%CI:1.04-4.37) and 1.61 (additive, 95%CI: 1.00-2.59). Additionally, the minor allele for SNP rs3798220 showed increased death risk from colorectal cancer (CRC) in men (HR: 3.29, 95% CI:1.59 - 6.81) and decreased CRC incidence risk in women (HR: 0.46, 95%CI: 0.22-0.94). Minor allele carrier of any of 4SNPs could have risk of prostate cancer incidence (e.g., rs9365171 dominant, HR: 1.71, 95%CI: 1.06-2.77)., Conclusions: None of the 25 SNPs in the LPAL2-LPA region was found to be significantly associated with cancer incidence or mortality. Considering the possible association between SNPs in LPAL2-LPA region and colorectal, prostate and stomach cancer incidence or mortality, further analysis using different cohorts is warranted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Risk prediction models offer a promising approach to lifestyle modification. We evaluated the effect of personalized advice based on cancer risk prediction in improving five lifestyle habits (smoking, alcohol consumption, salt intake, physical activity, and body mass index) compared with standard advice without risk prediction among a Japanese general population with at least one unhealthy lifestyle habit., Methods: In a parallel-design, single-blind, randomized controlled trial between February 2018 and July 2019, 5984 participants aged 40-64 years with unhealthy lifestyle habits were recruited from persons covered under a life insurance policy. They were randomly assigned to an intervention or control group and received personalized or standard advice, respectively. They were also sent an invitation to participate in a lifestyle modification program aimed at improving lifestyle. Primary outcome was an improvement in lifestyle, defined as an increase in healthy lifestyle habits within 6 months., Results: The proportion of participants who improved their lifestyle within 6 months in the intervention group did not significantly differ from that in the control group (18.4% vs. 17.7%; P = 0.488). Among participants with low health literacy and two or fewer of five healthy habits, the proportion of participants subscribing to the lifestyle modification program was higher in the intervention group than in the control group., Conclusions: Compared with standardized advice, personalized advice based on cancer risk prediction had no effect on improving lifestyle., Impact: Provision of predicted cancer risk information did not induce change in unhealthy lifestyle., (©2021 American Association for Cancer Research.)

Background: Although gastric cancer is one of the Lynch syndrome (LS)-related tumors, the clinicopathological features of gastric cancer in patients with LS remain uncertain. To investigate the incidence risk and clinicopathological features of gastric neoplasms in LS, we conducted a retrospective cohort study in Japanese LS patients., Methods: LS patients with pathogenic mismatch repair (MMR) gene variants were extracted from the LS registry of the National Cancer Center Hospital, Japan. Cumulative risks of gastric neoplasm, including dysplasia and cancer, were estimated using the Kaplan-Meier method. Gastric atrophy was evaluated endoscopically and/or histologically. Immunohistochemical staining for MMR proteins was performed for all available specimens., Results: Of 118 eligible patients, 26 patients were diagnosed with 58 gastric neoplasms. The cumulative incidence of gastric neoplasm was 41.0% (95% confidence interval, 26.9-55.0) at the age of 70. Of these, 13 (50%) patients developed synchronous and/or metachronous multiple gastric neoplasms. Among the 49 gastric neoplasms available for detailed pathological evaluation, all were associated with intestinal metaplasia. Immunohistochemically, 42 (86%) were MMR-deficient. The individuals with gastric atrophy had a significantly higher risk of developing gastric neoplasms compared with those without gastric atrophy (26 cases/54 individuals vs. 0 cases/53 individuals) (P = 0.026)., Conclusion: LS patients, particularly those with atrophic gastritis, are at high risk of gastric neoplasm and often develop multiple tumors. Endoscopic surveillance for gastric cancer is recommended for LS patients, especially those with atrophic gastritis.

