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Aim: To validate a ‘drug score’ that stratifies patients receiving immunotherapy based on concomitant medications (antibiotics/proton pump inhibitors/corticosteroids) in urothelial carcinoma (UC). Materials & methods: We assessed oncological outcomes according to the drug score in 242 patients with advanced UC treated with pembrolizumab. Results: The drug score classified patients into three risk groups with significantly different survivals. Heterogeneous treatment effect analyses showed that the primary cancer site (bladder UC [BUC] or upper-tract UC [UTUC]) significantly affected the prognostic capability of the drug score; it significantly correlated with survivals in BUC, while there were no such correlations in UTUC. Conclusion: A drug score was examined in advanced UC treated with pembrolizumab and was validated in BUC but not in UTUC.

Although the albumin-to-globulin ratio (AGR) is a promising biomarker, no study has investigated its prognostic significance for advanced urothelial carcinoma (UC). This study conformed to the REporting recommendations for tumor MARKer prognostic studies (REMARK) criteria. We retrospectively reviewed 176 patients with advanced UC treated with pembrolizumab between 2018 and 2020. We evaluated the associations between pretreatment clinicopathological variables, including the AGR and performance status (PS), with progression-free survival, cancer-specific survival, and overall survival. The Cox proportional hazards model was used for univariate and multivariable analyses. The AGR was dichotomized as

Purpose Renal function is frequently impaired in the patients with upper tract urothelial carcinoma. We aimed to evaluate the impact of renal function and its change after surgery on survival rates in patients with upper tract urothelial carcinoma after nephroureterectomy. Methods The study cohort comprised 755 patients with upper tract urothelial carcinoma who underwent nephroureterectomy between 1995 and 2016 at nine hospitals in Japan. Estimated glomerular filtration rate was calculated using the three-variable Japanese equation for glomerular filtration rate estimation from serum creatinine level and age. Outcomes were recurrence-free, cancer-specific and overall survivals. Univariate and multivariate Cox proportional hazards regression analyses were used. Results Median patients’ age was 72 years old. Pre- and post-surgical median estimated glomerular filtration rate were 55.5 and 42.9 ml/min/1.73 m2, respectively. Median estimated glomerular filtration rate decline after surgery, which represents function of the affected side kidney, was 13.1 ml/min/1.73 m2. The 5-year recurrence-free, cancer-specific and overall survivals were 68.3, 79.4 and 74.0%, respectively. Multivariate analysis indicated that lower preoperative estimated glomerular filtration rate and estimated glomerular filtration rate decline were associated with poorer recurrence-free, cancer-specific and overall survivals, but post-operative estimated glomerular filtration rate was not. Estimated glomerular filtration rate decline was more significant poor-prognosticator than preoperative estimated glomerular filtration rate. Proportions of the patients with estimated glomerular filtration rate Conclusions Lower preoperative renal function, especially of the affected side kidney, was significantly associated with poor prognosis after nephroureterectomy for upper tract urothelial carcinoma. Many patients with locally advanced disease have reduced renal function at diagnosis and even more after surgery.

Although the treatment strategy for advanced urothelial carcinoma (aUC) has drastically changed since pembrolizumab was introduced in 2017, studies revealing current survival rates in aUC are lacking. This study aimed to assess (1) the improvement in survival among real-world patients with aUC after the introduction of pembrolizumab and (2) the direct survival-prolonging effect of pembrolizumab.This multicenter retrospective study included 531 patients with aUC undergoing salvage chemotherapy, including 200 patients treated in the pre-pembrolizumab era (2003-2011; earlier era) and 331 patients treated in a recent 5-year period (2016-2020; recent era). Using propensity score matching (PSM), cancer-specific survival (CSS) and overall survival (OS) were compared between the earlier and recent eras, in addition to between the recent era, both with and without pembrolizumab use, and the earlier era.After PSM, the recent era cohort had significantly longer CSS (21 months) and OS (19 months) than the earlier era cohort (CSS and OS: 12 months). In secondary analyses using PSM, patients treated with pembrolizumab had significantly longer CSS (25 months) and OS (24 months) than those in the earlier era cohort (CSS and OS: 11 months), whereas patients who did not receive pembrolizumab in the recent era had similar outcomes (CSS and OS: 14 months) as the earlier era cohort (CSS and OS: 12 months).Patients with aUC treated in the recent era exhibited significantly longer survival than those treated before the introduction of pembrolizumab. The improved survival was primarily attributable to the use of pembrolizumab.

Introduction The development of secondary tumors is a well-known late adverse event after urinary diversion. However, the frequency of secondary tumors after an ileal conduit is the lowest compared to other methods used for urinary diversion. We observed a rare case of a gastrointestinal stromal tumor in an ileal conduit detected by recurrent massive bleeding from the stoma. Case presentation An 87-year-old female was hospitalized at our hospital due to recurrent bleeding from a stoma 22 years after radical cystectomy. Contrast-enhanced computed tomography revealed a 5-cm mass in her ileal conduit. She underwent a complete resection of the tumor, a histological examination of which revealed it to be a gastrointestinal stromal tumor. The condition of the patient has been good showing no recurrence or metastases 4 years after surgery. Conclusion We report a rare secondary tumor, a gastrointestinal stromal tumor, arising from an ileal conduit.

Macrophages play a crucial role in the development of atherosclerosis. To explore the mechanism by which macrophages attain a proinflammatory phenotype for a sustained period, we stimulated macrophages with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) and measured the interleukin-1β (IL-1β) expression. The IL-1β expression increased transiently, and its expression lasted for, at least, 1 week after the cessation of LPS and IFN-γ stimulation. At the promoter region of the IL-1β gene, the demethylation of histone H3 lysine 27 (H3K27) was significantly induced for 1 week after transient stimulation with LPS and IFN-γ. The expression of H3K27 demethylases ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX) and jumonji domain-containing 3 (JMJD3) increased significantly for 1 week after transient stimulation with LPS and IFN-γ. When the UTX expression was inhibited by using small interfering RNA (siRNA) for UTX, the IL-1β expression was significantly suppressed in both transient and sustained phases, whereas siRNA for JMJD3 significantly inhibited only the sustained phase of the IL-1β expression. These results suggested that H3K27 demethylation was implicated in the transient and sustained increase in the IL-1β expression after LPS and IFN-γ stimulation.

