Coffee Consumption and All-Cause and Cardiovascular Mortality　- Three-Prefecture Cohort in Japan.

BACKGROUND: Coffee, which contains various bioactive compounds, is one of the most popular beverages. Further accumulation of evidence is needed, however, to confirm whether coffee consumption would be effective in preventing cardiovascular disease in the general Japanese population. Methods and Results: We evaluated the association between coffee consumption frequency (never, sometimes, 1-2 cups/day, 3-4 cups/day and ≥5 cups/day) and mortality from all causes, heart disease, and cerebrovascular disease, in 39,685 men and 43,124 women aged 40-79 years at baseline, in a 3-prefecture cohort study. The coffee consumption frequency was assessed on questionnaire. Cox proportional hazards regression modeling was used to assess the association between coffee consumption frequency and all-cause and cardiovascular disease mortality with adjustment for potential confounders. During 411,341 and 472,433 person-years in men and women, respectively, a total of 7,955 men and 5,725 women died. Coffee consumption frequency was inversely associated with all-cause mortality in both genders (P for trend<0.001). In addition, the risks of mortality from cerebrovascular disease in men (P for trend<0.001), and heart disease in women (P for trend=0.031) were inversely associated with coffee consumption. CONCLUSIONS: In this Japanese population, coffee drinking has a preventive effect on all-cause and on cardiovascular mortality in men and/or women.

Association between coffee consumption and all-sites cancer incidence and mortality.

The preventive effect of coffee on cancer at different sites has been reported, but the effect on all-sites cancer incidence has not been extensively investigated. We evaluated the association between frequency of coffee consumption and risk of all-sites cancer incidence and mortality among 39 685 men and 43 124 women (age 40-79 years, at baseline), in the Three-Prefecture Cohort Study. The association between frequency of coffee consumption and risk of all-sites cancer incidence and mortality was assessed by a Cox proportional hazards regression model, adjusted for potential confounders. During 411 341 person-years among men and 472 433 person-years among women, a total of 4244 men and 2601 women developed cancer at different sites and a total of 3021 men and 1635 women died of cancer at different sites. We showed an inverse association between frequency of coffee consumption and all-sites cancer incidence in both men and women. Comparing participants who consumed coffee with those who never drank coffee, the adjusted hazard ratios (95% confidential interval) for all-sites cancer incidence was 0.74 (0.62-0.88) for coffee consumption of ≥5 cups/day in men (P for trend < 0.001) and 0.76 (0.58-1.02) in women (P for trend = 0.020). Coffee consumption frequency was inversely associated with mortality from all-sites cancer. In this population, increasing coffee consumption resulted in a decreased risk of all-sites cancer incidence and mortality.

Rationale, design, and profile of the Three-Prefecture Cohort in Japan: A 15-year follow-up.

BACKGROUND: We reutilized the existing Three-Prefecture Cohort to evaluate the relationship between lifestyle factors and the incidence or mortality from non-communicable diseases. METHODS: This study was a prospective population-based observation conducted from the 1980s to 2000 in three prefectures (Miyagi, Aichi, and Osaka) in Japan. The study subjects were residents aged ≥40 years who received a questionnaire. The follow-up period was 15 years from the baseline survey in each study area. A self-administered questionnaire, which included items on participants' demographic factors and lifestyle characteristics, was administered. Vital status and date of death were collected from residence certificates by the local government, and cause of death was identified using vital statistics. Cancer incidence and the date of diagnosis were collected from local cancer registry data. RESULTS: A total of 46,421 men and 54,189 women were eligible for our analysis. The person-years of follow-up for cancer incidence were 464,664 and 567,271 for men and women, respectively, and those for death were 527,940 and 648,601 for men and women, respectively. There were 8479 cancer incidences (5106 men and 3373 women) and 20,240 total deaths (11,156 men and 9084 women). The stomach was the most common cancer incidence site for both men (25.6%) and women (18.6%). The leading cause of death was cancer among men (35.0%) and cardiovascular disease among women (41.0%). CONCLUSIONS: The Three-Prefecture Cohort Study enabled us to reveal the association of multiphasic lifestyle factors with cancer incidence and mortality. The study will also allow us to conduct a pooled analysis in combination with other large-scale cohorts.

