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The aim of this study was to evaluate the renal preservation effect of ubiquinol, the reduced form of coenzyme Q10 (CoQ10).Three-week-old heminephrectomized male Sprague-Dawley rats were divided into three groups (10 animals each): diet with normal (0.3%) salt, high (8%) salt, and high salt plus 600 mg/kg body weight/day of ubiquinol, for 4 weeks. Systolic blood pressure (SBP), urinary albumin (u-alb), superoxide anion generation (lucigenin chemiluminescence) and ubiquinol levels in renal tissues were examined.Salt loading increased SBP (111.0 ± 3.6 vs. 169.4 ± 14.3 mmHg, p0.01) and u-alb (43.8 ± 28.0 vs. 2528.7 ± 1379.0 µg/day, p0.02). These changes were associated with stimulation of superoxide generation in the kidney (866.3 ± 102.8 vs. 2721.4 ± 973.3 RLU/g kidney, p0.01). However, ubiquinol decreased SBP (143.9 ± 29.0 mmHg, p0.05), u-alb (256.1 ± 122.1 µg/day, p0.02), and renal superoxide production (877.8 ± 195.6 RLU/g kidney, p0.01), associated with an increase in renal ubiquinol levels.Ubiquinol, the reduced form of CoQ10, effectively ameliorates renal function, probably due to its antioxidant effect. Thus, ubiquinol may be a candidate for the treatment of patients with kidney disease.

Recent advances in cancer biology reveal that microRNAs (miRNAs) are involved in the regulation of cancer-related genes, or they function as tumor suppressors or oncogenes. In prostate cancer, evidence has accumulated for the contribution of the androgen-dependent gene network to tumor growth, although the precise functions of miRNAs in prostate cancer remain to be investigated. Here, we identified androgen-responsive miRNAs by the short RNA sequencing analysis in LNCaP prostate cancer cells. Among 10 miRNAs with known sequences, we have determined that miR-148a reduces the expression of cullin-associated and neddylation-dissociated 1 (CAND1), a negative regulator of SKP1-Cullin1-F-box (SCF) ubiquitin ligases, by binding to the 3'-untranslated region of CAND1 mRNA. CAND1 knockdown by small interfering RNA promoted the proliferation of LNCaP cells. Our study indicates the potential contribution of miR-148a to the growth of human prostate cancer.

Objectives: It has been reported that nitric oxide (NO) mainly contributes to prostate or urethral smooth muscles relaxation, and that nitrergic innervation and neuronal NO synthase (nNOS) levels are decreased in benign prostatic hyperplasia. The purpose of the present study was to evaluate the feasibility to gene therapy for benign prostatic hyperplasia by transferring nNOS gene into the rat prostate with in vivo electroporation (EP) procedure. Methods: Male Sprague–Dawley rats were divided into four groups (sham, only EP, only nNOS injection, and nNOS gene injection with EP groups). Fifty micrograms of luciferase gene and nNOS expression vectors in 50 µL of K-PBS (potassium-phosphate buffered saline) were injected into the prostate. Immediately after the injection of these vectors, the vector injection points were electroporated by the two-square parallel electrodes. Two days after gene transfer, luciferase analysis and an immunohistochemical staining for nNOS were performed, and NO2−/NO3− (NOX) release was measured using high-performance liquid chromatography coupled with the microdialysis procedure. Results: The optimal electric pulse conditions were 50 V, 1 Hz and 10 msec. In vivo EP with these conditions showed the increase in the luciferase gene expression approximately 300-fold of the control group. In the nNOS gene injection with EP group, the marked nNOS immunoreactivity was observed, and NOX release was significantly higher, as compared to other groups. Conclusion: The results suggest that EP is a feasible technique for in vivo gene transfer into the rat prostate, and that the transferred nNOS gene functionally expresses and contributes to NO production.

Prostate cancer is one of the most common malignancies and ranks the second most common cause of cancer-related deaths in men in the United States. Catechol-O-methyltransferase (COMT) is a phase II enzyme that detoxifies various catechol compounds that are reactive toward DNA and damaging to the cell. Studies have shown COMT to play a protective role against cancers such as renal and breast, but their effect on prostate is not well understood. In this study, the biological properties and function of COMT in prostate cancer were studied. Expression of COMT was initially measured in normal/benign and cancerous prostate tissues by immunohistochemistry, and cell lines by real-time PCR and western blotting. Cancerous cells displaying the lowest levels was then transfected with COMT. Gene effect on various cellular properties such as cell proliferation, migration, invasion and apoptosis, as well as growth in athymic nude mice were determined. COMT protein expression was lower in cancer regions compared to benign and normal regions of prostate tissues. Cancerous DU145 and DuPro cells also had reduced mRNA levels of COMT but with undetectable protein levels. Interestingly, re-expressing COMT in DU145 and DuPro cells led to decreased cell proliferation, migration, wound healing ability and invasion, and increased apoptosis compared to vector control. COMT also inhibited cell tumor formation in animal models. As a possible target, the TNFRSF11B gene was upregulated due to COMT. These results demonstrate COMT to protect against prostate cancer progression and to have a functional role by affecting apoptosis. COMT may thus be a potential biomarker or therapeutic target for prostate cancer. Citation Format: Shigekatsu Maekawa, Taku Kato, Yutaka Hashimoto, Marisa Shiina, Ryan K. Wong, Varahram Shahryari, Soichiro Yamamura, Sahana Majid, Sharanjot Saini, Laura Z. Tabatabai, Yukio Homma, Rajvir Dahiya, Yuichiro Tanaka. Role of catechol-O-methyltransferase gene in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1404.

Objective: To evaluate the efficacy of low dose tamsulosin for facilitating spontaneous passage of ureteral stones in Japanese male patients. Methods: A total of 71 patients with symptomatic ureteral stones, 10 mm or smaller in size, were randomly allocated into groups 1 and 2. Group 1 received tamsulosin (0.2 mg/day) for a maximum of 4 weeks and group 2 received no medication. The primary endpoint was the stone expulsion rate and the secondary endpoints were stone expulsion time and analgesic use. Results: There were no significant differences between the groups in terms of age, stone size and location. The stone expulsion rate was significantly higher in group 1 than in group 2 (77% vs 50%, P = 0.002). No significant differences were noted in the stone expulsion time and analgesic use between the groups. Conclusion: Low dose tamsulosin can significantly facilitate spontaneous passage of ureteral stones without significant side-effects in Japanese male patients.

