Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid (RESPECT-EPA).

BACKGROUND: Low plasma levels of eicosapentaenoic acid (EPA) are associated with cardiovascular events. This trial aimed to assess the clinical benefits of icosapent ethyl in patients with coronary artery disease, a low EPA/arachidonic acid (AA) ratio, and statin treatment. METHODS: In this prospective, multicenter, randomized, open-label, blinded end-point study, patients with stable coronary artery disease and a low EPA/AA ratio (<0.4) were randomized to EPA (1800 of icosapent ethyl administered daily) or control group. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina pectoris, and coronary revascularization. The secondary composite end points of coronary events included sudden cardiac death, fatal and nonfatal myocardial infarction, unstable angina requiring emergency hospitalization and coronary revascularization, or coronary revascularization. RESULTS: Overall, 3884 patients were enrolled at 95 sites in Japan. Among them, 2506 patients had a low EPA/AA ratio, and 1249 and 1257 patients were randomized to the EPA and control group, respectively. The median EPA/AA ratio was 0.243 (interquartile range, 0.180-0.314) and 0.235 (interquartile range, 0.163-0.310) in the EPA and control group, respectively. Over a median period of 5 years, the primary end point occurred in 112 of 1225 patients (9.1%) and 155 of 1235 patients (12.6%) in the EPA and control group, respectively (hazard ratio, 0.79 [95% CI, 0.62-1.00]; P=0.055). Meanwhile, the secondary composite end point of coronary events in the EPA group was significantly lower (81/1225 [6.6%] versus 120/1235 [9.7%] patients; hazard ratio, 0.73 [95% CI, 0.55-0.97]). Adverse events did not differ between the groups, but the rate of new-onset atrial fibrillation was significantly higher in the EPA group (3.1% versus 1.6%; P=0.017). CONCLUSIONS: Icosapent ethyl treatment resulted in a numerically lower risk of cardiovascular events that did not reach statistical significance in patients with chronic coronary artery disease, a low EPA/AA ratio, and statin treatment. REGISTRATION: URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000012069.

Prevalence of survivors of childhood cancer based on a population-based cancer registry in Osaka, Japan.

Although the survival rate of patients with childhood cancer has greatly improved, long-term survivors face specific problems such as the late effects of cancer treatment. In this study, we estimated the number of people who had experienced childhood cancer to predict their needs for medical care and social resources. Using data from the population-based Osaka Cancer Registry, we identified children aged 0-14 years who were diagnosed with cancer between 1975 and 2019. We estimated the prevalence on December 31, 2019, and the 5- and 10-year prevalence (i.e., the number of survivors living up to 5 or 10 years after the diagnosis of cancer) over time. The prevalence proportion was age-standardized using a direct standardization method. The prevalence estimates for Osaka were applied to the national population to determine the national prevalence in Japan. Among 8186 patients diagnosed with childhood cancer in Osaka, 5252 (987 per million) survived until December 31, 2019. The 5-year prevalence per million increased from 194 in 1979 to 417 in 2019 (+116%), while the 10-year prevalence increased from 391 in 1984 to 715 in 2019 (+83%). Based on the long-term registry data, an estimated 73,182 childhood cancer survivors were living in Japan by the end of 2019. The increasing 5-year and 10-year prevalence proportions indicate the continued need for cancer survivorship support for children, adolescents, and young adults. These estimates of the prevalence of childhood cancer survivors, including long-term survivors, may be useful for policymakers and clinicians to plan and evaluate survivorship care.

NRSF-GNAO1 Pathway Contributes to the Regulation of Cardiac Ca2+ Homeostasis.