Stroke mortality associated with environmental tobacco smoke among never-smoking Japanese women: a prospective cohort study.

OBJECTIVE: This study examined the association of exposure to environmental tobacco smoke (ETS) during adulthood with stroke and its subtypes using data from a large-scale prospective cohort study in Japan. METHODS: The study population included 36,021 never-smoking Japanese women who were enrolled between 1983 and 1985 and were followed-up for 15 years. We used Cox proportional hazard regression models to estimate hazard ratios (HRs) for stroke death associated with ETS exposure at home during adulthood. RESULTS: A total of 906 cases of stroke death were observed during 437,715 person-years of follow-up. Compared with never-smoking women without smoking family members, HRs for stroke mortality among never-smoking women living with smoking family members in all subjects, in those aged 40-79 years, and in those aged ≥ 80 years were 1.14 (95% confidence interval: 0.99-1.31), 1.24 (95% CI: 1.05-1.46), and 0.89 (95% CI: 0.66-1.19), respectively, after adjustment for possible confounders. The risk was most evident for subarachnoid hemorrhage [HR: 1.66 (95% CI: 1.02-2.70) in all subjects]. CONCLUSION: This study suggests that exposure to ETS at home during adulthood is associated with an increased risk of stroke among never-smoking Japanese women.

Association between blood levels of PCDDs/PCDFs/dioxin-like PCBs and history of allergic and other diseases in the Japanese population.

BACKGROUND: Previous studies reported that exposure to dioxins was associated with an increased risk of various diseases in general populations. OBJECTIVES: The aim of this study was to examine the association between levels of dioxins in blood and allergic and other diseases. METHODS: We conducted a cross-sectional study on 1,063 men and 1,201 women (aged 15-76 years), who were living throughout Japan and not occupationally exposed to dioxins, during 2002-2010. In fasting blood samples, polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like PCBs (DL-PCBs) were analyzed by isotope dilution high-resolution gas chromatography/mass spectrometry. We obtained information on life style and self-reported history of diseases using a questionnaire. Blood pressure, blood levels of hemoglobin A1c, and serum lipids were also measured. Multiple logistic regression models were used to analyze the association between dioxin levels in blood and various diseases. RESULTS: Toxic equivalents of PCDDs/PCDFs and total dioxins showed significant inverse dose-response relationships with atopic dermatitis, after adjustments for potential confounders. The highest quartile for total dioxins had an adjusted odds ratio of 0.26 (95 % confidence interval 0.08-0.70) compared to the reference group (first quartile). The odds ratios for hypertension, diabetes mellitus, hyperlipidemia, gout in men, and gynecologic diseases in women significantly increased with increasing toxic equivalents of PCDDs/PCDFs, DL-PCBs, and total dioxins in blood. CONCLUSIONS: The present findings suggest that background exposure to dioxins was associated with reduced risk of atopic dermatitis. The results also support the idea that low-level exposure to dioxins is associated with an increased risk of diabetes, hypertension, and hyperlipidemia.

Projected cancer mortality among Japanese males under different smoking prevalence scenarios: evidence for tobacco control goal setting.

OBJECTIVE: Male smoking prevalence is still high in Japan, and quantitative information for tobacco control is scarce. The aim of the present study was to project cancer mortality among Japanese males under different future scenarios of smoking prevalence. METHODS: The target population comprised Japanese males aged 40-79 years in 2007, whose smoking prevalence was 35%. On the basis of the pooled data from three large-scale cohort studies in Japan, the effects of age, years of smoking and years after smoking cessation on the time to all-cancer or lung cancer death were estimated by an accelerated failure time model. The parameter estimates were used to project the annual number of deaths from all cancers and lung cancer by running simulations for different future scenarios of smoking prevalence. Each scenario was evaluated by the cumulative number of avoided deaths when compared with the status quo and by the percent change (from the baseline year) in age-standardized rate of mortality. RESULTS: Reducing the smoking prevalence from 35% in 2007 to 0% in 2017 was estimated to avoid 333 900 all-cancer deaths and 171 100 lung cancer deaths in 20 years. Even when we shortened the projection period to 10 years, these numbers of avoided deaths would be 81 100 and 38 800, respectively. The age-standardized rate of all-cancer mortality was estimated to decrease by 9.6% in 10 years and 18.1% in 20 years. CONCLUSIONS: Reducing the prevalence of smoking among males would be effective in reducing the cancer burden even within 10 years in countries with a high male smoking prevalence.