Background Darolutamide, an oral androgen receptor inhibitor, has been approved for treating nonmetastatic castration-resistant prostate cancer (nmCRPC), based on significant improvements in metastasis-free survival (MFS) in the ARAMIS clinical trial. Efficacy and safety of darolutamide in Japanese patients are reported here. Methods In this randomized, double-blind, placebo-controlled phase III trial, 1509 patients with nmCRPC and prostate-specific antigen (PSA) doubling time ≤ 10 months were randomized 2:1 to darolutamide 600 mg twice daily or matched placebo while continuing androgen deprivation therapy. The primary endpoint was MFS. Results In Japan, 95 patients were enrolled and randomized to darolutamide (n = 62) or placebo (n = 33). At the primary analysis (cut-off date: September 3, 2018), after 20 primary end-point events had occurred, median MFS was not reached with darolutamide vs. 18.2 months with placebo (HR 0.28, 95% CI 0.11–0.70). Median OS was not reached due to limited numbers of events in both groups but favored darolutamide in the Japanese subgroup. Time to pain progression, time to PSA progression, and PSA response also favored darolutamide. Among Japanese patients randomized to darolutamide vs. placebo, incidences of treatment-emergent adverse events (TEAEs) were 85.5 vs. 63.6%, and incidences of treatment discontinuation due to TEAEs were 8.1 vs. 6.1%. Conclusions Efficacy outcomes favored darolutamide in Japanese patients with nmCRPC, supporting the clinical benefit of darolutamide in this patient population. Darolutamide was well tolerated; however, due to the small sample size, it is impossible to conclude with certainty whether differences in the safety profile exist between Japanese and overall ARAMIS populations.

Background Intraplaque hemorrhage (IPH) has been implicated in plaque instability and rupture in atherosclerotic lesions, although the mechanisms by which IPH progresses remain largely unknown. In this study, apolipoprotein E-deficient mice with carotid artery ligation and cuff placement around the artery were used, and pro-inflammatory cytokines that are implicated in IPH were analyzed.Methods and Results:The expression of interleukin-1β (IL-1β) increased significantly following cuff placement compared with mice with carotid artery ligation alone. IPH occurred in the cuff-placed carotid artery following treatment with the negative control (NC) small interfering RNA (siRNA). However, the occurrence was significantly reduced in the cuff-placed carotid artery following treatment with an IL-1β siRNA. Neovessel formation was significantly reduced in the carotid artery treated with the NC siRNA compared with that treated with IL-1β siRNA. IL-1β significantly inhibited the tube formation and wound healing capacities of vascular endothelial cells in vitro. Furthermore, immunostaining of matrix metalloproteinase-9 (MMP-9) significantly increased in the carotid artery treated with the NC siRNA compared with that treated with IL-1β siRNA. Conclusions These results suggest that endogenous IL-1β is implicated in the progression of IPH via the inhibition of physiological angiogenesis in the atherosclerotic plaque, leading to the formation of leaky neovessels. Furthermore, the stimulation of MMP-9 expression may also contribute to the formation of leaky neovessels.

To evaluate the efficacy of adjuvant systemic chemotherapy for locally advanced (pT3-4pN0/xM0) upper tract urothelial carcinoma (UTUC). We retrospectively reviewed the medical records of 109 patients with pT3-4pN0/xM0 UTUC who had undergone radical nephroureterectomy between 1996 and 2013 at our four institutions. The patients were divided into two groups: those who received adjuvant chemotherapy (AC group) and those who did not (surgery-alone: SA group). All chemotherapy regimens were cisplatin-based. Cox proportional hazards regression models addressed the associations between clinicopathological factors and recurrence-free survival (RFS) and cancer-specific survival (CSS). Forty-three (39.5%) out of the 109 patients underwent one to four cycles of adjuvant chemotherapy after nephroureterectomy. Median follow-up was 46.5 months. There were no significant differences in the background characteristics of the two groups, except for age. Recurrence developed in 11 (25.6%) and 29 (43.9%) patients in the AC and SA groups, respectively. Ultimately, six (14.0%) and 18 (27.3%) patients in the AC and SA groups, respectively, died of disease progression. On univariate analysis, hydronephrosis, nuclear grade, lymphovascular invasion, and adjuvant chemotherapy were significantly associated with both RFS and CSS. Charlson comorbidity index was associated only with CSS. On multivariate analysis, adjuvant chemotherapy was the only independent factor associated with improved RFS (p = 0.0178, HR = 0.41). Moreover, adjuvant chemotherapy (p = 0.0375, HR = 0.33), lower nuclear grade (p = 0.0070), and the absence of hydronephrosis (p = 0.0493) were independently associated with better CSS. Locally advanced (pT3-4pN0/xM0) UTUC patients who underwent cisplatin-based adjuvant chemotherapy demonstrated better RFS and CSS than those without adjuvant chemotherapy.

Purpose: To compare the efficacy of a newly developed hybrid pencil-type energy device (HD) generating simultaneously monopolar high-frequency electric energy and ultrasonic energy with that of a c...

Small cell carcinoma of the urinary bladder (SCCB) is known for its aggressive clinical features and poor prognosis. No prognostic factor has been established so far. The aim of this study was to assess the significance of possible prognostic factors, including serum neuron-specific enolase (NSE), an established biomarker for small cell lung carcinoma. We retrospectively reviewed 31 patients with primary SCCB treated at our eight affiliate institutions between 2001 and 2014. The association of various clinicopathological factors at diagnosis, including the serum NSE value, with cancer-specific survival (CSS) was assessed. The log-rank test and Cox proportional hazards model were used for univariate and multivariate analyses, respectively. Nineteen (61.3 %) died of SCCB during the follow-up, with a median survival time of 12.7 months. Prognostic factors were analyzed for the 25 patients after excluding six with missing data. Univariate analysis demonstrated that stage (extensive disease) and serum NSE ≥25 ng/ml were significantly associated with worse CSS. Multivariate analysis identified increased serum NSE value as a sole independent predictor of CSS (hazard ratio 18.52, p = 0.0022). Serum NSE value at diagnosis was an independent prognostic factor for primary SCCB and may serve as a useful biomarker in the management of SCCB.

