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Objective To study the role of transient receptor potential melastatin 2 in bladder function and inflammation-associated hypersensitivity. Methods We evaluated physiological function of the bladder and intravesical lipopolysaccharide-induced inflammatory nociceptive responses in female wild-type and transient receptor potential melastatin 2-knockout mice. In vivo frequency/volume and decerebrated unanesthetized cystometry measurements, as well as in vitro detrusor strip functional studies, were carried out to evaluate bladder function. Mice received intravesical lipopolysaccharide (2.0 mg/mL) or saline instillation to evaluate responses to bladder inflammation. Voiding and bladder pain-like behaviors, cystometry measurements and histological evaluation were carried out before and after intravesical lipopolysaccharide instillation. Results Few phenotypic differences in in vivo and in vitro physiological function were found between the two genotypes. Comparison of measurements taken before and 24-48 h after intravesical lipopolysaccharide instillation showed that voiding parameters did not change in transient receptor potential melastatin 2-knockout mice, whereas an increased voiding frequency was observed in wild-type mice. At 24 h after intravesical lipopolysaccharide instillation, the numbers of bladder pain-like behaviors and of infiltrated inflammatory cells in the bladder submucosal layer were significantly increased, and the voided volume and the intercontraction interval were significantly decreased on cystometry measurements in wild-type mice compared with those in both transient receptor potential melastatin 2-knockout mice and in wild-type mice treated with saline instillation. Conclusions Although the physiological roles of transient receptor potential melastatin 2 channels in the bladder might be limited, inflammation and associated hypersensitivity of the bladder caused by intravesical lipopolysaccharide instillation are attenuated in transient receptor potential melastatin 2-knockout mice, suggesting pathophysiological roles of transient receptor potential melastatin 2 channels in these processes.

Interstitial cystitis/bladder pain syndrome is a debilitating condition of unknown etiology characterized by persistent pelvic pain with lower urinary tract symptoms and comprises a wide variety of potentially clinically useful phenotypes with different possible etiologies. Current clinicopathological and genomic evidence suggests that interstitial cystitis/bladder pain syndrome should be categorized by the presence or absence of Hunner lesions, rather than by clinical phenotyping based on symptomatology. The Hunner lesion subtype is a distinct inflammatory disease with proven bladder etiology characterized by epithelial denudation and enhanced immune responses frequently accompanied by clonal expansion of infiltrating B cells, with potential engagement of infection. Meanwhile, the non-Hunner lesion subtype is a non-inflammatory disorder with little evidence of bladder etiology. It is potentially associated with urothelial malfunction and neurophysiological dysfunction, and frequently presents with somatic and/or psychological symptoms, that commonly result in central nervous sensitization. Animal models of autoimmune cystitis and neurogenic sensitization might serve as disease models for the Hunner lesion and non-Hunner lesion subtypes, respectively. Here, we revisit the taxonomy of interstitial cystitis/bladder pain syndrome according to current research, and discuss its potential pathophysiology and representative animal models. Categorization of interstitial cystitis/bladder pain syndrome based on cystoscopy is mandatory to design optimized treatment and research strategies for each subtype. A tailored approach that specifically targets the characteristic inflammation and epithelial denudation for the Hunner lesion subtype, or the urothelial malfunction, sensitized/altered nervous system and psychosocial problems for the non-Hunner lesion subtype, is essential for better clinical management and research progress in this complex condition.

Introduction In the development of terminology of the lower urinary tract, due to its increasing complexity, the terminology for male lower urinary tract and pelvic floor symptoms and dysfunction needs to be updated using a male-specific approach and via a clinically-based consensus report. Methods This report combines the input of members of the Standardisation Committee of the International Continence Society (ICS) in a Working Group with recognized experts in the field, assisted by many external referees. Appropriate core clinical categories and a subclassification were developed to give a numeric coding to each definition. An extensive process of 22 rounds of internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). Results A Terminology Report for male lower urinary tract and pelvic floor symptoms and dysfunction, encompassing around 390 separate definitions/descriptors, has been developed. It is clinically-based with the most common diagnoses defined. Clarity and user-friendliness have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in male lower urinary tract and pelvic floor dysfunction. Male-specific imaging (ultrasound, radiology, CT, and MRI) has been a major addition whilst appropriate figures have been included to supplement and help clarify the text. Conclusions A consensus-based Terminology Report for male lower urinary tract and pelvic floor symptoms and dysfunction has been produced aimed at being a significant aid to clinical practice and a stimulus for research.

Objectives To evaluate the long-term safety (primary objective) and efficacy (secondary objective) of antimuscarinic add-on therapy in patients receiving mirabegron. Methods During a 2-week screening period, patients (aged ≥20 years, mirabegron treatment for ≥6 weeks, residual overactive bladder symptoms) received mirabegron 50 mg once daily. These patients were subsequently randomized to 52 weeks' treatment with mirabegron 50 mg/day plus an antimuscarinic (solifenacin 5 mg, propiverine 20 mg, imidafenacin 0.2 mg, or tolterodine 4 mg) with the potential to double the antimuscarinic dose (except for tolterodine) at week 8. Safety assessments included treatment-emergent adverse events, vital signs, 12-lead electrocardiograms, post-void residual volume, and laboratory evaluations. Efficacy was assessed using changes from baseline in overactive bladder symptom score total score; overactive bladder questionnaire short form score; micturitions, urgency episodes, urinary incontinence episodes, and urgency urinary incontinence episodes/24 h; mean volume voided per micturition; and number of night-time micturitions. Results Overall, 80.2% of patients (88.1% women, mean age 65 years) experienced at least one treatment-emergent adverse event, with similar rates for all treatments. The adverse events most commonly reported were dry mouth, nasopharyngitis, and constipation. No marked change was observed in systolic or diastolic blood pressure for any treatment, although pulse rate increased slightly in the mirabegron and propiverine, and mirabegron and tolterodine groups. For all treatments, significant improvements were observed in all efficacy parameters, including overactive bladder symptom score total and questionnaire short form scores. Conclusions Antimuscarinic add-on therapy is well tolerated and effective after initial treatment with mirabegron in patients with overactive bladder symptoms.

Aims The efficacy of perioperative pelvic floor muscle training (PFMT) for continence recovery after robot-assisted radical prostatectomy (RARP) remains unclear. Visualization of the bladder neck and urethra using transperineal ultrasound (US) may promote self-recognition of urethral closure during PFM contraction. This study aimed to examine whether transperineal US-guided PFMT promotes early recovery of post-RARP incontinence. Methods This prospective cohort study included 116 men undergoing RARP. All men were offered to undergo transperineal US-guided PFMT, and 36 men agreed. The protocol consisted of biofeedback PFMT using transperineal US before RARP and 1-month after RARP with verbal instruction of PFMT immediately after urethral catheter removal. The remaining 80 patients received verbal instruction for PFMT alone. Continence recovery was defined as the number of days requiring a small pad (20 g) per day by self-report. Results No differences were observed in demographic or peri-operative parameters between the two groups except the longer operative time in the US-guided PFMT group. The mean time until continence recovery was significantly shorter in the US-guided PFMT group (75.6 ± 100.0 days) than in the verbal-PFMT group (121.8 ± 132.0 days, P = 0.037). Continence recovery rates within 30 days were 52.8% (19/36) and 35.4% (28/80) in the US-guided PFMT and verbal-PFMT groups, respectively (P = 0.081). US-guided PFMT was associated with better postoperative continence status (adjusted hazard ratio [95% confidence interval]: 0.550 [0.336-0.900], P = 0.017). Conclusions The results showed that transperineal US-guided PFMT perioperatively was associated with early recovery of urinary continence after RARP.