Objectives:α1-blockers have commonly been used as first-line medical therapy for symptomatic benign prostatic hyperplasia (BPH). Recently, a highly selective α1A-adrenoceptor antagonist, silodosin, was developed in Japan. We examined the efficacy and safety of conversion from conventional α1-blockers to silodosin in men with BPH. Methods: Conversion to silodosin was proposed to consecutive patients on conventional α1-blockers for symptomatic BPH for at least 6 months. The effects of conversion were examined by the International Prostate Symptom Score, quality of life index, overactive bladder symptom score, peak flow rate, residual urine volume, and adverse events at 12 weeks. The efficacy of silodosin was also evaluated by patients' impression. Results: Eighty-one men underwent conversion, for the most part because of dissatisfaction with the efficacy of their current treatment in improving nocturia or weak stream. The International Prostate Symptom Score total score significantly improved from 12.7 ± 5.9 at baseline to 10.6 ± 5.4 at 4 weeks (P < 0.001) and 10.9 ± 5.8 at 12 weeks (P < 0.01). The progress was mostly due to improvement in voiding symptoms, although reduction of storage symptoms was also significant. The quality of life index also significantly decreased with conversion to silodosin. Efficacy as judged by patients' impression was 76% (37/49) at 12 weeks of treatment. None of the overactive bladder symptom score, peak flow rate, and residual urine volume exhibited significant change. No serious adverse events were observed during the study period. Conclusion: Conversion to silodosin may be beneficial in men who are dissatisfied with conventional α1-blockers for BPH, and be particularly useful in improving voiding symptoms.

We propose an automated needle hydrophone-based scanning system to measure high-resolution 3-D acoustic pressure distributions generated by high-intensity focused ultrasound (HIFU). The hardware consists of a host computer, subsystems for HIFU generation, and an oscilloscope to sample the pressure response from a sensor in a water tank. Software was developed to control the hardware subsystems, to search for the initial scan position, and to design the scanning path and volume. A preoperative scanning plan with three perpendicular planes is used to manipulate the position of the HIFU transducer and to automate the acquisition of the spatial acoustic pressure distribution. The post-processing process displays the scanning results, compensates time delays caused by continuous linear scans, and quantifies the focal region. A method to minimize the displacement error induced by the time delay improves the scanning speed of a conventional needle hydrophone-based scanning system. Moreover, a noise-robust, automatic-focus searching algorithm using Gaussian function fitting reduces the total number of iterations and prevents the initial scanning position search from diverging. Finally, the minimum-volume enclosing ellipsoid approximation is used to quantify the size and orientation of the 3-D focal region thresholded by the minimum pressure of interest for various input conditions and to test the reproducibility of the scanning system.

Estrogen-related receptor (ERR) is a nuclear receptor that modulates the estrogen-signaling pathway. Here, we investigated the expression of both ERRbeta and ERRgamma in human prostate tissues. Using original rabbit polyclonal anti-ERRbeta and anti-ERRgamma antibodies, the expression of ERRbeta and ERRgamma was evaluated by immunohistochemical analysis of cancerous lesions (n = 107) and benign foci (n = 92), obtained by radical prostatectomy. Stained slides were evaluated for the proportion of immunoreactive cells and their staining intensity. Total immunoreactivity scores (IR scores; range, 0-8) were calculated as the sum of the proportion and intensity scores. The relationship between the clinicopathological characteristics of the patients and the expression of the three ERRs (ERRalpha, ERR beta, and ERR gamma) was evaluated. IR scores for ERRbeta and ERRgamma were significantly lower in cancerous lesions than that in benign foci (P < 0.0001, for both). Clinicopathological analyses revealed that the patients with low ERRgamma IR scores (

We propose a non-invasive ultrasound theragnostic system that tracks movement in an affected area (kidney stones, in this study) by irradiating it with high-intensity focused ultrasound (HIFU). In this paper, the concept behind a novel medical support system that integrates therapy and diagnostics (theragnostics), is illustrated. The required functions for the proposed system are discussed and an overview of the constructed system configuration is illustrated. Problems of stone motion tracking by ultrasonography are described. To overcome with this problem, we should take 2 approaches. The first approach is to minimize the servoing error to enhance both the efficiency of the therapy and the safety of the patient. The second approach is to reduce the effect of the servoing error. Concerning the first approach, we showed 2 solutions. One is robust detection of the stone position by shape information. Another is the controller that compensates for periodic motion of the affected area. Concerning the second approach, we propse a solution to control HIFU irradiation power in accordance with the servoing error, mainly to enhance the safety of the patient.

The use of replication-competent viruses that can selectively replicate in and destroy neoplastic cells is an attractive strategy for treating cancer. Various oncolytic viruses have been taken to clinical trials since a recombinant virus was first applied to cancer patients a decade ago. The concept of the therapy is simple: infectious virus kills the host cancer cells in the course of viral replication. It is important, however, that the virus does not harm the surrounding normal tissue. Oncolytic viruses can be classified largely into two groups: DNA viruses genetically engineered to achieve cancer specificity (e.g. adenovirus, herpes simplex virus and vaccinia) and RNA viruses of which human is not the natural host (e.g. Newcastle disease virus and reovirus). Prostate cancer has always been one of the major targets of oncolytic virus therapy development. The result of six clinical trials for prostate cancer has been published and several trials are now going on. Forty-eight of 83 (58%) patients evaluated in the phase I studies demonstrated a >25% decrease in serum prostate-specific antigen level without evidence of severe toxicities. The result shows the oncolytic virus therapy is promising toward clinical application. Here, we review the recent advances in the field and summarize the results from clinical trials.