[Backgrounds] Upper urinary tract urothelial carcinomas (UTUCs) are rare malignancies with a histological similarity to urothelial bladder carcinomas (UBCs). Unlike UBCs, little is known about the genetic basis of UTUCs, for which no useful biomarkers are currently available. [Material & Methods] Surgical specimens and matched normal samples were obtained from 209 UTUC patients with various stages and were subjected to integrated molecular analysis including whole exome/transcriptome sequencing. We also investigated a possibility of UTUC diagnosis using urinary sediment-derived DNA. [Result] Hypermutation (≥20/Mb) was observed in 15 samples (6.7%), of which 12 harbored biallelic mismatch repair genes alterations suggestive of Lynch syndrome. The most frequently affected driver genes included TERT (promoter) (50%), followed by KMT2D (46%), FGFR3 (44%), CDKN2A (44%), and TP53 (36%). Mutually exclusive patterns were observed among alterations in FGFR3, RAS (H-/K-/NRAS), TP53, and MDM2, which covered 93.8% of the entire cohort. Approximately 40% of the samples showed highly complexed karyotype (CK) with frequent aneuploidy and chromothripsis. Based on these findings, UTUC cases were classified into 5 genetic subgroups: hypermutated, FGFR3-mutated, RAS-mutated, TP53-mutated with CK, and other cases with none of these features, which were significantly associated distinct clinical outcomes. While hypermutated and FGFR3 subtypes showed favorable prognosis, the TP53/CK subtype exhibited an aggressive clinical course and a shorter survival. Expression-based molecular classification identified unique gene expression subtypes: clusters 1-5, which showed a strong correlation with the mutation-based classification. Of interest, cluster 3 was highly enriched for TP53/CK and showed high expression of PDL1 and PDL2, suggesting a possible role of checkpoint inhibitions. The sequencing analysis of urinary sediment-derived DNA successfully captured those mutations and copy number alterations (CNAs) that had been detected in the corresponding preoperative samples in 84.4% of the cases (38/45), which was significantly higher than the positive diagnosis in urine cytology (class 4 and 5, 31.1%). Failure of detecting mutations were found in 5 tumors that were associated with severe hydronephrosis, which might prevented tumor-containing urinary flow. None of the post operative (0/34) and control (0/19) samples showed mutations/CNAs, including two with positive cytology (class4), both of which were diagnosed as benign pelvis tumors after surgery. [Conclusion] UTUC are classified into 5 distinct genetic subtypes characterized by unique profiles of gene mutations, expression and clinical outcomes, which help an optimal choice of therapeutics, including novel molecular-targeted drugs and checkpoint-inhibitors. Sequencing urinary sediments is a useful, non-invasive biomarker for precise diagnosis and proper treatment. Citation Format: Yoichi Fujii, Yusuke Sato, Hiromichi Suzuki, Tetsuichi Yoshizato, Kenichi Yoshida, Yuichi Shiraishi, Taketo Kawai, Tohru Nakagawa, Hiroaki Nishimatsu, Toshikazu Nishimatsu, Masashi Sanada, Hideki Makishima, Satoru Miyano, Haruki Kume, Seishi Ogawa. Distinct molecular subtypes and a high diagnostic urinary biomarker of upper urinary tract urothelial carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1309.

OBJECTIVES To assess epidemiological and chronological trends of upper urinary tract stones in Japan in 2015. METHODS Patients with a first episode of upper urinary tract stones in 2015 were enrolled in this nationwide survey. The study included all hospitals approved by the Japanese Board of Urology, therefore covering most of the hospitals where urologists practice in Japan. The annual incidence and composition of urolithiasis were evaluated by age and sex. These results were compared with the previous results of the nationwide surveys from 1965 to 2005 to analyze temporal trends. RESULTS The estimated annual incidence of a first-episode upper urinary tract stone in 2015 was 137.9 (191.9 in men and 86.9 in women) per 100 000. The estimated age-standardized first-episode upper urinary tract stone incidence in 2015 was 107.8 (150.6 in men and 63.3 in women) per 100 000, which did not represent a significant increase since 2005. An equivalent incidence was observed in patients aged >50 years, whereas a reduced incidence was observed in patients aged

Resection of metastatic lesions (metastasectomy) is performed for highly selected patients with metastatic urothelial carcinoma (mUC). This study aimed to identify the clinicopathologic factors associated with oncologic outcome for patients who underwent metastasectomy for mUC. This analysis included 37 UC patients who underwent metastasectomy with curative intent at nine Japanese hospitals. The primary end point was cancer-specific survival. The Kaplan–Meier method with the log-rank test and the multivariable Cox proportional hazards model addressed the relationship between clinical characteristics and survival. Metastasectomy was performed for pulmonary (n = 23), nodal (n = 7), and other (n = 7) metastases. The median survival time was 35.4 months (interquartile range [IQR] 15.5, not reached) from the detection of metastasis and 34.3 months (IQR 13.1, not reached) from metastasectomy. The 5-year cancer-specific survival rate after detection of metastasis was 39.7%. In the multivariate analysis, the time from primary surgery to detection of metastasis (time-to-recurrence [TTR]) of 15 months or longer (hazard ratio [HR] 0.23; p = 0.0063), no symptoms of recurrence (HR 0.23; p = 0.0126), and serum C-reactive protein (CRP) levels lower than than 0.5 mg/dl (HR 0.24; p = 0.0052) were significantly associated with better survival. Long-term survival could be achieved for some patients with mUC who underwent metastasectomy. Lung and lymph nodes were predominant sites for metastasectomy. Symptoms, TTR, and CRP value were identified as associated with survival and should be taken into account when metastasectomy is considered.