Aims We investigated the effects of silodosin, an α1A-adrenoceptor (AR) antagonist, on bladder function, especially on non-voiding contractions (NVCs), in a male rat model of bladder outlet obstruction (BOO) by evaluating cystometry (CMG) findings and bladder mechanosensitive single-unit afferent activities (SAAs), related with microcontractions, which may be similar with NVCs and to be of myogenic origin, in the rat model. Methods BOO was created by partial ligation of the posterior urethra. At 4 days after surgery for BOO, an osmotic pump filled with silodosin (0.12 mg/kg/day) or its vehicle was subcutaneously implanted. At 10 days after surgery, CMG and SAAs measurements were taken under conscious and urethane-anesthetized conditions, respectively. The SAAs of Aδ- and C-fibers, which were identified by electrical stimulation of the pelvic nerve and by bladder distention, and intravesical pressure were recorded during constant bladder-filling with saline. Microcontractions were divided into three phases: "ascending," "descending," and "stationary." Results The silodosin-treated group showed a smaller number of NVCs in CMG measurements and lower SAAs of both Aδ- and C-fibers than the vehicle-treated group during bladder-filling. Moreover, in the vehicle-treated groups, the SAAs of both fibers for the ascending phase of microcontractions were significantly higher than those for the other two phases. On the contrary, no significant change was found between any of these three phases in the silodosin-treated group. Conclusion The present results suggest that silodosin inhibits the SAAs of mechanosensitive Aδ- and C-fibers at least partly due to suppressing myogenic bladder contractions in male BOO rats.

Aims To develop a comprehensive patient-reported bladder assessment tool (BAT) for assessing overactive bladder (OAB) symptoms, bother, impacts, and satisfaction with treatment. Methods Subjects were consented and eligibility was confirmed by a recruiting physician; subjects were then scheduled for in-person interviews. For concept elicitation and cognitive interviews, 30 and 20 subjects, respectively, were targeted for recruitment from US sites. All interviews were conducted face-to-face, audio-recorded, transcribed verbatim, anonymized, and analyzed using a qualitative data analysis software program. A draft BAT was created based on the results of the concept elicitation interviews and further revised based on cognitive interviews as well as feedback from an advisory board of clinical and patient-reported outcome (PRO) experts. Results Nocturia, daytime frequency, and urgency were reported by all subjects (n = 30, 100.0%), and incontinence was reported by most subjects (n = 25, 83.3%). The most frequently reported impacts were waking up to urinate (n = 30, 100.0%), embarrassment/shame (n = 24, 80.0%), stress/anxiety (n = 23, 76.7%), and lack of control (n = 23, 76.7%). Following analysis, item generation, cognitive interviews, and advisory board feedback, the resulting BAT contains four hypothesized domains (symptom frequency, symptom bother, impacts, and satisfaction with treatment) and 17 items with a 7-day recall period. Conclusions The BAT has been developed in multiple stages with input from both OAB patients and clinical experts following the recommended processes included in the FDA PRO Guidance for Industry. Once fully validated, we believe it will offer a superior alternative to use of the bladder diary and other PROs for monitoring OAB patients in clinical trials and clinical practice.

Aims To evaluate the significance of mast cell infiltration in interstitial cystitis (IC) by comparison with equally inflamed controls using a digital quantification technique. Methods Bladder biopsy specimens from 31 patients with Hunner type IC and 38 patients with non-Hunner type IC were analyzed. Bladder biopsy specimens from 37 patients without IC, including 19 non-specific chronic cystitis ("non-IC cystitis") specimens and 18 non-inflamed bladder ("normal bladder") specimens, were used as controls. Mast cell tryptase-, CD3-, CD20-, and CD138-immunoreactive cells were quantified using digital image analysis software to evaluate both mast cell and lymphoplasmacytic cell densities. Mast cell and lymphoplasmacytic cell densities were counted independently in the entire lamina propria and detrusor areas and compared among the four groups. Results In the lamina propria, there were no significant differences in mast cell and lymphoplasmacytic cell densities between Hunner type IC and non-IC cystitis or between non-Hunner type IC and normal bladder specimens. In the detrusor, the mast cell densities were not significantly different among the four groups. Mast cell density was correlated with lymphoplasmacytic cell density, but not with clinical parameters. Conclusions Mast cell density is not significantly different between IC specimens and non-IC control specimens with a similar degree of background inflammation. The intensity of mast cell infiltration generally correlated with that of lymphoplasmacytic cells. We conclude that mast cell count is of no value in the differential diagnosis between IC and other etiologies.

Aims To examine the outcomes of lower urinary tract symptoms (LUTS) and urodynamic test results after cerebrospinal fluid (CSF) shunt surgery in idiopathic normal pressure hydrocephalus (iNPH). Methods Records of 48 patients (33 men; 15 women), who met the definite iNPH criteria and underwent CSF shunt surgery, were retrospectively analyzed. LUTS and their impact on quality of life (QOL) were evaluated using an all-or-none questionnaire targeting four symptoms, the Overactive Bladder Symptoms Score (OABSS), and the QOL index. Urodynamic investigations included filling cystometry and pressure-flow studies performed before and after surgery. Results Forty-seven (98%) patients complained of LUTS, 41 (87%) patients of whom experienced LUTS improvement after surgery. The OABSS and QOL index, which before surgery were 6.8 ± 0.7 and 4.1 ± 0.4, respectively, significantly decreased to 4.6 ± 0.6 and 3.2 ± 0.3, respectively, after surgery. The maximum cystometric capacity (174.9 ± 13.3 mL to 222.4 ± 14.7 mL) and bladder compliance (35.8 ± 4.4 ml/cmH2O to 52.1 ± 5.4 ml/cmH2O) significantly increased after surgery. Detrusor overactivity, which was observed in 37 (77%) patients preoperatively, became undetectable in 7 patients postoperatively. Voiding dysfunction (defined as maximum flow rate 100 mL) was observed in 29 (60%) patients, 22 (75%) of whom had detrusor underactivity before surgery. None of the voiding urodynamic parameters significantly improved postoperatively. Conclusions iNPH is often associated with LUTS and both storage and voiding dysfunctions. CSF shunt surgery improved LUTS and storage dysfunction, with limited effects on voiding dysfunction.