BACKGROUND: During the development of heart failure, a fetal cardiac gene program is reactivated and accelerates pathological cardiac remodeling. We previously reported that a transcriptional repressor, NRSF (neuron restrictive silencer factor), suppresses the fetal cardiac gene program, thereby maintaining cardiac integrity. The underlying molecular mechanisms remain to be determined, however. METHODS: We aim to elucidate molecular mechanisms by which NRSF maintains normal cardiac function. We generated cardiac-specific NRSF knockout mice and analyzed cardiac gene expression profiles in those mice and mice cardiac-specifically expressing a dominant-negative NRSF mutant. RESULTS: We found that cardiac expression of Gαo, an inhibitory G protein encoded in humans by GNAO1, is transcriptionally regulated by NRSF and is increased in the ventricles of several mouse models of heart failure. Genetic knockdown of Gnao1 ameliorated the cardiac dysfunction and prolonged survival rates in these mouse heart failure models. Conversely, cardiac-specific overexpression of GNAO1 in mice was sufficient to induce cardiac dysfunction. Mechanistically, we observed that increasing Gαo expression increased surface sarcolemmal L-type Ca2+ channel activity, activated CaMKII (calcium/calmodulin-dependent kinase-II) signaling, and impaired Ca2+ handling in ventricular myocytes, which led to cardiac dysfunction. CONCLUSIONS: These findings shed light on a novel function of Gαo in the regulation of cardiac Ca2+ homeostasis and systolic function and suggest Gαo may be an effective therapeutic target for the treatment of heart failure.

Study protocol and baseline characteristics of Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid: RESPECT-EPA, the combination of a randomized control trial and an observational biomarker study.

BACKGROUND: Omega-3 polyunsaturated fatty acids (PUFAs) have been a hot topic since the Japan EPA Lipid Intervention Study (JELIS), the first landmark study using a highly purified eicosapentaenoic acid (EPA), indicated that EPA could decrease the incidence of cardiovascular events. Over 20 years have passed since the JELIS was conducted, and the standard treatment for dyslipidemia has altered significantly since then. The JELIS subjects did not undertake the current risk management especially current standard statins and did not exclusively target secondary prevention patients. In addition, the subjects included are relatively high EPA population. Furthermore, the clinical implication of the plasma EPA/arachidonic acid (AA) ratio as a biomarker has not yet been validated. Therefore, the Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy - Statin and EPA (RESPECT-EPA) was planned and is currently underway in Japan. METHODS: The RESPECT-EPA comprises two parts: the open-label randomized controlled trial (RCT) and biomarker study (prospective cohort study design). The RCT included patients with a low EPA/AA ratio. These patients were then randomized to highly purified EPA (1800 mg/day) or control groups. The primary endpoint was cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, unstable angina pectoris, and clinically indicated coronary revascularization. The biomarker study assesses the EPA/AA ratio's usefulness as a biomarker for cardiovascular events prediction. RESULTS: In the RCT, a total of 2,460 patients were enrolled in 95 sites in Japan. Patients' baseline characteristics were similar between intervention and control groups in the RCT. The baseline median EPA/AA ratio was 0.243 and 0.235, respectively. A total of 1,314 patients were participated in the observational part, and the baseline median EPA/AA ratio was 0.577. CONCLUSIONS: After this study is completed, we will have further evidence on whether a highly purified EPA is effective in reducing cardiovascular events for secondary prevention or not, as well as whether if EPA/AA ratio is a predictor for future cardiovascular events. This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000012069).

Patterns of staging, treatment, and mortality in gastric, colorectal, and lung cancer among older adults with and without preexisting dementia: a Japanese multicentre cohort study.

BACKGROUND: Little is known about dementia's impact on patterns of diagnosis, treatment, and outcomes in cancer patients. This study aimed to elucidate the differences in cancer staging, treatment, and mortality in older cancer patients with and without preexisting dementia. METHODS: Using cancer registry data and administrative data from 30 hospitals in Japan, this multicentre retrospective cohort study examined patients aged 65-99 years who were newly diagnosed with gastric, colorectal, or lung cancer in 2014-2015. Dementia status (none, mild, and moderate-to-severe) at the time of cancer diagnosis was extracted from clinical summaries in administrative data, and set as the exposure of interest. We constructed multivariable logistic regression models to analyse cancer staging and treatment, and multivariable Cox regression models to analyse three-year survival. RESULTS: Among gastric (n = 6016), colorectal (n = 7257), and lung (n = 4502) cancer patients, 5.1%, 5.8%, and 6.4% had dementia, respectively. Patients with dementia were more likely to receive unstaged and advanced-stage cancer diagnoses; less likely to undergo tumour resection for stage I, II, and III gastric cancer and for stage I and II lung cancer; less likely to receive pharmacotherapy for stage III and IV lung cancer; more likely to undergo tumour resection for all-stage colorectal cancer; and more likely to die within three years of cancer diagnosis. The effects of moderate-to-severe dementia were greater than those of mild dementia, with the exception of tumour resection for colorectal cancer. CONCLUSION: Older cancer patients with preexisting dementia are less likely to receive standard cancer treatment and more likely to experience poorer outcomes. Clinicians should be aware of these risks, and would benefit from standardised guidelines to aid their decision-making in diagnosing and treating these patients.