Introduction: A major concern is that few cancer survivors meet the guidelines for recommended levels of physical activity. No studies have investigated physical activity among breast cancer survivors nationwide in Japan. Therefore, the aims of this study are to identify the levels of physical activity among breast cancer survivors, to examine factors-related physical activity among breast cancer survivors and to identify breast cancer survivors' preferences for and interest in exercise programmes in order to inform the future programme development., Methods and Analysis: We will administer a cross-sectional survey using a self-report questionnaire to breast cancer survivors. At each of 50 facilities selected to include a variety of institutional backgrounds according to the population distribution of different regions throughout Japan, we will consecutively distribute the questionnaire to 30 outpatients who have completed initial treatments, except for hormone therapy. The target sample size is 1500 survivors. We will calculate descriptive statistics for each measurement item and perform univariate and multivariate analyses using outcome measures (eg, physical activity and quality of life) related to physical, psychological, social and environmental factors., Discussion: This is the first nationwide survey of physical activity levels among breast cancer survivors in Japan. Identifying the factors associated with physical activity will help us to develop, disseminate and implement programmes that encourage more survivors to adhere to physical activity guidelines., Ethics and Dissemination: The protocol was approved by the Institutional Review Board (IRB) of the National Cancer Center on 11 January 2019 (ID: 2018-295). In addition, many of the participating facilities required ethical approval from their local IRBs, while others did not. Accordingly, approval from the local IRBs of individual facilities was obtained when required. The findings will be disseminated through peer-reviewed publications and conference presentations., Competing Interests: Competing interests: EO has received research support from Nippon Suisan Kaisha. YM has received speaker fees from Pfizer, Mochida, Eli Lilly, Morinaga Milk and NTT Data and has conducted collaborative research with Morinaga Milk. AK has received speaking fees from Chugai Pharmaceutical. All other authors declare that they have no competing interests regarding this work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective To assess the impact of the duration of diabetes mellitus (DM) on the outcomes of pancreatic cancer patients undergoing chemotherapy. Methods We reviewed the medical records of patients with metastatic pancreatic cancer who received gemcitabine monotherapy as the standard therapy before the introduction of combination regimens. The treatment outcomes of gemcitabine were compared among three groups classified according to the duration of DM: no DM, short DM (<4 years), and long DM (≥4 years). Results Among 350 patients, 218, 87, and 45 patients were classified into the no DM, short DM, and long DM groups, respectively. In comparison to the no DM group, the univariate hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were 1.44 [95% confidence interval (CI), 1.02-2.02; p=0.027] and 1.33 (95% CI, 0.93-1.89; p=0.081), respectively, in the long DM group, and 1.12 (95% CI, 0.85-1.46; p=0.426) and 1.06 (95% CI, 0.81-1.40; p=0.678), respectively, in the short DM group; the multivariate-adjusted HRs were 1.33 (95% CI, 0.94-1.89; p=0.103) and 1.37 (95% CI, 0.95-1.98; p=0.095) in the long DM group and 1.12 (95% CI, 0.85-1.47; p=0.410) and 1.10 (95% CI, 0.82-1.46; p=0.533) in the short DM group. The survival outcomes of the long DM group tended to remain poorer in analyses using different cutoffs of DM duration as, well as in hospital-specific analyses. Conclusion Long-standing DM may be associated with shorter PFS and OS in patients with metastatic pancreatic cancer.

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., (© 2018 UICC.)

We previously developed and validated a risk prediction model for colorectal cancer in Japanese men using modifiable risk factors. To further improve risk prediction, we evaluated the degree of improvement obtained by adding a genetic risk score (GRS) using genome-wide association study (GWAS)-identified risk variants to our validated model. We examined the association between 36 risk variants identified by GWAS and colorectal cancer risk using a weighted Cox proportional hazards model in a nested case-control study within the Japan Public Health Center-based Prospective Study. GRS was constructed using six variants associated with risk in this study of the 36 tested. We assessed three models: a nongenetic model that included the same variables used in our previously validated model; a genetic model that used GRS; and an inclusive model, which included both. The c-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were calculated by the 5-fold cross-validation method. We estimated 10-year absolute risks for developing colorectal cancer. A statistically significant association was observed between the weighted GRS and colorectal cancer risk. The mean c-statistic for the inclusive model (0.66) was slightly greater than that for the nongenetic model (0.60). Similarly, the mean IDI and NRI showed improvement when comparing the nongenetic and inclusive models. These models for colorectal cancer were well calibrated. The addition of GRS using GWAS-identified risk variants to our validated model for Japanese men improved the prediction of colorectal cancer risk. Cancer Prev Res; 10(9); 535-41. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Although global hypomethylation of leukocyte DNA has been associated with an increased risk of several sites of cancer, including breast cancer, determinants of global methylation level among healthy individuals remain largely unexplored. Here, we examined whether postmenopausal endogenous sex hormones were associated with the global methylation level of leukocyte DNA., Methods: A cross-sectional study was conducted using the control group of a breast cancer case-control study in Nagano, Japan. Subjects were postmenopausal women aged 55 years or over who provided blood samples. We measured global methylation level of peripheral blood leukocyte DNA by luminometric methylation assay; estradiol, estrone, androstenedione, dehydroepiandrosterone sulfate, testosterone and free testosterone by radioimmunoassay; bioavailable estradiol by the ammonium sulfate precipitation method; and sex-hormone binding globulin by immunoradiometric assay. A linear trend of association between methylation and hormone levels was evaluated by regression coefficients in a multivariable liner regression model. A total of 185 women were included in the analyses., Results: Mean global methylation level (standard deviation) was 70.3% (3.1) and range was from 60.3% to 79.2%. Global methylation level decreased 0.27% per quartile category for estradiol and 0.39% per quartile category for estrone while it increased 0.41% per quartile category for bioavailable estradiol. However, we found no statistically significant association of any sex hormone level measured in the present study with global methylation level of leukocyte DNA., Conclusions: Our findings suggest that endogenous sex hormones are not major determinants of the global methylation level of leukocyte DNA.

