Dehydrogenative Coupling of Alkylamines with Primary Alcohols Forming α-Amino Ketones.

Acceptorless dehydrogenative coupling reactions between C-H bonds offer straightforward and atom-economical methods connecting readily available materials while liberating gaseous hydrogen as the sole byproduct. Despite the growing interest in such transformations, their realization still poses a significant challenge. Here we report a photoinduced dehydrogenative coupling reaction of alkylamines with primary alcohols. C-H bonds adjacent to nitrogen and oxygen are site-selectively cleaved, and a C-C bond is created between the carbon atoms in a cross-selective manner to produce α-amino ketones. Diverse polar functionalities such as esters, amides, and carboxylic acids survived, demonstrating the broad applicability of the present method.

Determination of enzalutamide long-term safety and efficacy for castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy: a multicenter prospective DELC study.

BACKGROUND: Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of subsequent agents targeting the androgen receptor axis. We conducted the prospective observational DELC (Determination of Enzalutamide Long-term safety and efficacy for Castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy) study to evaluate the efficacy of enzalutamide in patients with castration-resistant prostate cancer who underwent prior combined androgen blockade with bicalutamide and then alternative anti-androgen therapy with flutamide. METHODS: The DELC study enrolled 163 Japanese patients with castration-resistant prostate cancer who underwent alternative anti-androgen therapy with flutamide following failure of initial combined androgen blockade with bicalutamide in multiple institutions between January 2016 and March 2019. Primary endpoint was overall survival. Administration of enzalutamide was started at 160 mg orally once daily in all patients. RESULTS: The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05 months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3 ng/mL; P = 0.004), neuron-specific enolase (P = 0.014) and interleukin-6 (≥2.15 pg/mL; P = 0.004) were independent risk factors for overall survival. Fatigue (30.0%), constipation (19.6%) and appetite loss (17.8%) were the most common clinically relevant adverse events. The enzalutamide dose was not reduced in any patient under the age of 70, but adherence was decreased in those over 70. CONCLUSIONS: In the DELC study, the safety of enzalutamide was comparable to that in previous reports. Serum levels of neuron-specific enolase and interleukin-6 were suggested as prognostic factors for castration-resistant prostate cancer with potential clinical utility.

Diagnostic and prognostic significance of tartrate-resistant acid phosphatase type 5b in newly diagnosed prostate cancer with bone metastasis: A real-world multi-institutional study.

OBJECTIVES: Approximately, 90% of men with advanced prostate cancer will develop bone metastasis. However, there have been few reports about noninvasive biomarker to detect and predict clinical outcome of bone metastasis (BM) in prostate cancer patients. METHODS: We examined 1127 patients who underwent prostate biopsy from August 2012 to June 2017. We also investigated bone turnover markers such as bone-specific alkaline phosphatase, type I collagen cross-linked N-terminal telopeptide, C-terminal pyridinoline cross-linked telopeptide of type I collagen, and tartrate-resistant acid phosphatase type 5b (TRACP 5b). RESULTS: A total of 282 patients were diagnosed as prostate cancer with complete clinical data, and 34 patients with bone metastasis. Multivariate analysis revealed C-terminal pyridinoline cross-linked telopeptide of type I collagen, tartrate-resistant acid phosphatase type 5b, and prostate-specific antigen (PSA) were independent biomarkers in detection of BM (p < 0.05, respectively). Furthermore, we developed predictive model formula based on tartrate-resistant acid phosphatase type 5b and PSA, for which the area under the curve was 0.95. In patients with bone metastasis, multivariate cox proportional hazards analysis revealed that this model was significantly associated with poor clinical outcome of cancer-specific survival (p < 0.05). In validation cohort with 137 patients, we also confirmed the utility of this model for diagnosis of BM (the area under the curve = 0.95). CONCLUSIONS: Our developed formula of tartrate-resistant acid phosphatase type 5b in accordance with PSA may serve as the useful tool in diagnosis and prediction of clinical outcome for prostate cancer with bone metastasis.

