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Aims To examine the effects of RQ-00434739, a novel selective TRPM8 antagonist, on deep body temperature (DBT) and normal bladder sensory function and overactivity and its associated facilitation of mechanosensitive primary bladder single-unit afferent activities (SAAs) induced by intravesical l -menthol or prostaglandin E2 (PGE2) instillation in rats. Main methods The effect of RQ-00434739 on DBT was evaluated using intravenous administration of RQ-00434739 (1 mg/kg) or its vehicle under urethane anaesthesia. Cystometry (CMG) was performed on conscious and freely moving rats. SAAs were measured from the left L6 dorsal root under urethane anaesthesia, and the fibers were grouped as Aδ- or C-fiber based on their conduction velocity. For both CMG and SAA measurements, after baseline recording with saline instillation, further recording was performed with intravesical l -menthol (6 mM) or PGE2 (60 μM) instillation after pretreatment with intravenous RQ-00434739 (1 mg/kg) or its vehicle. Key findings RQ-00434739 did not significantly affect DBT. In CMG measurements, RQ-00434739 administration increased mean voided volume. Both l -menthol and PGE2 instillation decreased mean voided volume following vehicle pretreatment, whereas such effects were not observed following RQ-00434739 pretreatment. In SAA measurements, either l -menthol or PGE2 instillations increased SAAs of C-fibers, but not SAAs of Aδ-fibers, in the presence of vehicle. RQ-00434739 pretreatment significantly inhibited the l -menthol- and PGE2-induced activation of C-fiber SAAs. Significance The present results demonstrate that blockade of TRPM8 channels can inhibit the pathological activation of mechanosensitive C-fibers and suggest that RQ-00434739 may be a promising therapeutic drug candidate for bladder hypersensitive disorders without affecting DBT.

Background Analyses of associations between clinicopathologic outcomes and recurrent somatic mutations in clear cell renal cell carcinoma (ccRCC) have been limited to individual cohorts. Objective To define clinicopathologic associations between specific mutations and ccRCC disease characteristics. Design, setting, and participants DNA sequencing data were pooled from three collaborative genomic cohorts ( n =754) and our institutional database ( n =295). All patients had clinical data and identification of somatic mutations from their primary tumors. Outcome measurements and statistical analysis Analysis of gene mutations for associations with maximal tumor size (linear regression) and pathologic stage (logistic regression). Cancer-specific survival (CSS) and recurrence-free survival (RFS) were calculated using competing risks methods. Analyses were adjusted for cohort site, and results were adjusted for multiple testing ( q value). Relevant genes were used in multivariable models that included confounding variables and the validated Mayo Clinic Stage, Size, Grade, and Necrosis (SSIGN) score. Results and limitations Association with tumor size was found for mutations in BAP1 ( q =0.013). No mutations were found to be associated with stage after adjusted analysis. Mutations in BAP1 ( q =0.004) and TP53 ( q =0.001) were associated with decreased CSS in a multivariable model; only TP53 ( q =0.005) remained significant when SSIGN score was included. SETD2 mutations ( q =0.047) were associated with decreased RFS in multivariable models, including models with SSIGN score. Conclusions In >1000 patients with ccRCC, pooled analysis and multivariable modeling demonstrated that three mutated genes have statistically significant associations with poor clinical outcomes. This included the more commonly mutated BAP1 and SETD2 and the less frequently mutated TP53 . After adjustment for clinical confounders, mutations of TP53 and SETD2 were associated with decreased CSS and RFS, respectively. Patient summary Using rigorous statistical methods, this study affirmed that certain mutations in clear cell renal cell carcinoma may portend inferior survival and an increased risk of recurrence.

More than 95% of prostate cancers are adenocarcinoma, and neuroendocrine carcinomas (NECs) are very rare, representing less than 1% of prostate cancers. Among NECs of the prostate including small cell carcinoma (SmCC), carcinoids, and large cell neuroendocrine carcinoma (LCNEC), LCNEC is extremely rare. Only 15 cases have been reported to date and their prognoses were very poor. Here, we report a patient with de novo LCNEC of the prostate that was successfully treated with radical surgery and adjuvant androgen deprivation therapy (ADT).

