Search

Purpose: Binimetinib is a potent, selective MEK1/2 inhibitor with demonstrated efficacy against BRAF- and RAS-mutant tumors. Retinal adverse events associated with MEK inhibitors have been reported in some cases. The aim of this study was to assess single-agent binimetinib, with detailed ophthalmologic monitoring, in Japanese patients with advanced solid tumors. Methods: This was an open-label phase I dose-escalation and dose-expansion study (NCT01469130). Adult patients with histologically confirmed, evaluable, advanced solid tumors were enrolled and treated with binimetinib 30 or 45 mg twice daily (BID). The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of single-agent binimetinib in Japanese patients. Results: Twenty-one patients were enrolled; 3 and 8 patients had documented BRAF and KRAS mutations, respectively. Two of 6 patients (33 %) receiving binimetinib 45 mg BID in dose-escalation experienced recurrent grade 2 retinal adverse events (AEs) which were reversible, and this dose was declared the MTD and RP2D. All patients experienced ≥1 AE suspected to be treatment related; the most common (>50 %) were blood creatine phosphokinase increase (76 %), retinal detachment and aspartate aminotransferase increase (62 % each), and diarrhea (52 %). There were no complete or partial responses; 14 patients (67 %) had stable disease, which lasted >180 days in 5 patients. Expression of phospho-ERK decreased in the skin following binimetinib treatment at both dose levels, indicating target inhibition. Conclusions: Binimetinib demonstrated efficacy and acceptable safety in Japanese patients with solid tumors, supporting the 45 mg BID dose of binimetinib as the RP2D. [ABSTRACT FROM AUTHOR]

Abstract: Background: The prevention and early detection of post-transplantation rejection and infection are key clinical points to achieve long-term survival after lung transplantation. Although surveillance bronchoscopy (SB) is performed in many transplantation centers, it is still controversial because of its undefined clinical significance and its possible complications. We evaluated the clinical utility of SB after cadaveric lung transplantation in Japan, where bilateral transplantation is officially limited to patients medically requiring bilateral grafts. Patients and Methods: Twenty-eight patients who underwent cadaveric lung transplantation followed by SB were retrospectively analyzed with reference to the results of bronchoscopy. SB is routinely performed at 1, 2, 3, 6, and 12 months after lung transplantation and annually thereafter. Clinically indicated bronchoscopy (CIB) is considered in patients with suspected rejection or airway infection, and for follow-up examination after treatment for acute rejection. Results: There were 206 bronchoscopies, including 189 SBs and 17 CIBs, performed in 28 patients who underwent cadaveric lung transplantation between 2000 and 2013 at Osaka University Hospital. Among SBs, 92 (49%) showed positive results of transbronchial lung biopsy (TBLB) or bronchoalveolar lavage (BAL), and intervention was applied following 34 SBs (18%). Among CIBs, 8 (47%) showed positive results of TBLB or BAL, with intervention performed in 3 patients (18%). A2-3 and B2R findings according to the revised International Society for Heart and Lung Transplantation (ISHLT) rejection score and airway infection/colonization were frequently observed within a year following lung transplantation. Cytomegalovirus infection was found in 7 SBs (6%) by TBLB only within 2 months after transplantation. Regarding complications, moderate bleeding occurred in 21 (11%), pneumothorax in 2 (1%), prolonged hypoxemia in 1 (0.5%), and pneumonia in 1 (0.5%) among the 189 SBs. Conclusion: SB frequently detects rejection and airway infection or colonization with minimum complications, especially within 12 months after cadaveric lung transplantation. [Copyright &y& Elsevier]

Background/Objectives:There has been no study with regard to the association between dietary fibers and the incidence of stroke and coronary heart disease (CHD) in Asia. We investigated the association between dietary fiber and the risk of cardiovascular disease (CVD), which we defined as stroke or CHD, in a Japanese population.Subjects/Methods:We studied 86 387 Japanese subjects (age 45-65 years, without CVD or cancer in 1995 as Cohort I and in 1998 as Cohort II) and used a self-administered questionnaire to follow-up the participants until the end of 2004. Dietary fiber intake was estimated from food-frequency questionnaires comprising 138 food items.Results:After 899 141 person-years of follow-up, we documented the incidence of 2553 strokes and 684 cases of CHD. Multivariable-adjusted hazard ratios (95% confidence intervals (CIs)) of CVD for the third to fifth quintiles of total fiber were 0.79 (0.63-0.99), 0.70 (0.54-0.89) and 0.65 (0.48-0.87) in women, respectively, compared with the lowest quintile. Total fiber intake was inversely associated with the incidence of stroke, either cerebral infarction or intracerebral hemorrhage in women. The results for insoluble fiber in women were similar to those for total fiber, whereas those for soluble fiber were weak. An inverse association of total fiber with CVD was observed primarily in non-smokers (P for trend=0.045 and 0.001) and not in smokers (probability values for interaction between total fiber and smoking were 0.06 and 0.01 in men and women, respectively).Conclusions:Higher total dietary fiber was associated with reduced risk of CVD in Japanese non-smokers. [ABSTRACT FROM AUTHOR]