The association between uric acid levels and renal function of CKD patients with hyperlipidemia: a sub-analysis of the ASUCA trial.

BACKGROUND: The influence of uric acid (UA) on renal function and the significance of UA-lowering therapy are unclear. The purpose of the sub-analysis of the Assessment of Clinical Usefulness in chronic kidney disease patients with Atorvastatin (ASUCA) trial was to evaluate the influence of serum UA levels on renal function in Japanese chronic kidney disease patients with hyperlipidemia. METHODS: Of 344 participants in the ASUCA trial, 279 participants whose UA levels at both baseline and 24 months were available were included. Based on UA level at baseline or mean UA level during the trial period, they were divided into four groups: < 5.0, 5.0-6.0, 6.0-7.0, or ≥ 7.0 mg/dL, irrespective of allocation. Changes in the estimated glomerular filtration rate (eGFR) after 24 months were compared among the groups in relation to baseline or mean UA levels. RESULTS: For baseline UA levels (< 5.0, 5.0-6.0, 6.0-7.0, or ≥ 7.0 mg/dL), the change in eGFR after 24 months was - 1.32 ± 10.3, - 1.74 ± 8.94, - 2.53 ± 7.34, and - 3.51 ± 9.10 mL/min/1.73 m2, respectively. A negative correlation between changes in eGFR after 24 months and baseline UA level was observed with adjustment for confounding factors. The relationship between changes in eGFR and mean UA levels during trial period showed a similar trend. CONCLUSION: In CKD patients with dyslipidemia, hyperuricemia was an independent risk factor for CKD progression. An ongoing clinical trial (TARGET-UA, UMIN-ID 000,026,741) may reveal the significance of strict UA-lowering therapy in CKD patients.

Intensive uric acid-lowering therapy in CKD patients: the protocol for a randomized controlled trial.

BACKGROUND: Hyperuricemia would be a risk factor for the development/progression of CKD. However, several studies showed U-shape association between serum uric acid level and renal impairment, suggesting that hypouricemia was rather associated with renal dysfunction. Perhaps, there is the optimal target level of serum UA for renal function. METHODS: The Target-UA study is a multicenter randomized controlled trial. Eligible CKD patients (eGFR ≥ 30, < 60 mL/min/1.73 m2 and urine protein < 0.5 g/gCr or urine albumin to creatinine ratio (ACR) < 300 mg/gCr) with serum UA ≥ 8.0 mg/dL (≥ 7.0 mg/dl: under the treatment) will be enrolled and be randomly assigned to the intensive therapy group (target serum UA level ≥ 4.0 mg/dL, < 5.0 mg/dL) or the standard therapy group (serum UA level ≥ 6.0 mg/dL, < 7.0 mg/dL). Topiroxostat, a new xanthine oxidase inhibitor, will be administered to treat hyperuricemia. The primary endpoint is a change in logarithmic value of urine ACR between baseline and week 52 of treatment. The secondary endpoints include changes in serum UA, eGFR, urine protein, lipid profile, and onset of composite cardiovascular events, renal events, gouty arthritis, and attack of urolithiasis. The number of subjects has been set to be 185 in each group for a total of 370. DISCUSSION: This is the first study, to the best of our knowledge, to determine the optimal target level of serum UA for renal protection and is expected to lead to progress in CKD treatment. TRIAL REGISTRATION: (UMIN000026741 and jRCTs051180146).

Reciprocal expression of MRTF-A and myocardin is crucial for pathological vascular remodelling in mice.