An association between long-term exposure to ambient air pollution and mortality from lung cancer and respiratory diseases in Japan.

BACKGROUND: Evidence for a link between long-term exposure to air pollution and lung cancer is limited to Western populations. In this prospective cohort study, we examined this association in a Japanese population. METHODS: The study comprised 63 520 participants living in 6 areas in 3 Japanese prefectures who were enrolled between 1983 and 1985. Exposure to particulate matter less than 2.5 µm in aerodynamic diameter (PM(2.5)), sulfur dioxide (SO(2)), and nitrogen dioxide (NO(2)) was assessed using data from monitoring stations located in or nearby each area. The Cox proportional hazards model was used to calculate the hazard ratios associated with the average concentrations of these air pollutants. RESULTS: The 10-year average concentrations of PM(2.5), SO(2), and NO(2) before recruitment (1974-1983) were 16.8 to 41.9 µg/m(3), 2.4 to 19.0 ppb, and 1.2 to 33.7 ppb, respectively (inter-area range). During an average follow-up of 8.7 years, there were 6687 deaths, including 518 deaths from lung cancer. The hazard ratios for lung cancer mortality associated with a 10-unit increase in PM(2.5) (µg/m(3)), SO(2) (ppb), and NO(2) (ppb) were 1.24 (95% confidence interval: 1.12-1.37), 1.26 (1.07-1.48), and 1.17 (1.10-1.26), respectively, after adjustment for tobacco smoking and other confounding factors. In addition, a significant increase in risk was observed for male smokers and female never smokers. Respiratory diseases, particularly pneumonia, were also significantly associated with all the air pollutants. CONCLUSIONS: Long-term exposure to air pollution is associated with lung cancer and respiratory diseases in Japan.

Correlations of fish intake and plasma docosahexaenoic acid levels with each congener of PCDDs/PCDFs/dioxin-like PCBs in blood from the Japanese population.

PURPOSE: The purpose of the present study was to investigate the factors associated with blood levels of each congener of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (DL-PCBs) in the Japanese population. METHODS: A cross-sectional study was performed on 1,656 subjects (755 men and 901 women) aged 15-73 years, who were living in 90 different areas of 30 prefectures in Japan. Blood levels of 29 PCDD, PCDF, and DL-PCB congeners were determined by high-resolution gas chromatography/mass spectrometry. In addition, a questionnaire survey on life style, including dietary habit, was carried out. RESULTS: The median total toxicity equivalent (TEQ) was 17 pgTEQ/g lipid. After adjustment for age, sex, body mass index, smoking habit, and consumption of other food groups, six PCDDs/PCDFs with 4-6 substituted chlorine atoms and 10 DL-PCBs, but not HeptaCDD/F or OctaCDD, showed significant positive correlations with the frequency of intake of fish and shellfish. Furthermore, significant positive relationships were also found between plasma levels of docosahexaenoic acid (DHA), a biomarker of fish intake, and 10 PCDDs/PCDFs with 4-6 chlorine atoms and 10 DL-PCBs. The partial correlation coefficients with plasma DHA were significantly higher for DL-PCBs than for PCDDs/PCDFs, and partial correlation coefficients for PCDDs/PCDFs significantly decreased with increasing number of chlorine atoms (Spearman r = -0.80, P = 0.001). CONCLUSIONS: Blood levels of PCDDs/PCDFs with 4-6 chlorine atoms and DL-PCBs were positively associated with fish intake in the Japanese population. These results may be explained by the higher degree of bioaccumulation of these congeners in fish and shellfish in the ecosystem, and the high consumption of fish among the Japanese population.