Both small cell carcinoma and sarcomatoid carcinoma of the urinary bladder are highly aggressive tumors, and a concurrence of these tumors is extremely rare. We report a case of urinary bladder cancer with small cell carcinoma as a predominant component, accompanied by sarcomatoid carcinoma and conventional urothelial carcinoma (UC). Although the small cell carcinoma component had resolved on receiving chemoradiotherapy, rapid growth of the residual tumor led to a fatal outcome. A 47-year-old man presented with occasional bladder irritation and had a 2-year history of asymptomatic hematuria. Cystoscopy revealed a huge mass in the urinary bladder, and transurethral resection was performed. Microscopically, small cell carcinoma was detected as the major tumor component. Spindle-shaped sarcomatoid cells were also observed that were intermingled with small cell carcinoma and conventional UC. In addition, a sheet-like growth of the lipoblast-like neoplastic cells was observed focally. Initially, by providing chemoradiotherapy, we achieved a marked tumor regression; however, the tumor rapidly regrew after the completion of chemoradiotherapy, and the patient underwent radical cystectomy. Only conventional UC and sarcomatoid carcinoma were identified in the cystectomy specimen. The patient died of the disease 4 months after cystectomy. Urinary bladder cancer may include a combination of multiple aggressive histologies as in the present case. Because the variation in the tumor components may affect the efficacy of therapy, a correct diagnosis of every tumor component is necessary.

Background The androgen receptor (AR) plays a key role in the development of prostate cancer. AR signalling mediates the expression of androgen-responsive genes, which are involved in prostate cancer development and progression. Our previous chromatin immunoprecipitation study showed that the region of abhydrolase domain containing 2 (ABHD2) includes a functional androgen receptor binding site. In this study, we demonstrated that ABHD2 is a novel androgen-responsive gene that is overexpressed in human prostate cancer tissues. Methods The expression levels of ABHD2 in androgen-sensitive cells were evaluated by quantitative reverse transcription polymerase chain reaction and western-blot analyses. LNCaP and VCaP cells with ABHD2 overexpression or short interfering RNA (siRNA) knockdown were used for functional analyses. ABHD2 expression was examined in clinical samples of prostate cancer by immunohistochemistry. Results We showed that ABHD2 expression is increased by androgen in LNCaP and VCaP cells. This androgen-induced ABHD2 expression was diminished by bicalutamide. While stable expression of ABHD2 affected the enhancement of LNCaP cell proliferation and migration, siRNA-mediated ABHD2 knockdown suppressed cell proliferation and migration. In addition, the siRNA treatment significantly repressed the tumour growth derived from LNCaP cells in athymic mice. Immunohistochemical analysis of ABHD2 expression in tumour specimens showed a positive correlation of ABHD2 immunoreactivity with high Gleason score and pathological N stage. Moreover, patients with high immunoreactivity of ABHD2 showed low cancer-specific survival rates and a resistance to docetaxel-based chemotherapy. Conclusion ABHD2 is a novel androgen-regulated gene that can promote prostate cancer growth and resistance to chemotherapy, and is a novel target for diagnosis and treatment of prostate cancer.

Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant cancer syndrome caused by a germline mutation of the folliculin (FLCN) gene. Previous studies have suggested that truncated mutant folliculin proteins generated by disease causing FLCN mutations may retain partial functionality and contribute to disease phenotype. A 38-year-old Russian man presented with a left renal tumor. He underwent a left radical nephrectomy and histological examination confirmed the diagnosis of chromophobe renal cell carcinoma. He had papulae on his face suggestive of fibrofolliculomas, and pulmonary cysts on his computed tomography of the chest. He had a family history of skin manifestations. Genetic analysis identified a genomic deletion including the putative promoter region of FLCN exon 1 in the germline, and the second hit on the remaining wild-type FLCN in the renal carcinoma cells, which is expected to cause the complete lack of folliculin protein. Immunohistochemistry with the use of anti-folliculin antibody showed no antibody-binding on chromophobe renal carcinoma cells. These findings suggest that the decreased FLCN expression itself without producing mutated folliculin proteins can be at risk for developing clinical manifestations of BHDS: fibrofolliculomas, lung cysts, and tumorigenesis in the kidneys. This sheds light on the pathogenesis of BHDS and the role of FLCN as a tumor suppressor gene.