Myocardin-related transcription factor (MRTF)-A is a Rho signalling-responsive co-activator of serum response factor (SRF). Here, we show that induction of MRTF-A expression is key to pathological vascular remodelling. MRTF-A expression was significantly higher in the wire-injured femoral arteries of wild-type mice and in the atherosclerotic aortic tissues of ApoE(-/-) mice than in healthy control tissues, whereas myocardin expression was significantly lower. Both neointima formation in wire-injured femoral arteries in MRTF-A knockout (Mkl1(-/-)) mice and atherosclerotic lesions in Mkl1(-/-); ApoE(-/-) mice were significantly attenuated. Expression of vinculin, matrix metallopeptidase 9 (MMP-9) and integrin ß1, three SRF targets and key regulators of cell migration, in injured arteries was significantly weaker in Mkl1(-/-) mice than in wild-type mice. In cultured vascular smooth muscle cells (VSMCs), knocking down MRTF-A reduced expression of these genes and significantly impaired cell migration. Underlying the increased MRTF-A expression in dedifferentiated VSMCs was the downregulation of microRNA-1. Moreover, the MRTF-A inhibitor CCG1423 significantly reduced neointima formation following wire injury in mice. MRTF-A could thus be a novel therapeutic target for the treatment of vascular diseases.

Ectopic automaticity induced in ventricular myocytes by transgenic overexpression of HCN2.

Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) are expressed in the ventricles of fetal hearts but are normally down-regulated as development progresses. In the hypertrophied heart, however, these channels are re-expressed and generate a hyperpolarization-activated, nonselective cation current (Ih), which evidence suggests may increase susceptibility to arrhythmia. To test this hypothesis, we generated and analyzed transgenic mice overexpressing HCN2 specifically in their hearts (HCN2-Tg). Under physiological conditions, HCN2-Tg mice exhibited no discernible abnormalities. After the application of isoproterenol (ISO), however, ECG recordings from HCN2-Tg mice showed intermittent atrioventricular dissociation followed by idioventricular rhythm. Consistent with this observation, 0.3 µmol/L ISO-induced spontaneous action potentials (SAPs) in 76% of HCN2-Tg ventricular myocytes. In the remaining 24%, ISO significantly depolarized the resting membrane potential (RMP), and the late repolarization phase of evoked action potentials (APs) was significantly longer than in WT myocytes. Analysis of membrane currents revealed that these differences are attributable to the Ih tail current. These findings suggest HCN2 channel activity reduces the repolarization reserve of the ventricular action potential and increases ectopic automaticity under pathological conditions such as excessive ß-adrenergic stimulation.

Pro-B-type natriuretic peptide is cleaved intracellularly: impact of distance between O-glycosylation and cleavage sites.

We investigated the molecular mechanism underlying the processing of pro-B-type natriuretic peptide (proBNP). Rat neonatal atrial and ventricular myocytes were cultured separately. We examined the molecular forms of secreted and intracellular BNP in atrial and ventricular myocytes; levels of corin and furin mRNA in atrial and ventricular myocytes; the effect their knockdown on proBNP processing; plasma molecular forms of BNP from rats and humans with and without heart failure; and the impact of the distance between the glycosylation and cleavage sites in wild-type and mutant human proBNP, expressed in rat myocytes transfected with lentiviral vectors. BNP was the major molecular form secreted by atrial and ventricular myocytes. Transfection of furin siRNA reduced proBNP processing in both atrial and ventricular myocytes; however, transfection of corin siRNA did not reduce it. BNP was the major molecular form in rat plasma, whereas proBNP was the major form in human plasma. The relative fraction of human BNP in rat myocytes expressing human proBNP was about 60%, but increasing the distance between the glycosylation and cleavage sites through mutation, increased the processed fraction correspondingly. These results suggest that proBNP is processed into BNP intracellularly by furin. The level of proBNP processing is lower in humans than rats, most likely due to the smaller distance between the O-glycosylation and cleavage sites in humans.

Risk of thoracic soft tissue sarcoma after breast cancer radiotherapy: a population-based cohort study in Osaka, Japan.