Introduction: We hypothesized that presence of plasma cell neoplasms might be a risk for thrombosis of arteriovenous fistulas (AVFs) as well as other well-known factors including age, sex, race, and presence of diabetes mellitus or certain vascular disorders. Methods: In this single-center, retrospective study based on medical record data, we investigated the influence of plasma cell neoplasms and the above-mentioned factors on the occurrence of complete occlusive thrombosis of the AVF within 30 days after surgery for creation of the AVF. Thrombosis was defined as the absence of bruit or thrill on auscultation and palpation, throughout systole and diastole. Findings: We retrospectively assessed the medical records of 91 patients with end-stage renal failure, including 8 patients with plasma cell neoplasm (5 with multiple myeloma and 3 with amyloid light-chain amyloidosis), who underwent surgical creation of an AVF at the wrist or anatomical snuff box for the first time between April 2014 and December 2016. Early thrombosis (i.e., within 30 days of surgery) occurred in 50.0% (4/8) and 10.8% (9/83) of patients with and without plasma cell neoplasm, respectively (P = 0.013). Multivariate analysis revealed that, after adjusting for baseline characteristics, plasma cell neoplasm was the only significant risk factor for early AVF thrombosis (odds ratio, 38.8; 95% confidence interval, 4.0–378.9; P = 0.0017). Discussion: Considering the poor prognosis of plasma cell neoplasm and its association with higher risk for AVF thrombosis, another type of vascular access is likely to be more suitable than AVF in such patients.

The present article is the abbreviated English translation of the Japanese guidelines for male lower urinary tract symptoms and benign prostatic hyperplasia updated as of the end of 2016. The target patients are men aged >50 years complaining of lower urinary tract symptoms, with or without benign prostatic hyperplasia, and the target readers are non-urological general physicians and urologists. Mandatory assessment for general physicians is medical history, physical examination, urinalysis and measurement of serum prostate-specific antigen. Additional mandatory assessment for urologists is symptoms and quality of life assessment by questionnaires, uroflowmetry, residual urine measurement, and prostate ultrasonography. Nocturia requires special attention, as it can result from nocturnal polyuria and/or sleep disturbance rather than lower urinary tract disorders. Functional lower urinary tract disorders with or without benign prostatic hyperplasia are primarily managed by conservative therapy and medications, such as α1 -blockers and phosphodiesterase-type 5 inhibitors. Use of other medications or combination pharmacotherapy is to be reserved for urologists. 5α-Reductase inhibitors and anticholinergics or β3 agonists are indicated for men with enlarged prostates and overactive bladder symptoms, respectively. Surgical intervention for bladder outlet obstruction is considered for persistent symptoms or benign prostatic hyperplasia-related comorbidities. Surgical modalities should be optimized by the patient's characteristics, performance of equipment and the surgeon's experience.

Objective Our objective was to investigate predictors of early continence outcome after robot-assisted radical prostatectomy (RARP). Methods Clinical records were prospectively collected in 272 patients who underwent RARP. Clinical parameters, continence rates, and time to achieve continence were investigated and analyzed. Recovery of continence was defined as achieving complete continence (pad-free). Results In the univariate analysis, young age (≤67 years) and low pT stage (≤pT2) were significantly associated with continence achieved within 2 weeks after RARP (P = 0.0343 and P = 0.0406, respectively). Low prostate weight was the only factor associated with recovery of continence within 1 month (P = 0.0461). Multivariate analysis revealed that young age (≤67 years) and low pT stage (≤pT2) were statistically significant predictors of continence within 2 weeks after RARP (P = 0.040 and P = 0.015, respectively). Conclusion Young age and low pT stage were independent predictors of early continence.

Objectives To investigate predictors of continence outcomes after robot-assisted radical prostatectomy. Methods Clinical records of 272 patients who underwent robot-assisted radical prostatectomy were investigated. Preoperative Overactive Bladder Symptom Score, International Prostate Symptom Score and clinicopathological factors were investigated, and relationships between factors and recovery of continence after robot-assisted radical prostatectomy were assessed. The presence of overactive bladder was defined as having urgency for more than once a week and having ≥3 points according to the Overactive Bladder Symptom Score. Results Age (≤66 years) was significantly associated with continence within 6 months after robot-assisted radical prostatectomy (P = 0.033). The absence of overactive bladder and lower Overactive Bladder Symptom Score (

Oncolytic virus therapy has recently been recognized as a promising new option for cancer treatment. Oncolytic viruses replicate selectively in cancer cells, thus killing them without harming normal cells. Notably, T-VEC (talimogene laherparepvec, formerly called OncoVEXGM-CSF), an oncolytic herpes simplex virus type 1, was approved by the US Food and Drug Administration for the treatment of inoperable melanoma in October 2015, and was subsequently approved in Europe and Australia in 2016. The efficacies of many types of oncolytic viruses against urological cancers have been investigated in preclinical studies during the past decade, and some have already been tested in clinical trials. For example, a phase I trial of the third-generation oncolytic Herpes simplex virus type 1, G47Δ, in patients with prostate cancer was completed in 2016. We summarize the current status of clinical trials of oncolytic virus therapy in patients with the three major urological cancers: prostate, bladder and renal cell cancers. In addition to Herpes simplex virus type 1, adenoviruses, reoviruses, vaccinia virus, Sendai virus and Newcastle disease virus have also been used as parental viruses in these trials. We believe that oncolytic virus therapy is likely to become an important and major treatment option for urological cancers in the near future.

Tripartite motif 44 (TRIM44) is one of the TRIM family proteins that are involved in ubiquitination and degradation of target proteins by modulating E3 ubiquitin ligases. TRIM44 overexpression has been observed in various cancers. However, its association with testicular germ cell tumor (TGCT) is unknown. We aimed to investigate the clinical significance of TRIM44 and its function in TGCT. High expression of TRIM44 was significantly associated with α feto-protein levels, clinical stage, nonseminomatous germ cell tumor (NSGCT), and cancer-specific survival (P = 0.0009, P = 0.0035, P = 0.0004, and P = 0.0140, respectively). Multivariate analysis showed that positive TRIM44 IR was an independent predictor of cancer-specific mortality (P = 0.046). Gain-of-function study revealed that overexpression of TRIM44 promoted cell proliferation and migration of NTERA2 and NEC8 cells. Knockdown of TRIM44 using siRNA promoted apoptosis and repressed cell proliferation and migration in these cells. Microarray analysis of NTERA2 cells revealed that tumor suppressor genes such as CADM1, CDK19, and PRKACB were upregulated in TRIM44-knockdown cells compared to control cells. In contrast, oncogenic genes including C3AR1, ST3GAL5, and NT5E were downregulated in those cells. These results suggest that high expression of TRIM44 is associated with poor prognosis and that TRIM44 plays significant role in cell proliferation, migration, and anti-apoptosis in TGCT.

Chronic pelvic pain (CPP) presents an etiology that is often unknown, difficult to classify and multifactorial, which leads to difficult therapeutic management. The symptoms often suggest dysfunction of one or more systems in the pelvis, accompanied by negative consequences from a cognitive, behavioral, sexual and emotional point of view, with a significant impact on the quality of life. In a patient with CPP, there are many factors involved, a number of different pathologies or phenomena of peripheral and central sensitization, so it is recommended to initially focus the study on the location and characteristics of the pain, without ruling out the study of other organs, Hence the importance of an interdisciplinary and multidisciplinary approach for a correct diagnosis and treatment. Myofascial pelvic pain should be considered in all women who consult for pelvic pain. Musculoskeletal changes may be related to CPP, either as the primary problem or as a secondary reaction to pelvic pain. The importance of musculoskeletal pain is often underestimated. Considering myofascial syndrome early in the management of pelvic pain may prevent the performance of certain unnecessary procedures.