Integrated sequencing analysis identified a group of tumors among clear cell renal cell carcinomas characterized by hotspot mutations in TCEB1 (a gene that contributes to the VHL complex to ubiquitinate hypoxia-inducible factor). We analyzed 11 tumors from two distinct cohorts with TCEB1 mutations along with an expanded cohort to assess whether these should be considered an entity distinct from clear cell renal cell carcinoma and clear cell papillary renal cell carcinoma. All tumors were characterized by hotspot mutations in TCEB1 Y79C/S/F/N or A100P. Morphological and immunohistochemical characteristics of the tumors were assessed by two experienced genitourinary pathologists. Clinical and pathological variables, copy number alterations, mutations, and expression signatures were compared with a cohort of TCEB1 wild-type tumors. All TCEB1-mutated tumors were VHL and PBRM1 wild type and contained distinct copy number profiles including loss of heterozygosity of chromosome 8, the location of TCEB1 (8q21.11). All tumors lacked the clear cell renal cell carcinoma signature 3p loss and contained distinct gene expression signatures. None of the clear cell papillary tumors harbored TCEB1 mutations. Pathologically, all TCEB1-mutated tumors shared characteristic features including thick fibromuscular bands transecting the tumor, pure clear cell cytology frequently with cells showing voluminous cytoplasm, and clear cell renal cell carcinoma-like acinar areas associated with infolding tubular and focally papillary architecture. The presence of voluminous cytoplasm, absence of luminal polarization of tumor nuclei, and lack of extensive cup-like distribution of carbonic anhydrase-IX expression distinguish it from clear cell papillary carcinoma. None of the patients developed metastases at last follow-up (median 48 months). In sum, TCEB1-mutated renal cell carcinoma is a distinct entity with recurrent hotspot mutations, specific copy number alterations, pathway activation, and characteristic morphological features. Further clinical follow-up is needed to determine whether these tumors are more indolent compared with the conventional clear cell renal cell carcinoma.

Our previous study indicates that hyperinsulinemia in metabolic syndrome in the absence of nephropathy may promote hypertension by stimulating renal proximal tubule (PT) sodium transport via insulin receptor substrate (IRS) 2/phosphoinositide 3-kinase pathway. In the present study we showed that the stimulatory effect of insulin on the Na(+)-HCO3(-) cotransporter NBCe1 in isolated PTs was completely preserved in type 2 diabetic rats with overt nephropathy. Furthermore, the IRS2 expression and insulin-induced Akt phosphorylation in kidney cortex were preserved in these rats. By contrast, the IRS1 expression in kidney cortex was markedly reduced, which might be relevant to enhanced renal gluconeogenesis consistently reported in diabetes. The stimulatory effect of insulin on NBCe1 was preserved also in a human type 2 diabetic patient with advanced nephropathy. These results revealed that insulin can stimulate PT sodium transport even in type 2 diabetes with overt nephropathy. In addition to hypoglycemia, insulin-induced renal sodium retention might also play a role in increased cardiovascular risk associated with intensive glycemic control in type 2 diabetic patients with nephropathy.

Objective To assess the psychometric properties of the English version of the overactive bladder symptom score (OABSS) among overactive bladder (OAB) patients in the United States. Methods The reliability and validity of the OABSS were examined using data collected online from OAB patients residing in the United States. Results A total of 199 patients responded to the first questionnaire administration. Of those, 149 completed the second questionnaire. The results of the reliability assessment indicated that the intraclass correlation coefficient of the total OABSS score was 0.74 (weighted kappa coefficients of individual item score, 0.55-0.84) and that the Cronbach α coefficient was 0.56. In the analysis of the validity, the OABSS total score was correlated with all the external criteria (symptom bother of the overactive bladder questionnaire, patient perception of bladder condition, and International Prostate Symptom Score) to a moderate to strong degree. The results of known-group validity showed that the OABSS score tended to increase as the symptom severity increased (trend test; P Conclusion The present study demonstrated the reliability and validity of the English version of the OABSS. It is expected that the English version of the OABSS will be useful in clinical studies and medical practice among English-speaking OAB patients.

Xanthogranulomatous cystitis (XC) is a rare benign chronic inflammatory disease of unknown etiology. Curative treatment of XC requires surgical resection, and most of reported cases were treated by partial cystectomy. Here we describe a case with XC that was treated using transurethral resection.