Efficacy of oral tegafur-uracil (UFT) as adjuvant therapy as compared with classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in early breast cancer: a pooled analysis of two randomized controlled trials (N.SAS-BC 01 trial and CUBC trial).

Two randomized clinical studies comparing the efficacy of oral UFT (2 years) with that of classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (six courses) have been conducted in patients with resected early breast cancer. We have performed a pooled analysis of these two randomized studies. A pooled analysis was performed using individual patient data from the two trials. Hazard ratios (HRs) were determined with a Cox model stratified by study and adjusted for clinical characteristics. We preplanned to verify the following two hypotheses: UFT is non-inferior to CMF in all patients (hypothesis 1) or in ER-positive patients (hypothesis 2) with respect to relapse-free survival (RFS). Non-inferiority of UFT versus CMF was established if the upper limit of the two-sided confidence interval (CI) of the HR for RFS did not exceed 1.30. Hochberg multiplicity adjustment for the significance level was performed. A total of 1,057 patients were analyzed (CMF, n = 528; UFT, n = 529). Median follow-up time was 5.6 years. The HR for RFS was 1.04 (95% CI, 0.78-1.40) in all patients and 0.79 (97.5% CI, 0.49-1.27) in ER-positive patients. UFT was shown to be non-inferior to CMF in ER-positive patients. An exploratory subgroup analysis showed that RFS was better with UFT than with CMF in ER-positive patients who were 50 years or older (HR, 0.58; 95% CI, 0.34-1.01). UFT is non-inferior to CMF in terms of inhibiting recurrence of ER-positive, early breast cancer.

The effects of smoking and smoking cessation on mortality from cardiovascular disease among Japanese: pooled analysis of three large-scale cohort studies in Japan.

OBJECTIVES: To estimate the gender-specific risk of mortality from cardiovascular disease according to smoking status and time since smoking cessation among former smokers in Japan. DESIGN: Prospective study. SETTING: 140,026 males and 156,810 females aged 40-79 years who participated in one of three cohort studies conducted in Japan between 1980 and 1990. OUTCOME: The gender-specific hazard ratios (HRs) for cardiovascular disease mortality were calculated after adjustment for age and cohort. RESULTS: The age-adjusted and cohort-adjusted HRs for current smokers compared with lifelong non-smokers were 1.51 (95% CI 1.38 to 1.64) for total cardiovascular diseases, 2.19 (95% CI 1.79 to 2.67) for coronary heart disease and 1.24 (95% CI 1.10 to 1.41) for total stroke in males, and were 1.85 (95% CI 1.65 to 2.06), 2.84 (95% CI 2.24 to 3.60) and 1.70 (95% CI 1.44 to 2.01), respectively, in females. The age-adjusted and cohort-adjusted HRs for former smokers compared with current smokers according to the time period since smoking cessation decreased by approximately 5 years after smoking cessation and reached the same level as lifelong non-smokers approximately 10 years after smoking cessation among both males and females. CONCLUSIONS: The present study confirmed the association between smoking and mortality from cardiovascular disease in both males and females. Smoking cessation is a crucial preventive measure against death from cardiovascular disease.

A longitudinal study of trends in blood dioxins and dioxin-like compounds levels in residents from two locations in Japan during 2002-2006.

To investigate the recent changes in background exposure to dioxin-related compounds, the concentrations of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (dl-PCBs) in the blood of individual residents in Japan were repeatedly examined. Twenty-six subjects (mean age, 52.7 +/- 1.8) from District A and 23 subjects (mean age, 56.1 +/- 1.2) from District B were longitudinally analyzed from 2002 to 2006. District A is a rural area in Osaka prefecture, and District B is an urban area in Saitama prefecture. For the longitudinal analysis of these concentrations, we used the generalized estimating equation (GEE). The PCDD + PCDF concentrations decreased significantly between 2002 and 2006 (p < 0.0001), but the concentrations of dl-PCBs declined to a smaller degree over the 5-year period. A time x body mass index (BMI) interaction suggests that the reduction rate of blood PCDDs + PCDFs and dl-PCB concentrations in subjects with a BMI greater than the 75th percentile is lower than that of subjects with a BMI less than the 75th percentile from 2002 to 2004 over the 5-year period. From other reports on the dietary intake of PCDDs, PCDFs, and dl-PCBs in Japan, the total amount of daily dioxin intake decreased, but the percentage of dl-PCBs increased yearly in the first half of the 2000s. The reason for the difference in the 5-year change in blood concentrations between PCDDs +PCDFs and dl-PCBs may be explained by the yearly change in the dietary dioxin intake.

