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.

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.

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 1b study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced melanoma (KEYNOTE-041).

PURPOSE: This phase I b study evaluated the safety and anti-tumor activity of pembrolizumab in Japanese patients with advanced melanoma. METHODS: Pembrolizumab (2 mg/kg) was given every 3 weeks (Q3W) for up to 2 years or until confirmed progression or unacceptable toxicity. The tumor response was assessed as per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by both investigator review and central review. RESULTS: Forty-two patients with advanced melanoma received pembrolizumab. A primary cutaneous histology was observed in 34 patients (81.0%), while a primary mucosal histology was observed in 8 patients (19.0%). Thirty-four patients (81.0%) experienced treatment-related adverse events (AEs). The most common treatment-related AEs were pruritus, maculopapular rash, malaise, and hypothyroidism. Grade 3-5 treatment-related AEs occurred in 8 patients (19.0%). The only grade 3-5 treatment-related AE reported in at least two patients was anemia. There were two treatment-related deaths (unknown cause and cerebral hemorrhage). Among the 37 evaluable patients, the confirmed overall response rates (ORRs) determined by central review were 24.1% (95% CI 10.3-43.5) for cutaneous melanoma and 25.0% (95% CI 3.2-65.1) for mucosal melanoma. The responses were durable, and the median duration of response was not reached in either population. The median overall survival (OS) was not reached, with a 12-month OS of 82.7% for cutaneous melanoma and 51.4% for mucosal melanoma. CONCLUSION: The safety profile of pembrolizumab in Japanese patients was similar to that reported in the previous clinical studies. Pembrolizumab provided promising anti-tumor activity in Japanese patients with advanced melanoma.

Phase I study of pegylated interferon-alpha-2b as an adjuvant therapy in Japanese patients with malignant melanoma.

In the adjuvant setting for malignant melanoma, interferon (IFN)-α-2b and pegylated (PEG) IFN-α-2b were approved in several countries including the USA before these were approved in Japan. To resolve the "drug-lag" issue, this phase I study was designed to evaluate the safety and tolerability in Japanese patients with stage II or III malignant melanoma who had undergone surgery, by treating with PEG IFN-α-2b. As with a previously reported phase III study, patients were to receive PEG IFN-α-2b 6 µg/kg per week s.c. during an 8-week induction phase, followed by a maintenance phase at a dose of 3 µg/kg per week up to 5 years. Dose-limiting toxicity and pharmacokinetics were assessed during the initial 8 weeks. Of the nine patients enrolled, two patients had dose-limiting toxicities that resolved after discontinuation of treatment. The most frequently reported drug-related adverse events (DRAE) included pyrexia, decreased neutrophil and white blood cell counts, and arthralgia. Grade 3 DRAE included decreased neutrophil count. No deaths, serious adverse events and grade 4 adverse events were reported. Distant metastasis occurred in one patient. No apparent differences in area under the concentration-time curve and maximum observed serum concentration were observed between Japanese and historical non-Japanese pharmacokinetic data, suggesting no marked racial differences. No neutralizing antibody was detected in these patient samples. PEG IFN-α-2b was tolerated in Japanese patients, and eventually approved in Japan in May 2015 for adjuvant therapy in patients with stage III malignant melanoma. Because the number of patients was limited, further investigation would be crucial.

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 phase I study of vorinostat combined with bortezomib in Japanese patients with relapsed or refractory multiple myeloma.

