Pembrolizumab versus chemotherapy in recurrent, advanced urothelial cancer in Japanese patients: a subgroup analysis of the phase 3 KEYNOTE-045 trial.

BACKGROUND: The open-label, randomized, active-controlled KEYNOTE-045 study (NCT02256436) showed that second-line pembrolizumab significantly improved overall survival (OS) of patients with advanced/metastatic urothelial cancer (UC) that progressed after first-line platinum-containing chemotherapy, compared with standard chemotherapy (paclitaxel, docetaxel, or vinflunine). Pembrolizumab is approved for patients with bladder cancer in Japan. PATIENTS AND METHODS: Analysis was performed in the subgroup of Japanese patients enrolled in the KEYNOTE-045 study. Coprimary end points were OS and progression-free survival (PFS). Objective response rate (ORR) and safety were secondary end points. RESULTS: Fifty-two Japanese patients (pembrolizumab, n = 30; chemotherapy, n = 22) were followed up for a median of 26.1 months. Patients who received pembrolizumab compared with chemotherapy had a 19% lower risk for death (hazard ratio [HR] 0.81, 95% CI 0.44-1.50); after adjusting for baseline covariates, the HR for OS was 0.61 (95% CI 0.32-1.15). The 24-month OS rate was higher with pembrolizumab (26.9% vs 14.3%). PFS was 2.0 and 4.9 months for pembrolizumab and chemotherapy, respectively (HR 1.71, 95% CI 0.95-3.08). ORR was similar for pembrolizumab and chemotherapy (20.0% vs 18.2%); durability of response was higher with pembrolizumab: 67% and 33% of patients, respectively, maintained a response for > 12 months. Treatment-related adverse events, including grade 3-5 events, occurred less frequently with pembrolizumab. CONCLUSIONS: Pembrolizumab provided durable antitumor activity in patients with locally advanced/metastatic UC that progressed after platinum-containing chemotherapy in the overall population and in the Japanese subgroup; safety profile was consistent with that previously observed for pembrolizumab.

KEYNOTE-025: Phase 1b study of pembrolizumab in Japanese patients with previously treated programmed death ligand 1-positive advanced non-small-cell lung cancer.

Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has been shown to improve overall survival (OS) in patients with previously treated advanced non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥1%. We report safety and efficacy results from the phase 1b KEYNOTE-025 study, which evaluated pembrolizumab in Japanese patients with previously treated NSCLC. Eligible patients had histologically/cytologically confirmed advanced NSCLC with PD-L1 TPS ≥1% and had received ≥1 platinum-doublet chemotherapy. Patients received pembrolizumab 10 mg/kg once every 3 weeks for 2 years or until disease progression/unacceptable toxicity. Primary objectives were to evaluate the safety of pembrolizumab in patients with PD-L1 TPS ≥1% and the objective response rate (ORR) per RECIST version 1.1 in patients with PD-L1 TPS ≥50%. Thirty-eight patients were enrolled and received ≥1 pembrolizumab dose. The median (range) age was 66.0 (41-78) years, and 61% had received ≥2 prior systemic therapies. Eleven patients (29%) experienced grade 3-5 treatment-related adverse events (AE); 9 patients (24%) experienced immune-mediated AE and infusion reactions, with pneumonitis (11%; any grade) being most common. Among evaluable patients with PD-L1 TPS ≥50% (n = 11), ORR was 27% (95% CI, 6-61). Among evaluable patients with PD-L1 TPS ≥1% (n = 37), ORR was 22% (95% CI, 10-38). Median (95% CI) progression-free survival and OS were 3.9 (2.0-6.2) months and 19.2 (8.0-26.7) months, respectively. In summary, pembrolizumab was generally well tolerated and showed promising antitumor activity in Japanese patients with previously treated PD-L1-expressing NSCLC. Outcomes were consistent with those from the phase 3 KEYNOTE-010 study. (Trial registration number: ClinicalTrials.gov, NCT02007070.).

Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced solid tumors.