Postoperative radiotherapy for breast cancer reportedly increases the risk of thoracic soft tissue sarcomas, particularly angiosarcomas; however, the risk in the Japanese population remains unknown. Therefore, this study aimed to investigate the incidence of thoracic soft tissue sarcoma among patients with breast cancer in Japan and determine its association with radiotherapy. This retrospective cohort study used data from the population-based cancer registry of the Osaka Prefecture. The inclusion criteria were female sex, age 20-84 years, diagnosis of breast cancer between 1990 and 2010, no supraclavicular lymph node or distant metastasis, underwent surgery and survived for at least 1 year. The primary outcome was the occurrence of thoracic soft tissue sarcomas 1 year or later after breast cancer diagnosis. Among the 13 762 patients who received radiotherapy, 15 developed thoracic soft tissue sarcomas (nine angiosarcomas and six other sarcomas), with a median time of 7.7 years (interquartile range, 4.0-8.6 years) after breast cancer diagnosis. Among the 27 658 patients who did not receive radiotherapy, four developed thoracic soft tissue sarcomas (three angiosarcomas and one other sarcoma), with a median time of 11.6 years after diagnosis. The 10-year cumulative incidence was higher in the radiotherapy cohort than in the non-radiotherapy cohort (0.087 vs. 0.0036%, P < 0.001). Poisson regression analysis revealed that radiotherapy increased the risk of thoracic soft tissue sarcoma (relative risk, 6.8; 95% confidence interval, 2.4-24.4). Thus, although rare, breast cancer radiotherapy is associated with an increased risk of thoracic soft tissue sarcoma in the Japanese population.

Prognostic impact of coexisting cardiovascular disease in patients with cancer: A multicenter retrospective cohort study.

Background: The incidence of malignancy and cardiovascular disease (CVD) is increasing worldwide. However, it is not entirely clear how the coexistence of CVD at the time of cancer diagnosis affects the overall survival of patients with cancer. Methods and results: We used the cancer registries and administrative claims data of patients diagnosed with cancer at 36 designated cancer care hospitals in Osaka, Japan, from 2010 to 2015. The Cox proportional hazard model was used to examine how coexisting CVD (heart failure [HF], ischemic heart disease, peripheral arterial disease, cerebrovascular accidents, and atrial fibrillation) affected overall survival and the impact of HF severity, as documented by the New York Heart Association (NYHA) classification. Of the 131,701 patients with cancer, 9704 had coexisting CVD. The 3-year survival rates for patients with and without coexisting CVD were 62.9 % and 77.6 %, respectively. The adjusted hazard ratio (aHR) for all-cause mortality for coexisting CVD was 1.47 (95 % confidence interval, 1.41-1.52). Among the CVD subtype, patients with coexisting HF had the poorest prognosis. The aHRs in patients with HF by NYHA classification, using the patients without HF as a reference, were as follows: Class I: 1.33 (p = 0.217); II: 1.68 (p < 0.001); III: 1.54 (p = 0.011); IV: 2.47 (p < 0.001). Conclusion: Coexisting CVD and HF severity at cancer diagnosis is associated with survival in patients with cancer.

A Randomized Controlled Trial of Betamethasone on Fatigue in Patients With Advanced Cancer.

CONTEXT: Fatigue is one of the most uncomfortable physical symptoms seen in patients with advanced cancer. Previous studies have reported on the efficacy of corticosteroids from Western countries. OBJECTIVES: To assess the effectiveness of 4mg betamethasone improving fatigue among Japanese patients with advanced cancer. METHODS: A randomized, double-blind, placebo-controlled trial enrolled eligible patients with advanced cancer expected to survive 1-2 months, with an Eastern Cooperative Oncology Group Performance Status of 2-3, and experiencing fatigue according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-15-palliative criteria. Participants received twice-daily oral administration of 2 mg betamethasone (4 mg/d) or placebo for seven days, with fatigue assessed using EORTC QLQ-C15-PAL subscale and numerical rating scale (NRS) score (at baseline and day seven). The trial was registered under the University Hospital Medical Information Network (UMIN)000011913. RESULTS: Among the 267 screened patients, 81 were eligible, of which 70 were evaluable (betamethasone, 33; placebo, 37). The mean difference in the EORTC-QLQ-C15-PAL fatigue subscale was -8.2 (95% CIs: -22.3, 0.0; P = 0.178) and in a NRS for fatigue was -1.2 (95% CIs: -2.5, -0.01; P = 0.048), respectively. Emotional function, appetite loss, and global-health were slightly better in the betamethasone group than in the placebo group. CONCLUSION: The impact of betamethasone 4 mg/d on alleviating fatigue in patients with advanced cancer in the last weeks of life did not reach statistical significance in the EORTC-QLQ-C15-PAL as the primary endpoint, however, it was significant in the NRS, the secondary endpoint.