OBJECTIVE To assess the relationship between symptom severity and patient perceptions in patients with overactive bladder (OAB), as estimated by OAB Symptom Score (OABSS) and patient-reported outcome measures, respectively. PATIENTS AND METHODS Post-hoc analyses were conducted on the existing data from patients with OAB. In addition to the OABSS, patients completed three patient-reported outcome measures, the OAB questionnaire (OAB-q), Patient Perception of Bladder Condition (PPBC) and Medical Outcomes Study Short-Form 36 (SF-36). Relationships of the OABSS were assessed through correlations with the OAB-q, PPBC and SF-36; all analyses were exploratory. RESULTS In all, 194 participants were analysed; the OABSS correlated relatively closely with the PPBC and OAB-q subscales of health-related quality of life (r = 0.36–0.57). There was a particularly good correlation with the OAB-q symptom bother (r = 0.73). However, the OABSS correlated somewhat less with the SF-36 subscales (r = 0.16–0.27). There were fairly close correlations between the OABSS and the OAB-q items; for daytime frequency with ‘frequency of urination during daytime hours’ (r = 0.44); night-time frequency with ‘night-time urination’ (r = 0.44), ‘waking up at night because you had to urinate’ (r = 0.51) and ‘awakening from sleep’ (r = 0.44); urgency with ‘a sudden urge to urinate with little or no warning’ (r = 0.65) and ‘an uncontrollable urge to urinate’ (r = 0.69), urgency incontinence with ‘accidental loss of small amounts of urine’ (r = 0.74) and ‘urine loss associated with a strong desire to urinate’ (r = 0.79). All the items except ‘awakening from sleep’ belonged to the OAB-q symptom bother domain. CONCLUSIONS It is possible to roughly but sufficiently infer patient perceptions of bladder condition and symptom bother by measuring symptom severity, as estimated by the OABSS.

We are heartily grateful for the warm support of all of the people concerned, including the moderators and panelists of both societies for giving us the opportunity to hold the 4th American Urological Association/Japanese Urological Association (AUA/JUA) Joint Meeting, held once again at the 104th Annual Meeting of the American Urological Association (25-30 April 2009, Chicago, Illinois, USA). 2009 is a memorable year, being the start of new collaborations between AUA and JUA. The JUA in collaboration with AUA is promoting an academic exchange program whereby outstanding and promising Japanese and American junior faculty members will be given the opportunity to work in the USA and Japan for one month. The program not only allows the sharing of knowledge and experience, but is designed to foster a closer alliance between the AUA and JUA, and assists in identifying future leaders within both organizations. The JUA will have an exhibit booth at the AUA annual meeting, promoting our new joint activities. The Journal of Urology and International Journal of Urology will share reviewers. The JUA will participate in developing AUA guidelines. With all of these activities, the JUA hopes it will provide greater opportunities to young Japanese urologists to participate in educational projects in the US. We would like to thank Professor Robert C. Flanigan, the Secretary General of AUA, Professor Glenn M. Preminger, the Chairman of the AUA Office of Education and the staff of AUA and JUA for supporting our program. We hope to keep holding the joint meeting and have plenty of ideas on themes and forums. We believe that this international program helps to establish a closer relationship between JUA and AUA in the scientific field.

BK polyomavirus (BKV) is essentially ubiquitous in all human populations worldwide. Asymptomatic infection with this virus occurs during early childhood, leading to life-long persistence in the kidney. BKV has four subtypes that can be identified using serological and genotyping methods. The evolutionary aspects of BKV have remained poorly understood due to the limited availability of BKV genomes, since urinary excretion of BKV DNA is detected primarily in immunocompromised individuals. However, we have found that BKV DNA sequences can often be amplified from non-immunocompromised elderly individuals, using a highly sensitive polymerase chain reaction (PCR) with highly concentrated urinary DNA as the source of viral DNA. Using this approach, we have PCR-amplified and sequenced a large number of partial and complete BKV genomes from various human populations worldwide and conducted a series of evolutionary studies using these sequences. We have shown that subtypes I and IV evolved into four and six subgroups, respectively, with each having a close relationship with a particular human population. In addition, we have provided evidence supporting the hypothesis that BKV strains with the archetypal transcriptional control region (TCR) circulate in the human population. In this review, we describe these findings and discuss their epidemiological, anthropological and clinical implications. Copyright © 2009 John Wiley & Sons, Ltd.

BKV is widespread among humans, infecting children asymptomatically and then persisting in renal tissue. Based on the serological or phylogenetic method, BKV isolates worldwide are classified into four subtypes (I-IV), with subtypes I and IV further divided into several genetically-distinct subgroups. Since, similarly to JCV, a close relationship exists between BKV lineages and human populations, BKV should be useful as a marker to trace human migrations. To elucidate ancient human migrations in northeast Asia, urine samples were collected from immunocompetent elderly patients in Shanghai, China; Anyang, South Korea; and various locations in Japan. Partial and complete BKV genomes from these samples were amplified and sequenced using PCR, and the determined sequences were classified into subtypes and subgroups by phylogenetic and SNP analyses. In addition, based on an SNP analysis, the major subtype I subgroup (I/c) was classified into two subdivisions, I/c/Ch and I/c/KJ. The distribution patterns of BKV subgroups and subdivisions among the three regions were compared. Some aspects of the subgroup and subdivision distribution were more similar between Korea and Japan, but others were more similar between China and Korea or between China and Japan. Based on these findings, we inferred various northeast Asian migrations. Most of the JCV-based inferences of northeastern Asian migrations were consistent with those based on BKV, but the previously suggested migration route from the Asian continent to the Japanese archipelago seemed to need revision.

The objective of this study was to assess disease-associated pain and quality of life (QOL) in patients with prostate cancer (PC). A total of 102 PC patients (clinical stage B, C: 20, D2: 82) patients were enrolled. QOL was assessed using the Functional Assessment of Cancer Therapy, General and Prostate (FACT-G/P). Disease-specific pain response was assessed using the visual analog scale and the face rating scale. In patients with stage D2 PC, mean age, serum prostate-specific antigen level, and performance status were 72.5 ± 7.1 years (range, 55–88), 217 ± 467 ng/mL (range, 0.1–2600), and 1.4 (0–4), respectively. The score of physical well-being and FACT-P was significantly lower in stage D2 patients, compared with those of stage B/C (P = 0.02, 0.0088, respectively). Performance status, extent of disease, and the visual analog scale were related with a poor QOL score (P = 0.0054, 0.01

Objectives: To compare the efficacy and tolerability of imidafenacin, a novel antimuscarinic agent, with propiverine and a placebo in Japanese patients with overactive bladder (OAB). Methods: Men and women having OAB symptoms were randomized to double-blind treatment with 0.1 mg of imidafenacin twice daily, 20 mg of propiverine once daily, or a placebo for 12 weeks, and assessed for efficacy and safety. Results: Overall, 781 patients were randomized to imidafenacin (324), propiverine (310), or a placebo (147). After 12 weeks of treatment, a significantly larger reduction in the mean number of incontinence episodes was observed in the imidafenacin group than in the placebo group (P

Objectives: To explore whether Lys262Arg polymorphism of the Cytochrome P450 2B6 (CYP2B6) gene could act as a genetic marker for prostate cancer risk among Japanese men. Methods: A total of 350 patients with sporadic prostate cancer and 328 controls were examined. A single nucleotide polymorphism with non-synonymous amino acid change located at Lys262Arg of the CYP2B6 gene was genotyped using a TaqMan assay. Results: The frequency of the Arg/Arg genotype among prostate cancer patients was significantly higher than that among the controls (P = 0.027). The frequency of the G allele of the Lys262Arg polymorphism was also significantly higher in prostate cancer patients than in the controls (30.4% vs 24.8%, P = 0.025). Patients with the Lys/Arg plus Arg/Arg genotypes carried a low Gleason score more frequently than those with the Lys/Lys genotype (P = 0.042). The frequency of the G allele of the Lys262Arg polymorphism was significantly higher in the low Gleason score group than that in the high Gleason score group (34.3% vs 26.8%, P = 0.038). Conclusions: Lys262Arg polymorphism of the CYP2B6 gene may be a genetic marker for evaluating the risk of sporadic prostate cancer in native Japanese men.