Background This phase I study evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics, immunogenicity, and antitumor activity of pembrolizumab in Japanese patients with advanced solid tumors. Methods Following an initial dose and a 28-day rest (cycle 1), pembrolizumab was administered as an intravenous infusion at escalating doses (2 or 10 mg/kg) every 2 weeks (Q2W) until disease progression or unacceptable toxicity. Adverse events (AEs) were assessed using CTCAE v4.0, and tumor response was assessed using both RECIST v1.1 and immune-related response criteria (irRC). Full pharmacokinetic sampling was performed during cycle 1. Results Three patients received pembrolizumab at 2.0 mg/kg and seven at 10 mg/kg. No dose-limiting toxicities were observed during cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1 or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2 each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety and pharmacokinetic profiles of Japanese patients were similar to those previously reported for Caucasian patients. A partial tumor response was observed in one patient with non-small-cell lung cancer (NSCLC) and in one patient with melanoma. Conclusions Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated in Japanese patients with advanced solid tumors and showed encouraging anti-tumor activity against melanoma and NSCLC.

A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma.

Although initial rituximab-containing chemotherapies achieve high response rates, indolent B-cell non-Hodgkin lymphoma (B-NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B-NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21-d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression-free survival (PFS). Fifty-six eligible patients were enrolled; 50 patients (39 with FL, seven with other B-NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab-containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted.

Adult height and body mass index in relation to risk of total stroke and its subtypes: the circulatory risk in communities study.

BACKGROUND: Several studies have reported that height and risk of stroke are inversely associated based on the hypothesis that height is a marker of childhood physical condition. However, a limited number of studies have taken account of the effect of current physical condition on the relationship between height and risk of stroke. METHODS: We conducted a prospective cohort study of 12,222 40- to 69-year-old Japanese patients under systematic surveillance for stroke incidence. Because body mass index (BMI) is regarded as a surrogate marker of current physical condition for cardiovascular risk, we performed a stratified analysis of this risk based on BMI. RESULTS: During the median 17-year follow-up, there were 565 incident strokes (326 ischemic and 186 hemorrhagic strokes) showing an inverse association between height and risk of stroke independent of classical cardiovascular risk factors. Compared with the lowest height group (<159 cm for men and <148 cm for women) as reference, the multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the highest height group (>166 cm for men and >154 cm for women) were 0.70 (95% CI 0.49-1.00; P = .043) for men and 0.44 (95% CI 0.27-0.70; P < .001) for women. When the analysis was restricted to those with BMI <23 kg/m(2), the associations were stronger for both hemorrhagic and ischemic stroke. CONCLUSIONS: Height was found to be inversely associated with risk of stroke for middle-aged Japanese men and women, especially with lower BMIs. Our findings suggest that childhood social and physical conditions may contribute to the development of stroke in adulthood because height is a surrogate marker of these conditions.

Alkaline phosphatase and risk of stroke among Japanese: the Circulatory Risk in Communities Study (CIRCS).

Although serum alkaline phosphatase (ALP) levels have been associated with mortality from all-cause and from either ischemic or hemorrhagic stroke, no study has been published of the associations between ALP and the incidence of stroke. We therefore examined the associations of ALP with risk of stroke among Japanese, stratified by drinking status because ALP is known as an enzyme affected by alcohol consumption. We conducted a prospective cohort study of 10,754 Japanese subjects (4098 men and 6656 women) aged 40-69 years and living in 4 communities under systematic surveillance for stroke incidence. During the 16-year follow-up, we documented 264 strokes (164 ischemic strokes and 69 hemorrhagic strokes) for men and 225 strokes (118 ischemic strokes and 89 hemorrhagic strokes) for women. There was a U-shaped association between ALP level and stroke incidence in both men and women, which was confined primarily to nondrinkers. For nondrinkers, higher ALP levels were associated with an elevated risk of ischemic stroke for men and of hemorrhagic stroke for women, whereas lower ALP levels were associated with elevated risks of ischemic and hemorrhagic strokes in both men and women. Our data indicate that not only higher, but also lower, serum ALP level may be a predictor for the risk of stroke in nondrinking men and women.

Chronic kidney disease and drinking status in relation to risks of stroke and its subtypes: the Circulatory Risk in Communities Study (CIRCS).

