Association between vascular endothelial dysfunction and stroke incidence in the general Japanese population: Results from the tohoku medical megabank community-based cohort study.

Background: Flow-mediated dilation (FMD) measures vascular endothelial function by evaluating the vasodilatory response of blood vessels to increased blood flow. Nevertheless, the association between FMD and stroke incidence in a general population remains unclear. This study investigated the association between vascular endothelial function and stroke incidence in the general Japanese population. Methods: Based on cohort data from the Tohoku Medical Megabank Community-based Cohort Study, participants aged ≥18 years were recruited from Iwate Prefecture, with the final sample comprising 2952 subjects. Results: The FMD level was 0.5%-27.1%, with a median of 5.0% (interquartile, 4.2%-11.3%). The mean follow-up period was 5.5 ± 1.8 years (range, 0.6-6.9 years). After dividing the participants into two subgroups according to the median FMD value, a multivariate Cox regression analysis adjusting for gender, age, smoking, alcohol consumption, systolic blood pressure, low-density lipoprotein cholesterol, estimated glomerular filtration rate, N-terminal pro-brain natriuretic peptide, high-sensitivity cardiac troponin T and hemoglobin A1c revealed that a lower FMD value was strongly associated with incidences of total stroke (hazard ratio[HR] = 2.13, 95% confidence interval[CI] = 1.48-3.07, p < 0.001), ischemic stroke (HR = 3.33, 95%CI = 2.00-5.52, p < 0.001), nonlacunar stroke (HR = 2.77, 95%CI = 1.49-5.16, p = 0.001), and lacunar stroke (HR = 5.12, 95%CI = 1.74-16.05, p = 0.003). Conclusions: This study showed that a low FMD value might reflect vascular endothelial dysfunction and then was associated with ischemic stroke incidence in the general Japanese population, suggesting that FMD can be used as a tool to identify future stroke risk.

Association between Plasma Xanthine Oxidoreductase Activity and the Renal Function in a General Japanese Population: The Tohoku Medical Megabank Community-Based Cohort Study.

INTRODUCTION: Xanthine oxidoreductase (XOR) has been identified as a critical source of reactive oxygen species in various pathophysiological conditions, including hypertension, endothelial dysfunction, and atherosclerosis. This study investigated the association between XOR and renal function in a general Japanese population. METHODS: The Iwate Tohoku Medical Megabank Organization pooled individual participant data from a community-based cohort study in Iwate prefecture. Chronic kidney disease (CKD) was estimated using the estimated glomerular filtration rate of cystatin C (eGFRcys). Individuals with a history of hyperuricemia or severe renal dysfunction (eGFRcys <15 mL/min/1.73 m2 or undergoing dialysis) were excluded from the study. We performed a multinominal multivariate logistic analysis adjusted for age, blood pressure, uric acid, glycated hemoglobin A1c, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol to associate XOR activity and renal function. RESULTS: The present study included 4,248 participants (male/female: 1,373/2,875, age: 62.9 ± 11.7 years). When participants were divided according to XOR quartiles, blood pressure, body mass index, uric acid, low-density lipoprotein cholesterol, and glycated hemoglobin A1c were highest in the highest XOR quartile (all p < 0.001). The XOR activity was significantly higher in the subgroup with CKD stage G3 and G4 (G1 vs. G2 vs. G3-G4: 44.8 ± 40.5 vs. 52.0 ± 42.9 vs. 54.1 ± 43.9 pmol/h/mL, p = 0.02). The higher XOR activity was significantly associated with an increase of CKD stage: the odd ratios (95% confidence intervals) per 1 pmol/h/mL increase in XOR activity with CKD stage G1 as a reference were 1.37 (1.13-1.73) in G2 and 1.51 (1.30-1.84) in G3-G4. CONCLUSION: The present study concluded that high XOR activity was associated with the severity of CKD in a general Japanese population, suggesting that upregulated XOR activity may be involved in advanced renal dysfunction.

Association between total type I collagen N-terminal propeptide and coronary artery disease risk score in the general Japanese population.