A case of ventricular fibrillation without left ventricular systolic dysfunction induced by trastuzumab emtansine for breast cancer.

Trastuzumab-induced cardiomyopathy is a known complication of its use in breast cancer treatment. However, cardiac complications of trastuzumab without left ventricular systolic dysfunction have been rarely reported. These include left bundle branch block, sinus node dysfunction, and ventricular tachycardia. We herein report a case of a 47-year-old female with human epidermal growth factor receptor 2-positive, stage IV breast cancer without a history of cardiovascular disease. During treatment with trastuzumab emtansine (T-DM1), she presented with out-of-hospital cardiac arrest and was resuscitated by automated cardioverter defibrillator (AED). Emergent cardiac catheterization revealed no organic obstruction and coronary vasospasm in her coronary arteries, and no left ventricular systolic dysfunction. Ventricular fibrillation (VF) was documented by an event memory of AED. T-DM1 was withdrawn and implantable cardioverter defibrillator was implanted. Thereafter, VF or life-threatening arrhythmia were not documented for 36 months until her death by breast cancer. We concluded that the etiology of her VF event was T-DM1-induced cardiotoxicity. We believe this is the first report of life-threatening VF event without cardiomyopathy induced by T-DM1. .

Unique left pulmonary vein isolation in straight common trunk based on longitudinal conduction of left lateral ridge.

BACKGROUND: A left common pulmonary vein (LCPV) is the most common anatomical variation in the pulmonary vein (PV) and often influences strategies of PV isolation for atrial fibrillation (AF). Our objective was to elucidate the electrical properties of the specific shape of LCPV and to apply it to an ablation procedure. METHODS AND RESULTS: We investigated consecutive 12 out of 204 paroxysmal AF patients who had the shape of a straight common trunk in LCPV defined by the formation of a single conduit with parallel cranial and caudal walls after the coalescence of superior and inferior PVs on the distal side. The distance between the top of the bifurcation of LPVs and the level coinciding with the middle of the anterior wall of LCPV (left lateral ridge: LLR) was more than 10 mm in all the patients. The activation pattern of the LLR showed longitudinal conduction without outside connections. All the LCPV except one were successfully isolated without ablating the LLR (C-shape ablation). Only one patient had AF recurrence during the follow-up period. CONCLUSION: The LLR in LCPV with a straight common trunk has longitudinal conduction without outside connections, which permits the isolation of LCPV without ablating LLR.

FAN score comprising fibrosis-4 index, albumin-bilirubin score and neutrophil-lymphocyte ratio is a prognostic marker of urothelial carcinoma patients treated with pembrolizumab.

It is important to identify prognostic and predictive markers of metastatic urothelial carcinoma (mUC) treated with immunocheckpoint inhibitors. We sought to establish a prognostic marker for patients with mUC treated with pembrolizumab based on only blood test results. We included 165 patients with mUC in the discovery cohort and 103 with mUC who were treated with pembrolizumab in the validation cohort. Multivariate and Cox regression analyses were used to analyse the data. In the discovery cohort, the fibrosis-4 index (hazard ratio [HR]: 2.13, 95% confidence interval [CI] 1.20-3.76, p = 0.010), albumin-bilirubin score (HR 1.91, 95% CI 1.27-2.88, p = 0.002), and neutrophil-lymphocyte ratio (HR: 1.84, 95% CI 1.22-2.79, p = 0.004) were independent significant prognostic factors. We established a 'FAN score' that included these three aforementioned items, which were assigned one point each. We divided patients into the 0-1 point (n = 116) and 2-3 points (n = 49) groups. The FAN score was a significant prognostic marker for cancer-specific survival (CSS) (HR 1.48, 95% CI 1.19-1.83, p < 0.001) along with the Eastern Cooperative Oncology Group Performance Status. The FAN score was also a prognostic factor of progression-free survival (PFS) (HR: 1.25, 95% CI 1.01-1.54, p = 0.036) along with the presence of liver metastasis. In the validation cohort, the FAN score was a significant prognostic factor for CSS (HR: 1.48, 95% CI 1.19-1.85, p = 0.001) and PFS (HR: 1.29, 95% CI 1.02-1.62, p = 0.034). We established the FAN score as a prognostic marker for patients with mUC treated with pembrolizumab.