Department of Urology, Fukushima Medical University, Fukushima, Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, Department of Urology, University of Yamanashi Interdisciplinary Graduate School of Medicine and Engineering, Chuo, Yamanashi, Department of Urology, University of Fukui Faculty of Medicine, Fukui, Department of Urology, University of Tokyo Faculty of Medicine, Tokyo, Department of Urology, Asahikawa Medical College, Asahikawa, Hokkaido, Department of Urology, Niigata University School of Medicine, Niigata, Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Department of Urology, Graduate School of Medical Science, Kyushu University, Fukuoka, Department of Urology, Graduate School of medical Science, Kumamoto University, Kumamoto, Japan

Objective: To evaluate the psychometric properties of the Japanese version of the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF). Methods: Two study samples of 180 patients with urinary incontinence were used for this psychometric evaluation. Analyses were carried out to examine the instrument's reliability and validity, as well as its responsiveness to change. Results: For the ICIQ-SF items and total scores, there was no particular floor or ceiling effect. The internal consistency was sufficiently high, with a Cronbach's alpha coefficient of 0.78. In the analysis of test-retest reliability, high correlations were observed, with Kappa coefficients of 0.61 for item 1 and 0.62 for item 2, and with intra-class correlation coefficients of 0.90 for item 3 and 0.91 for the total score. For the concurrent validity, the ICIQ-SF scores were moderately to highly correlated with most of the King's Health Questionnaire (KHQ) subscales. When the severity groups, divided in quartiles, were compared with respect to the 1-h pad test and the number of daily incontinence episodes, there seemed to be linear trends in most of the ICIQ-SF scores. For responsiveness, changes in the ICIQ-SF after treatment demonstrated statistically significant correlations of more than 0.5 with changes in some of the KHQ subscale scores. All of the ICIQ-SF items and total scores significantly decreased after treatment. Conclusions: The Japanese version of the ICIQ-SF is a reliable, valid and responsive measure that performs well among patients with urinary incontinence.

Objectives: We previously demonstrated that estrogen receptor-binding fragment-associated gene 9 (EBAG9) is a tumor promoting factor in renal cell carcinoma (Ogushi T, Cancer Res. 2005; 65: 3700). Here, we evaluated EBAG9 expression and its clinical significance in normal and malignant human testicular tissues. Methods: We investigated the expression of EBAG9 in 90 testicular specimens (28 benign testicular tissue and 62 testicular germ cell tumor samples) by immunohistochemistry using rabbit polyclonal anti-EBAG9 antibody. Results: Positive immunostaining of EBAG9 in the cytoplasm was found in 32 (52%) cancerous lesions, whereas the immunoreactivity of EBAG9 was weak in benign testicular tissues. Serum lactate dehydrogenaze (LDH) level was significantly higher in EBAG9-positive cases (715.0 ± 727.3) compared with the negative cases (221.4 ± 126.8) (P = 0.0016). The EBAG9-positive cases among the patients with advanced clinical stage (Stage II and III) more frequently belonged to the intermediate or poor risk group in the International Germ Cell Consensus Prognostic Classification System (IGCCPCS), compared with the EBAG9-negative cases (P = 0.0012). Conclusions: These findings suggest that increased expression of EBAG9 may play a significant role in cancer progression and aggressiveness in testicular germ cell tumors.

Interstitial cystitis (IC) is a disease of the urinary bladder with lower urinary tract symptoms such as urinary frequency, bladder hypersensitivity and/or bladder pain and resultant serious impairment of quality of life. In Japan, assuming that IC is very rare, research activity and medical care of IC have been sparse until 2001, when the Society of Interstitial Cystitis of Japan (SICJ) and a patient support group were founded.(1,2) Subsequently the International Consultation on Interstitial Cystitis Japan (ICICJ) was held in Kyoto in 2003.(3) On the other hand, the etiology of IC has not been well clarified, which complicates its diagnosis and treatment at clinical settings. We have thus developed the Japanese Clinical Guideline,(4) which is targeted at healthcare professionals including specialists in urology and women's health care who may engage in the diagnosis and treatment of IC. This article is the English translation of a shortened version of the Guideline for convenience of readers worldwide.

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.

Objectives To identify the symptoms of higher relevance in patients complaining of lower urinary tract symptoms (LUTS). Methods A questionnaire covering 25 LUTS as defined by the International Continence Society (ICS) terminology committee was administered to 1000 adults complaining of LUTS and 360 not complaining (controls). Symptoms were defined as 'highly relevant (core LUTS)' when indicated by at least 25% of symptomatic patients with nine common diseases/conditions as one of the three symptoms that had a significant impact on their daily life. Results Ten symptoms (daytime frequency, nocturia, urgency, urgency incontinence, stress incontinence, slow urinary stream, straining, feeling of incomplete emptying, bladder pain, and urethral pain) were selected as being of high relevance. Core LUTS all showed significantly higher scores in the symptomatic patients than in the controls and they were not correlated with other more prevalent symptoms. The Core LUTS score (CLSS) questionnaire derived from these 10 symptoms was confirmed as showing test-retest reliability. Conclusions Of 25 LUTS defined by the ICS committee, 10 symptoms were selected as core LUTS. The CLSS, a questionnaire for core LUTS, provides an overall assessment of relevant symptoms without significant omissions. It might be useful for new patients, those with multiple diseases, and those without a definite diagnosis, as well as before and after interventions that may cause other symptoms.