Background: Bone metabolic dysregulation plays an important role in the pathogenesis of atherosclerosis; however, whether its markers contribute to coronary artery disease (CAD) risk in the general population remains unclear. Therefore, this study aimed to analyze the association between bone metabolic markers and CAD risk score in the general Japanese population. Methods: The Iwate Medical Megabank Organization collected individual participant data during a community-based cohort study in the Iwate prefecture (n = 5,095, age = 58.9 ± 12.4 years). Participants with osteoporosis, chronic kidney disease, malignant disease, or primary wasting disease were excluded from the study. The present study measured the levels of circulating bone metabolic markers, including total type I collagen N-terminal propeptide (TP1NP), bone-type alkaline phosphatase, cross-linked N-telopeptide of type 1 collagen (NTX), and intact parathyroid hormone. CAD risk and atherosclerosis were evaluated using the Suita score and brachial-ankle pulse wave velocity (baPWV) measurement, respectively. Results: Among the bone metabolic markers, TP1NP was strongly associated with a high Suita score (≥56 points) (OR = 0.77, 95% CI = 0.69-0.82, P < 0.001). When participants were divided into quartiles of TP1NP levels, the subgroup with the lowest TP1NP level was associated with a high Suita score (≥56 points) and high baPWV (>1,400 cm/s). Conclusions: This study demonstrated that TP1NP levels decreased in participants with high Suita scores and high baPWV, suggesting that TP1NP downregulation may indicate future CAD risk and atherosclerosis progression in the general Japanese population.

Association between high-sensitivity cardiac troponin T levels and incident stroke in the elderly Japanese population: Results from the Tohoku Medical Megabank Community-based Cohort Study.

Elevated levels of circulating high-sensitivity cardiac troponin T (hs-cTnT) are associated with cardiovascular disease. This study aimed to examine whether hs-cTnT levels are associated with incident stroke in the elderly population. The Iwate Tohoku Medical Megabank Organization pooled participant data for a community-based cohort study (n = 15,063, 69.6 ± 3.4 years), with a mean follow-up period of 5.23 years for all-cause death and incident stroke. The follow-up revealed 316 incident strokes, including atherothrombotic (n = 98), cardioembolic (n = 54), lacunar (n = 63), hemorrhagic (n = 101), and 178 all-cause deaths. Participants were classified into quartiles according to hs-cTnT levels (Q1 ≦ 4 ng/L, Q2: 5-6 ng/L, Q3: 7-9 ng/L, and Q4 > 9 ng/L). After adjusting for sex, age, smoking, drinking, systolic blood pressure, estimated glomerular filtration rate, N-terminal pro-brain natriuretic peptide, hemoglobin A1c, and lipid profile, a Cox proportional hazard model showed that higher hs-cTnT levels were associated with ischemic stroke (Q1 vs. Q4, hazard ratio [HR] = 2.24, 95 % confidence interval [CI] = 1.12-4.51, p = 0.023). The incident of total stroke was not associated with hs-cTnT levels (Q1 vs. Q4, HR 1.39, 95 % CI = 0.89-1.74, p = 0.145). Numerical differences were highest regarding incident lacunar stroke subtypes; however, this association was not statistically significant. Higher hs-cTnT concentrations were associated with ischemic stroke in the elderly Japanese population.

A genome-wide association study for highly sensitive cardiac troponin T levels identified a novel genetic variation near a RBAK-ZNF890P locus in the Japanese general population.

BACKGROUND: Cardiovascular disease (CVD) is a major cause of mortality worldwide. High-sensitivity cardiac troponin T (hs-cTnT) is released into the bloodstream due to cardiomyocyte damage and is associated with a high CVD risk. This study aimed to investigate hs-cTnT-related genetic variation and to examine whether this is an associated risk factor for CVD in the Japanese general population. METHODS: This was a genome-wide association study (GWAS) based on a cohort from the 2013 Tohoku Medical Megabank Project community study. The GWAS was performed using a HumanOmniExpressExome BeadChip array with 914,035 autosomal single-nucleotide polymorphisms. The Framingham Risk Score and the Suita score were used to evaluate the future risk of CVD. RESULTS: The GWAS identified 10 loci reaching suggestive significance in the discovery cohort. A replication analysis confirmed that one of the 10 loci, rs7798496, is associated with elevated hs-cTnT levels. The combined P value in the discovery and replication cohorts for the association between the rs7798496 and hs-cTnT levels was 3.4 × 10-8, which indicates that the novel variant reached genome-wide significance. The rs7798496 loci was located at an intergenic region between the retinoblastoma gene product (RB)-associated Krüppell-associated box (KRAB) zinc finger, zinc finger protein 890, and pseudogene (ZNF890P). Logistic regression analysis revealed that the presence of the rs7798496 T allele was strongly associated with a high risk for CVD. CONCLUSIONS: This study provides insights into a link between a novel genetic variant, T allele of rs7798269, and elevated hs-cTnT levels as a future risk for CVD in the general Japanese population.