Objectives To examine whether systemic resiniferatoxin treatment can desensitize the single-unit afferent activities of Aδ- and C-fibers in rat primary bladder mechanosensitive afferent nerves. Methods Female Sprague–Dawley rats were divided into two groups (resiniferatoxin-treated: n = 9, vehicle-treated: n = 9). Resiniferatoxin (0.3 mg/kg) or its vehicle (10% ethanol) was injected subcutaneously after the first eye-wipe behavior test with capsaicin. The second eye-wipe behavior test was carried out 48 h after the injection under urethane (1.2 g/kg intraperitoneally) anesthesia. The bladder mechanosensitive single-unit afferent activities originating from the left L6 dorsal roots were identified by electrical stimulation of the left pelvic nerve and bladder distension, and classified by conduction velocity as either Aδ-fibers or C-fibers. The single-unit afferent activity measurements were carried out with constant bladder filling with saline (0.1 mL/min

Objectives To assess the efficacy and feasibility of ultrasound-assisted prompted voiding for the management of urinary incontinence in nursing homes. Methods Nursing home residents who had received prompted voiding care for urinary incontinence were enrolled. The voided urinary volume and residual urinary volume were initially measured for a few days. The sum of the mean values of these volumes was considered as the optimal intravesical urinary volume for voiding. Thereafter, the participants underwent regular monitoring of intravesical urinary volume using an ultrasound device, and were prompted to void in a toilet when the monitored volume almost reached the optimal volume. The primary outcome for efficacy was the change in the absorbent cost before and after ultrasound-assisted prompted voiding care over 12 weeks. The feasibility was assessed by the change in activity of daily living of residents and quality of life measures of the care workers. Results A total of 77 residents completed the 12-week ultrasound-assisted prompted voiding intervention. The absorbent cost decreased in 40 participants (51.9%), and the overall cost decreased by 11.8% from the baseline value (P = 0.006). The activity of daily living did not significantly change. The quality of life of the care workers significantly improved for subscales of role emotional (P = 0.020) and mental health (P = 0.007). Conclusions The management of urinary incontinence for nursing homes residents through ultrasound-assisted prompted voiding seems to reduce the absorbent cost and to partially improve care workers' quality of life.

Clinical guidelines for interstitial cystitis and hypersensitive bladder have been updated as of 2015. The guidelines define interstitial cystitis by the presence of hypersensitive bladder symptoms (discomfort, pressure or pain in the bladder usually associated with urinary frequency and nocturia) and bladder pathology, after excluding other diseases explaining symptoms. Interstitial cystitis is further classified by bladder pathology; either Hunner type interstitial cystitis with Hunner lesions or non-Hunner type interstitial cystitis with mucosal bleeding after distension in the absence of Hunner lesions. Hypersensitive bladder refers to a condition, where hypersensitive bladder symptoms are present, but bladder pathology or other explainable diseases are unproven. Interstitial cystitis and hypersensitive bladder severely affect patients' quality of life as a result of disabling symptoms and/or comorbidities. Reported prevalence suggestive of these disorders varies greatly from 0.01% to >6%. Pathophysiology would be an interaction of multiple factors including urothelial dysfunction, inflammation, neural hyperactivity, exogenous substances and extrabladder disorders. Definite diagnosis of interstitial cystitis and hypersensitive bladder requires cystoscopy with or without hydrodistension. Most of the therapeutic options lack a high level of evidence, leaving a few as recommended therapeutic options.

Aims 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. Methods 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). Results 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. Conclusion Kv7 channels are likely to be implicated in inhibition of bladder mechano- and nociceptive sensory transduction. Neurourol. Urodynam. © 2015 Wiley Periodicals, Inc.

OBJECTIVES To clarify the involvement of bladder α1-adrenoceptors (α1-ARs) in afferent pathways by investigating the effects of silodosin and BMY7378, selective α1A- or α1D-AR antagonists, respectively, on single-unit afferent nerve fibre activity (SAA) of the primary bladder afferent nerves and their relationship with bladder microcontractions in rats. MATERIALS AND METHODS A total of 63 female Sprague-Dawley rats were anaesthetized with urethane. The SAA of Aδ and C fibres generated from the left L6 dorsal roots was determined using electrical stimulation of the left pelvic nerve and bladder distension. After measuring baseline SAA during constant filling cystometry, the procedure was repeated with i.v. (0.3-30 μg/kg) or intravesical (10 μm) administration of each antagonist. In separate rats, the bladder was filled with saline until the intravesical pressure reached 30 cmH2 O, and was kept under isovolumetric conditions, then the recording was performed with i.v.-administered vehicle and silodosin (0.3 μg/kg). RESULTS A total of Aδ fibres and 33 C fibres were isolated from 63 rats. The SAA of Aδ fibres, but not C fibres, were dose-dependently decreased after both i.v. and intravesical administrations of each of the antagonists. In the experiments under bladder isovolumetric conditions, silodosin administration significantly decreased the SAA of Aδ fibres, but not C fibres, compared with vehicle administration. There were no significant effects on either the mean basal bladder pressure or microcontractions. CONCLUSION The present study suggests that both α1A- or α1D-ARs in the rat bladder are involved in the activation of the bladder mechanosensory Aδ fibres during bladder filling, and that this activation may not be related to bladder microcontractions.

Objectives To describe the clinicopathological features and oncological outcomes of renal cell carcinoma diagnosed in Japan in 2007, the results of the large-scale renal cell carcinoma registration study carried out by the Japanese Urological Association are reported. Methods The renal cell carcinoma survey was carried out by the Japanese Urological Association in 2012 to register newly diagnosed renal cell carcinoma cases in 2007 from 340 institutions nationwide. The survey included clinicopathological details, such as sex, age, family history, past history, smoking history, body mass index, reason for diagnosis, TNM classification, stage, histopathology, treatment and clinical outcomes. Results A total of 3663 cases diagnosed in 2007 were registered in this renal cell carcinoma registry program from 340 institutions. A total of 15 patients with a final diagnosis of oncocytoma were excluded, and 3648 cases of renal cell carcinoma were analyzed to evaluate oncological outcomes. The patients’ median age was 63.9 years (range 5.9–95.1 years). Clear cell renal cell carcinoma was the most common histological subtype (77.2%), followed by papillary (5.0%) and chromophobe (3.2%) renal cell carcinoma. The most common initial treatment was radical nephrectomy (72.6%), and the most common secondary treatment was cytokine therapy (13.1%). Five-year overall survival rates in stages I, II, III, and IV were 94.8%, 90.2%, 78.8% and 39.6%, respectively. The 5-year overall survival rates for clear cell, papillary and chromophobe renal cell carcinomas, and carcinoma of the collecting ducts of Bellini were 88.6%, 79.8%, 93.0% and 40.0%, respectively. Conclusions The present report is the first nationwide large-scale study to describe the clinicopathological characteristics and oncological outcomes of patients with renal cell carcinoma in Japan. Oncological outcomes depend on the clinical stage and histological subtype. Further investigations will be required to show improved oncological outcomes in the molecular targeted therapy era using the results of the present study as a baseline.