Objective To evaluate the efficacy of imidafenacin for nocturia and nocturnal polyuria in patients with overactive bladder. Materials and Methods A stratified analysis was conducted on data from a phase III randomized, double-blind, controlled trial of imidafenacin performed at 158 centers in Japan. The subjects received imidafenacin (0.1 mg) twice daily (group I) or placebo twice daily (group P). The 24-hour urine volume, daytime and nighttime voiding frequency, and volume voided/micturition were evaluated from 3-day voiding diaries recorded every 4 weeks during the 12-week study period. Longitudinal data analysis was performed, with all values expressed as the least squares mean ± standard error. Results A total of 46 patients (mean age 66.54 ± 9.38 years, 9 men and 37 women) with nocturia and nocturnal polyuria (>33% of urine production at night) were enrolled. Group I (n = 35) and group P (n = 11) showed no baseline differences in the daily voided volume, concomitant diseases, age, or body weight. However, the average daily number of micturitions differed (11.22 ± 2.17 vs 14.45 ± 2.85). Therefore, longitudinal data analysis was performed for each micturition pattern. After 12 weeks of treatment, nighttime micturition was significantly less frequent in group I than in group P (P = .0292), and the nocturnal percentage of 24-hour production was significantly smaller (P = .0053). The interval to the first nighttime void was significantly longer in group I than in group P, but no difference was found in the first nighttime voided volume. Conclusion The novel antimuscarinic agent, imidafenacin, decreases the number of urinations and reduces nocturnal urine production, thereby improving both nocturia and nocturnal polyuria.

We have developed a non-invasive ultrasound theragnostic system (NIUTS) that tracks and follows the movement of an affected area (kidney stone/tumor, in this study) while irradiating it with high-intensity focused ultrasound (HIFU). In this paper, we propose a method to simplify extracting, tracking and following, monitoring the affected area by using a bed-type non-invasive ultrasound theragnostic system.

We conducted present study to address whether the rs6983561 polymorphism, an established genetic marker for prostate cancer susceptibility, was a prognostic indicator. We genotyped 518 Japanese patients with prostate cancer and analysed their survival retrospectively. As a result, patients with the CA/CC genotype of rs6983561 survived significantly longer than those with the AA genotype (P = .033).Genome-wide association studies have revealed several genetic variants at 8q24 that are associated with prostate cancer susceptibility. Rs6983561 (A/C) is a single-nucleotide polymorphism located at 8q24 that has been established as a genetic risk marker for prostate cancer susceptibility. The present study investigated the association between the rs6983561 polymorphism and prostate cancer mortality in a Japanese population.The study examined 518 native Japanese male patients with sporadic prostate cancer. Germline DNA samples were obtained from all participants and genotyping of rs6983561 was performed using a TaqMan assay. Observation periods were from the date of diagnosis of prostate cancer to May 21, 2010. The Cox proportional hazards model was used to estimate the cause-specific survival (CSS) and the overall survival (OS).Patients with the CA/CC genotype of rs6983561 survived significantly longer than those with the AA genotype. In a multivariate model, the hazard ratios (HRs) and 95% confidence intervals (CIs) of the CSS and the OS for the rs6983561 polymorphism were 2.438 (1.262 - 5.046, P = .007) and 1.957 (1.142 - 3.485, P = .014), respectively. When the analysis was restricted to subjects with metastatic disease, the HRs of the CSS and the OS were 3.353 (95% CI, 1.689 - 7.446; P = 3.76 x 10(-4)) and 3.361 (95% CI, 1.741 - 7.136; P = 1.70 x 10(-4)), respectively.In the Japanese population examined in this study, the rs6983561 polymorphism at 8q24 was significantly associated with prostate cancer mortality, especially among patients with metastatic disease.

Objectives To compare the Overactive Bladder Symptom Score (OABSS) and a bladder diary as a tool for assessing symptoms of overactive bladder (OAB). Methods Treatment-naive OAB patients received an antimuscarinic agent, solifenacin. At baseline and 12 weeks after treatment, patients completed a 3-day bladder diary and the OABSS. Relationships between the 2 methods were evaluated by comparison of changes after treatment, agreement between variables and correlation between changes. Results In total, 79 patients (42 male and 37 female, mean age 71.1 years) were included in the analysis. Statistically significant improvements were noted for all the OABSS and the corresponding diary variables. The effect size (ES) was largest for the OABSS urgency score (2.00), followed by the OABSS total score (1.54), and then by the diary urgency score (0.92). All of the ESs for the OABSS, except daytime frequency, were larger than those of the corresponding diary variables. The standard response means followed a similar pattern to the ESs. A fairly good agreement between OABSS items and the corresponding diary variables was found at baseline and 12 weeks (kappa coefficient, 0.33-0.80). High correlations (Spearman's rho, ≥ 0.5) between changes in OABSS items and the corresponding diary variables were found for urgency incontinence and night-time frequency. Conclusions The OABSS is highly sensitive to treatment-related changes of OAB symptoms. Because of its simplicity and dependability, the OABSS can be an alternative to a bladder diary for symptom and efficacy assessment in daily clinical practice.