Objectives: To evaluate the efficacy, safety/tolerability, and dose–response relationship of imidafenacin in Japanese patients with overactive bladder. Methods: Men and women who had overactive bladder symptoms were randomized equally to double-blind treatment with 0.05, 0.1, or 0.25 mg of imidafenacin twice daily or a placebo for 12 weeks, and assessed for efficacy and safety. Results: Overall, 401 patients were enrolled and randomized for treatment with 0.1 mg of imidafenacin/day (99 patients), 0.2 mg of imidafenacin/day (100), 0.5 mg of imidafenacin/day (101), or a placebo (101). After 12 weeks of treatment, the number of incontinence episodes was reduced in a dose-dependent manner, and a significant difference between the imidafenacin treatment and the placebo was observed (P

Overactive bladder (OAB), according to the International Continence Society (ICS) definition, is a symptom syndrome, with urgency as the cornerstone symptom. However, the word 'urgency' and its definition continue to be the subject of much debate and confusion. It is generally difficult for patients to differentiate urgency from normal urge, particularly when the desire to void is strong. To investigate the micturition behavior associated with OAB, we conducted a Patient Trust Study in 21 intelligent (i.e., to be 'trusted') female patients who could clearly and accurately discriminate between urgency and urge. The results showed that in 43% of patients seeking medical care, urgency episodes occurred less than once/day, and some patients had days without urgency. Our patients deferred voiding until bladder sensation was relatively strong, suggesting that coping was not common among these patients. Four of the 21 patients studied experienced spontaneous resolution of several urgency episodes. At volumes exceeding 40% of the maximum bladder volume (MBV), urgency episodes occurred frequently and independently of the bladder volume, indicating that 40% of the MBV may be a threshold of bladder volume to induce urgency. A linear relationship was observed between bladder volume and increasing bladder sensation. However, compared with normal subjects, urge sensation increased markedly at any given bladder volume among patients with OAB in our study. This hypersensitivity was observed in our patients regardless of urgency episodes. We therefore hypothesized that OAB may be more accurately defined as a hypersensitivity disorder rather than a syndrome characterized by urgency.

Introduction: Lower extremity neuropathy (LEN) is a well-recognized complication that arises during robotic surgeries in lithotomy-Trendelenburg position (L-T position). It is caused by persistent compression to the nerves. Our aim was to investigate the levels of compression to the nerves by measuring the contact pressure of the lower extremities in men undergoing robot-assisted radical prostatectomy (RARP). Materials and Methods: A total of 138 patients undergoing RARP were enrolled prospectively. The contact pressure of the lower extremities was measured using a portable contact pressure measurement device (Cello®, Cape Co., Kanagawa, Japan) in lithotomy position (L position) and L-T position preoperatively, and in L position postoperatively. Patient positioning was readjusted when the preoperative contact pressure was over 32 mm Hg. The contact pressure was compared between pre- and postoperative values. Results: A total of 33 patients (23.9%) needed readjustment of positioning due to high contact pressure. No one developed LEN. The contact pressure in the L position significantly increased postoperatively (right: 21.4 mm Hg, p < 0.0001; left: 18.6 mm Hg, p = 0.0011). A high body mass index (BMI) was associated with a postoperative increment of pressure in the L position. Conclusions: The contact pressure of the lower extremities increased after RARP and the increase was correlated with BMI.

Many prognostic biomarkers associated with androgen signaling have been proposed in PC. The role of tripartite motif (TRIM) proteins remains unclear in PC. We investigated TRIM protein 47 (TRIM47) expression levels in human prostate tissues.We performed immunohistochemistry using original TRIM47 antibody in prostate tissues obtained by radical prostatectomy (n = 105). Stained slides were evaluated for the proportion and staining intensity of immunoreactive cells. Total immunoreactivity (IR) scores (range, 0-8) were calculated as the sum of the proportion and intensity scores. TRIM47 expression levels were confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Associations between the clinicopathologic features of the patients and their TRIM47 status were analyzed.Western blot analysis validated the specificity of the anti-TRIM47 antibody in 293T cells. TRIM47 expression levels were found to be significantly increased in PC compared to benign tissues by both immunohistochemistry (P .0001) and qRT-PCR (P = .003). Additionally, advanced pathologic stage (≥ T3b) was found to be associated with high TRIM47 IR scores (≥ 4; P = .04). Furthermore, high TRIM47 IR scores were also significantly correlated with worse cancer-specific survival rates in multivariate regression analyses (hazard ratio, 6.82; P = .016).The results of the present study indicated differential TRIM47 expression levels in human prostate tissues compared to benign tissues. Because high levels of TRIM47 expression were found to be a strong prognostic factor in PC, TRIM47 may represent a novel therapeutic target.

Background Although radical prostatectomy (RP) and external beam radiotherapy (EBRT) have been considered as comparable treatments for localized prostate cancer (PC), it is controversial which treatment is better. The present study aimed to compare outcomes, including mortality, of RP and EBRT for localized PC. Methods We retrospectively analyzed 891 patients with cT1-4N0M0 PC who underwent either RP (n = 569) or EBRT (n = 322) with curative intent at our single institution between 2005 and 2012. Of the EBRT patients, 302 (93.8%) underwent intensity-modulated radiotherapy. Primary endpoints were overall survival (OS) and cancer-specific survival (CSS). Related to these, other-cause mortality (OCM) was also calculated. Biochemical recurrence-free survival was assessed as a secondary endpoint. Cox proportional hazards model was used for multivariate analysis. Results Median follow-up durations were 53 and 45 months, and median ages were 66 and 70 years (P

Tumors commonly harbor multiple genetic alterations, some of which initiate tumorigenesis. Among these, some tumor-specific somatic mutations resulting in mutated protein have the potential to induce antitumor immune responses. To examine the relevance of the latter to immune responses in the tumor and to patient outcomes, we used datasets of whole-exome and RNA sequencing from 97 clear cell renal cell carcinoma (ccRCC) patients to identify neoepitopes predicted to be presented by each patient's autologous HLA molecules. We found that the number of nonsilent or missense mutations did not correlate with patient prognosis. However, combining the number of HLA-restricted neoepitopes with the cell surface expression of HLA or β2-microglobulin(β2M) revealed that an A-neohi/HLA-Ahi or ABC-neohi/β2Mhi phenotype correlated with better clinical outcomes. Higher expression of immune-related genes from CD8 T cells and their effector molecules [CD8A, perforin (PRF1) and granzyme A (GZMA)], however, did not correlate with prognosis. This may have been due to the observed correlation of these genes with the expression of other genes that were associated with immunosuppression in the tumor microenvironment (CTLA-4, PD-1, LAG-3, PD-L1, PD-L2, IDO1, and IL10). This suggested that abundant neoepitopes associated with greater antitumor effector immune responses were counterbalanced by a strongly immunosuppressive microenvironment. Therefore, immunosuppressive molecules should be considered high-priority targets for modulating immune responses in patients with ccRCC. Blockade of these molecular pathways could be combined with immunotherapies targeting neoantigens to achieve synergistic antitumor activity. Cancer Immunol Res; 4(5); 463–71. ©2016 AACR.