BACKGROUND AND PURPOSE: Several epidemiological studies have established an association between chronic kidney disease (CKD), based on estimated glomerular filtration rate (GFR), and risk of stroke. However, sex-specific evidence for the relationship between CKD and risk of stroke and its subtypes is still limited. METHODS: We conducted a prospective cohort study of 12 222 Japanese men and women age 40 to 69 years living in 4 communities under systematic surveillance of stroke incidence to determine the relationship between CKD and risk of stroke and its subtypes. RESULTS: During the 17-year follow-up, there were 566 strokes (327 ischemic and 186 hemorrhagic strokes). GFR was inversely associated with age- and community-adjusted risk of total stroke for both men and women. Compared with the reference group without CKD (GFR ≥60 mL/min per 1.73m(2)), the adjusted risks of total stroke for subjects with CKD (GFR <60 mL/min per 1.73m(2)) were 1.63 (1.22-2.17) for men and 1.51 (1.13-2.02) for women. Excess risk of stroke associated with CKD was identified primarily for hemorrhagic stroke among men and for ischemic stroke among women. After adjustment for traditional cardiovascular risk factors, associations remained statistically significant. When stratified by drinking status, excess risk of hemorrhagic stroke with CKD was confined to drinkers; adjusted risks were 4.18 (2.31-7.57) for men and 7.00 (1.92-25.56) for women. CONCLUSIONS: CKD was associated with increased risk of hemorrhagic stroke for men, and of ischemic stroke for women. This sex difference may partly be explained by the difference in prevalence of drinkers between men and women.

Low-density lipoprotein cholesterol and risk of coronary heart disease among Japanese men and women: the Circulatory Risk in Communities Study (CIRCS).

OBJECTIVE: The objective of this study was to assess the association between serum LDL-cholesterol levels and risk of coronary heart disease (CHD) among Japanese who have lower means of LDL-cholesterol than Western populations. METHODS: The predictive power of estimated serum LDL-cholesterol levels in casual blood samples for risk of CHD was evaluated among residents from four Japanese communities participating in the Circulatory Risk in Communities Study (CIRCS). A total of 8131 men and women, aged 40 to 69 years with no history of stroke or CHD, completed baseline risk factor surveys between 1975 and 1987. By 2003, 155 cases of incident CHD (myocardial infarction, angina pectoris and sudden cardiac death) had been identified. RESULTS: Mean LDL-cholesterol values were 99.4 mg/dL for men and 109.4 mg/dL for women. The crude incidence rate (per 100,000 person-years) of CHD was 152.0 for men and 51.9 for women. The respective multivariable hazard ratios for ≥ 140 mg/dL versus <80mg/dL LDL-cholesterol were 2.80 (95% confidence interval: 1.59 to 4.92) for total CHD, 3.83 (1.78-8.23) for myocardial infarction, 4.07 (2.02-8.20) for non-fatal CHD, and 1.24 (0.44-3.47) for fatal CHD. CONCLUSION: Serum LDL-cholesterol levels ranging from around 80 mg/dL to 200mg/dL were positively associated with risk of CHD in a Japanese population.

Pembrolizumab plus pomalidomide and dexamethasone for relapsed or refractory multiple myeloma (KEYNOTE-183): subgroup analysis in Japanese patients.

The global, randomized, open-label KEYNOTE-183 phase 3 study was closed early after an interim analysis showed unfavorable risk-benefit when pembrolizumab was added to pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (MM). This subgroup analysis reported outcomes in 27 Japanese patients randomly assigned to receive pembrolizumab plus pomalidomide and dexamethasone (n = 15) or pomalidomide and dexamethasone alone (n = 12). Co-primary endpoints were progression-free survival (PFS) and overall survival (OS). After a median (range) follow-up of 9.6 (1.4-15.3) months in Japanese patients, median PFS [6.5 vs 2.8 months; hazard ratio (HR) 0.16 (95% CI 0.03-0.83)] and OS [not reached vs 14.8 months; HR 0.46 (95% CI 0.05-4.20)] seemed to favor the pembrolizumab plus pomalidomide and dexamethasone arm. Objective response rate was numerically higher in this group (47%) than in the pomalidomide and dexamethasone group (25%). The safety profile was consistent with that of the overall study population. No deaths were attributed to a study drug by the investigators. Although adding pembrolizumab to pomalidomide and dexamethasone did not show unfavorable risk-benefit in the Japanese subgroup of KEYNOTE-183, the analysis is limited by short follow-up and small sample size, which affects the generalizability of the results.

gamma-Glutamyltranspeptidase and incident stroke among Japanese men and women: the Circulatory Risk in Communities Study (CIRCS).