Reproductive and lifestyle factors related to breast cancer among Japanese women: An observational cohort study.

The incidence of breast cancer among Japanese women is substantially increasing. This study evaluated the effects of reproductive and lifestyle factors with respect to breast cancer overall and separately among pre- and postmenopausal women using data from the Three-Prefecture Cohort Study of Japan.A total of 33,410 women aged 40 to 79 years completed a self-administered questionnaire, which included items about menstrual and reproductive history and other lifestyle factors. The follow-up period was from 1984 to 1992 in Miyagi and 1985 to 2000 in Aichi Prefectures. We used Cox proportional hazards regression models to estimate hazards ratios (HRs) and 95% confidence intervals (CIs) after adjusting for confounding factors.After 9.8 mean years of follow-up, 287 cases of breast cancer were recorded. In the overall analysis, later menarche (≥16 years) and parity were significantly associated with a decreased risk of breast cancer, with HRs of 0.69 (95% CI 0.48-0.99) and 0.72 (95% CI 0.52-0.99), respectively. Further, there was a significant decline in the risk of breast cancer with increasing number of birth among parous women (P for trend = .010). On the contrary, a family history of breast cancer in the mother was significantly associated with an increased risk of breast cancer (HR 3.22, 95% CI 1.52-6.84). Analyses based on menopausal status at baseline indicated that height (≥160 cm) and weight (≥65 kg) were significantly associated with an increased risk of postmenopausal breast cancer, with HRs of 1.34 (95% CI 0.72-2.50) and 3.13 (95% CI 1.75-5.60), respectively. Risk associated with BMI significantly differs by menopausal status.Our findings suggest the important role of reproductive factors in the development of breast cancer in Japanese women; however, body mass index (BMI) may have different effects on breast cancer in Japanese women compared with western women.

Dietary intake of PCDDs/PCDFs and coplanar PCBs among the Japanese population estimated by duplicate portion analysis: a low proportion of adults exceed the tolerable daily intake.

Dietary intake of dioxins was estimated by duplicate portion analysis of consecutive 3-day food samples among 86 men and 288 women (aged 17-72 years), who were living in 75 different areas of 25 prefectures in Japan. The mean (median) intake of PCDDs+PCDFs, coplanar PCBs (co-PCBs), and total dioxins, expressed on the basis of toxicity equivalents (TEQ), was 0.46 (0.34), 0.59 (0.39), and 1.06 (0.79)pg/kg body weight/day, respectively. Dietary intake was highest in fishing areas, followed by farming and urban areas. In multiple regression analysis, TEQs of PCDDs+PCDFs, co-PCBs, and total dioxins were positively associated with age and intake amount of fish and shellfish, and milk and dairy products, and negatively associated with survey year. There were significant positive correlations between dietary intake and blood levels for TEQs of PCDDs+PCDFs, co-PCBs, and total dioxins (Pearson r=0.35-0.36). The proportion of those whose dietary intake exceeded the tolerable daily intake (TDI), set by the World Health Organization (4pg TEQ/kg/day) and European Union (2pg TEQ/kg/day), was estimated at 2.1% and 10.4%, respectively. However, these proportions were considered to be overestimated because of the effect of day-to-day within-person variation. Therefore, the ratio of within- and between-person variance was estimated by applying random effects one-way analysis of variance to repeated measurements for another group of 35 persons. When the effect of within-person variation of dietary intake was accounted for, the proportion of subjects whose long-term intake exceeded the TDI of WHO and EU decreased to 0.06% and 2.9%, respectively.