To determine if inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) can counteract the changes in urodynamic variables and bladder afferent activities induced by intravesical prostaglandin E2 (PGE2 ) instillation in rats.In female Sprague-Dawley rats we studied the effects of URB937, a peripherally restricted FAAH inhibitor, on single-unit afferent activity (SAA) during PGE2 -induced bladder overactivity (BO). SAA measurements were made in urethane-anaesthetised rats and Aδ- and C-fibres were identified by electrical stimulation of the pelvic nerve and by bladder distention. Cystometry (CMG) in conscious animals and during SAA measurements was performed during intravesical instillation of PGE2 (50 or 100 μm) after intravenous administration of URB937 (0.1 and 1 mg/kg) or vehicle. In separate experiments, the comparative expressions of FAAH and cannabinoid receptors, CB1 and CB2 , in microsurgically removed L6 dorsal root ganglion (DRG) were studied by immunofluorescence.During CMG, 1 mg/kg URB937, but not vehicle or 0.1 mg/kg URB937, counteracted the PGE2 -induced changes in urodynamic variables. PGE2 increased the SAAs of C-fibres, but not Aδ-fibres. URB937 (1 mg/kg) depressed Aδ-fibre SAA and abolished the facilitated C-fibre SAA induced by PGE2 . The DRG nerve cells showed strong staining for FAAH, CB1 and CB2 , with a mean (sem) of 77 (2)% and 87 (3)% of FAAH-positive nerve cell bodies co-expressing CB1 or CB2 immunofluorescence, respectively.The present results show that URB937, a peripherally restricted FAAH inhibitor, reduces BO and C-fibre hyperactivity in the rat bladder provoked by PGE2 , suggesting an important role of the peripheral endocannabinoid system in BO and hypersensitivity.

Aims 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. Methods 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. Results 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). Conclusions 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. © 2015 Wiley Periodicals, Inc.

We report two cases of urinary bladder urothelial carcinoma (UC). In both, histological examination of a transurethral resection specimen of the bladder tumor revealed UC with plasmacytoid and micropapillary differentiations. In Case 1, residual plasmacytoid UC deeply invaded the extravesical fat tissue of the radical cystectomy specimen, and metastatic carcinoma was found in almost all the dissected lymph nodes. Despite adjuvant chemotherapy and radiotherapy, the patient died 25 months postdiagnosis. Elevated serum carbohydrate antigen 19-9 (CA19-9) returned to near normal levels after radical cystectomy, but they increased shortly before death. In Case 2, no residual carcinoma was found in the radical cystectomy specimen or lymph nodes. Postoperative serum CA19-9 was maintained at normal levels, and the patient remains alive without recurrence or metastasis. Although plasmacytoid and micropapillary UC are known aggressive variants of UC, plasmacytoid UC may be more aggressive. Serum CA19-9 could serve as a useful biomarker to monitor progression of plasmacytoid UC.

Objectives To determine whether botulinum toxin type A can represent an alternative treatment option for patients with interstitial cystitis refractory to conventional therapies. Methods This is a single-center, prospective, open labeled, randomized comparative study. Patients with refractory interstitial cystitis were randomly divided into two groups: immediate injection (group A) or 1-month delayed injection (group B) of botulinum toxin type A after allocation. The rate of treatment response (global response assessment ≥+1: slightly improved), and changes in symptom scores and frequency volume chart variables were compared between groups 1 month after allocation. Using subjects of both groups as a single cohort, predictive factors for treatment response at 1 month post-injection and the duration of response were explored. Results A total of 34 patients (group A n = 18, group B n = 16) were allocated. The response rate was significantly higher in group A than group B (72.2% vs 25.0%, P = 0.01). All symptom measures showed significant improvement in group A than group B. When both groups were combined as a single cohort, the response rate was 73.5% at 1 month, 58.8% at 3 months, 38.2% at 6 months and 20.6% at 12 months. The mean duration of response was 5.4 months. Multivariate analysis showed that past exposure to hydrodistension more than three times correlated with better outcomes. Conclusions Botulinum toxin type A injection could be an alternative treatment option for patients with interstitial cystitis refractory to conventional therapies, especially for those who have received repeated hydrodistensions and transurethral fulguration.

Objectives To investigate brain activity related to bladder sensation in interstitial cystitis patients. Methods A total of 10 interstitial cystitis patients (all women; mean age 68 years) and 10 healthy controls (all women; mean age 64 years) participated in the present study. Frontal lobe blood flow was measured non-invasively by using multichannel near-infrared spectroscopy with large and small bladder volumes (created by infusing water) up to the first desire to void. Results The frontal cortex of the right and left hemisphere was activated, and the activation was detected as an increase in oxyhemoglobin concentration. The increase during the first desire to void in the interstitial cystitis group was greater than that in the control group. In addition, this difference was particularly observed in Brodmann's areas 9, 44, 45 and 46, reportedly associated with micturition and sensory modulation. Conclusions The present study shows that the frontal area is largely activated during bladder filling in interstitial cystitis patients. Our findings suggest that the major change in cerebral blood flow is related to the characteristic urinary symptoms of interstitial cystitis patients.

Objectives To evaluate the prognostic significance of the pretreatment neutrophil-to-lymphocyte ratio in patients with metastatic urothelial carcinoma who underwent salvage chemotherapy. Methods We reviewed 200 metastatic urothelial carcinoma patients who received salvage chemotherapy at our five affiliate institutions between 2003 and 2011. The associations of pretreatment clinicopathological factors, including neutrophil-to-lymphocyte ratio, with cancer-specific survival and overall survival from the start of chemotherapy were assessed. Cox proportional hazards model was used for multivariate analysis. Results A total of 15 cases with missing data were excluded. Among the remaining 185 patients, 157 died during follow up, with a median survival of 13.0 months. Multivariate analysis showed that the pretreatment neutrophil-to-lymphocyte ratio ≥3, Eastern Cooperative Oncology Group performance status ≥2 and liver metastasis were independent poor prognostic factors, both for cancer-specific survival and overall survival. A prognostic model predicting overall survival was constructed based on the number of these three variables (0, 1 and ≥ 2). The classified patients showed significantly different overall survival (each P

Objectives We investigated the direct effects of sildenafil, a phosphodiesterase type 5 inhibitor, on the single-unit mechanosensitive afferent activities (SAAs) primarily originated from the bladder in the rat. Methods Female Sprague–Dawley rats were anesthetized with urethane. SAAs were recorded from the left L6 dorsal roots and classified by conduction velocity as Aδ- or C-fibers. A catheter was inserted into the bladder dome, and a separate catheter was placed in the carotid artery and external iliac vein for monitoring of blood pressure and sildenafil-administration, respectively. After measuring control SAA during constant filling cystometry with saline, the procedure was repeated with cumulative intravenous administrations of sildenafil (1, 3 and 10 mg/kg). Results Thirteen single units were isolated (Aδ-fibers: n = 6, C-fibers: n = 7) from 11 rats. After sildenafil-administrations, SAAs of Aδ-fibers significantly decreased in a dose-dependent manner, whereas SAAs of C-fibers decreased significantly only at the highest dose used. In addition, blood pressure significantly decreased after sildenafiladministration even at the lowest dose used. Bladder compliance significantly increased after sildenafil administration at higher doses. Conclusions These results indicate that sildenafil can inhibit Aδ-fibers (partly also C-fibers) of the primary bladder mechanosensitive afferents of the rat although these effects may be partially influenced by systemic hypotension. The present results support the view that the NO/cGMP signaling pathway plays an inhibitory role in the bladder afferent transduction, and thus improves storage symptoms.