BACKGROUND AND PURPOSE: Although serum gamma-glutamyltranspeptidase (GGT) levels have been associated with cardiovascular disease incidence, few studies have taken into account the effect of alcohol intake on GGT levels. In this study, we examined the relationship between GGT and stroke incidence according to drinking status. METHODS: We conducted a prospective cohort study of Japanese women (N=6281) and men (N=3471) aged 40 to 69 years living in communities under systematic surveillance for stroke incidence. RESULTS: During the 18-year follow-up, 202 (3.2%) women and 230 (6.6%) men had strokes. Serum GGT levels were positively associated with risk of total stroke for women but not men. The multivariable hazard ratios of total stroke for the highest quartile of GGT compared with the lowest quartile were 1.56 (95% CI, 1.01 to 2.39) for women and 1.37 (95% CI, 0.89 to 2.11) for men. Moreover, GGT was associated with total and ischemic stroke risks for never-drinking women. CONCLUSIONS: Serum GGT is associated with risk of total and ischemic strokes for Japanese women, especially never-drinkers.

Nocturnal intermittent hypoxia and C reactive protein among middle-aged community residents: a cross-sectional survey.

BACKGROUND: There are conflicting results for the association between obstructive sleep apnoea and raised C reactive protein (CRP) levels. A study was undertaken to investigate whether nocturnal intermittent hypoxia, a surrogate marker for obstructive sleep apnoea, was associated with CRP levels among a community-dwelling Japanese population. METHODS: Among participants in the Circulatory Risk in Communities Study (CIRCS), 1422 male and 2466 female community residents aged 40-69 years were tested during sleep. No nocturnal intermittent hypoxia, mild nocturnal intermittent hypoxia and moderate to severe nocturnal intermittent hypoxia were defined using 3% oxygen desaturation index cut-off points at 5 and 15 events/h, respectively. High-sensitivity CRP levels were measured using a latex particle-enhanced immunonephelometric assay. Multivariate analysis was adjusted for age, sex, body mass index, smoking status, current alcohol intake, hypertension, hypercholesterolaemia, diabetes mellitus and menopausal status for women. RESULTS: Multivariable-adjusted mean CRP levels among men were 0.70 mg/l (95% CI 0.65 to 0.75) for no nocturnal intermittent hypoxia, 0.82 mg/l (95% CI 0.74 to 0.89) for mild nocturnal intermittent hypoxia and 0.84 mg/l (95% CI 0.70 to 1.00) for moderate to severe nocturnal intermittent hypoxia (p for trend=0.03). The values for women were 0.59 mg/l (95% CI 0.57 to 0.62), 0.66 mg/l (95% CI 0.59 to 0.73) and 0.82 mg/l (95% CI 0.62 to 1.03), respectively (p for trend=0.008). Compared with no nocturnal intermittent hypoxia, the prevalence of a high CRP level (>or=1.0 mg/l) was 1.4-1.7-fold higher for mild to severe nocturnal intermittent hypoxia in both sexes. CONCLUSIONS: Nocturnal intermittent hypoxia is associated with raised serum CRP levels among middle-aged Japanese subjects.

Pembrolizumab plus lenalidomide and dexamethasone in treatment-naive multiple myeloma (KEYNOTE-185): subgroup analysis in Japanese patients.