The melanoma-associated antigen A (MAGE-A) family comprises cancer-testis antigens that represent promising prognostic biomarkers and immunotherapy targets in several cancer types. The aim of this study was to investigate the significance of MAGE-A expression in upper urinary tract urothelial carcinoma in relation to clinicopathological features, lymphocytic infiltration, and clinical outcome. We immunohistochemically examined the expression of MAGE-A in 171 patients with upper urinary tract urothelial carcinoma. High (≥ 50% positive) and low MAGE-A expression levels were observed in 33 (19%) and 49 (29%) cases, respectively. MAGE-A was negative in 89 cases (52%). MAGE-A expression was positively correlated with high histologic grade; concomitant carcinoma in situ; higher Ki-67 proliferation index; and infiltration of CD3-, CD8-, and CD45RO-positive T lymphocytes, but not with CD20-positive B lymphocytes. High MAGE-A expression was significantly associated with shorter metastasis-free survival after nephroureterectomy (log-rank P = .019; multivariate hazard ratio, 1.98; 95% confidence interval, 1.00-3.92). MAGE-A expression in metastatic lymph nodes was highly correlated with its expression in primary lesions. MAGE-A expression was retained in chemotherapy-resistant metachronous metastatic lesions of urothelial carcinoma. MAGE-A may be a promising prognostic biomarker and potential immunotherapeutic target for patients with upper urinary tract urothelial carcinoma.

The authors have investigated a construction methodology for a non-invasive ultrasound theragnostic system, called NIUTS, to track and follow moving body targets, such as tumors / stones located in moving organs (kidneys, livers, etc.), robustly and precisely, so as to compensate for nearly 90 percent of target motions in ultrasound images, while irradiating therapeutic ultrasound to focal lesions. In the present report, we propose a novel servo recovery algorithm for NIUTS. We confirm the effectiveness of the implemented servo recovery algorithm for a real human kidney, which, as far as we know, is the first successful report of semi-autonomous servo recovery systems for lost body targets. This robust servo recovery method could provide an indispensable tool for precise, safe, and efficient treatments of tumors and stones.

Kv7 voltage-gated potassium channels have been suggested to modulate mechano-afferent transduction and nociception in the bladder. We investigated the effects of retigabine, a Kv7 channel activator, on rhythmic bladder contractions (RBCs), and single-unit afferent activities (SAAs) of the primary bladder mechanosensitive afferent nerve fibers in urethane-anesthetized rats. In addition, the effects of pretreatment with retigabine on the nociceptive behaviors provoked by an intravesical instillation of resiniferatoxin (RTX) were evaluated in the conscious condition.Female Sprague-Dawley rats were used. Under urethane anesthesia, saline was instilled into the bladder until RBCs were induced reproducibly. Then, the effects of intravenous, cumulative administrations of retigabine (0.1-3 mg/kg) or vehicle (saline) on RBCs were assessed. In separate animals, SAAs of Aδ- and C-fibers were identified by electrical stimulation of the pelvic nerve and by bladder distention with saline. After baseline recording, vehicle or retigabine (0.01-1 mg/kg) was administered intravenously and further recordings were performed. Under pretreatment with vehicle or retigabine (3 mg/kg intraperitoneally), the frequencies of lower abdominal licking and freezing were counted and scored as the bladder nociceptive behaviors induced by intravesical RTX instillation (3 µM, 0.3 ml).Retigabine dose-dependently decreased both the frequency and the amplitude of RBCs and SAAs of both Aδ- and C-fibers. The effect on RBCs was more potent on the frequency than the amplitude. Retigabine inhibited the RTX-induced abdominal licking, but not freezing.Kv7 channels are likely to be implicated in inhibition of bladder mechano- and nociceptive sensory transduction. Neurourol. Urodynam. 36:280-285, 2017. © 2015 Wiley Periodicals, Inc.

金沢大学医薬保健研究域医学系, Interstitial cystitis (IC) is a chronic bladder disease with urinary frequency, bladder discomfort or bladder pain of unknown etiology. Based on cystoscopic findings, patients with IC are classified as either Hunner-type/classic IC (HIC), presenting with a specific Hunner lesion, or non-Hunner-type IC (NHIC), presenting with no Hunner lesion, but post-hydrodistension mucosal bleeding. Inflammatory cell infiltration, composed predominantly of lymphocytes, plasma cells and epithelial denudation, has in the past been documented as a major pathological IC finding. However, the significance of the pathological evaluation of IC, especially with regard to the difference between HIC and NHIC, has been downplayed in recent years. In this study, we performed immunohistochemical quantification of infiltrating T-lymphocytes, B-lymphocytes and plasma cells, and measured the amount of residual epithelium in urinary bladder biopsy specimens taken from patients with HIC and NHIC, and those with no IC, using image analysis software. In addition, in situ hybridization of the light chains was performed to examine clonal B-cell expansion. Lymphoplasmacytic infiltration was significantly more severe in HIC specimens than in NHIC specimens (P

Objective To evaluate the role of the transient receptor potential melastatin 8 (TRPM8) channel on bladder mechanosensory function by using L-menthol, a TRPM8 agonist, and RQ-00203078 (RQ), a selective TRPM8 antagonist. Materials and methods Female Sprague–Dawley rats were used. In conscious cystometry (CMG), the effects of intravesical instillation of L-menthol (3 mm) were recorded after intravenous (i.v.) pretreatment with RQ (3 mg/kg) or vehicle. The direct effects of RQ on conscious CMG and deep body temperature were evaluated with cumulative i.v. administrations of RQ at 0.3, 1, and 3 mg/kg. Single-unit mechanosensitive bladder afferent activities (SAAs) were monitored in a newly established ex vivo rat bladder model to avoid systemic influences of the drugs. Recordings were performed after cumulative intra-aortic administration of RQ (0.3 and 3 mg/kg) with or without intra-vesical L-menthol instillation (3 mm). Results Intravesical L-menthol decreased bladder capacity and voided volume, which was counteracted by RQ-pretreatment. RQ itself increased bladder capacity and voided volume, and lowered deep body temperature in a dose-dependent manner. RQ decreased mechanosensitive SAAs of C-fibres, and inhibited the activation of SAAs induced by intravesical L-menthol. Conclusion Our results suggest that TRPM8 channels have a role in activation of bladder afferent pathways during filling of the bladder in the normal rat. This effect seems, at least partly, to be mediated via mechanosensitive C-fibres.