Fifteen-year survival and conditional survival of women with breast cancer in Osaka, Japan: A population-based study.

BACKGROUND: In recent years, the survival of patients with breast cancer has improved. However, few published studies have a longer than 10-year follow-up. Conditional relative survival (CRS), which is relative survival (RS) of patients who have survived beyond a certain period after diagnosis, is useful for assessing excess mortality among long-term survivors compared with the general population. METHODS: This was a retrospective observational cohort study. Population-based cancer registry data in Osaka, Japan were used to determine 15-year RS and 5-year CRS of women with breast cancer diagnosed between 2001 and 2002 and followed up for at least 15 years. Fifteen-year RS and age-standardized RS (ASR) were calculated by Ederer II and cohort methods. Five-year CRS according to age group and extent of disease (localized, regional, and distant) was estimated for every year from diagnosis to 10 years. RESULTS: In the cohort of 4006 patients, the ASR declined progressively, the 5-year ASR being 85.8%, 10-year ASR 77.3%, and 15-year ASR 71.6%. The overall 5-year CRS exceeded 90% at 5 years after diagnosis, reflecting a small excess mortality compared with the general population. The 5-year CRS of patients with regional and distant disease did not reach 90% within 10 years of follow-up (89.4% for regional and 72.9% for distant disease 10 years after diagnosis), indicating that these patients had substantial excess mortality. CONCLUSION: Long-term survival data can help cancer survivors plan their lives and receive better medical care and support.

Socioeconomic disparities in cancer survival: Relation to stage at diagnosis, treatment, and centralization of patients to accredited hospitals, 2005-2014, Japan.

BACKGROUND: Cancer survival varies by socioeconomic status in Japan. We examined the extent to which survival disparities are explained by factors relevant to cancer control measures (promoting early-stage detection, standardizing treatment, and centralizing patients to government-accredited cancer hospitals [ACHs]). METHODS: From the Osaka Cancer Registry, patients diagnosed with solid malignant tumors during 2005-2014 and aged 15-84 years (N = 376,077) were classified into quartiles using the Area Deprivation Index (ADI). Trends in inequalities were assessed for potentially associated factors: early-stage detection, treatment modality, and utilization of ACH (for first contact/diagnosis/treatment). 3-year all-cause survival was computed by the ADI quartile. Multivariable Cox regression models were used to assess survival disparities and their trends through a series of adjustment for the potentially associated factors. RESULTS: During 2005-2014, the most deprived ADI quartile had lower rates than the least deprived quartile for early-stage detection (42.6% vs. 48.7%); receipt of surgery (58.1% vs. 64.1%); and utilization of ACH (83.5% vs. 88.4%). While rate differences decreased for receipt of surgery and utilization of ACH (Annual Percent Change = -3.2 and - 11.9, respectively) over time, it remained unchanged for early-stage detection. During 2012-2014, the most deprived ADI quartile had lower 3-year survival than the least deprived (59.0% vs. 69.4%) and higher mortality (Hazard Ratio [HR] = 1.32, adjusted for case-mix): this attenuated with additional adjustment for stage at diagnosis (HR = 1.23); treatment modality (HR = 1.20); and utilization of ACH (HR = 1.19) CONCLUSIONS: Despite improvements in equalizing access to quality cancer care during 2005-2014, survival disparities remained. Interventions to reduce inequalities in early-stage detection could ameliorate such gaps.

Impact of coexisting diabetes on survival and risk of developing second primary cancer in diabetes patients receiving drug therapy: A multicenter retrospective cohort study of patients with cancer in Japan.