Oncostatin M is a novel biomarker for coronary artery disease - A possibility as a screening tool of silent myocardial ischemia for diabetes mellitus.

OBJECTIVE: Oncostatin M (OSM) is an inflammatory cytokine of the interleukin-6 family which plays a crucial role in the pathogenesis of atherosclerosis. Therefore, we tested our hypothesis that serum OSM levels are increased in patients with coronary artery diseases (CAD). METHODS AND RESULTS: Serum OSM level was measured by sandwich technique immunoassay in 315 consecutive patients and who underwent coronary angiography at the International University of Health and Welfare Hospital from April 2019 to March 2021. A diagnosis of CAD was made in 169 patients. Serum OSM levels were significantly higher in patients with significant coronary stenosis compared to those without it. [123.0 ± 46.7 pg/mL (n = 169) vs. 98.3 ± 47.9 pg/mL (n = 146), p < 0.001]. A positive correlation was noted between serum OSM levels and severity and complexity of coronary stenosis. Importantly, the coronary revascularization significantly decreased the serum OSM levels. We furthermore detected a positive correlation between serum OSM levels and HbA1c levels. Finally, our data suggested that 120 pg/mL of serum OSM was the potential cutoff value for screening of silent myocardial ischemia related with diabetic mellitus (DM). CONCLUSION: Serum OSM can be a novel biomarker for CAD and may be useful for the screening of asymptomatic CAD in patients with DM.

Risk of de-novo heart failure and competing risk in asymptomatic patients with structural heart diseases.

AIMS: Asymptomatic patients with structural heart diseases are classified as a population at high risk for heart failure (HF) in Stage B. However, limited data are available regarding incidence and related factors of de-novo HF (DNHF) considering competing risk in this population. METHODS AND RESULTS: In 3362 Stage B patients (mean age 68 yrs, male 76%) from the CHART-2 Study (N = 10,219), we examined incidence of death and DNHF, defined as the first episode of either HF hospitalization or HF death, and factors related to DNHF. RESULTS: During the median 6.0-year follow-up, 627 deaths (31/1000 person-years) and 293 DNHF (15/1000 person-years) occurred. Among the 627 deaths, 212 (34%) and 325 (52%) were specified as cardiovascular and non-cardiovascular deaths, respectively. During the follow-up of 271 DNHF hospitalizations, we observed 124 deaths, including 65 (52%) cardiovascular and 47 (40%) non-cardiovascular deaths. The competing risk model showed that age, diabetes mellitus, stroke, atrial fibrillation, diastolic blood pressure, hemoglobin levels, estimated glomerular filtration ratio and left ventricular ejection fraction was significantly associated with DNHF. Bayesian structural equation modeling showed that many of these cardiac and non-cardiac variables contribute to DNHF by affecting each other, while diabetes mellitus was independently associated with DNHF. CONCLUSIONS: Stage B patients had a high incidence of DNHF as well as that of death due to both cardiovascular and non-cardiovascular causes. Thus, management of Stage B patients should include multidisciplinary approaches considering both cardiac and non-cardiac factors, in order to prevent DNHF as well as non-HF death as a competing risk. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00418041.

Adjuvant chemotherapy improves survival of patients with high-risk upper urinary tract urothelial carcinoma: a propensity score-matched analysis.