The global, randomized, open-label KEYNOTE-185 study closed early after an interim analysis showed an unfavorable benefit-risk profile with pembrolizumab plus lenalidomide and low-dose dexamethasone (Rd) versus Rd alone in treatment-naive, transplant-ineligible multiple myeloma. This subgroup analysis reported outcomes in the Japanese population. Patients were randomly assigned (1:1) to pembrolizumab plus Rd or Rd alone, stratified by age and International Staging System. The primary end point was progression-free survival (PFS). Fifty-two Japanese patients were randomly assigned to pembrolizumab plus Rd (n = 27) or Rd (n = 25). The median follow-up was 7.2 months (range, 0.4-13.8). The median PFS was not reached (NR); 6-month PFS was 91.2% versus 86.2% with pembrolizumab plus Rd versus Rd [hazard ratio (HR), 0.31; 95% CI, 0.06-1.63]. The median overall survival (OS) was NR; 6-month OS was 96.2% versus 95.7% with pembrolizumab plus Rd versus Rd (HR, 0.33; 95% CI, 0.03-3.72). With pembrolizumab plus Rd versus Rd, grade 3-5 adverse events occurred in 70.4% versus 69.6% of patients; serious adverse events occurred in 40.7% versus 52.5%. Although in the Japanese subgroup of KEYNOTE-185 adding pembrolizumab to Rd did not show an unfavorable risk-benefit, the analysis is limited by short follow-up and small sample size, affecting generalizability of the results.

Trends for blood pressure and its contribution to stroke incidence in the middle-aged Japanese population: the Circulatory Risk in Communities Study (CIRCS).

BACKGROUND AND PURPOSE: Hypertension is a major risk factor for stroke. However, a substantial decrease in blood pressure levels in Japanese during the past 3 decades may have reduced contributions of hypertension to risk of stroke. The population attributable fraction, the percentage of outcomes attributable to exposure, of blood pressure for the incidence of stroke was investigated during 3 survey periods between 1963 and 1994 by means of a population-based cohort study. METHODS: We explored 3 cohort data of residents aged 40 to 69 years in 4 Japanese communities in 1963 to 1971 (n=5439), 1975 to 1984 (n=9945), and 1985 to 1994 (n=11 788) baseline surveys. Mean follow-up period for each cohort was 10 years. RESULTS: Higher blood pressure levels were associated with higher risk of stroke. Positive associations were also observed even within nonhypertension levels. From the first to the third cohorts, the blood pressure category with a majority of stroke incidence shifted from severe or moderate hypertension to mild hypertension. The population attributable fraction of the severe hypertension category in the first, second, and third cohorts were 20%, 14%, and 9%, respectively, and those of the moderate hypertension category were 19%, 24%, and 11%, respectively, whereas those of the mild hypertension category were 17%, 26%, and 23%, respectively. The results were similar when participants on antihypertensive medication were excluded. CONCLUSIONS: The higher risk of stroke incidence with higher blood pressure levels even in nonhypertension categories and the shift of stroke burden from severe/moderate hypertension to mild hypertension support the early management of hypertension and primary prevention of high blood pressures for the prevention of stroke.

Trends in dietary intakes of vitamins A, C and E among Japanese men and women from 1974 to 2001.

OBJECTIVE: To investigate long-term trends in dietary intakes of vitamins A, C and E in Japanese adults. DESIGN: Time series by community-based nutrition survey. SETTING: Two rural communities (Ikawa and Kyowa) between 1974 and 2001 in Japan. SUBJECTS: A total of 3713 men and 3726 women aged 40-69 years. METHODS: Dietary intake data were collected by the 24 h dietary recall. RESULTS: In Ikawa, mean intake of vitamin A (beta-carotene and retinol) increased by 13-40%; vitamins C and E increased by approximately 23-33% among men and women from 1974-1977 to 1998-2000. In Kyowa, mean intake of vitamin A, primarily retinol, increased by 13-21% among men and women; vitamin C from fruits decreased by 16% among men; and vitamin E increased by 29% among women from 1982-1986 to 1998-2001. Mean intake of vitamin E in the latest survey period was lower than the Adequate Intake among men and women in both communities. Generally, there were increased intakes of beta-carotene and vitamin C from green/yellow and other vegetables; increased retinol intake from fish/shellfish, eggs, milk/dairy products and fats/oils; and increased vitamin E intake from green/yellow and other vegetables, fish/shellfish, eggs, milk/dairy products and fats/oils. CONCLUSIONS: Mean intakes of the antioxidant vitamins A, C and E increased among middle-aged Japanese men and women between the 1970s and the 1990s except for decreased vitamin C among Kyowa men. The lower mean intake of vitamin E than the Adequate Intake should be considered a potential public health issue for the prevention of CVD.