This study was undertaken to evaluate safety and pharmacokinetics and to determine treatment doses of vorinostat plus bortezomib in Japanese patients with relapsed or refractory multiple myeloma (MM). Of 9 originally enrolled patients, 2 were refractory to bortezomib, and both experienced dose-limiting toxicity (DLT), prompting a protocol amendment to exclude bortezomib-refractory individuals. Patients not considered bortezomib refractory (N = 7) received 21-day cycles of 1.3 mg/m(2) intravenous bortezomib (Days 1, 4, 8, and 11) and oral vorinostat 400 mg (Days 1 through 14) and were further evaluated. Vorinostat and bortezomib treatment doses were determined by DLT and safety, tolerability, and treatment response were assessed. Of 7 enrolled patients, 6 were evaluated, and one developed DLTs. The most common adverse events were leukopenia, neutropenia, thrombocytopenia, diarrhea, nausea, decreased appetite, and vomiting. Combination of vorinostat plus bortezomib did not increase vorinostat exposure at Day 11 [AUC0-24 h ratio (95% CI) = 1.08 (0.80, 1.45)]; geometric mean AUC0-24 h ratio for bortezomib (90% CI) was 1.96 (1.24-3.12). Objective therapeutic response occurred in 3 patients, including 1 complete response and 2 partial responses. Vorinostat 400 mg plus bortezomib 1.3 mg/m(2) was safe and well-tolerated in Japanese patients with relapsed or refractory MM not considered bortezomib refractory (NCT00858234).

Phase 1 pharmacokinetic study of the oral pan-AKT inhibitor MK-2206 in Japanese patients with advanced solid tumors.

PURPOSE: MK-2206 is an oral, highly selective inhibitor of AKT. The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of MK-2206 was evaluated in Japanese patients with advanced solid tumors. METHODS: Patients received a single oral dose of MK-2206 according to an every other day (QOD) dosing schedule or a once weekly (QW) dosing schedule in repeating 28-day treatment cycles, with a 7-day rest after only the first cycle. The dose-limiting toxicities (DLTs) were evaluated during Cycle 1. Full PK sampling was performed during Cycle 1. RESULTS: Twenty-four patients were treated at 45 mg (n = 3) or 60 mg (n = 9) QOD or at 135 mg (n = 3) or 200 mg (n = 9) QW. One patient experienced a DLT at 60 mg QOD, and three patients experienced DLTs at 200 mg QW. No DLTs were observed at 45 mg QOD or at 135 mg QW. The DLTs included mucosal inflammation, hyponatremia, face edema, erythema multiforme, and hyperglycemia. Common adverse events related to MK-2206 included rash, an elevated insulin c-peptide level, stomatitis, pyrexia, eosinophilia, leukopenia, and hyperglycemia. PK differences in MK-2206 exposure were observed between Japanese patients and non-Japanese patients. The higher exposure in Japanese patients was likely caused by the relatively lower weight of Japanese patients versus non-Japanese patients. No tumor responses were observed, but six patients exhibited stable disease lasting longer than 4 months. CONCLUSIONS: MK-2206 has an acceptable safety profile in Japanese patients with advanced solid tumors and warrants further investigation.

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.

Phase 1 pharmacokinetic study of MK-0646 (dalotuzumab), an anti-insulin-like growth factor-1 receptor monoclonal antibody, in combination with cetuximab and irinotecan in Japanese patients with advanced colorectal cancer.

PURPOSE: The safety, tolerability, and pharmacokinetic (PK) interactions of MK-0646 in combination with cetuximab and irinotecan were investigated in Japanese patients with advanced colorectal cancer. METHODS: Twenty patients were treated in the following study arms in combination with cetuximab and irinotecan: A [MK-0646 (10 mg/kg) weekly starting on Day 22], B [MK-0646 (15 mg/kg) on Day 8, followed by 7.5 mg/kg every 2 weeks], or C [MK-0646 (10 mg/kg) on Day 1 and weekly starting on Day 22]. Dose limiting toxicities (DLTs) were evaluated during a prespecified 4-week period in arms A and B. Full PK sampling was performed to evaluate the PK interactions. RESULTS: One of the 6 evaluable patients in arm A developed a DLT (grade 3 hyperglycemia); no DLTs occurred in the 6 patients in arm B. Common treatment-related adverse events included leukopenia, neutropenia, dermatitis acneiform, paronychia, nausea, stomatitis, diarrhea, and decreased appetite. The co-administration of cetuximab and irinotecan with MK-0646 increased the MK-0646 AUC0-168h by 25 %, with MK-0646 accumulation from the previous dose contributing to the observed increase. The co-administration of MK-0646 with cetuximab and irinotecan did not affect the PK of cetuximab and irinotecan, but reduced the C max (from 16.8 to 13.0 ng/mL) and the AUC0-24h (by 13 %) of SN-38, the active metabolite of irinotecan. CONCLUSIONS: The triple combination of MK-0646, cetuximab, and irinotecan was well tolerated in Japanese patients with advanced colorectal cancer. These results indicate a minimal potential for PK interactions between MK-0646 and cetuximab and between MK-0646 and irinotecan/SN-38.