BACKGROUND: The purposes of this study were to determine whether adjuvant chemotherapy (AC) improved the prognosis of patients with high-risk upper urinary tract urothelial carcinoma (UTUC)and to identify the patients who benefited from AC. METHODS: Among a multi-center database of 1014 patients who underwent RNU for UTUC, 344 patients with ≥ pT3 or the presence of lymphovascular invasion (LVI) were included. Cancer-specific survival (CSS) estimates were calculated by the Kaplan-Meier method, and groups were compared by the log-rank test. Each patient's probability of receiving AC depending on the covariates in each group was estimated by logistic regression models. Propensity score matching was used to adjust the confounding factors for selecting patients for AC, and log-rank tests were applied to these propensity score-matched cohorts. Cox proportional hazards regression modeling was used to identify the variables with significant interaction with AC. Variables included age, pT category, LVI, tumor grade, ECOG performance status and low sodium or hemoglobin score, which we reported to be a prognostic factor of UTUC. RESULTS: Of the 344 patients, 241 (70%) had received RNU only and 103 (30%) had received RNU+AC. The median follow-up period was 32 (range 1-184) months. Overall, AC did not improve CSS (P = 0.12). After propensity score matching, the 5-year CSS was 69.0% in patients with RNU+AC versus 58.9% in patients with RNU alone (P = 0.030). Subgroup analyses of survival were performed to identify the patients who benefitted from AC. Subgroups of patients with low preoperative serum sodium (≤ 140 mEq/ml) or hemoglobin levels below the normal limit benefitted from AC (HR 0.34, 95% CI 0.15-0.61, P = 0.001). In the subgroup of patients with normal sodium and normal hemoglobin levels, 5-year CSS was 77.7% in patients with RNU+AC versus 80.2% in patients with RNU alone (P = 0.84). In contrast, in the subgroup of patients with low sodium or low hemoglobin levels, 5-year CSS was 71.0% in patients with RNU+AC versus 38.5% in patients with RNU alone (P < 0.001). CONCLUSIONS: High-risk UTUC patients, especially subgroups of patients with lower sodium and hemoglobin levels, could benefit from AC after RNU.

Influence of Left Ventricular Ejection Fraction on the Effects of Supplemental Use of Angiotensin Receptor Blocker Olmesartan in Hypertensive Patients With Heart Failure.

BACKGROUND: There is no robust evidence of pharmacological interventions to improve mortality in heart failure (HF) patients with preserved left ventricular ejection fraction (LVEF) (HFpEF). In this subanalysis study of the SUPPORT Trial, we addressed the influence of LVEF on the effects of olmesartan in HF. METHODS AND RESULTS: Among 1,147 patients enrolled in the SUPPORT Trial, we examined 429 patients with reduced LVEF (HFrEF, LVEF <50%) and 709 with HFpEF (LVEF ≥50%). During a median follow-up of 4.4 years, 21.9% and 12.5% patients died in the HFrEF and HFpEF groups, respectively. In HFrEF patients, the addition of olmesartan to the combination of angiotensin-converting enzyme inhibitor (ACEI) and ß-blocker (BB) was associated with increased incidence of death (hazard ratio (HR) 2.26, P=0.002) and worsening renal function (HR 2.01, P=0.01), whereas its addition to ACEI or BB alone was not. In contrast, in HFpEF patients, the addition of olmesartan to BB alone was significantly associated with reduced mortality (HR 0.32, P=0.03), whereas with ACEIs alone or in combination with BB and ACEI was not. The linear mixed-effect model showed that in HFpEF, the urinary albumin/creatinine ratio was unaltered when BB were combined with olmesartan, but significantly increased when not combined with olmesartan (P=0.01). CONCLUSIONS: LVEF substantially influences the effects of additive use of olmesartan, with beneficial effects noted when combined with BB in hypertensive HFpEF patients. (Circ J 2016; 80: 2155-2164).

Anatomical "C"-shaped double-bundle versus single-bundle anterior cruciate ligament reconstruction in pre-adolescent children with open growth plates.

