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.
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.)
In the phase 1b KEYNOTE‐025 study, 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.
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.
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.
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).
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.
The metabolic syndrome is a major determinant of ischemic cardiovascular disease among middle-aged Japanese men and women, in particular among smokers.
Few cohort studies have examined the association of carotid intima-media thickness (IMT) and plaque characteristics with the risk of stroke in apparently healthy persons. We examined the relationship ...of carotid IMT and the surface, morphology, and calcification of carotid plaques with the incidence of stroke among Japanese men.
Carotid IMT and plaque were evaluated bilaterally with ultrasonography in 1289 men aged 60 to 74 years without a previous stroke or coronary heart disease. In this cohort, the subsequent incidence of stroke was investigated.
During the 4.5-year follow-up, 34 strokes occurred. The multivariate-adjusted relative risk (95% CI) for the highest versus lowest quartiles of maximum IMT of the common carotid artery (CCA; > or =1.07 versus < or =0.77 mm) was 3.0 (1.1 to 8.3) for stroke. The combination of CCA and internal carotid artery (ICA) wall thickness was a better predictor of the risk of stroke than was CCA wall thickness alone. Men with a plaque, defined as a focal wall thickness of > or =1.5 mm, in the ICA had a 3-fold higher risk of stroke than those without a plaque, and the plaque surface irregularity further increased the stroke risk. A significant excess risk of stroke was confined to men with an uncalcified plaque.
Increased IMT of the CCA and an uncalcified plaque in the ICA, as assessed by ultrasonography, are risk factors for stroke in elderly Japanese men.
The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. In order to determine whether G-quadruplex-interactive telomerase inhibitor, ...telomestatin (SOT-095), might have effects on telomere dynamics and to evaluate the clinical utility, we assessed the effects of telomestatin on BCR-ABL-positive human leukemia cells. We found that treatment with telomestatin reproducibly inhibited telomerase activity in the BCR-ABL-positive leukemic cell lines OM9;22 and K562, resulting in telomere shortening. Inhibition of telomerase activity by telomestatin disrupts telomere maintenance and ultimately results in telomere dysfunction. Telomestatin completely suppressed the plating efficiency of K562 cells at 1 microM; however, telomestatin had less effects on BFU-Es and CFU-GMs colony formation from normal bone marrow CD34-positive cells. Enhanced chemosensitivity toward imatinib and chemotherapeutic agents was also observed in telomestatin-treated K562 cells. Further, the combination of telomestatin plus imatinib more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. Last, telomestatin induced the activation of ATM and Chk2, and subsequently increased the expression of p21(CIP1) and p27(KIP1). These results demonstrate that telomere dysfunction induced by telomestatin activates the ATM-dependent DNA damage response. We conclude that telomerase inhibitors combined with the use of imatinib and other chemotherapeutic agents may be very useful for the treatment of human leukemia.
Unsupervised domain adaptation is considered as an effective technique to reduce the large amount supervised data. In order to solve this problem, unsupervised domain adaptation is considered to be ...an effective technique. In this work, three types of domain adaptation: image-level domain adaptation, inter-domain adaptation, and intra-domain adaptation are introduced to achieve better semantic segmentation accuracy. The proposed method achieved an mean IoU of 45.0%. Furthermore, by combining the proposed method with intra-domain adaptation, an mean IoU improvement of 1.2% is achieved compared to previous work.
Abstract 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 < 80 mg/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 200 mg/dL were positively associated with risk of CHD in a Japanese population.
Background: Accurate and precise measurements of total cholesterol (TC) and HDL-cholesterol (HDL-C) are necessary for effective diagnosis and treatment of lipid disorders. We studied the impact of TC ...certification and HDL-C evaluation in Japanese clinical laboratories to standardize their measurements. Methods: We selected 78 laboratories participated at least twice for TC and 46 laboratories participated twice for HDL-C in the standardization protocols developed by the Cholesterol Reference Method Laboratory Network (CRMLN). We compared the initial and subsequent results using the performance guidelines established by US National Cholesterol Education Program (NCEP). Results: For TC, mean percentage bias of all participants was - 0.93% and - 0.49% for the initial and second rounds, respectively. Mean within-sample CV was 0.72% and 0.69% for the initial and second rounds, respectively. For HDL-C, mean percentage bias of all participants was - 1.86% and - 0.06% for the initial and second events, respectively. Mean among-run CV was 1.56% and 1.58% for the initial and second events, respectively. Conclusions: TC accuracy in the second round than the initial round tended to improvement although statistically not significant, however in the five years follow-up, mean absolute percentage bias was reduced over time. HDL-C accuracy was statistically improved in the second event than the initial event. The precision for both TC and HDL-C did not change. This study shows CRMLN protocols contribute effectively to improvement of TC and HDL-C performance.
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