Retroperitoneal tumors present diagnostic challenges, although a definitive diagnosis can be established based on a histopathological analysis. We herein report the case of a 62-year-old woman with a massive retroperitoneal tumor who was referred to our department for surgery. Although we initially planned to perform an incisional biopsy, we unexpectedly detected gingival swelling, and a gingival biopsy subsequently confirmed a pathological diagnosis of Burkitt's lymphoma (BL). We successfully avoided the use of more invasive diagnostic procedures and were able to promptly initiate chemotherapy. Obtaining an immediate pathological diagnosis is essential for providing successful treatment in such cases, as the disease is potentially curable with chemotherapy. BL should therefore be considered in the differential diagnosis of massive retroperitoneal tumors, highlighting the importance of routine systemic screening.

Objectives To establish a mentoring program that allows novice surgeons to use robotics while maintaining surgical quality during robot-assisted radical prostatectomy. Methods A total of 242 cases of robot-assisted radical prostatectomy for patients with localized prostate cancer were considered for this study. Each novice surgeon carried out a step-by-step robot-assisted radical prostatectomy procedure by following technical checkpoints and time limits that were established on the basis of previous surgical performance by a mentor. If technical checkpoints could not be accomplished, or the times were being exceeded, a mentor replaced the novice surgeon to finish the operative step or the surgery. Furthermore, if total blood loss exceeded 500 mL, a mentor completed the surgery. The primary end-point was the number of cases required for a new surgeon to successfully complete the entire robot-assisted radical prostatectomy procedure. Clinicopathological outcomes and any cases that deviated more than the standard deviation were also analyzed. Results Median patient age, serum prostate-specific antigen level (ng/mL), and Gleason score at diagnosis were 68 years, 7.6 and 7, respectively. Mean console and total operative times were 184 and 237 min, respectively. Mean perioperative blood loss was 300 mL. Seven out of eight new surgeons finished the total procedure after 10.7 cases (range 8–12). Four cases (1.7%) exceeded perioperative total blood loss and operative time. Positive surgical margin rates for total, T2, and T3 were 22, 9.3 and 47%, respectively. Positive surgical margin localized at bladder neck 19%, lateral lobe 39%, apex 32% and peripheral fat 9.4%. Conclusions Herein we demonstrate an institutional mentoring program that effectively balances surgeon robot-assisted radical prostatectomy training and surgical quality control.

Objective To elucidate whether the lower ureteral lesion can predict subsequent intravesical recurrence (IVR) in patients with upper tract urothelial carcinoma (UTUC) who underwent radical nephroureterectomy (RNU). Patients and methods We retrospectively reviewed 186 consecutive patients with UTUC who underwent RNU at our institution between 1996 and 2013. Associations of various clinicopathological factors with subsequent IVR were assessed. Lower ureteral lesion was defined as the pathologically confirmed lowest carcinoma component within 5 cm from the lower end of the ureter. The log-rank test and Cox proportional hazards model were used for univariable and multivariable analysis, respectively. Results Overall, 86 patients (46%) developed IVR during the follow-up, with a median follow-up period of 43 months (interquartile range: 17–79 mo). In all, 53 patients (28%) had lower ureteral lesions, and 34 (64%) of them developed IVR. Univariable analysis demonstrated that lower ureteral lesion was significantly associated with IVR, as well as tumor multifocality, lymphatic invasion, and history of bladder cancer. Multivariable analysis identified the lower ureteral lesion as a sole independent predictor of IVR ( P = 0.0304, hazard ratio = 1.74). Conclusions Lower ureteral lesion was an independent predictor of IVR in patients with UTUC treated with RNU. Such patients may deserve prophylactic treatment and intensive follow-up.

Hydrodistension of the bladder, with optional fulguration of Hunner lesions, is one of the recommended therapies for interstitial cystitis (IC). The aims of this study are to evaluate long-term outcomes of hydrodistension and identify outcome predictors.The study cohort was 191 newly diagnosed IC patients (155 women and 36 men) who underwent hydrodistension with fulguration of Hunner lesions if detected between 2007 and 2013 at our institution. The primary outcome was therapeutic failure, which was defined as repeat hydrodistension, bladder instillation therapy, or narcotic use for pain control. Clinical features, including comorbidities and endoscopic findings, were analyzed along with the outcome.The cohort comprised 126 patients of Hunner type IC and 65 patients of non-Hunner type IC. The mean time to therapeutic failure was 28.5 months in Hunner type IC and 25.2 months in non-Hunner type IC. The therapeutic failure rate was higher in non-Hunner type IC at 17.3 months; however, the long-term outcomes reversed thereafter. The mean time to therapeutic failure was shorter in patients with lumbar spinal stenosis (LSS) or irritable bowel syndrome (IBS). Multivariate analysis identified LSS as a predictor for failure in Hunner type IC and non-Hunner type IC (HR = 18.8, P = 0.001; HR = 3.8, P = 0.028, respectively) and IBS in non-Hunner type IC (HR = 18.0, P = 0.008).Bladder hydrodistension, with fulguration of the Hunner lesions, improved IC symptoms. The outcome was worse in non-Hunner type IC shortly after hydrodistension but eventually comparable across the two types. Concomitant LSS and IBS were predictors for poor outcome. Neurourol. Urodynam. 35:965-969, 2016. © 2015 Wiley Periodicals, Inc.

Idiopathic thrombocytopenic purpura associated with renal cell carcinoma is relatively rare. We report the case of a 48-year-old woman with massive renal cell carcinoma, measuring approximately 20 × 14 × 14 cm, who presented with severe thrombocytopenia: platelet count, 2000 cells/μL. After confirming normal bone marrow, she received high-dose dexamethasone and intravenous gamma globulin, which raised the platelet count to normal levels. She then underwent left radical nephrectomy. The pathological examination showed chromophobe renal cell carcinoma. After the resection, the platelet count was maintained within the normal range without any treatment. The current case is the first report of chromophobe renal cell carcinoma causative of severe idiopathic thrombocytopenic purpura.

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.