Mesenchymal stem cells (MSCs) are multipotent stem cells that reside in various organs. They have the capacity to differentiate into various cell types, including cardiomyocytes, vascular endothelial cells, and vascular smooth muscle cells. Among the various MSCs, bone marrow-derived MSCs (BMMSCs) have been widely used for treating acute myocardial infarction (AMI) and ischemic heart failure (IHF) in preclinical and clinical studies. Although the beneficial effects of BMMSCs in treating AMI and IHF were originally attributed to their capacity to differentiate into cardiac cell types, recent evidence suggests that the differentiation capacity of BMMSCs appears to be minimal and that BMMSCs exert cardioprotective effects by secreting paracrine factors. In this context, MSC-derived exosomes have recently gained much attention. In this chapter, we introduce preclinical studies in which MSC-derived exosomes are used for treating cardiovascular diseases (CVDs) such as AMI, stroke, pulmonary hypertension, and septic cardiomyopathy. Future clinical studies are required to confirm the efficacy of exosome administration in treating CVDs.

In 2012, Japanese national insurance started covering robot-assisted surgery. We carried out a population-based comparison between robot-assisted and three other types of radical prostatectomy to evaluate the safety of robot-assisted prostatectomy during its initial year. We abstracted data for 7202 open, 2483 laparoscopic, 1181 minimal incision endoscopic, and 2126 robot-assisted radical prostatectomies for oncological stage T3 or less from the Diagnosis Procedure Combination database (April 2012–March 2013). Complication rate, transfusion rate, anesthesia time, postoperative length of stay, and cost were evaluated by pairwise one-to-one propensity-score matching and multivariable analyses with covariants of age, comorbidity, oncological stage, hospital volume, and hospital academic status. The proportion of robot-assisted radical prostatectomies dramatically increased from 8.6% to 24.1% during the first year. Compared with open, laparoscopic, and minimal incision endoscopic surgery, robot-assisted surgery was generally associated with a significantly lower complication rate (odds ratios, 0.25, 0.20, 0.33, respectively), autologous transfusion rate (0.04, 0.31, 0.10), homologous transfusion rate (0.16, 0.48, 0.14), lower cost excluding operation (differences, −5.1%, −1.8% [not significant], −10.8%) and shorter postoperative length of stay (–9.1%, +0.9% [not significant], –18.5%, respectively). However, robot-assisted surgery also resulted in a + 42.6% increase in anesthesia time and +52.4% increase in total cost compared with open surgery (all P < 0.05). Introduction of robotic surgery led to a dynamic change in prostate cancer surgery. Even in its initial year, robot-assisted radical prostatectomy was carried out with several favorable safety aspects compared to the conventional surgeries despite its having the longest anesthesia time and the highest cost.

We evaluated possible changes in the function and expression of T-type and N-type Ca(2+) channels in the bladder of rats with bladder outlet obstruction.Female Sprague Dawley® rats were divided into a group with bladder outlet obstruction created by partial urethral ligation and a sham operated group. Six weeks postoperatively we determined the mRNA expression of T-type and N-type Ca(2+) channels in the bladder, dorsal root ganglion and spinal cord. We also cystometrically investigated expression by intravenous administration of the T-Ca blocker RQ-00311610 or the N-type Ca(2+) channel blocker ω-conotoxin GVIA. We then performed in vitro functional studies of detrusor strips using these blockers.mRNA expression of T-type Ca(2+) channels in the bladder detrusor and mucosa layers, and the spinal cord dorsal horn, and N-type Ca(2+) channels in the whole bladder and detrusor layer, and the spinal cord dorsal horn was greater in the obstructed group than the sham operated group. In obstructed rats bladder capacity and voided volume increased after RQ-00311610 administration but the number of nonvoiding contractions decreased after ω-conotoxin GVIA administration. Detrusor strips from obstructed rats showed weaker contractile responses to electrical field stimulation, particularly in regard to the purinergic component. ω-Conotoxin GVIA suppressed electrical field stimulation induced contractions only in the detrusor of obstructed rats, especially the cholinergic component.Blocking T-type Ca(2+) channels increased bladder capacity while N-type Ca(2+) channel blockade inhibited nonvoiding contractions in rats with bladder outlet obstruction. Decreased bladder efferent neurotransmission occurred after bladder outlet obstruction, predominantly in its purinergic component and detrusor contractions via cholinergic neurotransmission were activated in a compensatory manner, probably via N-type Ca(2+) channel up-regulation.

YPERTROPHIC CARDIOMYOPATHY (HCM) often includes asymmetric (or nonphysiologic) massive left ventricular hypertrophy, which can be diagnosed by electrocardiography and echocardiography. In patients with HCM, hypertrophy is more common in the ventricular septum below the aortic valve, leading to left ventricular outflow tract (LVOT) obstruction. 1-3 There have been many reports of anesthetic management for noncardiac surgery of patients with ischemic heart disease. However, there have been only a few reports concerning the anesthetic management of patients with HCM undergoing noncardiac surgery. 4-7 Hreybe et al reported that the presence of HCM significantly increased the risk of death and myocardial infarction associated with noncardiac surgery. 8 Patients with HCM undergoing elective procedures may require more careful preoperative assessment and perioperative monitoring. However, it is not known exactly what factors associated with HCM have harmful effects on the perioperative condition of a patient. Left ventricular hypertrophy and LVOT, which induce left ventricular diastolic dysfunction and a pressure gradient, may be involved. In addition, better ways for decreasing the risks have not yet been established. Permanent dual-chamber pacing has been proposed as an adjunct treatment to lessen symptoms in markedly symptomatic patients with obstructive HCM refractory to drugs. 9 This approach is based on the concept that pre-excitation of the interventricular septum by right ventricular pacing would cause the septum to move away from the left ventricular wall during systole and artificially make dyssynchrony, resulting in an increase in LVOT dimensions and, hence, a decrease in LVOT blood velocities. This would, in turn, decrease the systolic anterior motion of the mitral valve, resulting in further relief of the LVOT obstruction and less severe mitral regurgitation. However, the application of this procedure in perioperative management has been rare. Here, the authors describe a case of noncardiac surgery with left ventricular hypertrophy and LVOT obstruction. The surgery included resection of a catecholamine-secreting endocrine tumor that was having a harmful effect on the patient’s hypertrophic heart. After assessing the effect with temporary pacing, the authors performed temporary dual-chamber pacing to decrease the perioperative risks. Noncardiac surgery then was performed successfully without any adverse cardiac events. The clinical course of left ventricular hypertrophy and LVOT obstruction complicated with a catecholamine-secreting tumor involves significant implications in clinical practice.