The Value of a Cystatin C-based Estimated Glomerular Filtration Rate for Cardiovascular Assessment in a General Japanese Population: Results From the Iwate Tohoku Medical Megabank Project.

BACKGROUND: Epidemiological studies have shown that high circulating cystatin C is associated with a risk of cardiovascular disease (CVD) independent of creatinine-based renal function measurements. The present study investigated the comparison between the cystatin C-based estimated glomerular filtration rate (GFRcys) and creatinine-based GFR (GFRcr) to determine whether these measurements are associated with CV biomarkers and elevated CVD risk in a general Japanese population. METHODS: The Iwate Tohoku Medical Megabank Organization pooled individual participant data from a general population-based cohort study in Iwate prefecture (n = 29,375). Chronic kidney disease (CKD) was estimated using the GFRcys, GFRcr and the urine albumin-to-creatinine ratio (UACR). RESULTS: The prevalence of CKD in the participants was found to be higher based on the GFRcr than the GFRcys. Multiple variable analyses after adjusting for baseline characteristics showed that high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were associated with the GFRcys. The area under the receiver operating characteristic (AUROC) curve for identifying individuals with a high Suita score was higher for the GFRcys (AUROC = 0.68) than it was for the GFRcr (AUROC = 0.64, P < 0.001). The GFRcys provided reclassification improvement for the CVD risk prediction model by the GFRcr (net reclassification improvement = 0.341; integrated discrimination improvement = 0.018, respectively, P < 0.001). CONCLUSIONS: The GFRcys is more closely associated with CV biomarkers, including hs-cTnT and NT-proBNP levels, and a high Suita score than the GFRcr, and it provides additional value in the assessment of CVD risk using GFRcr.

Identification of curable high-risk prostate cancer using radical prostatectomy alone: who are the good candidates for undergoing radical prostatectomy among patients with high-risk prostate cancer?

BACKGROUND: Currently, there is no consensus regarding which patients with high-risk prostate cancer (PCa) would benefit the most by radical prostatectomy (RP). We aimed to identify patients with high-risk PCa who are treatable by RP alone. METHODS: We retrospectively reviewed data on 315 patients with D'Amico high-risk PCa who were treated using RP without neoadjuvant or adjuvant therapy at the institutions of the Yamaguchi Uro-Oncology Group between 2009 and 2013. The primary endpoint was biochemical progression-free survival (bPFS) after RP. Risk factors for biochemical progression were extracted using the Cox proportional hazard model. We stratified the patients with high-risk PCa into 3 subgroups based on bPFS after RP using the risk factors. RESULTS: At a median follow-up of 49.9 months, biochemical progression was observed in 20.5% of the patients. The 2- and 5-year bPFS after RP were 89.4 and 70.0%, respectively. On multivariate analysis, Gleason score (GS) at biopsy (≥ 8, HR 1.92, p < 0.05) and % positive core (≥ 30%, HR 2.85, p < 0.005) were independent predictors of biochemical progression. Patients were stratified into favorable- (0 risk factor; 117 patients), intermediate- (1 risk factor; 127 patients), and poor- (2 risk factors; 57 patients) risk groups, based on the number of predictive factors. On the Cox proportional hazard model, this risk classification model could significantly predict biochemical progression after RP (favorable-risk, HR 1.0; intermediate-risk, HR 2.26; high-risk, HR 5.03; p < 0.0001). CONCLUSION: The risk of biochemical progression of high-risk PCa after RP could be stratified by GS at biopsy (≥ 8) and % positive core (≥ 30%).

Dysregulation of ossification-related miRNAs in circulating osteogenic progenitor cells obtained from patients with aortic stenosis.

CAVD (calcific aortic valve disease) is the defining feature of AS (aortic stenosis). The present study aimed to determine whether expression of ossification-related miRNAs is related to differentiation intro COPCs (circulating osteogenic progenitor cells) in patients with CAVD. The present study included 46 patients with AS and 46 controls. Twenty-nine patients underwent surgical AVR (aortic valve replacement) and 17 underwent TAVI (transcatheter aortic valve implantation). The number of COPCs was higher in the AS group than in the controls (P<0.01). Levels of miR-30c were higher in the AS group than in the controls (P<0.01), whereas levels of miR-106a, miR-148a, miR-204, miR-211, miR-31 and miR-424 were lower in the AS group than in the controls (P<0.01). The number of COPCs and levels of osteocalcin protein in COPCs were positively correlated with levels of miR-30a and negatively correlated with levels of the remaining miRNAs (all P<0.05). The degree of aortic valve calcification was weakly positively correlated with the number of COPCs and miR-30c levels. The number of COPCs and miR-30c levels were decreased after surgery, whereas levels of the remaining miRNAs were increased (all P<0.05). Changes in these levels were greater after AVR than after TAVI (all P<0.05). In vitro study using cultured peripheral blood mononuclear cells transfected with each ossification-related miRNA showed that these miRNAs controlled levels of osteocalcin protein. In conclusion, dysregulation of ossification-related miRNAs may be related to the differentiation into COPCs and may play a significant role in the pathogenesis of CAVD.