PURPOSE: To analyse the clinical, rotational and radiological (MRI) results of paediatric anatomical "C-shaped" double-bundle (DB) anterior cruciate ligament (ACL) reconstruction with anteromedial and posteromedial bundle compared to single-bundle (SB) ACL reconstruction. METHODS: Between 2008 and 2014, 57 consecutive patients received a paediatric ACL reconstruction with open physis and were allocated into two groups, according to the surgical procedure. Transepiphyseal SB technique was used until 2012 and DB consecutively thereafter. Follow-up consisted of a clinical evaluation with assessment of the International Knee Documentation Committee (IKDC) form, the Lysholm knee score, Tegner activity score, KT-1000 arthrometer evaluation, VAS Scores for satisfaction, MRI and testing of rotational stability using a robotic system. RESULTS: The mean time from ACL reconstruction to follow-up was 48.1 ± 15.8 in the SB group (n = 17) and 23.1 ± 13.2 in the DB group (n = 16; p < 0.001). No differences were found in the subjective scores. Biomechanically, there were significant differences identified in the KT-1000 (p < 0.03) and total tibial axial rotation (p < 0.04) when evaluating the reconstructed knee only. Ten of 17 (59%) of the SB patients had a Joint Play Area within the acceptable range of the median healthy knee value compared to 100 % in the DB group. Decreased patient satisfaction was associated with increased total tibial axial rotation. No growth disturbance was observed. Overall, 98% of patients were reached and either examined or interviewed. Re-rupture rate was 3 of 21 (14.3%) for DB and 9 of 35 (25.7%) for SB. All but one re-ruptures (92%) happened in the first 16 postoperative months independent of technique. CONCLUSIONS: The re-rupture rate after pre-adolescent ACL reconstruction is too high both historically and in this mixed cohort. Anatomical transepiphyseal DB ACL reconstruction with open physis may result in a reduction in this re-rupture rate, which may be related to a tighter control of the Joint Play Area. While subjective clinical results were similar between SB and DB, decreased patient satisfaction was associated with increased total tibial axial rotation in the entire cohort. Despite the need for two transepiphyseal tunnels in the DB technique, there did not appear to be an increased risk in growth plate disturbance. Transepiphyseal DB ACL reconstruction appears to be a reasonable alternative to current techniques in pre-adolescent children with an ACL rupture. LEVEL OF EVIDENCE: IV.

Attenuation of cartilage degeneration by calcitonin gene-related paptide receptor antagonist via inhibition of subchondral bone sclerosis in osteoarthritis mice.

Osteoarthritis (OA) is a progressive joint disorder which affects cartilage and subchondral bone. Calcitonin gene-related peptide (CGRP) plays a role in bone metabolism. The purpose of this study is to examine the therapeutic effect of the blocking CGRP on OA progression in mice by inhibition of subchondral bone sclerosis. OA was induced by the resection of the medial meniscotibial ligament of the knee in C57/BL6 mice. An intraperitoneal injection of the CGRP receptor antagonist (BIBN4096) was administered after OA surgery. At 1, 4, and 8 weeks after injection, histological analysis were performed. In vitro, the effect of CGRP and BIBN4096 on osteogenesis and osteoclastogenesis was analyzed. BIBN4096 could prevent cartilage degeneration and subchondral bone sclerosis. The OARSI score in the BIBN4096 group was significantly lower than that in the control. In vitro, CGRP up regulated osteocalcin expression, but its expression was down regulated by BIBN4096. CGRP inhibited osteoclastogenesis of raw 267.4 cells, but its effect was reduced by the addition of BIBN4096.The current study showed that subchondral bone sclerosis and increasing expression of CGRP occurs in the early phase of OA in relation to cartilage degeneration, and that BIBN4096 could effectively attenuate OA progression. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1177-1184, 2016.

[Renal Epithelioid Angiomyolipoma with Spontaneous Rupture: A Case Report].