Endothelial dysfunction is a major contributor to cardiovascular disease (CVD), particularly in elderly people. Studies have demonstrated the role of glycation in endothelial dysfunction in nonphysiological models, but the physiological role of glycation in age-related endothelial dysfunction has been poorly addressed. Here, to investigate how vascular glycation affects age-related endothelial function, we employed rats systemically overexpressing glyoxalase I (GLO1), which detoxifies methylglyoxal (MG), a representative precursor of glycation. Four groups of rats were examined, namely young (13 weeks old), mid-age (53 weeks old) wild-type, and GLO1 transgenic (WT/GLO1 Tg) rats. Age-related acceleration in glycation was attenuated in GLO1 Tg rats, together with lower aortic carboxymethyllysine (CML) and urinary 8-hydroxydeoxyguanosine (8-OHdG) levels. Age-related impairment of endothelium-dependent vasorelaxation was attenuated in GLO1 Tg rats, whereas endothelium-independent vasorelaxation was not different between WT and GLO1 Tg rats. Nitric oxide (NO) production was decreased in mid-age WT rats, but not in mid-age GLO1 Tg rats. Age-related inactivation of endothelial NO synthase (eNOS) due to phosphorylation of eNOS on Thr495 and dephosphorylation on Ser1177 was ameliorated in GLO1 Tg rats. In vitro, MG increased phosphorylation of eNOS (Thr495) in primary human aortic endothelial cells (HAECs), and overexpression of GLO1 decreased glycative stress and phosphorylation of eNOS (Thr495). Together, GLO1 reduced age-related endothelial glycative and oxidative stress, altered phohphorylation of eNOS, and attenuated endothelial dysfunction. As a molecular mechanism, GLO1 lessened inhibitory phosphorylation of eNOS (Thr495) by reducing glycative stress. Our study demonstrates that blunting glycative stress prevents the long-term impact of endothelial dysfunction on vascular aging.

Background Although drug-eluting stents (DES) have been widely used for the treatment of coronary artery disease, they potentially increase the risk of late thrombosis. It is, therefore, desirable to establish a strategy to stimulate reendothelialization. Endothelial injury models have been widely used to analyze the mechanisms of coronary restenosis. However, animal models deployed with coronary stents in the blood vessels are necessary to accurately analyze the mechanisms of coronary restenosis and late thrombosis because persistent inflammation occurs around the coronary stents. Methods and results Coronary stents were implanted into rat abdominal aorta and adipose tissue-derived stem cells (ASC) were administered from the adventitial side. Reendothelialization was then visualized by Evans blue staining, and neointimal formation was analyzed histologically. ASC significantly stimulated reendothelialization and inhibited neointimal formation in bare metal stents (BMS)-implanted aorta. In addition, ASC promoted reendothelialization in DES-implanted aorta; however, the effects were weaker than in BMS-implanted aorta. Among the cytokines that ASC produce, adrenomedullin (AM) significantly stimulated reendothelialization and inhibited neointimal formation in BMS-implanted aorta, when an adenovirus expressing AM was administered from the adventitial side. Conclusions These results suggest that ASC produce several cytokines that stimulate reendothelialization and inhibit neointimal formation in stent-deployed vessels, and that AM could mediate these effects.

[Introduction] Accounting for 5-10% of all urothelial malignancies, upper urinary tract urothelial carcinoma (UTUC) is a relatively rare, whose molecular pathogenesis is poorly understood. We performed comprehensive genetic analysis in a large cohort of UTUC. [Materials and Methods] Surgical specimens of UTUC and matched normal samples were obtained from 209 patients with various stages who underwent nephroureterectomy, and were subjected to whole exome/RNA sequencing and methylation array. [Results] In total, we identified 33 significantly mutated genes (SMG) in UTUC, of which most frequently observed was the TERT promoter (53%), followed by KMT2D (46%), FGFR3 (42%), CDKN2A (42%), TP53 (35%), and RAS family genes (H-/K-/NRAS, 18%). More than 94% cases harbored either TP53, MDM2, FGFR3, or RASalterations in a largely mutually exclusive manner. Dirichlet process clustering based on the SMG identified 3 distinct subgroups. Group 1 cases were frequently affected by TP53, MDM2, and CCND1 alterations with complex copy number alterations (CNAs) and characterized by high stage/grade and poor prognosis. Group2 tumors were characterized by FGFR3 and CDKN2A alterations and associated with lower stage/grade and favorable prognosis, while all cases in Group3 harbored RAS-family gene alterations, showing intermediate prognosis. Gene expression analysis using unsupervised clustering identified 5 clusters. These subtypes showed strong correlation with the mutation status; cluster 1 was enriched for FGFR3 mutations, while clusters 3-5 were dominated by TP53 mutations. Most of the RAS-mutated cases were classified into cluster 2. Cluster 1,2, and 5 showed high expression of luminal markers, while clusters 3 and 4 showed high expression of basal markers. Cluster 5 also had strong expression of p53-like and EMT markers, showing a worse prognosis than other 2 luminal (+) subtypes. Cluster 3 was characterized by strong expression of SCC and immune markers, including CD274 and PDCD1LG2, with frequent squamous differentiation. Finally, clustering analysis combining UBC from TCGA revealed a close association between UTUC and UBC expression subtypes: cluster 1 was similar to the ‘luminal-papillary’ and ‘luminal’, cluster 5 to luminal-infiltrated’, and clusters 3 and 4 to ‘basal-squamous’. Interestingly, cluster 2 was totally different from any of the TCGA subgroups, which might represent an expression profile unique to UTUC. Hierarchical analysis of methylation data revealed that approximately 60% of examined samples showed CpG island methylator phenotype (CIMP). Although there was no correlation between mutation/expression subgroups and methylation profile, KMT2D mutations were significantly enriched in CIMP (-) cases (p=0.0063). [Conclusion] UTUC showed a distinct genetic landscape, associated with various clinical features. Our findings of molecular characteristics in UTUC will contribute to the development of novel diagnostics and therapeutics. Citation Format: Yoichi Fujii, Yusuke Sato, Hiromichi Suzuki, Tetsuichi Yoshizato, Kenichi Yoshida, Yuichi Shiraishi, Taketo Kawai, Tohru Nakagawa, Hiroaki Nishimatsu, Toshikazu Okaneya, Masashi Sanada, Hideki Makishima, Hiroyuki Aburatani, Satoru Miyano, Haruki Kume, Seishi Ogawa. Integrated analysis of urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3405.