Use of preoperative performance status and hemoglobin concentration to predict overall survival for patients aged ≥ 75 years after radical cystectomy for treatment of bladder cancer.

BACKGROUND: The standard of care for treatment of localized muscle-invasive bladder cancer (MIBC) is radical cystectomy (RC). The patient's condition may affect management of MIBC, especially for elderly patients with more comorbid conditions and lower performance status. We retrospectively evaluated the association between clinicopathological data and outcomes for patients with bladder cancer (BCa) treated by RC. We particularly focused on elderly patients (age ≥75 years) with BCa. METHODS: We enrolled 254 patients with BCa who underwent RC and urinary diversion with or without pelvic lymph node dissection. We assessed perioperative complications and clinicopathological data affecting overall survival (OS) after RC. RESULTS: The incidence of complications was 34.3 %, and that of severe complications (Grade 3-5) was 16.5 %. The elderly group experienced more severe complications (P = 0.042). Median follow-up was 43.0 months (range 1.0-155.6). Five-year OS after RC was 62.7 %. OS after RC was no different for patients aged ≥75 and <75 years (P = 0.983). Multivariate analysis revealed that Eastern Cooperative Oncology Group performance status (ECOG PS) and hemoglobin (Hb) concentration were associated with all-cause mortality. Hb concentration of <12.6 g/dl was an independent predictor of a poor prognosis among elderly patients after RC for BCa. ECOG PS >1 tended to affect OS after RC in this group. CONCLUSION: ECOG PS and preoperative Hb concentration were useful for prediction of clinical outcome after RC for elderly patients. This information may aid decision-making in the treatment of elderly patients with MIBC.

Impact of variant histology on disease aggressiveness and outcome after nephroureterectomy in Japanese patients with upper tract urothelial carcinoma.

BACKGROUND: Patients with urinary bladder urothelial carcinoma (UC) with variant histology have features of more advanced disease and a likelihood of poorer survival than those with pure UC. We investigated the impact of variant histology on disease aggressiveness and clinical outcome after radical nephroureterectomy (RNU) in Japanese patients with upper tract UC (UTUC). Information on variant histology might guide appropriate patient selection for adjuvant therapy after RNU. METHODS: We enrolled 502 UTUC patients treated with RNU in this retrospective cohort study, and analyzed associations of variant histology with clinicopathological variables and disease-specific survival. RESULTS: The median follow-up was 41.4 months. A total of 60 (12.0 %) UTUC patients had variant histology. UTUC with variant histology was significantly associated with advanced pathological T stage (pT ≥ 3), higher tumor grade (G3), and more lymphovascular invasion (P < 0.0001). Variant histology in all patients was significantly associated with worse disease-specific survival after RNU on univariate analysis (P = 0.0004), but this effect did not remain significant on multivariate analysis. However, variant histology was a significantly independent predictor for disease-specific survival in patients with pT ≥ 3 tumors (P = 0.0095). CONCLUSIONS: UTUC with variant histology might be a phenotype of high-grade, locally aggressive advanced tumors rather than of systemic disease. Variant histology may be useful for selection of patients with pT ≥ 3 UTUC for adjuvant therapy. Prospective studies in a larger number of patients with a centralized pathological review are needed to confirm our results.

Risk group stratification based on preoperative factors to predict survival after nephroureterectomy in patients with upper urinary tract urothelial carcinoma.