Associations of environmental exposure to dioxins with prevalent diabetes among general inhabitants in Japan.

The aim of this study was to evaluate the associations of environmental exposure to dioxins with diabetes among general inhabitants in Japan. A cross-sectional study was performed on 1374 participants, who were not occupationally exposed to dioxins, aged 15-73 years, living widely in 75 different residential areas of 25 prefectures in Japan through 2002-2006. Seven polychlorinated dibenzo-p-dioxins (PCDDs), 10 polychlorinated dibenzofurans (PCDFs), 12 dioxin-like polychlorinated biphenyls (PCBs), which are assigned a toxic equivalency factor, and biochemical factors were determined in fasting blood. A questionnaire survey on life-style including past history of diseases and treatments was also performed. We examined the associations of the accumulated toxic equivalents (TEQs) of PCDDs+PCDFs, dioxin-like PCBs and total dioxins with prevalent diabetes. Simple and partial correlation analyses revealed that HbA1c correlated with the accumulated TEQs of PCDDs+PCDFs, dioxin-like PCBs and total dioxins. In logistic regression analyses, the third and the highest quartiles of dioxin-like PCBs had adjusted odds ratios (ORs) of 3.07 (95% CI 1.16-8.81) and 6.82 (95% CI 2.59-20.1) compared to the reference (first plus second quartiles). On the other hand, the highest but not the third quartiles of PCDDs+PCDFs and total dioxins had significantly higher adjusted ORs compared to the respective references. These associations persisted when the subjects with poor liver or poor renal function were removed from the analysis. This recent representative data from general inhabitants in Japan showed associations of environmental exposure to dioxins, especially dioxin-like PCBs, with diabetes.

Reduced life expectancy due to smoking in large-scale cohort studies in Japan.

BACKGROUND: To show the reduction in life expectancy due to smoking and the recovery of normal life expectancy by smoking cessation is useful for tobacco control health policy. METHODS: This study included 140,026 males and 156,810 females aged 40-79 years, who were participants of large-scale cohort studies in Japan (Japan Health Center-based Prospective Study [JPHC]-I, JPHC-II, Three-Prefecture Study, and Japan Collaborative Cohort [JACC] Study), which commenced around 1990. The mean follow-up period (+/-standard deviation) was 9.6 +/- 2.3 years, during which 16,282 men and 9,418 women died. For persons aged 40-79 years grouped according to each defined smoking status in the baseline questionnaire, sex- and age-specific death rates at attained ages were calculated. The age-specific death rate was calculated by dividing the number of persons who died at the age by the number of persons who were followed-up at the attained age. From these death rates, current life tables were constructed according to the smoking status, and survival curves were plotted. RESULTS: The life expectancy of male smokers, ex-smokers, and never-smokers at age 40 years was 38.5, 40.8, and 42.4 years respectively. In women, the corresponding life expectancies were 42.4, 42.1, and 46.1 years. In both sexes, the age by which half of the current smokers had died was approximately 4 years younger than that for never-smokers. The life expectancies of male ex-smokers who quit smoking before ages 40, 50, 60, and 70 years were 4.8, 3.7, 1.6, and 0.5 years longer than those of smokers, respectively. CONCLUSION: Smoking considerably reduced the life expectancy, and earlier smoking cessation resulted in a better survival than that seen with continued smoking.

Population attributable fraction of mortality associated with tobacco smoking in Japan: a pooled analysis of three large-scale cohort studies.