A 66-year-old woman was referred to our hospital for a right renal mass found in the examination for sudden right flank pain. Abdominal computed tomography (CT) revealed a right renal tumor, 8.0 cm in diameter, with massive hemorrhage due to spontaneous tumor rupture. After transcatheter arterial embolization, right radical nephrectomy was successfully performed. The histopathological diagnosis of the renal tumor was epithelioid angiomyolipoma (eAML). Postoperative chest CT showed two lung tumors. Therefore, the lung tumors were resected and diagnosed as a primary lung adenocarcinoma and a sclerosing angioma. Although renal eAML is thought to have malignant potential, there has been no local reccurence nor distant metastases of renal eAML 11 months after the surgery.

Bach1 deficiency reduces severity of osteoarthritis through upregulation of heme oxygenase-1.

INTRODUCTION: BTB and CNC homology 1 (Bach1) is a transcriptional repressor of Heme oxygenase-1 (HO-1), which is cytoprotective through its antioxidant effects. The objective of this study was to define the role of Bach1 in cartilage homeostasis and osteoarthritis (OA) development using in vitro models and Bach1 (-/-) mice. METHODS: HO-1 expression in Bach1 (-/-) mice was analyzed by real-time PCR, immunohistochemistry and immunoblotting. Knee joints from Bach1 (-/-) and wild-type mice with age-related OA and surgically-induced OA were evaluated by OA scoring systems. Levels of autophagy proteins and superoxide dismutase 2 (SOD2) were determined by immunohistochemistry. The relationship between HO-1 and the protective effects for OA was determined in chondrocytes treated with small interfering RNA (siRNA) targeting HO-1 gene. RESULTS: HO-1 expression decreased with aging in articular cartilages and menisci of mouse knees. Bach1 (-/-) mice showed reduced severity of age-related OA and surgically-induced OA compared with wild-type mice. Microtubule-associated protein 1 light chain 3 (LC3), autophagy marker, and SOD2 were increased in articular cartilage of Bach1 (-/-) mice compared with wild-type mice. Interleukin-1ß (IL-1ß) induced a significant increase in Adamts-5 in wild-type chondrocytes but not in Bach1(-/-) chondrocytes. The expression of SOD2 and the suppression of apoptosis in Bach1 (-/-) chondrocytes were mediated by HO-1. CONCLUSIONS: Bach1 deficiency reduces the severity of OA-like changes. This may be due to maintenance of cartilage homeostasis and joint health by antioxidant effects through HO-1 and downregulation of extracellular matrix degrading enzymes. These results suggest that inactivation of Bach1 is a novel target and signaling pathway in OA prevention.

[CLINICAL SURVEILLANCE OF PROSTATE CANCER--COMPARISON WITH CLINICAL MASS STUDY IN JAPAN].

OBJECTIVES: We report on the treatment trends and outcomes for prostate cancer in our clinic retrospectively, and compared our data with the domestic clinical mass study for prostate cancer. We then validated the legitimacy of our selected therapy for prostate cancer. PATIENTS AND METHODS: Eight hundred and eighteen patients at our clinic had histologically confirmed adenocarcinomas of the prostate between January, 2000 and January, 2013. RESULTS: The age distribution was from 47 to 100 years-old, with a median age of 72 years-old at diagnosis. Clinical TNM staging indicated that 301 cases (36.8%) were stage I, 303 cases (37.0%) were stage II, 101 cases (12.3%) were stage III and 113 cases (13.8%) were stage IV. Three hundred and fifty two cases (43.0%) received some form of androgen deprivation therapy (ADT). Retropubic prostatectomy (RPX) or radiation therapy (RT), including external beam radiation therapy and brachytherapy, was performed in 242 (29.6%) and 136 (16.6%) cases, respectively. The median overall survival was 56.3 months and the respective cause specific 5 year and 10 year survival rates of the 818 cases were 92.0% and 77.8%. Respectively, they were 100% and 100% for T1, 98.7% and 97.4% for T2, 90.7% and 38.5% for T3, and 60.8% and 38.9% for T4. JUA (Japanese Urological Association) Cancer Registration Statistics includes 11,385 eligible cases of prostate cancer, and had the same distribution and the same therapy trends as our data base. NUORG (Nara Uro-oncological Research Group), the data base of 2,303 prostate cancer patients, and our clinical study had the same distribution of D'Amico risk groups. Finally we validated JCAP (Japan Study Group of Prostate Cancer) recommended J-CAPRA scores in our prostate cancer patients who received primary androgen deprivation therapies. Progression free survival and cause specific survival were related to J-CAPRA scores. DISCUSSION/CONCLUSION: The Japanese prostate cancer patients have higher prostate-specific antigen at diagnosis, higher Gleason score and higher clinical stage than the US patients. The higher rate of primary androgen deprivation therapy is characteristic for the Japanese patients.