BACKGROUND: After radical nephroureterectomy (RNU), substantial numbers of patients with upper urinary tract urothelial carcinoma (UUT-UC) are ineligible for adjuvant chemotherapy owing to diminished renal function. Accurate preoperative prediction of survival is considered important because neoadjuvant chemotherapy may be as effective for high-risk UUT-UC as for muscle-invasive bladder cancer. We performed risk group stratification to predict survival based on specific preoperative factors. METHODS: We enrolled 536 UUT-UC patients treated with RNU in this retrospective cohort study and assessed preoperative clinical and laboratory variables influencing disease-specific survival. RESULTS: The median follow-up was 40.9 months. Using univariate analysis, tumor location; number of tumors; hydronephrosis; clinical T stage; clinical N category; voided urine cytology; neoadjuvant chemotherapy; hemoglobin; white blood cell (WBC) counts; and C-reactive protein had a significant influence on disease-specific survival (P < 0.05). Multivariate analysis revealed that clinical T stage, voided urine cytology, and WBC were independent predictors (P = 0.041, P = 0.020, and P = 0.017, respectively). We divided patients into three risk groups based on the number of the three independent predictors: 0, low risk; 1, intermediate risk; 2 and 3, high risk. Significant differences in disease-specific survival were found among these risk groups (P ≤ 0.0047). CONCLUSIONS: Our results suggest that risk group stratification based on preoperative clinical T stage, voided urine cytology, and WBC counts may be useful for selection of UUT-UC patients for neoadjuvant chemotherapy. Prospective studies with larger numbers of patients and a longer follow-up period are needed to confirm our results.

Can docetaxel therapy improve overall survival from primary therapy compared with androgen-deprivation therapy alone in Japanese patients with castration-resistant prostate cancer? A multi-institutional cooperative study.

BACKGROUND: To verify the actual clinical benefit of docetaxel (DOC) therapy and to explore the prognostic factors that may predict overall survival in Japanese patients with castration-resistant prostate cancer (CRPC). METHODS: Baseline characteristics-matched CRPC patients who received conventional androgen-deprivation therapy (ADT) or ADT plus DOC were compared retrospectively. The primary endpoint was overall survival (OS) from primary therapy. Secondary endpoints were response of tumor(s), prostate-specific antigen (PSA) levels, and toxicity. RESULTS: Median OS was significantly longer in the DOC group (n = 117) than the control group (n = 118) (94.0 vs. 70.0 months, P = 0.0077) and the corresponding hazard ratio (HR) for death in DOC group was 0.566 [95% confidence interval (95%CI) 0.370-0.867; P = 0.0088]. Effective DOC groups [medium dose (50-69 mg/m(2)) and high dose (≥70 mg/m(2))] had significantly longer median OS than control even when survival times were calculated from the start of castration-resistant events (151 vs. 36 months; P = 0.0173) and the corresponding HR for death in the DOC group was 0.515 (95%CI 0.293-0.903; P = 0.0205). In multivariate analysis, statistically significant prognostic indicators were Gleason score, time to CRPC events, and receipt of DOC therapy. Response rate of both measurable lesion and PSA was not significantly different between each DOC dose group. Grade 3 or 4 adverse events associated with low- [30-49 mg/m(2)], medium-, and high-dose DOC were 21.9, 35.7, and 90.7%, respectively. No death due to DOC therapy was reported. CONCLUSION: Treatment with DOC improves OS from primary therapy compared with conventional ADT alone in Japanese patients with CRPC.

[Epidemiologic investigation on incidences of urological malignant tumors for 10 years in eastern part of Yamaguchi prefecture].

OBJECTIVE: In Japan, there is not enough information regarding the incidences of cancer, especially in the field of urology. In order to investigate the accurate occurrence of urological malignant tumors, an epidemiologic study was conducted in the eastern part of Yamaguchi prefecture over a period of 10 years. METHOD: The target areas for this study were 8 cities (Yamaguchi city, Hofu city, Shin-nanyo city, Tokuyama city, Kudamatsu city, Hikari city, Yanai city and Iwakuni city), and 7 districts (Oshima Gun, Kuga Gun, Kumage Gun, Tsuno Gun, Saba Gun, Abu Gun and Yoshiki Gun) in eastern Yamaguchi prefecture. The investigation period was 10 years: i.e. 1994-2003. Urological malignant tumors in this study were bladder cancer, tumors of the renal pelvis and ureter, renal cell carcinoma, prostatic carcinoma and testicular tumor. RESULT: Age-adjusted incidence rates for bladder cancer per 100,000 per year by world population from 1994 to 2003 were 11.26-15.88 for male and 1.91-3.15 for female. The age-adjusted incidence rates for prostatic carcinoma were 10.57-41.78. The age-adjusted incidence rates for tumors of the renal pelvis and ureter were 0.76-1.81, for renal cell carcinoma 1.85-2.68 and for testicular tumor 1.85-2.68.