Objective:The Japan Public Health Center-based prospective Study examined the association of body mass index (BMI) and weight change with incident stroke in Japanese individuals, for whom BMI levels are generally low.Methods:We used initial data from 1990 to 1994 and 5-year follow-up surveys from 1995 to 1999. We calculated weight change over a 5-year period for 32 847 men and 38 875 women, aged 45-74 years, with no history of cardiovascular disease or cancer. Subjects were followed from the 1995-1999 survey to the end of 2005, and hazard ratios of self-reported BMI levels and weight change for incident stroke were estimated using Cox's proportional hazard models adjusted for potential confounders.Results:During the follow-up period (median 7.9 years) there were 2019 incident strokes, including subtypes. Multivariable-adjusted hazard ratios for all stroke events by BMI levels of 27.0-29.9 and 30 kg m-2 versus 23.0-24.9 kg m-2 were 1.09 (95% confidence interval 0.88, 1.36) and 1.25 (0.86, 1.84) in men (P for trend=0.22), and 1.29 (1.01, 1.65) and 2.16 (1.60, 2.93) in women (P for trend <0.001), respectively. A weight change of 10% in the previous 5 years was associated with total strokes and ischemic strokes in women.Conclusion:Higher BMI levels and a weight gain of 10% over 5 years were associated with an increased risk of stroke in women, whereas this association was weak in men. [ABSTRACT FROM AUTHOR]

Background:It is unclear whether weight change during adulthood influences subsequent mortality in Asian populations, who have a relatively lean body mass.Objective:To assess the relation of weight change over 5 years to all-cause, cancer and cardiovascular disease mortality among Japanese men and women.Design:Subjects were 36 220 men and 44 091 women aged between 45 and 75 years without a history of serious disease at baseline. Weight change was calculated as the difference of body weight between two surveys with a 5-year interval.Results:During 699 963 person-years of follow-up, we identified 4232 deaths of all-cause, 1872 cancer deaths and 1021 cardiovascular deaths. The relation between weight change and all-cause mortality was reverse J-shaped. Multivariate hazard ratios (95% confidence interval) for weight loss of 5 kg or more versus weight change of less than 2.5 kg were 1.62 (1.45–1.81) in men and 1.76 (1.51–2.05) in women, whereas those for weight gain of 5 kg or more were 1.40 (1.22–1.59) in men and 1.25 (1.02–1.54) in women. These associations remained statistically significant even after the exclusion of deaths in the first 3 years of follow-up. The weight change–mortality association was pronounced in underweight persons or in nonsmoking men. The risk of cancer mortality increased in both men and women who lost weight by 5 kg or more. With regard to cardiovascular disease, mortality risk tended to increase with weight loss both in men and women, whereas its increase with weight gain was observed only in women.Conclusions:A large weight change, both loss and gain, was associated with an increased risk of mortality. Weight loss and gain may be predictors of early death in apparently healthy adult Japanese. [ABSTRACT FROM AUTHOR]

Background:Obesity and weight gain are associated with increased risk of coronary heart disease in Western countries. However, their impact is not well elucidated in Asia, where body mass index (BMI) levels are generally lower than in Western countries. We examined associations of BMI (kg/m2) and weight change with risk of coronary heart disease in Japanese people.Methods and results:A total of 43 235 men and 47 444 women aged 40–69 years living in communities were followed up from 1990 to 2001 in the Japan Public Health Center-based (JPHC) prospective study . During 879 619 person-years of follow-up, we documented 399 cases of coronary heart disease (334 myocardial infarction and 65 sudden cardiac death) for men and 119 (95 myocardial infarction and 24 sudden cardiac death) for women. Compared with persons with BMI 23.0–24.9, men, but not women, with BMI 30.0 had higher risk of coronary heart disease and myocardial infarction; the multivariable relative risks for men were 1.8 (1.1–3.0) and 1.9 (1.1–3.2), respectively. When weight change was examined according to BMI at age 20 years, men with initial BMI <21.7 who gained more than 10 kg compared with men of no weight change had a twofold higher risk of coronary heart disease. Both men and women with initial BMI 21.7 showed no association between weight loss and the risk.Conclusions:High BMI was associated with increased risk of coronary heart disease among men. Also, weight gain was associated with increased risk among lean men.International Journal of Obesity (2008) 32, 144–151; doi:10.1038/sj.ijo.0803686; published online 17 July 2007 [ABSTRACT FROM AUTHOR]