The reproducibility of 24-h dietary recall for estimating mineral intakes and their food sources among middle-aged Japanese men and women.

The objective of the present study was to examine reproducibility for mineral intakes estimated by single 24-h dietary recall for middle-aged Japanese men and women. We conducted repeated cross-sectional study between 1973 and 1999. The subjects were 262 Japanese people (132 men and 130 women) aged 40-69 years. The median Spearman correlation coefficients (range) for mineral intakes were 0.43 (0.31-0.55) for men and 0.39 (0.32-0.50) for women. The correlation coefficients stratified by the survey periods 1973-1984 and 1985-1999 were 0.42 (0.31-0.53) for men and 0.44 (0.34-0.53) for women during the earlier period, and 0.43 (0.22-0.62) for men and 0.29 (0.21-0.65) for women during the later period. In conclusion, the reproducibility of single 24-h dietary recall was fairly good for estimating mineral intakes by middle-aged Japanese men and women, although the reproducibility for some minerals tended to decline from the mid-1980s.

Body fat distribution and the risk of hypertension and diabetes among Japanese men and women.

To identify anthropometrical indices of body fat distribution for predicting the risk of hypertension and diabetes, a population-based prospective study was designed. Subjects in two communities (n = 2,422 and 3,195), who were free of hypertension and diabetes, respectively, were followed-up. The area and gender-specific risk of hypertension and diabetes were compared among tertiles of body mass index (BMI) and body fat distribution, including waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), and subscapular skinfold-thickness (SSF). During the 10-year follow-up for hypertension and diabetes, the incident cases of hypertension were 72 for Yao men, 125 for Kyowa men, 160 for Yao women and 193 for Kyowa women and those of diabetes were 27, 64, 37 and 77, respectively. One SD differences in BMI and WC were associated with 1.2 to 1.6-fold higher risk of hypertension, and that of SSF was associated with 1.4 to 1.6-fold higher risk of diabetes for both men and women in Yao and for women, but not men, in Kyowa. One SD differences of BMI, WC and WHtR were also associated with 1.4 to 2.0-fold higher risk of diabetes for Yao and Kyowa women. In conclusion, the significant predictors for hypertension were BMI and WC and those for diabetes were BMI and SSF in both genders in both communities, except for men in Kyowa. WC and WHtR were also predictors for diabetes in women but not in men.

Associations of sleep-disordered breathing with excessive daytime sleepiness and blood pressure in Japanese women.

Sleep-disordered breathing (SDB) is a recognized risk factor for excessive daytime sleepiness (EDS) and hypertension, but evidence of this association in Asian women is limited. We conducted a cross-sectional study of 3,568 women aged 30-69 years living in three Japanese communities. The 3% oxygen desaturation index (ODI) was selected as the indicator of SDB, and blood oxygen fall was estimated by overnight pulse oximetry. The prevalence of SDB was 20.2% for 3% ODI>or=5, 6.4% for 3% ODI>or=10, and 2.8% for 3% ODI>or=15 among Japanese women aged 30-69 years. The 3% ODI was positively associated with the prevalence of self-reported EDS and mean values of systolic and diastolic blood pressure levels. The multivariate odds ratios for 3% ODI of 5-9, 10-14, and >or=15 in reference to 3% ODI<5 were 1.9 (1.2-3.0), 2.2 (1.0-4.6), and 1.8 (0.7-4.4) (p for trend=0.01), respectively, for EDS and 1.1 (0.9-1.4), 1.2 (0.8-1.8), and 2.2 (1.4-3.4) (p for trend<0.001), respectively, for hypertension. The severity of SDB was significantly associated with EDS and hypertension among Japanese women.

Caregiver burden for impaired elderly Japanese with prevalent stroke and dementia under long-term care insurance system.