Objective:To assess the clinicopathologic factors influencing survival in patients with meta-static urothelial carcinoma undergoing salvage chemotherapy.Methods: A retrospective review was conducted on cases of metastatic urothelial carcinomawho underwent cisplatin-based salvage chemotherapyat our institution between April 2003 andJuly 2011. The association of various clinicopathologic factors with survival was assessed.Survival curves were constructed by the Kaplan–Meier method. A log-rank test for univariateanalysis and a Cox proportional hazards model for multivariate analysis were used.Results: Eighty-three cases were identified in the study. Among them, 64 patients were deadduring the follow-up. The median survival was 14.6 months. Multivariate analysis evaluatingvariables at the start of chemotherapy demonstrated that liver metastasis, performance statusscore 2 and leukocyte counts 8000/ml were significant predictive factors for pooroutcome.Based on these three pre-induction variables, a risk model predicting the overall survival fromthe initiation of chemotherapy was constructed, which classified patients into three groups withsignificantly different overall survival (P , 0.0001). Additionally, factors after induction ofchemotherapy were studied, and poor response for chemotherapy and absence of focal treat-ment for metastatic lesions were also significantlyassociated with poorer survival.Conclusions: Liver metastasis, poor performance status and higher leukocyte counts were in-dependent poor prognostic indicators for metastatic urothelial carcinoma. Our risk classificationenables an accurate prediction of survival that can be useful in deciding which patients arelikely to benefit from salvage chemotherapy.Key words: bladdercancer – chemotherapy – metastasectomy – prognostic factor – urothelialcarcinoma

Introduction Erectile dysfunction (ED) is a major health problem. We have shown that adrenomedullin (AM) restores erectile function in diabetic rats. Aim The aim of this study is to explore a better treatment for ED, we examined whether combination of AM and angiopoietin‐1 (Ang‐1) was more effective to treat ED than treatment with AM alone or Ang‐1 alone. We also compared the effect of the combination therapy with that of treatment with vascular endothelial growth factor‐A (VEGF‐A). Methods Male Wistar rats were injected with streptozotocin (STZ) to induce diabetes. Adenoviruses expessing AM (AdAM), Ang‐1 (AdAng‐1), and VEGF‐A (AdVEGF‐A) were injected into the penis 6 weeks after STZ administration. Erectile function, penile histology, and protein expression were analyzed 4 weeks after the injection of the adenoviruses. Main Outcome Measures Intracavernous pressure and mean arterial pressure were measured to evaluate erectile function. The morphology of the penis was analyzed by Elastica van Gieson stain and immunohistochemistry. The expression of α‐smooth muscle actin (SMA), VE‐cadherin and type I collagen was assessed by Western blot analysis. Results Infection with AdAM plus AdAng‐1 more effectively restored erectile function than infection with AdAM alone or AdAng‐1 alone. This combination therapy restored erectile function to a level similar to that observed in the age‐matched Wistar rats. Expression of SMA and VE‐cadherin increased more significantly in the AdAM plus AdAng‐1‐treated group than in the AdAM‐ or AdAng‐1‐treated group. Although AdVEGF‐A infection restored erectile function significantly, it also caused enlargement of the trabeculae of the cavernous body, aberrant angiogenesis, and overproduction of type I collagen. Conclusions These results suggested that combination therapy with AM and Ang‐1 potently restored erectile function and normal morphology of the cavernous body compared with VEGF‐A administration. This combination therapy will be useful to treat ED patients with a severely damaged cavernous body. Nishimatsu H, Suzuki E, Nomiya A, Niimi A, Suzuki M, Fujimura T, Fukuhara H, and Homma Y. Adrenomedullin and angiopoietin‐1 additively restore erectile function in diabetic rats: Comparison with the combination therapy of vascular endothelial growth factor and angiopoietin‐1. J Sex Med **;**:**–**.