Objective To characterize nocturia in men based on frequency volume chart data and symptom profiles assessed using the Core Lower Urinary Tract Symptom Score and Athens Insomnia Scale questionnaires. Methods The Core Lower Urinary Tract Symptom Score and Athens Insomnia Scale questionnaires were administered to 299 consecutive treatment naive men with nocturia (≥one time per night). Frequency volume chart data were recorded for 2 days. Correlations between nocturia and clinical characteristics including symptom scores, clinical diagnosis, Charlson Comorbidity Index, estimated glomerular filtration rate, uroflowmetry and prostate volume were analyzed. Results Patients were divided into five groups: one time (n = 36), two times (n = 65), three times (n = 85), four times (n = 78) and five times (n = 34) of nocturia. Age, prevalence or severity of chronic kidney disease, hyperlipidemia, low bladder capacity, nocturnal polyuria, urgency, bladder pain and sleep disorders were significantly correlated with the severity of nocturia. The Spearman correlation analysis identified eight possible independent factors for nocturia: age, estimated glomerular filtration rate, urgency, bladder pain, sleep quality, sleepiness during the day, average voided volume and nocturnal volume divided by body weight. Logistic regression analysis showed that nocturnal volume divided by body weight was the strongest factor of nocturia, and ≥7, 9 and 9.7 mL/kg were practical cut-off values of three, four and five times per night of nocturia, respectively. Conclusions Nocturia in men is a chaotic condition dominated by nocturnal polyuria, and related to multiple factors including age, renal function, urgency, bladder pain, insomnia and bladder volume.

Objectives To assess individually tailored ultrasound-assisted prompted voiding as a means of managing urinary incontinence in hospitalized elderly patients. Methods A total of 88 incontinent elderly individuals who were inpatients in general hospitals were included. Each individual's mean bladder volume before starting to void (voided urine volume plus residual urine volume) was regarded as the optimal bladder volume. Bladder volume was regularly monitored with an ultrasound device, and when the urine volume had reached the individual's optimal bladder volume, the subject was prompted to void. The outcomes were evaluated on the basis of scores on a four-grade scale for items in six domains: urine volume, voiding function, urinary control, physical and cognitive function for toileting, and caregivers' burden in regard to continence care. The score for use of a pad/diaper, an item of urinary control domain, was used as the primary outcome measure. Results A total of 80 participants were included for analysis. After ultrasound-assisted prompted voiding care for a 4-week period, the score for use of a pad/diaper in 50 out of 80 participants (62.5%) had decreased, and 21 out of 80 participants (26.3%) no longer required the use of a pad/diaper at all. The scores of the other 30 out of 80 participants (37.5%) were unchanged. The improvement was not significantly affected by patients' backgrounds at baseline. The mean scores in the domains of urinary control, physical function, cognitive function and caregivers' burden improved significantly. Conclusion The present preliminary study suggests that individually tailored ultrasound-assisted prompted voiding can improved urinary incontinence of institutionalized elderly patients. Further studies are worth carrying out.

Objectives To investigate the association between the TMPRSS2 Met160Val polymorphism and the risk of prostate cancer in Japanese men. Methods Genomic DNA samples from 518 Japanese sporadic prostate cancer patients, 433 controls and 154 Japanese men who were diagnosed as having latent prostate cancer based on autopsy results were genotyped for the TMPRSS2 Met160Val polymorphism using a TaqMan assay. Logistic regression analyses were carried out to estimate the odds ratios and 95% confidence intervals. The relationship between the presence of the polymorphism, and clinicopathology and survival was also examined. Results The T allele frequency of the control group was 0.372, of the sporadic prostate cancer group was 0.435 and of the latent prostate cancer group was 0.370. The CT and TT genotypes were significantly associated with risk for sporadic prostate cancer; age-adjusted odds ratios (95% confidence intervals) were 1.418 (1.027–1.960) for CT, 1.907 (1.224–2.990) for TT and 1.524 (1.123–2.072) for CT/TT genotypes. There was no significant association observed between the TMPRSS2 Met160Val polymorphism and the risk for latent prostate cancer. The TMPRSS2 Met160Val polymorphism was not significantly associated with any clinicopathological features or prognosis. Conclusions The TMPRSS2 Met160Val polymorphism is a genetic risk factor for sporadic prostate cancer in a Japanese population.

Objectives To elucidate the differences in clinical practice between the USA and Japan in major types of uro-oncological surgery by a head-to-head comparison of national databases in the two countries. Methods We compared variations in surgical modality, length of stay, total charges, caseload centralization, transfusion incidence, and in-hospital mortality between the two countries for four major types of uro-oncological surgery (radical prostatectomy, radical cystectomy, nephrectomy and nephroureterectomy) in 2011. Additionally, the chronological changes in surgical modalities were investigated for 2009–11. The national estimates were based on data from the Japanese Diagnosis Procedure Combination database and the US National Inpatient Sample. Results For radical prostatectomy, radical cystectomy, nephrectomy and nephroureterectomy, minimally-invasive surgery accounted for 24.2% versus 70.2%, 0% versus 14.0%, 50.7% versus 30.7% and 50.2% versus 30.5%, respectively, in Japan versus the USA in 2011. Although minimally-invasive surgery has become increasingly frequent in both countries, the major procedures were robot-assisted surgery in the USA and laparoscopic surgery in Japan. The USA was generally characterized by a slightly younger age at operation, far higher hospital volume, a shorter length of stay, higher charges and less use of transfusion than Japan. Conclusions The findings suggest substantial differences between the USA and Japan regarding clinical practices in uro-oncological surgery. Standing at the beginning of robotic surgery era in Japan, the precise recognition of these differences will aid a proper understanding of clinical practices.

Objectives To describe the clinical and pathological characteristics and oncological outcomes of testicular cancer diagnosed in Japan, we report the results of the testicular cancer registration carried out by the Japanese Urological Association. Methods Testicular cancer survey was conducted by the Japanese Urological Association in 2011 to register newly diagnosed testicular cancers in 2005 and 2008. The survey included details such as age, presenting symptoms, physical examination findings, tumor markers, histopathology, clinical stage, initial treatment and clinical outcomes. Results We analyzed 1121 cases of testicular primary germ cell tumor among 1157 registered patients. The median age was 37.0 years. Seminomas and non-seminomatous germ cell tumors accounted for 61.9% and 38.1%, respectively. Measurements of tumor markers were documented in 98.6% of the patients; however, there was an unsatisfactory uniform measurement of human chorionic gonadotropin, which made it difficult to evaluate the International Germ Cell Consensus Classification in all patients. The 1- and 3-year overall survival rates from the entire cohort were 98.3% and 96.8%, respectively. According to the International Germ Cell Consensus Classification, 3-year overall survival rates in the good, intermediate, and poor prognosis group were 99.1%, 100% and 79.9%, respectively. Conclusions The present report is the first large-scale study of the characteristics and survival of testicular cancer patients in Japan based on multi-institutional registry data, and showed a good prognosis even in an advanced stage. The improved survival attributed substantially to accurate diagnosis and effective multimodal treatment.