BACKGROUND: Limited data are available on caregiver burden for stroke and dementia patients. We examined the associations of prevalent stroke and dementia with family caregiver burden in Japanese general populations. METHODS: A total of 916 Japanese home caregivers, whose family members were covered by long-term care insurance, responded to the caregiver burden questionnaire. The questionnaire included the caregiver's age, sex and employment status, the patient-caregiver relationship, the patient's history of stroke, symptoms of dementia, care levels under long-term care insurance and the Zarit Caregiver Burden Interview. RESULTS: The mean total score from the Zarit Caregiver Burden Interview was 12% higher in patients with stroke than in those without (p = 0.02) and 40% higher in those with dementia than in those without (p < 0.001). Compared with nonstroke patients without dementia, the mean total score was 21% higher in stroke patients without dementia (p = 0.01), 49% higher in nonstroke patients with dementia (p < 0.001) and 55% higher in stroke patients with dementia (p < 0.001). After adjustment for the caregiver's age, sex and employment status, the patient-caregiver relationship, and the patient's care level and community, the higher scores remained statistically significant for nonstroke patients with dementia and for stroke patients with dementia but not for stroke patients without dementia. CONCLUSIONS: Prevalent stroke and, more strongly, dementia were associated with increased family caregiver burden. Among patients with dementia, the presence of stroke did not enhance caregiver burden further.

Cigarette smoking and risk of disabling dementia in a Japanese rural community: a nested case-control study.

BACKGROUND: Previous prospective cohort studies have examined the association between smoking and the risk of dementia, but the results were inconsistent. METHODS: A prospective, nested, case-control study was conducted to examine the association between cigarette smoking and risk of disabling dementia within the cohort of 6,343 men and women aged 35-85 years. Incident dementia was documented in 208 men and women (95 cases with and 113 cases without a history of stroke). Two control subjects per case were selected by matching for sex, age and year of examination. RESULTS: The multivariable odds ratios (95% CI) for current versus never smokers were 2.3 (1.1-4.7) for total dementia, 2.6 (0.8-8.2) for dementia with a history of stroke and 2.2 (0.8-5.7) for dementia without it, yielding no effect of stroke history on the smoking-dementia association. A dose-response relationship was noted between the years of cigarette smoking and the risk of total dementia, and a significant excess risk was found for smoking duration of >or=45 years. CONCLUSIONS: The present prospective study suggests that long-term cigarette smoking may raise the risk of disabling dementia.

Metabolic syndrome and the risk of ischemic heart disease and stroke among Japanese men and women.

BACKGROUND AND PURPOSE: Limited evidence was available on the metabolic syndrome and risk of cardiovascular disease in Asia. The purpose of this study is to examine the association of the metabolic syndrome and risk of ischemic cardiovascular disease in Japanese men and women. METHODS: We conducted an 18-year prospective study of 9087 Japanese people aged 40 to 69 years (3595 men and 5492 women), initially free of ischemic heart disease or stroke. During follow-up, there were 116 (74 men and 42 women) cases of ischemic heart disease and 256 (144 men and 112 women) ischemic strokes. Metabolic syndrome was defined by the modified criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATPIII), with the presence of >/=3 of the following factors: (1) serum triglycerides >/=1.69 mmol/L (150 mg/dL); (2) HDL-cholesterol <1.03 mmol/L (40 mg/dL) for men and <1.29 mmol/L (50 mg/dL) for women; (3) glucose >/=6.11 mmol/L (110 mg/dL) fasting or >/=7.77 mmol/L (140 mg/dL) nonfasting, or on treatment; (4) blood pressure > or =130/85 mm Hg or medication use, and (5) body mass index >/=25.0 kg/m(2). RESULTS: For both sexes, high blood pressure, high triglycerides and low HDL cholesterol were associated with increased risks of ischemic heart disease or stroke after adjustment for cardiovascular risk factors. A dose-response relationship was found between the number of metabolic risk factors and incidence of these cardiovascular end points. The multivariable hazard ratio (95% CI) associated with metabolic syndrome was 2.4 (1.4 to 4.0) in men and 2.3 (1.2 to 4.3) in women for ischemic heart disease, and 2.0 (1.3 to 3.1) and 1.5 (1.0 to 2.3), respectively, for ischemic stroke. The contribution of metabolic syndrome to the risks was independent of serum total cholesterol levels but stronger among smokers. CONCLUSIONS: The metabolic syndrome is a major determinant of ischemic cardiovascular disease among middle-aged Japanese men and women, in particular among smokers.