Squamous differentiation is the most common histological variation in urothelial carcinoma (UC). However, the clinical significance of squamous differentiation in upper urinary tract UC is unclear. To investigate the significance of squamous differentiation, hematoxylin and eosin stained slides from 140 patients with upper urinary tract UC who underwent nephroureterectomy were reviewed by a single pathologist and the presence of squamous differentiation was recorded. Squamous differentiation was observed in 23 out of 140 studied cases (16%). Squamous differentiation significantly correlated with several adverse prognostic factors including histological grade 3 tumors, presence of lymphovascular invasion, concomitant carcinoma in situ, advanced tumor stage, and occurrence of lymph node metastasis. The Kaplan-Meier and univariate Cox regression analyses revealed that the presence of squamous differentiation was significantly associated with shorter metastasis-free survival [log-rank P = 0.030; univariate hazard ratio (HR), 2.30; 95% confidence interval (CI), 1.06-4.99], cancer-specific survival (log-rank P = 0.0024; univariate HR 3.34; 95% CI, 1.47-7.85), and overall survival (log-rank P = 0.018; univariate HR 2.39; 95% CI, 1.13-5.06) after nephroureterectomy. However, in multivariate analyses, squamous differentiation was not significantly associated with patient outcomes. These findings suggest that squamous differentiation is associated with disease progression, but is not an independent predictor of a worse prognosis in patients with upper urinary tract UC.

To investigate single or combined effect of silodosin, an α1A-adrenoceptor antagonist, and imidafenacin, an antimuscarinic agent, on bladder function in a subacute bladder outlet obstruction (BOO) model of male rats.Partial BOO was created in male Wistar rats by ligating the urethra with a steel rod. On day 10 after surgery, when frequent voiding was most remarkable on voiding behavior measurement in a metabolic cage, cystometric investigations in a conscious restrained condition were conducted with cumulative intravenous administration of silodosin alone (0.1, 1, 10, and 100 µg/kg), imidafenacin alone (1, 3, and 10 µg/kg), or a combination of the two drugs.When compared with the Sham rats, the BOO rats showed an increase in bladder capacity, residual volume, mean amplitude and the number of non-voiding contractions (NVCs), accompanied with an increase in bladder weight. In the BOO rats, silodosin alone at 100 µg/kg significantly decreased the number of NVCs, whereas imidafenacin alone at 3 and 10 µg/kg significantly decreased both the number and mean amplitude of NVCs. The combination administration with lower doses (silodosin at 10 µg/kg and imidafenacin at 1 µg/kg) significantly suppressed both the number and mean amplitude of NVCs.The present results indicate a suppressive effect of silodosin or imidafenacin alone and a synergic effect of the combination of these two drugs on NVCs in a subacute BOO model of male rats.

INTRODUCTION AND OBJECTIVES: Radiation cystitis (RC), a rare but serious complication with no effective pharmacotherapy, can occur as a result of radiation therapy for pelvic malignancies. Small Animal Radiation Research Platform (SARRP) was used for targeted irradiation of rat bladder. Use of the platform mimics clinical settings and permits quantitation of the radiation dosages that lead to RC. Changes in rat micturition patterns were used as an outcome measure for radiation dose selection in subsequent studies involving the evaluation of therapeutic potential of tacrolimus encapsulated liposomes (LP-10). METHODS: In phase I, 16 adult female Sprague-Dawley rats were split into 4 groups and their micturition patterns were analyzed before and after irradition with 20, 30, and 40 Gy’s using the 3-beam SARRP. Histological analysis was performed for the clinical symptoms of RC. In phase II, irradiated rats were randomly assigned to receive a single instillation of either saline or LP-10. Voiding studies were performed for 2 weeks after treatment. RESULTS: The dose of 40 Gy induced statistically significant reductions in inter-micturition intervals (IMI) compared to those recorded at lower radiation doses. Histological analysis of the bladder irradiated at 40 Gy indicated degenerative type epithelial changes, urothelial swelling, and ulceration with evidence of pseudocarcinomatous epithelial hyperplasia (red arrow). 40 Gy was therefore chosen for phase II efficacy studies. There was no measurable change in total voided urine volume after irradiation or after instillation of LP-10 or saline. LP-10 treatment significantly increased the post-irradiation IMI values by approximately 30 minutes (p < 0.000001) back to baseline levels. The saline treatment group did not show a statistically significant change in the IMI. CONCLUSIONS: 3-beam SAARP is an effective method to induce RC while mimicking clinical radiation therapy for pelvic cancer. The RC rat model demonstrated a dose-dependent decrease in intermicturition intervals without inducing acute skin or gastrointestinal damage. This study demonstrated that liposomal formulation of tacrolimus (LP-10) may be a promising new intravesical therapy for radiation cystitis.

INTRODUCTION AND OBJECTIVES: Urinary bladder cancer is the fourth most commonly diagnosed malignancy in males in the United States, accounting for 6.7% of all cancer cases. In muscle invasive tumor, radical cystectomy is the recommended treatment. It is clinically relevant to identify muscle invasive patients who were more likely to benefit from radical cystectomy. Recent studies showed that neutorophil-to-lymphocyte ratio (NLR) is a useful predicting prognosis score in several cancers. In bladder cancer, no reliable bio-marker to predict prognosis before surgery. This study was aimed to assess the usefulness of NLR in bladder cancer. METHODS: A total of 37 patients underwent laparoscopic radical cystectomy in Yokohama City University Hospital (Yokohama, JAPAN) from 2008 to 2014. In baseline patients characteristics, laboratory data were collected before radical cystectomy and pathological features were collected from the radical cystectomy specimens. NLR was calculated using neutrophils and lymphocytes counts obtained 2 or 3 days before surgery. Cut-off points were determined using ROC. Overall survival (OS) and progression free survival (PFS) were estimated using Kaplan-Meier methods and differences were compared using log-rank tests. RESULTS: The median and mean age were 67 (64.9 i A 10.1) and the follow-up dates were 726 (88.3 i A 727.4). 5 of 37 (13.5%) patients were dead from bladder cancer and 9 of 37 (24.3%) patients were progressed in bladder cancer. ROC showed the NLR value of 2.38 showed the largest area under the curve. The high NLR group (NLR iÝ 2.38) showed a significantly poor prognosis both in OS and PFS comparing to the low NLR group (NLR < 2.38) (p 1⁄4 0.018 and 0.014, respectively). CONCLUSIONS: NLR might be a new bio-marker to predict prognosis for the patients who receive radical cystectomy. Source of Funding: none