Objectives To investigate the perioperative outcomes of cytoreductive nephrectomy according to clinical T stage, and to analyze factors affecting these outcomes. Methods The Japanese Diagnosis Procedure Combination database from 2007 to 2012 was used to evaluate perioperative outcomes including in-hospital mortality, complications, blood transfusion, anesthesia time, postoperative length of stay and total cost in patients who underwent cytoreductive nephrectomy for metastatic renal cell carcinoma, according to clinical T stage. Multivariable regression analyses including sex, age, clinical N stage, hospital volume, type of hospital, Charlson Comorbidity Index and clinical T stage were carried out to identify outcome predictors. Results The present study enrolled 1074 patients including 270 with T1, 215 with T2, 479 with T3 and 110 with T4. Age, sex and Charlson Comorbidity Index were not significantly different among the four stages. A low clinical T stage was associated with minimally-invasive surgery (P

Taxonomy or nomenclature concerning interstitial cystitis and its related symptom syndromes is in a state of confusion. After analyzing the reasons for confusion in regard to three components (disease name, symptoms, Hunner's lesion), I would like to propose a new term, "hypersensitive bladder", taking after overactive bladder, as a solution. Hypersensitive bladder symptoms are defined as "increased bladder sensation, usually associated with urinary frequency and nocturia, with or without bladder pain." The proposal of hypersensitive bladder is based on: (i) it does not appear a symptom syndrome, but a disease by ending with an organ name, "bladder"; (ii) it does not contain confusable symptom terms (pain and urgency), but indicates irritative symptoms including pain and urgency; and (iii) it suggests pathophysiological hyperactivity of sensory nerves. Interstitial cystitis is defined by three requirements: (i) hypersensitive bladder symptoms; (ii) bladder pathology; and (iii) no other diseases, where bladder pathology should be clearly stated either as Hunner's lesion or glomerulations after hydrodistention. Hypersensitive bladder can be used for the condition with hypersensitive bladder symptoms, but no obvious disease explaining hypersensitive bladder symptoms identified. Interstitial cystitis is a representative disease causing hypersensitive bladder symptoms, most typically with pain, but might be painless and indistinguishable from overactive bladder. Introducing hypersensitive bladder as a counter concept of overactive bladder into bladder dysfunction taxonomy will facilitate clinical practice and research progress, and attract considerable attention from the medical world.

Objective To evaluate the efficacy and safety of the β3-adrenoceptor agonist mirabegron, in a Japanese population with overactive bladder (OAB). Patients and methods This randomised, double-blind, placebo-controlled phase III study enrolled adult patients experiencing OAB symptoms for ≥24 weeks. Patients with ≥ 8 micturitions/24 h and ≥1 urgency episode/24 h or ≥1 urgency incontinence episode/24 h were randomised to once-daily placebo, mirabegron 50 mg or tolterodine 4 mg (as an active comparator, without testing for non-inferiority of efficacy and safety) for 12 weeks. The primary endpoint was the change in the mean number of micturitions/24 h from baseline to final assessment. Secondary endpoints included micturition variables related to urgency and/or incontinence and quality-of-life domain scores on the King's Health Questionnaire. Safety assessments included adverse events (AEs), post-void residual urine volume, laboratory variables, vital signs and 12-lead electrocardiogram. Results A total of 1139 patients were randomised to receive placebo (n = 381), mirabegron 50 mg (n = 380) or tolterodine 4 mg (n = 378). Demographic and baseline characteristics were similar among the treatment groups. At final assessment, mirabegron was significantly superior to placebo in terms of mean [sd] change from baseline in number of micturitions/24 h (-1.67 [2.212] vs -0.86 [2.354]; P Conclusions Mirabegron 50 mg once daily is an effective treatment for OAB symptoms, with a low occurrence of side effects in a Japanese population.

Aims We measured single-unit mechanosensitive afferent activities (SAAs) during reflexic, rhythmic bladder contractions (RBCs), and examined whether L-arginine, an NO substrate, and mirabegron, a β3-adrenoceptor agonist, and oxybutynin, an antimuscarinic agent, can affect the SAAs in such condition. Methods Twenty-nine female Sprague-Dawley rats were anesthetized. SAA was identified by electro-stimulation of the left pelvic nerve and by bladder distension, and was divided into Aδ- or C-fibers by conduction velocity. To produce the RBCs, right L6 dorsal roots were kept intact. Under an isovolumetric condition, vehicle and L-arginine (300 mg/kg) or mirabegron (1 mg/kg) or oxybutynin (1 mg/kg) were administered intravenously. Results All of the Aδ- (n = 26) and C-fibers (n = 29) capable of responding to bladder distention were also responsive to bladder contractions during RBCs. The amplitude and duration of RBCs significantly decreased after mirabegron- and oxybutynin-administrations, but not after L-arginine-administration. The interval of RBC was significantly elongated after L-arginine- and mirabegron-administrations. Regarding the SAAs, the peaks of firing rate (FR) during RBCs and FR during the non-contractile phase were decreased after L-arginine-administration, which were more remarkable for Aδ-fibers than C-fibers. Similar results were observed after mirabegron-administration only for Aδ-fibers. After oxybutynin-administration, the peak of FR of both fiber-SAAs significantly decreased, but the change was not significant when the value was normalized by the amplitude of RBCs. Conclusions The present results indicate that mechanosensitive Aδ- and C-fibers were also responsive to bladder contractions, and that NO production and β3-adrenoceptor stimulation can inhibit SAAs mainly of Aδ-fibers synchronized with RBCs. Neurourol. Urodynam. 34:368–374, 2015. © 2014 Wiley Periodicals, Inc.

Aims We investigated the effect of resiniferatoxin (RTX)-treatment on cystometric parameters in the spinal cord injury (SCI) rats in both conscious and urethane-anesthetized conditions and evaluated the influence of urethane-anesthesia on the effect of RTX on lower urinary tract (LUT) function in SCI rats. Methods Female Sprague-Dawley rats were used. SCI was created by transection of the T8-T9 spinal cord. Four weeks after the transection, the animals were placed in a restraint cage for the first cystometric measurements in a conscious state. Secondary cystometric measurements were performed in a conscious condition following the 1 day after RTX-(0.3 mg/kg) or vehicle-subcutaneous injection. Then the animals were injected with urethane (1.5 g/kg, subcutaneously), and cystometric measurements were repeated four times every 1 hr-interval. Results After the RTX-treatment in a conscious condition, urinary retention was observed in three out of five animals. In addition, the number of non-voiding contractions (NVCs) significantly decreased although their amplitude did not change significantly. After the urethane-injection, all of the animals treated with RTX developed urinary retention. The amplitude of NVCs significantly decreased, whereas the number of NVCs did not change significantly in the RTX-treated group. No cystometric parameters significantly changed after either vehicle- or urethane-injection in the vehicle-treated group. Conclusions The present results indicate that the suppressive effects of RTX on NVCs as well as voiding contractions in SCI rats can be enhanced by urethane-anesthesia. Such suppressive effect of urethane-anesthesia itself should be taken into consideration when we evaluate a drug-effect on LUT function in rats with SCI. Neurourol. Urodynam. 34:274–279, 2015. © 2013 Wiley Periodicals, Inc.