JC polyomavirus (JCV) isolates worldwide are classified into three super-lineages (A, B and C), with A and B further split into several lineages and sub-lineages. The transcriptional control region (TCR) of the JCV genome generally has the archetypal configuration, but rearranged TCRs have occasionally been detected in isolates from immunocompetent individuals. To investigate the phylogenetic significance of these rearrangements, we analyzed 298 TCR sequences all derived from complete JCV genomes directly cloned from the urine of non-immunocompromised individuals. While sporadic rearrangements were found in many lineages and sub-lineages, common rearrangements were identified in all, or essentially all, isolates belonging to particular lineages or sub-lineages. Interestingly, several common rearrangements were also detected as sporadic rearrangements in other lineages or sub-lineages. This observation suggests that during the course of JCV evolution, JCV strains with sporadic rearrangements became predominant over archetypal TCRs in some JCV lineages or sub-lineages.

Oncolytic herpes simplex viruses type 1 (HSV-1) have been shown promising for treating a variety of tumor. G47Δ is a third-generation oncolytic HSV-1 that has triple mutations in the gamma34.5, alpha47 and ICP6 genes, and the first recombinant HSV-1 tried clinically in Japan. Clinical trials using G47Δ are currently ongoing in patients with glioblastoma, olfactory neuroblastoma or castration resistant prostate cancer. Preclinical studies have shown that G47Δ is also effective in many other types of cancer including breast cancer, schwannoma, renal carcinoma, and urothelial carcinoma. The purpose of this study was to investigate whether oncolytic HSV-1 can also be applied for treating testicular cancer.Testicular cancer is relatively rare, accounting for approximately 1% of male neoplasms and comprising morphologically diverse group of tumors, 90-95% of which are germ cell tumors (GCTs). GCTs are broadly classified as seminoma and non-seminoma (NSGCT). With the increase in early diagnosis and the development of cisplatin-based chemotherapy, a long-term survival can be expected for most GCT patients even with the initial presence of metastases. However, a group of NSGCT patients show resistance to chemotherapy and the five-year survival rate of such group is less than 50%, so clearly a new therapeutic approach is necessary for those patients.In this study, two recombinant HSV-1 were used. T-01 and T-mfIL12 are oncolytic HSV-1 with an empty cassette or the CMV promoter-driven murine interleukin 12 gene inserted into the backbone of G47Δ. Human NSGCT cell lines NTERA-2, Tera-1 and ITO-II, and a mouse NSGCT cell line F9 were used for in vitro evaluation. NTERA-2 and F9 were susceptible to T-01 at an MOI of 0.1: The percentages of surviving cells were less than11% at day 3. Cytopathic activities of T-mfIL12 were comparable to T-01. Athymic mice bearing established subcutaneous NTERA-2 tumors and immunocompetent mice bearing established subcutaneous F9 tumors were used for in vivo evaluation. When inoculated intraneoplastically, T-01 (4 × 10^4, 2 × 10^5 or 1 × 10^6 pfu) caused a significant inhibition of tumor growth compared with mock even at the lowest dose in the NTERA-2 model. In the F9 model, T-mfIL12 (4 × 10^4 pfu) caused a significant inhibition of tumor growth compared with T-01. Moreover, the combination of T-01 (4 × 10^4 pfu) with cisplatin (0.05mg per mouse injected intraperitoneally) was more efficacious than T-01 alone or cisplatin alone in the NTERA-2 model.These data suggest that oncolytic virus therapy using recombinant HSV-1 might be a useful strategy for treating NSGCT.