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.

Cost-effectiveness and budget impact analyses of a long-term hypertension detection and control program for stroke prevention.

OBJECTIVES: The nation-wide, community-based intensive hypertension detection and control program, as well as universal health insurance coverage, may well be contributing factors for helping Japan rank near the top among countries with the longest life expectancy. We sought to examine the cost-effectiveness of such a community-based intervention program, as no evidence has been available for this issue. METHODS: The hypertension detection and control program was initiated in 1963 in full intervention and minimal intervention communities in Akita, Japan. We performed comparative cost-effectiveness and budget-impact analyses for the period 1964-1987 of the costs of public health services and treatment of patients with hypertension and stroke on the one hand, and incidence of stroke on the other in the full intervention and minimal intervention communities. RESULTS: The program provided in the full intervention community was found to be cost saving 13 years after the beginning of program in addition to the fact of effectiveness that; the prevalence and incidence of stroke were consistently lower in the full intervention community than in the minimal intervention community throughout the same period. The incremental cost was minus 28,358 yen per capita over 24 years. CONCLUSION: The community-based intensive hypertension detection and control program was found to be both effective and cost saving. The national government's policy to support this program may have contributed in part to the substantial decline in stroke incidence and mortality, which was largely responsible for the increase in Japanese life expectancy.

Phase I and pharmacokinetic study of the oral histone deacetylase inhibitor vorinostat in Japanese patients with relapsed or refractory cutaneous T-cell lymphoma.

A phase I study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and efficacy of the oral histone deacetylase (HDAC) inhibitor vorinostat in Japanese patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL). Six patients received vorinostat (400 mg p.o., once daily). Dose-limiting toxicities (DLT) were evaluated in all six patients during the 28 days of the first cycle. One of the six patients who received vorinostat developed a DLT (grade 4 thrombocytopenia). The most common drug-related adverse events included nausea (4/6, 67%), thrombocytopenia (4/6, 67%), hyperbilirubinemia (3/6, 50%) and vomiting (3/6, 50%). Most of these events were reversible and were resolved by supportive care and/or the interruption of vorinostat treatment. The safety and PK profiles of vorinostat in Japanese patients with CTCL did not appear to differ from those previously observed in non-Japanese and Japanese patients with advanced solid tumors. None of the patients achieved an objective response in this study. However, one unconfirmed partial response and two cases of sustained stable disease for 12 weeks or longer were observed among the six patients in the study. One of the three evaluable patients experienced pruritus relief. Vorinostat was well tolerated at a dose of 400 mg p.o. once daily and showed potential efficacy in Japanese patients with CTCL, warranting further investigation.

Trends in sudden cardiac death and its risk factors in Japan from 1981 to 2005: the Circulatory Risk in Communities Study (CIRCS).

OBJECTIVE: There is little evidence whether sudden cardiac death (SCD) is increasing in Asia, although the incidence of coronary heart disease among urban middle-aged Japanese men has increased recently. We examined trends in the incidence of SCD and its risk factors in the Circulatory Risk in Communities Study. DESIGN AND SETTING: This was a population-based longitudinal study. Surveillance of men and women for SCD incidence and risk factors was conducted from 1981 to 2005. SUBJECTS: The surveyed population was all men and women aged 30-84 years who lived in three rural communities and one urban community in Japan. MAIN OUTCOME MEASURES: Trends in SCD incidence and its risk factors. RESULTS: Age-adjusted and sex-adjusted incidence of SCD decreased from 1981-1985 to 1991-1995, and plateaued thereafter. The annual incidence per 100 000 person-years was 76.0 in 1981-1985, 57.9 in 1986-1990, 39.3 in 1991-1995, 31.6 in 1996-2000 and 36.8 in 2001-2005. The prevalence of hypertension decreased from 1981-1985 to 1991-1995, and plateaued thereafter for men and women. The age-adjusted prevalence of current smoking for men decreased while that of diabetes mellitus increased for both sexes from 1981-1985 to 2001-2005. CONCLUSIONS: The incidence of SCD decreased from 1981 to 1995 but was unchanged from 1996 to 2005. Continuous surveillance is necessary to clarify future trends in SCD in Japan because of an increasing incidence of diabetes mellitus.