Background & Aims: Two major types of gastric cancer, intestinal and diffuse, develop through distinct mechanisms; the diffuse type is considered to be more influenced by genetic factors, although the mechanism is unknown. Our previous genome-wide association study associated 3 single nucleotide polymorphisms (SNPs) with diffuse-type gastric cancer (DGC); 1 was a functional SNP (rs2294008) in prostate stem cell antigen (PSCA), but the loci of the other 2 were not investigated., Methods: We performed high-density mapping to explore a linkage disequilibrium status of the 2 SNPs at chromosome 1q22. A DGC case-control study was conducted using DNA from 606 cases and 1264 controls (all Japanese individuals) and validated using DNA from Japanese (304 cases, 1465 controls) and Korean (452 cases, 372 controls) individuals. The effects of SNPs on function were analyzed by reporter assays and analyses of splice variants., Results: A region of a strong linkage disequilibrium with the 2 SNPs contained mucin 1 (MUC1) and other 4 genes and SNPs significantly associated with DGC (rs2070803: P = 4.33 × 10(-13); odds ratio [OR], 1.71 by meta-analysis of the studies on the 3 panels) but not with intestinal-type gastric cancer. Functional studies demonstrated that rs4072037 (P = 1.43 × 10(-11); OR, 1.66 by meta-analysis) in MUC1 affects promoter activity and determines the major splicing variants of MUC1 in the gastric epithelium. Individuals that carry both SNPs rs2294008 in PSCA and rs4072037 in MUC1 have a high risk for developing DGC (OR, 8.38)., Conclusions: MUC1 is the second major DGC susceptibility gene identified. The SNPs rs2070803 and rs4072037 in MUC1 might be used to identify individuals at risk for this type of gastric cancer., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Aim: We previously reported significant associations between mitochondrial single nucleotide polymorphisms (mtSNPs) and myocardial infarction, atherothrombotic cerebral infarction, metabolic syndrome and type 2 diabetes. Here, we assessed the hypothesis that mtSNPs may confer a risk for atherosclerosis, the most important intermediate phenotype of ischemic cardiovascular events., Methods: The subjects were 1,536 consecutive autopsy cases (827 men and 709 women). The average age at death was 80 years. The severity of coronary atherosclerosis was semi-quantitatively examined on cut sections. We examined 149 mtSNPs using the PCR-Luminex method, with a success rate of 97%. Phylogenetic tree analysis yielded 36 haplogroups. Multiple logistic regression analysis was performed after adjustments for sex, age, and conventional cardiovascular risk factors., Results: Among the 45 mtSNPs with minor genotype frequencies >0.05, 6 mtSNPs were associated with coronary atherosclerosis. Among 10 haplogroups with frequencies >0.04, haplogroups A and M7a were significantly associated with coronary atherosclerosis, with odds ratios (95% confidence intervals) of 1.80 (1.09-2.97; p=0.023) and 1.92 (1.23-3.01; p=0.004), respectively. Haplogroup D4a, which was previously reported to be associated with extreme longevity in a Japanese population, was associated with pathological myocardial infarction in men with an odds ratio of 2.05 (1.01-4.14; p=0.046)., Conclusions: The mitochondrial haplogroups A and M7a confer a significant risk for coronary atherosclerosis in the Japanese. The mitochondrial haplogroup may contribute some genetic risk for coronary heart disease.

The power of an SNP-based genome-wide association study (GWAS) was first demonstrated in Japan using the JSNP database and is currently a major strategy adopted around the world for a number of common diseases including cancers. The hypothesis-free strategy can lead us to a novel hypothesis for carcinogenesis and may contribute to identifying a high risk group for research and, in the future, practice of personalized prevention. We performed a GWAS on diffuse-type gastric cancer and identified a significant association with SNPs in the PSCA (prostate stem cell antigen) gene. The association was validated by a Korean gastric case-control analysis. The PSCA protein is expressed predominantly in the stem cell/precursor-rich region of the gastric epithelium, which is considered as the origin of diffuse-type gastric cancer, and showed tumor suppressor-like characteristics. Individuals with a low PSCA promoter activity are susceptible to diffuse-type gastric cancer. By contrast, the polymorphism does not significantly predispose to intestinal-type gastric cancer, congruous to the hypothesis of the two distinct carcinogenesis pathways for the two major types of gastric cancer. In addition to publication on a specific gene, the sharing of GWAS data through a database on the web is expected to accelerate validation and discovery by other investigators. GeMDBJ (Genome Medicine Database of Japan), started in 2005 in Japan, is one of such attempts. Moreover, the advent of "next generation" sequencers may herald a new era in which the poorly explored domains of the genetic architecture of disease susceptibility may be unveiled.