: The polymorphic enzyme cytochrome P450 2C19 affects omeprazole metabolism. This influence on metabolism might affect serum gastrin levels, and safety, during long-term treatment of reflux oesophagitis.: To examine the relationship between cytochrome P450 2C19 genotype and the safety profile of long-term omeprazole treatment.: A total of 119 Japanese patients with recurrent reflux oesophagitis underwent cytochrome P450 2C19 genotyping prior to receiving daily omeprazole 10 mg or 20 mg for 6–12 months, during which adverse event frequency, serum gastrin levels and endoscopic findings were monitored.: The incidences of adverse events, serious adverse events and adverse events leading to withdrawal did not differ between homozygous extensive metabolizer (n = 46), heterozygous extensive metabolizer (n = 53) or poor metabolizer (n = 20) groups. In all genotype groups, serum gastrin increased during the first 3 months of dosing but stabilized thereafter. No significant differences were seen either in the rate of reflux oesophagitis healing or symptom improvement among genotype groups.: Long-term treatment with omeprazole was well-tolerated in Japanese patients, irrespective of their cytochrome P450 2C19 metabolic genotype, indicating that dose adjustment depending on metabolic genotype is not required during treatment with omeprazole. [ABSTRACT FROM AUTHOR]

To investigate risk modification for lung cancer with diet in Japanese, we conducted a hospital-based case-control study and evaluated variation in influence with the histological type. We recruited 367 male and 240 female cases with adenocarcinomas, and 381 male and 57 female cases with squamous cell and small cell carcinomas. Controls comprised 2964 male and 1189 female cancer-free outpatients matched for sex and age with the cases. Odds ratios (ORs) and their 95% confidence intervals (Cls) for lung cancer were calculated with adjustment for potential confounding factors, using an unconditional logistic model. We found decreased ORs for adenocarcinomas in both males (OR = 0.51, 95% Cl 0.31-0.84) and females (OR = 0.48, 95% Cl 0.24-0.94) who consumed cooked/raw fish, but not dried/salted fish at the highest quartile frequency, compared with the lowest. Soybean curd consumption was associated with a decreased OR for female adenocarcinomas. Decreased ORs for squamous cell and small cell carcinomas were observed in males with frequent consumption of raw and green vegetables, fruit and milk, but consumption of carrot, pumpkin, egg and coffee was associated with increased ORs. This study suggests cooked/raw fish consumption lowers the risk of adenocarcinoma of the lung in Japanese. [ABSTRACT FROM AUTHOR]

In a population-based prospective study of 49 850 Japanese men, body mass index and height were not significantly associated with risk of prostate cancer (311 cases), although small positive effects could not be ruled out in advanced cases (91 cases).British Journal of Cancer (2006) 94, 740–742. doi:10.1038/sj.bjc.6602983 www.bjcancer.com Published online 7 February 2006 [ABSTRACT FROM AUTHOR]

Prospective evidence is inconsistent regarding the association between vegetable/fruit intake and the risk of gastric cancer. This pooled analysis of data from four large prospective studies in Japan suggests that vegetable intake reduces gastric cancer risk, especially the risk of distal gastric cancer among men.Background Prospective evidence is inconsistent regarding the association between vegetable/fruit intake and the risk of gastric cancer. Methods In an analysis of original data from four population-based prospective cohort studies encompassing 191 232 participants, we used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of gastric cancer incidence according to vegetable and fruit intake and conducted a meta-analysis of HRs derived from each study. Results During 2 094 428 person-years of follow-up, 2995 gastric cancer cases were identified. After adjustment for potential confounders, we found a marginally significant decrease in gastric cancer risk in relation to total vegetable intake but not total fruit intake: the multivariate-adjusted HR (95% CI; P for trend) for the highest versus the lowest quintile of total vegetable intake was 0.89 (0.77–1.03; P for trend = 0.13) among men and 0.83 (0.67–1.03; P for trend = 0.40) among women. For distal gastric cancer, the multivariate HR for the highest quintile of total vegetable intake was 0.78 (0.63–0.97; P for trend = 0.02) among men. Conclusion(s) This pooled analysis of data from large prospective studies in Japan suggests that vegetable intake reduces gastric cancer risk, especially the risk of distal gastric cancer among men. [ABSTRACT FROM PUBLISHER]