Objectives To describe the clinical and pathological characteristics and the outcomes of renal pelvic and ureteral cancer patients diagnosed in 2005 in Japan. Methods In 2011, data were collected from renal pelvic and ureteral cancer patients diagnosed in 2005. A total of 1509 registered patients from 348 institutions were analyzed. Epidemiology and survival were analyzed based on each cancer location and on cancer multiplicity. Results The 5-year overall survival of the 1509 patients was estimated at 0.64. Open surgery was carried out in 409 renal pelvic cancer cases (66.9%) and 315 ureteral cancer cases (63.0%). The retroperitoneal approach was common, and lymph node dissection was carried out in approximately one-third of open surgery cases and one-fifth of laparoscopic cases. Approximately 60% of the operated unilateral renal pelvic or ureteral cancer was diagnosed as invasive, and just 14.6% was diagnosed as stage pTa. Distribution of the estimated worst tumor grade was significantly different for renal pelvic cancer and ureteral cancer. Conclusions This article presents the first large population report of survival data in Japanese renal pelvic and ureteral cancer patients. In comparison with the Japanese bladder cancer database report in 1999–2001 from the Cancer Registration Committee of the Japanese Urological Association, the pathological characteristics of renal pelvic and ureteral cancer were diagnosed as aggressive.

Objective To evaluate whether mechanical bowel preparation before radical prostatectomy ameliorates damage from rectal injury in radical prostatectomy. Methods Among 35 099 radical prostatectomy cases in the Japanese Diagnosis Procedure Combination database 2007–2012, those where a rectal injury occurred were stratified into a preoperative mechanical bowel preparation group (polyethylene glycol electrolyte, magnesium citrate solution and sodium picosulfate) and a non-mechanical bowel preparation group. The associations between mechanical bowel preparation and rectal injury were evaluated by multivariate regression analysis for: (i) subsequent infectious complications; (ii) requirement of delayed colostomy formation after primary closure; (iii) postoperative length of stay; and (iv) total costs. Covariates were age, surgical approach, Charlson Comorbidity Index, T and N category, hospital volume, hospital academic status, and colostomy formation. Results Overall, 151 rectal injury cases (0.43%) were identified. Of those, 73 patients (48%) received mechanical bowel preparation. Multivariate analyses showed that all four outcomes were not statistically different between mechanical bowel preparation and non-mechanical bowel preparation groups (infectious complication rate: 12% vs 10%, P = 0.80; delayed colostomy rate: 21% vs 31%, P = 0.34; length of stay: 28 vs 30 days, P = 0.84; and total costs: $24 665 vs $23 837, P = 0.81). Conclusion Our analysis did not detect a beneficial impact of mechanical bowel preparation on perioperative morbidity associated with rectal injury during radical prostatectomy. This finding suggests that mechanical bowel preparation might be safely omitted before radical prostatectomy.

Objectives To evaluate the efficacy and safety of magnetic stimulation for the treatment of urinary incontinence in women with overactive bladder. Methods A total of 151 women with urgency incontinence were randomized to the active stimulation group or the sham stimulation group in a 2:1 order. An armchair type magnetic stimulator was used for 25-min magnetic stimulation twice a week, with the maximum magnetic flux density of 560 mT peak at 10 Hz. The sham device was set to deliver in a 5-s “on”-5-s “off” pulsing manner with the maximum intensity of 20.4% of active stimulation at 1 Hz. The study consisted of a baseline period for 1 week, and a treatment period for 6 weeks. The primary end-point was the number of leaks/week from the bladder diary. The secondary end-points were the number of voids and urgency/24 h, mean and maximum voided volume, and the quality of life assessment. Results Changes from baseline in the active and sham group, respectively, were −13.08 ± 11.00 and −8.68 ± 13.49 in leaks/week (P = 0.038), −2.65 ± 2.52 and −1.53 ± 2.39 in number of urgency/24 h (P = 0.011), and 14.03 ± 34.53 mL and −4.15 ± 40.60 mL in mean voided volume (P = 0.0056). As for safety, except for diarrhea and constipation, no patients experienced any device-related adverse event. Conclusions Magnetic stimulation is effective for the treatment of urgency incontinence in female patients with overactive bladder.

BACKGROUND Despite an initial response to hormonal therapy, patients with advanced prostate cancer (PC) almost always progress to castration-resistant disease (CRPC). Although serum testosterone (T) is reduced by androgen deprivation therapy, intratumoral T levels in CRPC are comparable to those in prostate tissue of eugonadal men. These levels could originate from intratumoral conversion of adrenal androgens and/or from de novo steroid synthesis. However, the relative contribution of de novo steroidogenesis to AR-driven cell growth is unknown. METHODS The relative contribution of androgen biosynthetic pathways to activate androgen receptor (AR)-regulated cell growth and expression of PSA, FKBP5, and TMPRSS2 was studied at physiologically relevant levels of adrenal androgen precursors and intermediates of de novo androgen biosynthesis in human prostate cancer cell lines, PC346C, VCaP, and LNCaP. RESULTS In PC346C and VCaP, responses to pregnenolone and progesterone were absent or minimal, while large effects of adrenal androgen precursors were found. VCaP CRPC clones overexpressing CYP17A1 did not acquire an increased ability to use pregnenolone or progesterone to activate AR. In contrast, all precursors stimulated growth and gene expression in LNCaP cells, presumably resulting from the mutated AR in these cells. CONCLUSIONS Our data indicate that at physiological levels of T precursors PC cells can generally convert adrenal androgens, while de novo steroidogenesis is not generally possible in PC cells and is not able to support AR transactivation and PC growth. Prostate 73: 1636–1650, 2013. © 2013 Wiley Periodicals, Inc.

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

High-throughput techniques have identified numerous antisense (AS) transcripts and long non-coding RNAs (ncRNAs). However, their significance in cancer biology remains largely unknown. Here, we report an androgen-responsive long ncRNA, CTBP1-AS, located in the AS region of C-terminal binding protein 1 (CTBP1), which is a corepressor for androgen receptor. CTBP1-AS is predominantly localized in the nucleus and its expression is generally upregulated in prostate cancer. CTBP1-AS promotes both hormone-dependent and castration-resistant tumour growth. Mechanistically, CTBP1-AS directly represses CTBP1 expression by recruiting the RNA-binding transcriptional repressor PSF together with histone deacetylases. CTBP1-AS also exhibits global androgen-dependent functions by inhibiting tumour-suppressor genes via the PSF-dependent mechanism thus promoting cell cycle progression. Our findings provide new insights into the functions of ncRNAs that directly contribute to prostate cancer progression.

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

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

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