AIMS/INTRODUCTION: We investigated the association between coexisting diabetes at the time of cancer diagnosis, and the overall survival and incidence of second primary cancer in patients with cancer and receiving drug therapy for diabetes. MATERIALS AND METHODS: We used cancer registry and administrative data of patients diagnosed with cancer at designated cancer care hospitals in Osaka Prefecture between 2010 and 2015. The presence of diabetes was identified from the prescription records of antidiabetic drugs in Diagnosis Procedure Combination System data. After adjusting for patient characteristics, we compared overall survival between patients with cancer with coexisting diabetes and those without coexisting diabetes using the Cox proportional hazards model. In addition, the impact of coexisting diabetes on the risk of developing second primary cancer was evaluated using a competing risk analysis. RESULTS: Of the 131,701 patients with cancer included in the analysis, 6,135 (4.7%) had coexisting diabetes. The 5-year survival rates for patients with and without coexisting diabetes were 56.2% (95% confidence interval 54.8-57.6) and 72.7% (95% confidence interval 72.4-73.0), respectively. Coexisting diabetes was associated with a higher risk of developing second primary cancer (subdistribution hazard ratio 1.23; 95% confidence interval 1.08-1.41). In site-specific analysis, coexisting diabetes was associated with an increased risk for the development of second primary cancer of multiple myeloma, and cancer of the uterus, pancreas and liver. CONCLUSIONS: Coexisting diabetes was associated with a higher mortality and risk of developing second primary cancer in Japanese patients with cancer and on drug therapy for diabetes.

Inhibition of TRPC6 channel activity contributes to the antihypertrophic effects of natriuretic peptides-guanylyl cyclase-A signaling in the heart.

RATIONALE: Atrial and brain natriuretic peptides (ANP and BNP, respectively) exert antihypertrophic effects in the heart via their common receptor, guanylyl cyclase (GC)-A, which catalyzes the synthesis of cGMP, leading to activation of protein kinase (PK)G. Still, much of the network of molecular mediators via which ANP/BNP-GC-A signaling inhibit cardiac hypertrophy remains to be characterized. OBJECTIVE: We investigated the effect of ANP-GC-A signaling on transient receptor potential subfamily C (TRPC)6, a receptor-operated Ca(2+) channel known to positively regulate prohypertrophic calcineurin-nuclear factor of activated T cells (NFAT) signaling. METHODS AND RESULTS: In cardiac myocytes, ANP induced phosphorylation of TRPC6 at threonine 69, the PKG phosphorylation site, and significantly inhibited agonist-evoked NFAT activation and Ca(2+) influx, whereas in HEK293 cells, it dramatically inhibited agonist-evoked TRPC6 channel activity. These inhibitory effects of ANP were abolished in the presence of specific PKG inhibitors or by substituting an alanine for threonine 69 in TRPC6. In model mice lacking GC-A, the calcineurin-NFAT pathway is constitutively activated, and BTP2, a selective TRPC channel blocker, significantly attenuated the cardiac hypertrophy otherwise seen. Conversely, overexpression of TRPC6 in mice lacking GC-A exacerbated cardiac hypertrophy. BTP2 also significantly inhibited angiotensin II-induced cardiac hypertrophy in mice. CONCLUSIONS: Collectively, these findings suggest that TRPC6 is a critical target of antihypertrophic effects elicited via the cardiac ANP/BNP-GC-A pathway and suggest TRPC6 blockade could be an effective therapeutic strategy for preventing pathological cardiac remodeling.

Trends in age-standardised net survival of stomach cancer by subsite and stage: A population-based study in Osaka, Japan, 2001-2014.