Recent genome wide association (GWA) studies on European and American populations revealed association with lung cancer risk of single-nucleotide polymorphisms (SNPs) in the locus containing two nicotine acetylcholine receptor (CHRNA) genes, whose involvement in tobacco addiction had been indicated. Association with lung cancer risk in smokers was consistently, but that in non-smokers as well as that with smoking behavior was inconsistently, observed in these studies. To obtain further information on the significance of CHRNA SNPs in lung cancer risk, association of seven SNPs in this locus with lung cancer risk as well as smoking status was examined in a Japanese population by a case-control study of 1250 cases (562 adenocarcinoma, 391 squamous cell carcinoma and 297 small cell carcinoma) and 936 controls. The frequency of the haplotype consisting of minor alleles for three SNPs, rs8034190, rs16969968 and rs1051730, which had been defined as a susceptible haplotype in the GWA studies, was much lower in the Japanese population (0.013) than in European and American populations (0.3-0.4). However, this haplotype was significantly associated with lung cancer risk also in Japanese (odds ratio = 2.3, 95% confidence interval = 1.5-3.7, P = 0.00028, respectively). The association was observed both in smokers and non-smokers and in all histological types of lung cancers. Individuals with this haplotype showed higher smoking doses than those without; however, the difference was not statistically significant. These results strongly indicate that CHRNA SNPs confer lung cancer susceptibility in a small subset of Japanese in a smoking-independent manner.

Atherosclerosis is a chronic inflammatory disease in the intima of the arterial wall, where cytokines play a crucial role in the pathogenesis of this disease. However, the question of whether or not genetic variations in the cytokine genes could influence the development of atherosclerosis has been poorly investigated. We investigated the relationship of nine common single-nucleotide polymorphisms (SNPs) in tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-10, IL-4 and transforming growth factor (TGF)-beta1 with the atherosclerotic severity in 10 different arteries based on 1503 consecutive autopsies of elderly Japanese subjects registered in the Japanese SNPs for geriatric research (JG-SNP) study. The -1031C allele of TNF-alpha was a significant protective factor for atherogenesis in the carotid, femoral and intracranial arteries [odds ratio (OR): 0.72, 0.73 and 0.70, respectively]. The -511T of IL-1beta and the +29T of TGF-beta1 were significant risk factors for atherogenesis in the subclavian and intracranial arteries (OR: 1.35 and 1.48, respectively). In contrast, conventional risk factors for atherogenesis, such as hypertension and diabetes mellitus, conferred independent risks for almost all arteries. Functional SNPs in TNF-alpha, IL-1beta and TGF-beta1 genes play a role in atherogenesis, although their influences are less pronounced than those of conventional risk factors and appear to be limited to specific arteries in the Japanese elderly.

Adenocarcinoma (ADC) is the most frequent histological type of lung cancer and comprises the majority of lung cancers in non-smokers. Thus, genetic factors responsible for ADC susceptibility need to be determined to establish efficient ways of preventing the disease. The OGG1 gene, encoding a glycosylase for 8-hydroxyguanine, an oxidatively damaged promutagenic base, has the polymorphism Ser326Cys, and OGG1-326Cys protein was indicated to have a lower ability to prevent mutagenesis than the OGG1-326Ser protein. Case-control studies to date suggest that the OGG1-326Cys allele is associated with a higher risk for several types of cancers, including overall lung cancer. However, the contribution of this polymorphism to lung ADC risk is unclear. In the present study, the OGG1-Ser326Cys polymorphism was assessed for association with lung ADC risk using a case-control study of a Japanese population consisting of 1097 cases and 394 controls. Odds ratios (OR) of the 326Cys allele carriers increased in a dose-dependent manner with allele number (P for the trend test = 0.04). The OR of homozygotes for the 326Cys allele was increased significantly when homozygotes for the 326Ser allele were used as a reference (OR = 1.5, 95% confidence interval [CI] = 1.0-2.1, P = 0.04). Furthermore, the overall OR for lung ADC of the Cys/Cys homozygotes out of a total of 1925 ADC patients and 3449 controls from six case-control studies reported up to the present were 1.43 (95% CI = 1.11-1.84, P = 0.0045). These results indicate that OGG1-326Cys functions as a risk allele for lung ADC development.