We have reported that adrenomedullin (AM)-induced vasodilation is at least in part nitric oxide (NO)-cGMP-dependent in the rat. Although it is well known that NO is much involved in the erectile function, it is controversial as to whether AM influences the erectile function. Thus, we examined the effects of AM on intracavernous pressure (ICP) during penile erection. The left carotid artery of rats was cannulated to monitor of mean arterial pressure (MAP). Bipolar electrodes were positioned on the cavernous nerve. The right cavernous body was cannulated with a needle connected to a pressure transducer to monitor ICP. Electrical stimulation (ES) increased ICP in a voltage-dependent manner. Elevation of ICP continued during ES. The intracavernous injection of 0.5 nmol AM significantly potentiated ES-induced increases in both maximal developed ICP/MAP and area under the curve (ICP trace; AUC). Since AM slightly lowered MAP, ICP was normalized by MAP. i.v. administration of N ω -nitro-L-arginine, a NO synthase inhibitor, markedly decreased AM/ES-induced ICP elevation. However, in the presence of E-4021, a cGMP-specific phosphodiesterase inhibitor, AM further increased both ICP/MAP and AUC. These results suggest that a NO-cGMP pathway is involved in the regulation of AM-induced rat cavernous vasorelaxation.

To investigate the clinical utility of fluorescence in situ hybridization (FISH) of voided urine in the detection of bladder cancer and the prediction of its recurrence.FISH with centromere-specific probes for chromosomes 9 and 17 was performed to evaluate the chromosomal alterations of exfoliated urothelial cells in voided urine obtained from 44 patients with bladder cancer and 20 controls. The analysis was also performed in 17 patients with bladder cancer after complete transurethral resection to prospectively determine whether FISH can predict tumor recurrence.The sensitivity to detect bladder cancer by FISH analysis (85%) was significantly higher than that by urine cytologic examination (32%) and by the bladder tumor antigen test (64%) (P0.0001 and P = 0.026, respectively). The specificity of FISH, cytologic analysis, and the bladder tumor antigen test was 95%, 100%, and 80%, respectively. Among the 17 patients tested after transurethral resection, 7 of 13 FISH-positive patients developed tumor recurrence within the 27-month follow-up period; none of 4 FISH-negative patients developed recurrence during the same period. The recurrence rate in patients with the loss of chromosome 17 was 100%, significantly higher than the 23% for patients without this alteration (P = 0.015).These findings suggest that FISH analysis of exfoliated urothelial cells in voided urine can efficiently detect bladder cancer and predict its recurrence.

Objectives. To determine the electromyographic features of the striated urethral sphincter in patients with type 3 stress incontinence (SI) due to intrinsic sphincteric deficiency (ISD). Methods. We performed electromyography (EMG) of the striated urethral sphincter muscle and urodynamic studies in a total of 51 women, 41 female patients with type 3 SI and 10 women with normal urinary control (NUC). The results were analyzed in both groups, and the correlation of EMG findings with the patient characteristics and urodynamic parameters was evaluated. Results. Motor unit potentials (MUP) of SI patients showed significantly shorter duration (P = 0.0014), lower amplitude (P = 0.0008), and larger number of phases (P = 0.0022) compared with those in the NUC group. Thirty (73%) of the SI patients showed an obvious low amplitude (less than 350 μV)/short duration (less than 4.5 milliseconds)/polyphasic pattern and early recruitment of interference activity with low amplitude at voluntary contraction of the striated sphincter, both indicating existence of myogenic damages. These patients showing myogenic damages had significantly lower Valsalva leak point pressure (P = 0.002) and more leakage in the pad-weigh test (P = 0.010) compared with the SI patients without myogenic damage findings. Conclusions. These results suggested that myogenic-dominant damages of the striated urethral sphincter may contribute to the etiology of ISD in most patients with type 3 SI.

To examine the reproducibility of cystometry in the overactive detrusor.The study sample involved 30 patients of the placebo arm in double-blind clinical trials for an overactive detrusor. They had demonstrated detrusor overactivity and underwent the second cystometry after 2-4 weeks. Nonparametric tests for paired data were used to examine the reproducibility of four variables: volume at first desire to void, volume at first involuntary contraction, cystometric capacity, and the maximum pressure of involuntary contraction. Percent change and within-subject standard deviation were calculated to assess intraindividual variability.The second test results showed a significant and systematic change for the better. Volume variables increased by 10-13% (p0.01), involuntary contraction was not elicited in 3 cases (10%), and the maximum contraction pressure decreased by 18% in the remaining cases. Intraindividual variability was not small. Seventeen patients (57%) demonstratedor = 25% change in one or more variables, and the 95% confidence interval of cystometric capacity, for example, was calculated as (x -57, x +57), where x is a test result. No specific patients' demographics were found related to variability.Repeat cystometry in the overactive detrusor is not highly reproducible and may be subject to a systematic effect for the 'better'. Whether this is due to the placebo effect or the learning effect could not be determined.