BACKGROUND: Quantitative measures of the burden of tobacco smoking in Asian countries are limited. We estimated the population attributable fraction (PAF) of mortality associated with smoking in Japan, using pooled data from three large-scale cohort studies. METHODS: In total, 296,836 participants (140,026 males and 156,810 females) aged 40-79 years underwent baseline surveys during the 1980s and early 1990s. The average follow-up period was 9.6 years. PAFs for all-cause mortality and individual tobacco-related diseases were estimated from smoking prevalence and relative risks. RESULTS: The prevalence of current and former smokers was 54.4% and 25.1% for males, and 8.1% and 2.4% for females. The PAF of all-cause mortality was 27.8% [95% confidence interval (CI): 25.2-30.4] for males and 6.7% (95% CI: 5.9-7.5) for females. The PAF of all-cause mortality calculated by summing the disease-specific PAFs was 19.1% (95% CI: 16.0-22.2) for males and 3.6% (95% CI: 3.0-4.2) for females. The estimated number of deaths attributable to smoking in Japan in 2005 was 163,000 for males and 33,000 for females based on the former set of PAFs, and 112,000 for males and 19,000 for females based on the latter set. The leading causes of smoking-attributable deaths were cancer (61% for males and 31% for females), ischemic heart diseases and stroke (23% for males and 51% for females), and chronic obstructive pulmonary diseases and pneumonia (11% for males and 13% for females). CONCLUSION: The health burden due to smoking remains heavy among Japanese males. Considering the high prevalence of male current smokers and increasing prevalence of young female current smokers, effective tobacco controls and quantitative assessments of the health burden of smoking need to be continuously implemented in Japan.

Long-term follow-up study of a population-based 1996-1998 mass screening programme for lung cancer using mobile low-dose spiral computed tomography.

Early diagnosis and treatment are important for improvement of the low survival rate of patients with lung cancer. The objective of this study was to evaluate the long-term survival rate of patients identified to have lung cancer by our population-based baseline and annual repeat low-radiation dose computed tomography (low-dose CT) screenings, conducted in 1996-1998. A total of 13,037 CT scans were obtained from 5480 subjects (2969 men, 2511 women) aged 40-74 years at the initial CT screening. Lung cancer was detected in 63 subjects (57 were detected by CT scans and underwent surgery; 1 was detected by sputum cytology and underwent surgery; 3 rejected treatment; and 2 were interval cases that developed symptoms prior to the next annual repeat CT screening). Follow-up study included review of medical records. Death certificates were examined to check for any deceased interval case among participants. Postoperative follow-up of the 50 survived patients ranged from 70 to 117 (median, 101) months. Eight patients died during follow-up (6 due to lung cancer from 20 to 67 months after surgery and 2 deaths unrelated to lung cancer, each 7 and 60 months following surgery). Three patients who rejected treatment died 14 months to 6 years after positive screening CT scans, and the 2 interval cases died at each 17 and 30 months, respectively, following negative screening CT scans. Survival was analysed in 59 patients with lung cancer detected by low-dose CT screening (excluding two patients; one was detected by sputum cytology and the other had mass lesion already noted on the chest radiograph of the previous year). The 10-year survival calculated by the Kaplan-Meier method was 83.1% (95% CI: 0.735-0.927) for death from all causes and 86.2% (95% CI: 0.773-0.951) for death from lung cancer. The survival rate was excellent for never-smokers, patients with BAC and adenocarcinoma/mixed types with non-solid CT density pattern, associated with Noguchi's type A or B and pathologic stage IA. A poorer prognosis was noted in smokers with adenocarcinomas/mixed types, associated with part-solid or solid CT density pattern and Noguchi's type C or D. All patients with non-solid tumours measuring 6-13.5mm at presentation are alive, patients with part-solid tumours, measuring 17mm or more, or solid tumours, measuring 13mm or more at presentation were associated with increased risk of lung cancer-related morbidity or mortality. The estimated rate of possible over-diagnosis was 13% in total and we failed to cure 17% of patients encountered in the programme. Low-dose CT screening substantially improves the 10-year survival for lung cancer with minimal use of invasive treatment procedures.

CT findings of early-stage small cell lung cancer in a low-dose CT screening programme.