INTRODUCTION: The burden of stomach cancer remains high, particularly among Asian countries. Although Japan is known to achieve high survival from stomach cancer, little is known regarding the survival trends for recent years and survival by subsite and stage. We report age-standardised 1-, 3-, 5- and 10-year net survival for patients diagnosed with stomach cancer in Osaka, Japan. METHODS: We analysed patients diagnosed with primary stomach cancer and registered in the population-based cancer registry in Osaka Prefecture between 2001 and 2014. We used the non-parametric Pohar Perme method to derive net survival for each year. Both cohort and period approaches were used. Age was standardised using weights of the external population of the International Cancer Survival Standard. Multiple imputation was applied to handle missing information on subsite and stage before estimating age-standardised net survival by subsite (cardia and non-cardia) and stage (localised, regional and distant metastasis). We then examined general trends in the cohort-based survival estimates, as well as by subsite and stage, using linear regression. RESULTS: A total of 97,276 patients were included in the analysis. Age-standardised net survival improved steadily (mean annual absolute change ≥1.2%). Net survival for both subsites improved, but cardia cancer showed 7-23% lower survival than non-cardia cancer throughout the study period. Five-year net survival remained high (≥80%) in the localised stage from the beginning of this study. Net survival increased steeply (≥1.4% per year) in the regional stage. Although 1-year net survival increased by 14% in the distant stage, 5-year and 10-year net survival remained below 10%. CONCLUSION: Age-standardised net survival for stomach cancer in Japan improved during the study period owing to an increase in the number of patients with localised stage at diagnosis and improved treatment. Monitoring both short- and long-term survival should be continued as management of stomach cancer progresses.

Incidence and relative risk of metachronous second primary cancers for 16 cancer sites, Osaka, Japan, 2000-2015: Population-based analysis.

BACKGROUND: An increasing number of cancer survivors have developed multiple primaries. This study aims to describe the incidence and risk patterns of metachronous second primary cancers (SPCs) in Osaka, Japan. METHODS: Data were obtained from the Osaka Cancer Registry, a population-based database of all cancers diagnosed in Osaka. The study subjects were individuals who were first diagnosed with invasive cancers in 16 major cancer sites during 2000-2014, aged 15-79 years, survived at least 3 months, and were followed up for 10 years. We measured incidence rates, cumulative risks, and standardized incidence ratios (SIRs: with the Osaka general population as the referent) of developing SPCs during 3 months to 10 years after the first diagnosis. RESULTS: During 2000-2015, among 418,791 cancer survivors, 24,368 (5.8%) developed SPCs within 10 years of first diagnosis. Males had higher incidence rates than females except among young-onset survivors (aged 15-39 years). 10-year cumulative risks among survivors aged 70-79 years (the most dominant age group) were 24.0% (male) and 11.8% (female). 10-year SIRs were 1.38 (95% CI, 1.36-1.40; male) and 1.44 (95% CI, 1.41-1.48; female) with higher estimates among younger survivors in both sexes. Strong bidirectional associations were observed between oral/pharyngeal, esophageal, and laryngeal cancers. Survivors of any smoking-related cancers had elevated SIRs of developing smoking-related SPCs. Similar results were observed for alcohol-related cancers. CONCLUSIONS: Cancer survivors are at excess risk of developing SPCs compared to the general population. Continued surveillance is warranted to inform survivorship care through risk-based long-term care planning and lifestyle-changing efforts to prevent new cancers.

The effect of the Original MethOd at pharmacy To ENhAnce Support for Health Improvement in the limited Japanese proficiency patients visiting local community pharmacy: A randomized controlled trial.

OBJECTIVES: With an increase in globalization, the number of non-native-speaking citizens and tourists visiting local pharmacies is rapidly growing worldwide, creating linguistic and sociological problems. The aim of this study is to compare the effect of adding our original method, Original MethOd at pharmacy To ENhAnce Support for Health Improvement (OMOTENASHI), to the conventional medication counselling method (CMC) when counselling non-Japanese patients at the pharmacy. METHODS: The OMOTENASHI consists of tools written in multiple languages and illustrations to clarify the effects and side effects, and to confirm patients' understanding. 71 non-Japanese patients were recruited and randomly assigned to the OMOTENASHI or to the CMC in a 1:1 ratio. Comprehension and satisfaction level were evaluated. RESULTS: The overall comprehension level was significantly higher in the OMOTENASHI than in the CMC (75% vs 38%, p = 0.002), with a prominent difference in the recognition of the name, effects, side effects, precautions, and how to deal with side effects of the prescribed medication. CONCLUSION: The OMOTENASHI to be a helpful tool in providing essential information to non-native-speaking patients. PRACTICE IMPLICATION: The study highlighted the need to ensure every patient's safety and interests, and to avoid disadvantages caused by limited language proficiency in the globalization era.