To assess the efficacy of urapidil, an alpha-blocker, on neurogenic bladder dysfunction in a placebo-controlled, double-blind trial.149 patients were randomly assigned to receive a placebo or 60 mg/day of urapidil for 4 weeks. The evaluation of efficacy included changes in urinary symptom scores and the results of a pressure/flow study.There were significant intergroup differences with regard to straining and the sum of urinary symptom scores, with the urapidil group showing marked improvements (p = 0.016 and p = 0.011, respectively). In the urapidil group, the average and maximum flow rates were unchanged, but the residual urine volume decreased significantly (p0.001) as compared with the baseline value. The pressure at maximum flow and the minimum urethral resistance decreased significantly (p = 0.040 and p = 0.040, respectively) in the urapidil group, and there was a significant (p = 0.005) intergroup difference with regard to pressure at maximum flow. There was also a significant (p0.001) inter-group difference with regard to the overall therapeutic effect. Side effects were noted in 2 patients treated with urapidil and 6 in the placebo group.Urapidil is effective for the treatment of voiding dysfunction in patients with neurogenic bladder.

Miao Liu , Motofumi Suzuki *, Takayuki Kurosaki , Haruki Kume , Akira Ishikawa , Yutaka Enomoto , Hiroaki Nishimatsu , Hiroshi Fukuhara , Tetsuya Fujimura , Tomio Arai , Motoji Sawabe , Yukio Homma , Tadaichi Kitamura a,c a Department of Urology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan b Department of Pathology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-cho, Itabashi-ku, Tokyo 1730015, Japan c Department of Urology, Asoka Hospital, 1-18-1 Sumiyoshi, Koutou-ku, Tokyo 135-0002, Japan

INTRODUCTION AND OBJECTIVES: The Wnt signaling pathway (canonical and non-canonical) regulates crucial aspects of embryonic development. Previously, we have reported that non-canonical Wnt members promote proliferation of cancer cells by increasing secretion of growth factors and expression of cancer related genes. We have also demonstrated that Wnt5a is predominantly expressed in prostatic stromal cells and plays a key role in stromalepithelial communication and in the development of prostate cancer. The purpose of this study is to reveal the relation between the noncanonical Wnt signaling and AR signaling on prostate. METHODS: Prostate tissue samples were obtained from patients undergoing radical prostatectomy or cystectomy for prostate and bladder cancer respectively. Cells, representing the cancer, stromal from around the cancer, as well as epithelium and stromal from pathologically normal tissues were isolated by laser capture microdissection Stromal cells (WPMY1 and PrSC) were cultured with DHT ligand and protein. The mRNA levels of Wnt5a, AR, and PSA were determined in both sample types. Wnt5a-knockdown in WPMY1 cells (shWnt5a) along with a vector control (shCTL) was performed and effects on growth evaluated by MTT assay. The cells were co-cultured with PC3 cells, and the mRNA expression of AR was evaluated. A DNA fragment upstream of the Wnt5a gene was inserted into pGL4.17 a vector and the luciferase activity representing Wnt5a inductionby DHT was measured. RESULTS: Wnt5a mRNA expression was prediminanly in the stromal cells of the human prostate samples and the expression levels observed were in proportion to PSA mRNA expression levels. DHT increased production of AR as well as PSA and Wnt5a mRNA expression in both WPMY1 and PrSC cells. Wnt5 knockdown decreased the proliferation of WPMY1cells by 50% compared to shCTR. Co-culture of PC3 cells and WPMY1shWnt5a formed fewer and smaller sized colonies than co-culture of PC3 cells and WPMY1shCTR. AR and PSA mRNA expression levels were remarkably lower in WPMY1shWnt5a than in the control. DHT ligand dramatically increased the luciferase activity of Wnt5a promoter in WPMY1 cells. CONCLUSIONS: The AR is expressed not only in prostatic epithelium but also prostatic stromal as measured by their response to DHT. In stromal cells, The studies presented here demonstrated an interplay between AR signaling and Wnt5a that appears to modulate the proliferation of prostate cancer cells providing further support for the importance of Wnt5a in the regulation of prostate cancer.