The survival of patients with small cell lung cancer (SCLC) is related to T, N, M components, and early diagnosis and treatment of limited stage SCLC may improve survival. The objective of this study was to review the initial and annual repeat screening computed tomography (CT) images of all five patients with SCLC, encountered in our 1996-1998 population-based screening for lung cancer, to clarify any subtle, characteristic CT findings of early-stage small cell lung cancer. The medical records of the patients were reviewed to examine demographic and clinical features. We identified characteristic CT features of SCLC in the lung periphery, which were related to gross pathologic findings with longitudinal spread along the bronchial wall: a small spindle-shaped or pyramidal lesion was found as a subtle CT finding of SCLC, and irregularly shaped nodular lesions (vermiform, pine-cone-like or tandem-like nodular lesions) appeared at a more advanced stage. Tumour volume doubling time of the cases ranged from 38 days to 217 days. All five patients were male smokers: four patients underwent surgery and adjuvant chemotherapy; three of them remain alive, while the remaining patient, an interval case, died of lung cancer. One patient refused treatment and died of a cause other than lung cancer. Annual repeat CT screening was useful for detecting SCLC cases mostly at a curable stage, and information about CT features, presented here, should help physicians identify SCLC at an earlier-stage and lead to a more successful treatment of the disease.

The efficacy of lung cancer screening conducted in 1990s: four case-control studies in Japan.

The efficacy of lung cancer screening is still controversial. In order to evaluate efficacy of mass screening for lung cancer in 1990s, the Japanese Ministry of Health and Welfare planned to conduct four independent case-control studies in four different regions; Miyagi, Gunma, Niigata, and Okayama Prefecture. The study design of all the four studies was a matched case-control study in which the decedents from lung cancer were defined as cases. In Gunma Prefecture, a screening examination is annual miniature chest X-ray only, whereas sputum cytology is added for high-risk screenees in others. Matching conditions were gender, year of birth, smoking histories (except Okayama), and municipality. Smoking adjusted odds ratio (OR) of dying from lung cancer for those screened within 12 months before case diagnosis compared with those not screened ranged 0.40-0.68. Three of four studies revealed statistically significant reduction of the risk for lung cancer death. OR of pooled analysis, where all sets were combined and analyzed, was 0.56 (95% confidence interval: 0.48-0.65). Recent mass screening program for lung cancer in Japan could reduce the risk for lung cancer death. However, the possibility exists that some confounding factors affected the results. In order to elucidate whether the results can be applied to Western countries, further studies will be required.

Early phase II study of the new aromatase inhibitor YM511 in postmenopausal patients with breast cancer. Difficulty in clinical dose recommendation based on preclinical and phase I findings.

BACKGROUND: A phase II study of a non-steroidal selective aromatase inhibitor, YM511, 4-[N-bromobenzyl]-N-(4H-1,2,4-triazol-4-yl)amino) benzonitrile, was conducted to evaluate the anti-tumor response, dose-dependence of response rate and tolerability in postmenopausal patients with advanced breast cancer. PATIENTS AND METHODS: Patients were randomly allocated to a dose of 0.3, 1, 3, 10 or 30 mg after stratification according to PS, previous therapy and ER, and were administered the drug orally once a day. RESULTS: Of 98 eligible patients, 6 achieved complete response (CR) and 14 partial response (PR), resulting in an objective response rate of 20.4%. In addition, 13 patients achieved NC lasting more than 24 weeks (L-NC), resulting in an overall success rate of 33.7%. However, no clear dose-dependence of response rate was observed. Significant reduction of serum estradiol level was observed at all doses. Median time to progression of disease was 61-233 days. Toxicity was mild or moderate in severity. Fifty-five adverse events were reported in 38 patients, the most common being gastrointestinal disorders such as nausea, vomiting and anorexia (18 events) and constitutional symptoms such as asthenia, hot flushes and common cold syndrome (14 events). The frequency of drug-related adverse events was not dose-related. Abnormalities in hematological laboratory values and blood biochemistry, which were probably drug-related, were less than 5% in frequency except for cholesterol level, and were light or moderate in severity. CONCLUSION: YM511 appeared to be effective and safe in postmenopausal patients with breast cancer. Dose-dependent increase in response rate was not clearly observed at doses from 0.3 mg/day to 30 mg/day. The recommended dose of YM511 for further studies is 0.3 mg or less than 0.3 mg.