What's known on the subject? and What does the study add? Recently, the ineffectiveness of bowel mechanical preparation prior to colorectal surgery was focused on. Although its effectiveness was widely accepted in laparoscopic prostatectomy, the data were limited. This retrospective multicentre study compared laparoscopic prostatectomy cases with and without bowel preparation and did not demonstrate the preparation's preferable effect in operation time and complication incidence, which suggested justification of the omission of bowel preparation. Objective To evaluate the effect of mechanical bowel preparation (MBP) prior to laparoscopic radical prostatectomy on peri-operative outcomes. Patients and Methods Patients undergoing laparoscopic radical prostatectomy for T1–T2 tumours between 2008 and 2010 were identified in the Japanese Diagnosis Procedure Combination database. Patients were classified into a preoperative MBP group and a non-MBP group. The effects of MBP were evaluated by multivariate regression analysis of overall complication rate, operation time, postoperative length of stay (PLOS) and total costs with generalized estimating equations adjustment involving age, body mass index, Charlson score, hospital academic status and hospital volume. Results Comparing the 154 non-MBP and 580 MBP patients, overall complication rate, operation time, PLOS and total costs were 6.5% vs 6.9% (P = 0.860), 222 vs 250 min (P = 0.001), 11 vs 10 days (P < 0.001) and 18 941 vs 19 015 US dollars (P = 0.032), respectively. In the multivariate analyses, no significant differences were observed for the four outcomes (P = 0.961, 0.194, 0.383 and 0.993, respectively). Complications were more frequently observed in older patients, and operation time tended to be longer in patients with higher body mass index and in hospitals with lower volumes. Longer PLOS and higher total costs were associated with older age, higher Charlson score and lower hospital volume. Conclusions We could not find any superiority of MBP on overall complications, operation time, PLOS and total costs in laparoscopic radical prostatectomy. The results support that MBP can be omitted prior to laparoscopic radical prostatectomy for T1–T2 prostate cancer.

Objectives Quinazoline-based α1-adrenoceptor antagonists are known to inhibit prostate tumor growth through induction of apoptosis. We investigated the effect of a naphthalene-based α1-adrenoceptor antagonist, naftopidil, on prostate cancer incidence, apoptosis of prostatic cell and transforming growth factor-β signaling. Methods Prescription records were linked to pathological data for men who continued naftopidil (n = 766) or tamsulosin (n = 1015) for 3 months or longer between 2003 and 2010. Prostate cancer incidence was analyzed by log–rank test and the Cox proportional hazards model. Apoptosis and cell cycle arrest in human tissues were assessed by immunohistochemical detection of Bcl2 and p21, respectively. Growth inhibition and apoptosis treatment with naftopidil and tamsulosin were assessed in cancer cell lines. Interference with transforming growth factor-β signaling was examined by western blot analysis. Results Prostate cancer incidence was significantly lower in men who received naftopidil for 3 months or longer compared with tamsulosin (P = 0.035). Multivariate analysis confirmed a decreased hazard ratio, 0.46, for naftopidil use (P = 0.013), which was more evident with longer treatment. Immunohistochemical positivity for Bcl2, a marker for resistance to apoptosis, was less frequently detected in prostate cancer cells of men who received naftopidil compared with tamsulosin (P

Objectives To evaluate risk factors of severe adverse events after percutaneous nephrolithotomy with an emphasis on operation time, and to develop a nomogram for predicting them. Methods This was an observational retrospective study including 1511 patients who underwent percutaneous nephrolithotomy in 332 hospitals identified from the Japanese Diagnosis Procedure Combination database between 2007 and 2010. Severe adverse events were defined as follows: (i) in-hospital mortality; (ii) postoperative medications including catecholamine, gamma-globulin products, protease inhibitors and medications for disseminated intravascular coagulation; and (iii) postoperative interventions including central vein catheterization, dialysis and mechanical cardiopulmonary support. Univariate and multivariate logistic regression analyses were carried out for the occurrence of severe adverse events, and a nomogram was generated from this model. Results Overall, 126 severe adverse events (8.34%) were identified. In the multivariate model, a linear trend between severe adverse events and operation time was observed (OR 4.72 for 120–179 min to 17.95 for ≥300 min compared with ≤119 min; each P

Objectives To examine outcomes of intravesical instillations of heparin and alkalized lidocaine in patients with interstitial cystitis. Methods Patients with interstitial cystitis refractory to conventional therapies were given a solution of 20 000 U heparin, 5 mL 4% lidocaine and 25 mL 7% sodium bicarbonate, intravesically, weekly for 12 weeks consecutively. The treatment was regarded as “effective”, when patients rated “slightly improved” or “better” on a seven-graded scale of global response assessment. Other assessment measures included O'Leary and Sant's symptom index and problem index, visual analog scale for pain, and frequency volume chart variables. Results A total of 32 patients were enrolled in the study. The average age was 63.3 years. All participants had received hydrodistension 2.2 times on average, and fulfilled National Institute of Diabetes and Digestive and Kidney Diseases criteria. The therapy was effective in 60.0% of the patients at the fourth instillation, in 76.7% at the last instillation, and 90.0%, 46.7% and 16.7% at 1, 2 and 6 months after the last instillation, respectively. Most of other assessment measures improved significantly at the fourth instillation and further beyond until the end of therapy. On termination of therapy, the efficacy gradually diminished, yet mostly maintained statistical significance by 2 months post-instillation. No severe adverse events occurred. Conclusions A 12-week course of weekly intravesical instillations of heparin combined with alkalized lidocaine is safe and effective in relieving symptoms in interstitial cystitis patients. The effect of the treatment is maintained for 6 months. Further studies are required to optimize the number of instillations and maintenance intervals in order to maximize the therapeutic potential of simple or combined instillations in the management of interstitial cystitis.

We compared perioperative outcomes and costs between open and laparoscopic radical prostatectomy for prostate cancer. The Japanese Diagnosis Procedure Combination database, including cases from 2007 to 2010, was used by one-to-one propensity-score matching. The following items were compared: complication rate; homologous and autologous transfusion rate; first cystography day and cystography repeat rate; anesthesia time; postoperative length of stay; and costs. Multivariate analyses were carried out by including age, Charlson Comorbidity Index, T stage, hospital volume and hospital academic status as variables. As a result, among 15 616 open and 1997 laparoscopic radical prostatectomies, 1627 propensity-score matched pairs were generated. The laparoscopic approach showed a better overall complication rate (3.4% vs 5.0%), homologous transfusion rate (3.3% vs 9.2%), autologous transfusion rate (44.9% vs 79.3%), first cystography day (mean 6th vs 7th day), mean postoperative length of stay (mean 11 vs 13 days), and cost without surgery and anesthesia (mean $7965 vs $9235; all P