Phase I study for ridaforolimus, an oral mTOR inhibitor, in Japanese patients with advanced solid tumors.

PURPOSE: Ridaforolimus is a non-prodrug mTOR inhibitor. The safety, pharmacokinetics (PK), and antitumor activity of oral ridaforolimus were assessed in Japanese patients with refractory solid tumors. METHODS: Ridaforolimus (20 or 40 mg) was administered as a single dose on Day 1, followed by once daily dosing five times a week for a 3-week cycle beginning on Day 8. Full PK sampling was performed on Days 1 and 26. RESULTS: Thirteen patients (7 at 20 mg and 6 at 40 mg) were enrolled. The median treatment duration was 82 days. The most common drug-related adverse events were stomatitis, hypertriglyceridemia, and proteinuria. Two patients had dose-limiting toxicities (grade 3 stomatitis at 20 mg, and grade 3 anorexia and vomiting at 40 mg). Four patients had grade 1 interstitial pneumonitis. Ridaforolimus in the whole blood was rapidly absorbed and slowly eliminated with a half-life of approximately 56-58 h after a single dose. Two patients (with non-small cell lung cancer and angiosarcoma, respectively) achieved a partial response, and five patients (one with thymic cancer and four with soft tissue sarcomas) had a stable disease for ≥ 16 weeks. CONCLUSIONS: Ridaforolimus was well tolerated up to a dose of 40 mg in Japanese patients. Preliminary evidence of antitumor activity was observed for patients with solid tumors. Further investigation at this dose is warranted.

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.

Ten-year evaluation of homogeneous low-density lipoprotein cholesterol methods developed by Japanese manufacturers. Application of the Centers for Disease Control and Prevention/Cholesterol Reference Method Laboratory Network lipid standardization protocol.

AIM: The risk index for atherosclerotic cardiovascular diseases in the Japanese metabolic syndrome-focused health checkup program was changed from total cholesterol (TC) to low-density lipoprotein cholesterol (LDL-C). We discuss the validity of this change with respect to standardization. METHODS: The beta-quantification procedure of the Centers for Disease Control and Prevention (CDC) uses the LDL-C reference value as a target. Clinical laboratories and commercial manufacturers use homogeneous LDL-C methods for standardization. (A) For clinical laboratories, LDL-C in 648 samples requested from 108 hospitals was analyzed. (B) Manufacturers participated in the CDC/Cholesterol Reference Method Laboratory Network LDL-C standardization protocol. The standardization was conducted with a performance follow-up for the 10-year period from 1998 to 2008 at 2-year intervals, 6 times. RESULTS: (A) In clinical laboratories, acceptable LDL-C levels within ±4% of the CDC's criteria remained 70.4%, 456 of 648 subjects. Negative maximum bias deviating from the LDL-C target value was -35.8%, -52.5 mg/dL, and positive maximum bias was +24.5%, +32.3 mg/dL. (B) For manufacturers, the standardization achievement rate of the analytical reagent/instrument/calibrator system in the last four standardizations from 2002 to 2008 remained on average 66.6%, far lower than the level required. CONCLUSIONS: The standardization achievement rate of homogeneous LDL-C methods was much low-er than that of TC. TC should still be used as a risk index for atherosclerotic cardiovascular diseases. The standardization achievement rate of homogeneous LDL-C should be maintained at 100%, at least using samples with normal lipoprotein profiles. The accuracy and specificity of LDL-C should be further improved before practical and clinical use.