Prognostic Impact of Anemia in Patients With Chronic Heart Failure- With Special Reference to Clinical Background: Report From the CHART-2 Study.

BACKGROUND: We aimed to elucidate the prognostic impact of anemia with special reference to the clinical background of patients with chronic heart failure (CHF). METHODS AND RESULTS: We examined 4,646 consecutive patients with Stage C/D CHF registered in the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (n=10,219). Among them, 1,627 (35%) had anemia and were characterized by higher age (74 vs. 66 years), lower estimated glomerular filtration rate (52.8 vs. 66.1 ml/min/1.73 m(2)) and higher B-type natriuretic peptide levels (154.5 vs. 81.8 pg/ml) (all P<0.001) but comparable left ventricular ejection fraction (LVEF; 57.5 vs. 56.7%). Anemic patients were more frequently treated with diuretics (55.1 vs. 42.3%) but less often treated with ß-blockers (45.4 vs. 51.1%) (both P<0.001). During a median follow-up of 3.8 years, 371 and 272 patients died with and without anemia, respectively (22.8 vs. 9.0%, adjusted hazard ratio 1.40; 95% confidence interval 1.15-1.71, P=0.001). Subgroup analysis revealed that the prognostic impact of anemia was comparable in terms of age, sex, renal function and double product, but differed by LVEF level and CHF etiology (both, P for interaction <0.001). In particular, a difference in the prognostic impact of LVEF level was noted in patients with ischemic heart disease. CONCLUSIONS: These results indicate that the prognostic impact of anemia is evident in CHF patients with preserved EF and it differs by CHF etiology.

Prognostic Impact of Diabetes Mellitus in Chronic Heart Failure According to Presence of Ischemic Heart Disease ­ With Special Reference to Nephropathy.

BACKGROUND: It is unclear whether the prognostic impact of diabetes mellitus (DM) in chronic heart failure (CHF) is influenced by ischemic heart disease (IHD) and/or nephropathy. METHODS AND RESULTS: We enrolled 4,065 consecutive patients with stage C/D CHF (mean age, 69.0 years; 68.7% male) in the CHART-2 Study (n=10,219). We defined DM as current history of DM treatment or HbA1c ≥6.5% (National Glycohemoglobin Standardization Program [NGSP]), and nephropathy as urine albumin:creatinine ratio ≥30 mg/g or urine dipstick test ≥(±) at enrollment. Impacts of DM and nephropathy on the composite of death, myocardial infarction, stroke, and HF admission were examined. Among the 4,065 patients, 1,448 (35.6%) had DM, while IHD and nephropathy were also noted in 1,644 (40.4%) and in 1,549 (38.1%), respectively. During the median follow-up of 2.88 years, 1,025 (25.2%) reached the composite endpoint. On multivariate Cox regression, DM was significantly associated with the composite endpoint in all patients (HR, 1.17; P=0.02), and in those with IHD (HR, 1.38; P=0.004), but not in those without IHD (HR, 1.12; P=0.22; P for interaction=0.12). Furthermore, when the patients were stratified by nephropathy, DM was associated with worse prognosis only in the IHD patients with nephropathy. CONCLUSIONS: The prognostic impact of DM was more evident in patients with IHD than in those without IHD, particularly when complicated with nephropathy.

Prognostic impact of statin use in patients with heart failure and preserved ejection fraction.