Purpose We aimed to identify prognostic clinicopathological factors and to create a nomogram able to predict overall survival (OS) in recurrent urothelial carcinoma of the bladder (UCB) after radical cystectomy (RC). Materials and methods Among 1,087 patients with UCB who had undergone RC at our 11 institutions between 1990 and 2010, 306 patients who subsequently developed distant metastasis or local recurrence or both were identified. Clinical data were collected with medical record review. Univariate and multivariate Cox regression models addressed OS after recurrence. A nomogram predicting postrecurrence OS was constructed based on Cox proportional hazards model, without using postrecurrence factors (systemic chemotherapy and resection of metastasis). The performance of the nomogram was internally validated by assessing concordance index and calibration plots. Results Of the 306 patients, 268 died during follow-up with a median survival of 7 months (95% CI: 5.8–8.5). Postrecurrence chemotherapy was administered in 119 patients (38.9%). Multivariable analysis identified 9 independent predictors for OS; period of time from RC to recurrence (time-to-recurrence), symptomatic recurrence, liver metastasis, hemoglobin level, serum alkaline phosphatase level, serum lactate dehydrogenase level, serum C-reactive protein level, postrecurrence chemotherapy, and resection of metastasis. A nomogram was formed with the following 5 variables to predict OS: time-to-recurrence, symptomatic recurrence, liver metastasis, albumin level, and alkaline phosphatase level. Concordance index rate was 0.75 (95% CI: 0.72–0.78) by internal validation using Bootstraps with 1,000 resamples. Calibration plots showed that the nomogram fitted well. Conclusions We identified 9 clinicopathological factors as independent OS predictors in postcystectomy recurrence of UCB. We also created a validated nomogram with 5 variables that efficiently stratified those patients regardless of eligibility for chemotherapy. The nomogram would be useful for acquiring relevant prognostic information and for stratifying patients for clinical trials.

Mesenchymal stem cells (MSCs) have been used to treat patients suffering from acute myocardial infarction (AMI) and subsequent heart failure. Although it was originally assumed that MSCs differentiated into heart cells such as cardiomyocytes, recent evidence suggests that the differentiation capacity of MSCs is minimal and that injected MSCs restore cardiac function via the secretion of paracrine factors. MSCs secrete paracrine factors in not only naked forms but also membrane vesicles including exosomes containing bioactive substances such as proteins, messenger RNAs, and microRNAs. Although the details remain unclear, these bioactive molecules are selectively sorted in exosomes that are then released from donor cells in a regulated manner. Furthermore, exosomes are specifically internalized by recipient cells via ligand-receptor interactions. Thus, exosomes are promising natural vehicles that stably and specifically transport bioactive molecules to recipient cells. Indeed, stem cell-derived exosomes have been successfully used to treat cardiovascular disease (CVD), such as AMI, stroke, and pulmonary hypertension, in animal models, and their efficacy has been demonstrated. Therefore, exosome administration may be a promising strategy for the treatment of CVD. Furthermore, modifications of exosomal contents may enhance their therapeutic effects. Future clinical studies are required to confirm the efficacy of exosome treatment for CVD.

What's known on the subject? and What does the study add? Ureteroscopic lithotripsy sometimes causes severe complications, e.g. septic shock, and the relationship between long operative duration and complication rate has been empirically recognised. But due to the rarity, evidence is limited. We analysed 12372 cases and showed that the complication rate increased according to operative duration, especially for operations taking >90 min. Also, we found that high-volume centres had lower complication rates. Objective To develop a nomogram to predict severe adverse events (AEs) after ureteroscopic lithotripsy (URSL) including the effects of operative duration and hospital volume. Patients and Methods We identified patients undergoing URSL from the Japanese Diagnosis Procedure Combination database between 2007 and 2010, and defined severe adverse events as (i) in-hospital mortality; (ii) postoperative medication including catecholamine, γ globulin, protease inhibitors, medications for disseminated intravascular coagulation and transfusion; and (iii) postoperative interventions including percutaneous nephrostomy, central vein catheterisation, intensive care unit, dialysis, mechanical cardiopulmonary support. Univariate and multivariate logistic regression models addressed the occurrence of severe AEs. Results Of 12 372 patients, 296 patients (2.39%) had severe AEs. Multivariate analysis showed a positive linear trend of operative duration and severe AEs (odds ratio [OR] 1.58 in 90–119 min to OR 4.28 in ≥210 min compared with ≤ 59 min; each P

Objectives To reveal individual, institutional and regional factors affecting selection of minimally invasive nephroureterectomy in Japan. Methods The Japanese Diagnosis Procedure Combination database was queried to retrieve cases of nephroureterectomy for pelvic or ureter malignancies carried out between 2007 and 2010. A multivariate logistic regression analysis with variables including age, sex, pre-existing comorbidities, tumor location, tumor–nodes–metastasis classification, academic status of hospitals, hospital volume, geographic region and year of surgery was modeled to evaluate predictors of carrying out a minimally invasive (including laparoscopic and minimum incision endoscopic) nephroureterectomy. Results Overall, 3863 open (58.2%), 2635 laparoscopic (39.7%) and 139 minimum incision endoscopic nephroureterectomy (2.1%) cases from 713 hospitals were identified. The proportion of minimally invasive procedures increased from 35.7% to 48.6%. Minimally invasive nephroureterectomy was the most frequently carried out in the Kinki and Chugoku regions (50.9% and 50.4%, respectively) compared with the least in the Kanto region (31.3%). Multivariate analysis showed that lower Charlson Comorbidity Index, lower tumor–nodes–metastasis stage, academic hospitals, higher operative volume centers, western regions of Japan and later year were independently associated with the use of minimally invasive nephroureterectomy. Age, sex and tumor location were not significant factors. Conclusions Despite regional and institutional variations, the proportion of minimally invasive nephroureterectomy has gradually increased in Japan. Minimally invasive nephroureterectomy is more likely to be carried out in patients with low tumor stage and low risk at higher volume academic hospitals. Our findings provide fundamental data for future health policies to foster nationwide healthcare uniformity.