BACKGROUND: The effectiveness of statins remains to be examined in patients with heart failure (HF) with preserved ejection fraction (EF). METHODS AND RESULTS: Among 4,544 consecutive HF patients registered in the Chronic Heart Failure Registry and Analysis in the Tohoku district-2 (CHART-2) between 2006 and 2010, 3,124 had EF ≥50% (HFpEF; mean age 69 years; male 65%) and 1,420 had EF <50% (HF with reduced EF (HFrEF); mean age 67 years; male 75%). The median follow-up was 3.4 years. The 3-year mortality in HFpEF patients was lower in patients receiving statins [8.7% vs. 14.5%, adjusted hazard ratio (HR) 0.74; 95% confidence interval (CI), 0.58-0.94; P<0.001], which was confirmed in the propensity score-matched cohort (HR, 0.72; 95% CI, 0.49-0.99; P=0.044). The inverse probability of treatment weighted further confirmed that statin use was associated with reduced incidence of all-cause death (HR, 0.71; 95% CI, 0.62-0.82, P<0.001) and noncardiovascular death (HR, 0.53; 95% CI, 0.43-0.66, P<0.001), specifically reduction of sudden death (HR, 0.59; 95% CI, 0.36-0.98, P=0.041) and infection death (HR, 0.53; 95% CI, 0.35-0.77, P=0.001) in HFpEF. In the HFrEF cohort, statin use was not associated with mortality (HR, 0.87; 95% CI, 0.73-1.04, P=0.12), suggesting a lack of statin benefit in HFrEF patients. CONCLUSIONS: These results suggest that statin use is associated with improved mortality rates in HFpEF patients, mainly attributable to reductions in sudden death and noncardiovascular death.

Clinical impacts of additive use of olmesartan in hypertensive patients with chronic heart failure: the supplemental benefit of an angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan (SUPPORT) trial.

We examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, ß-blockers, or both. In this prospective, randomized, open-label, blinded endpoint study, a total of 1147 hypertensive patients with symptomatic CHF (mean age 66 years, 75% male) were randomized to the addition of olmesartan (n = 578) to baseline therapy vs. control (n = 569). The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure. During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96-1.46, P = 0.112], while renal dysfunction developed more frequently in the olmesartan group (16.8 vs. 10.7%, HR 1.64; 95% CI 1.19-2.26, P = 0.003). Subgroup analysis revealed that addition of olmesartan to combination of ACE inhibitors and ß-blockers was associated with increased incidence of the primary endpoint (38.1 vs. 28.2%, HR 1.47; 95% CI 1.11-1.95, P = 0.006), all-cause death (19.4 vs. 13.5%, HR 1.50; 95% CI 1.01-2.23, P = 0.046), and renal dysfunction (21.1 vs. 12.5%, HR 1.85; 95% CI 1.24-2.76, P = 0.003). Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and ß-blockers was associated with increased adverse cardiac events. This study is registered at clinicaltrials.gov-NCT00417222.

[Unilateral synchronous occurrence of renal pelvic urothelial carcinoma and renal cell carcinoma : report of two cases].

Two cases of unilateral synchronous occurrence of renal pelvic urothelial carcinoma and renal cell carcinoma are presented. Case 1 : A 70-year-old woman presented with macroscopic hematuria. Retroperitoneoscopic nephroureterectomy was performed under the diagnosis of renal pelvic carcinoma. Pathological diagnosis was not only renal pelvic urothelial carcinoma but also renal cell carcinoma 1.5×0.5 mm in diameter. Case 2 : A 79-year-old man with hormonal therapy for prostate cancer complained of macroscopic hematuria. Right nephroureterectomy was performed under the diagnosis of right renal pelvic carcinoma and right renal cell carcinoma. Pathological findings were the same as preoperative diagnosis. To our knowledge, 21 cases of unilateral synchronous occurrence of renal pelvic urothelial carcinoma and renal cell carcinoma have been reported in the Japanese literature including our cases and the clinical features are reviewed.