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Purpose This multicenter, randomized, double-blind, placebo-controlled phase 2 study evaluated the efficacy and safety of TAC-302, a novel drug that restores neurite outgrowth, in patients with detrusor underactivity (DU) and overactive bladder (OAB). Methods After 2–4 weeks of observation, patients were randomized 2:1 to receive oral TAC-302 200 mg or placebo twice daily for 12 weeks. The primary endpoint was detrusor contraction strength, estimated by bladder contractility index (BCI) for males and projected isovolumetric pressure 1 (PIP1) for females. Secondary endpoints included changes in bladder voiding efficiency (BVE) and safety. Results Seventy-six patients were included (TAC-302, n = 52; placebo, n = 24). The mean (standard deviation [SD]) BCI for males was 64.6 (16.6) at baseline and 75.2 (21.1) at week 12 (p n = 27), and 61.3 (16.6) and 60.5 (16.7) (p = 0.82) with placebo (n = 11). The respective mean (SD) PIP1 for females was 18.8 (6.6) and 29.4 (9.4) (p n = 15), and 20.6 (7.5) and 25.5 (9.6) (p = 0.14) with placebo (n = 7). TAC-302 significantly increased BCI in males and BVE in both sexes. TAC-302 efficacy on OAB was not clearly shown. The incidences of adverse events (AEs), serious AEs, and AEs leading to dose interruption were similar between groups; no adverse drug reactions occurred. Conclusion Considering the significant effects on BCI in males and BVE in both sexes, TAC-302 may benefit patients with DU. Registration ClinicalTrials.gov Identifier NCT03175029 registered 6/5/2017.

Behavioral treatment for nocturia includes wearing compression stockings. However, a reading of the cited literature for evidence shows that there is not enough research data to support this recommendation, and it is controversial. The present study aimed to investigate and supplement evidence on the effects of wearing compression stockings during the daytime in patients with nocturia.This was a single-arm prospective study to investigate the effects of compression stockings on nocturia for four weeks. Patients were asked to record a frequency-volume chart and complete various questionnaires at baseline and after four weeks, and also provide feedback on treatment satisfaction. The primary endpoint was a change in night-time frequency in the frequency-volume chart from the baseline to the end of treatment.Thirty-four patients (19 men and 15 women; age: 72.3 ± 12.6 years) were included. Two patients dropped out because of pain associated with wearing compression stockings and one due to a refusal to wear compression stockings every day. Therefore 31 patients were analyzed. In the frequency-volume chart, night-time and 24-hour frequencies significantly decreased by 0.5 and 1.1 episodes, respectively (P = 0.004 and P = 0.035, respectively). The hours of undisturbed sleep significantly increased by 0.8 h (P = 0.013). No significant differences were observed in nocturnal or 24-h urine volumes, the number of urgency or urinary incontinence episodes, the mean or maximum voided volume, the nocturnal polyuria index, or the first night-time voided volume. The total overactive bladder symptom score significantly decreased (P = 0.006). Significant reductions were also observed in all overactive bladder symptom score subscores, except for the daytime frequency score.The present results suggest the effectiveness of wearing compression stockings during the day was satisfactory in most patients with nocturia, and the treatment was safely continued in patients who experienced no pain when wearing the stockings. Based on the results of this study, we believe that it is worth considering as a treatment for nocturia.

The present article is an abridged English translation of the Japanese Clinical Guidelines for Female Lower Urinary Tract Symptoms (second edition), published in September 2019. These guidelines consist of a total of 212 pages and are unique worldwide in that they cover female lower urinary tract symptoms other than urinary incontinence. They contain two algorithms for "primary treatment" and "specialized treatment," respectively. These guidelines, consisting of six chapters, address a total of 26 clinical questions including: (i) treatment algorithms; (ii) what are female lower urinary tract symptoms?; (iii) epidemiology and quality of life; (iv) pathology and illness; (v) diagnosis; and (vi) treatment. When the patient's symptoms mainly involve voiding and post-micturition symptoms, specialized treatment should be considered. In the event of voiding symptoms concurrent with storage symptoms, residual urine should be measured; if the residual urine volume is

Objectives To report the outcome of the ADRESU study, a multicenter, single-arm, investigator-initiated clinical trial to confirm the efficacy and safety of regenerative treatment for male patients with stress urinary incontinence. Methods The participants were male patients with mild-to-moderate stress urinary incontinence persisting for >1 year after prostatectomy. Autologous adipose-derived regenerative cells were isolated using the Celution system from adipose tissue obtained by liposuction. Adipose-derived regenerative cells and mixture of adipose-derived regenerative cells with adipose tissue were transurethrally injected into the rhabdosphincter and submucosal space of the urethra, respectively. The primary end-point was the proportion of patients with improvement of the urine leakage volume at 52 weeks (or last visit within 52 weeks). Improvement of leakage volume was defined as a decrease from baseline >50% by the 24-h pad test. A total of 10 secondary end-points were set. Results A total of 45 patients satisfying the eligibility criteria were enrolled. The primary end-point was met; the proportion of patients with improvement in leakage volume at 52 weeks was 37.2% (95% confidence interval 23.0-53.3%). No serious adverse events with causal relationships to the adipose-derived regenerative cells were encountered. There was a progressive improvement in secondary end-points. In the King's Health Questionnaire, improvement of quality of life scores showed greater improvement in responders, as compared with non-responders. Conclusions Findings from the ADRESU study suggest the efficacy and safety of regenerative treatment for male patients with mild-to-moderate stress urinary incontinence.

Aim To evaluate efficacy and safety of combination of tadalafil + mirabegron for overactive bladder/benign prostatic hyperplasia (OAB/BPH). Methods Male patients with lower urinary tract symptoms (50 to 89 years), with remaining OAB symptoms even after administering tadalafil for more than 8 weeks were randomly assigned to either tadalafil monotherapy group (5 mg/day) or tadalafil/mirabegron combination therapy group (5 mg/50 mg/day). The primary endpoint was change from baseline in total OAB symptom score (OABSS) at week 12. The secondary endpoints were changes in International Prostate Symptom Score (IPSS), NIH‐chronic prostatitis symptom index (NIH‐CPSI), and micturition chart parameters at weeks 4 and 12. Results A total of 176 patients were randomized to either monotherapy (87 patients) or combination therapy (89 patients). The baseline characteristics of patients in the two groups were similar. The total OABSS (95% confidence interval) of combination therapy was significantly decreased by 1.78 (1.05‐2.50) points compared with that of monotherapy (P

OBJECTIVE To evaluate the efficacy and safety of onabotulinumtoxinA (botulinum toxin type A) 100 U in patients with overactive bladder and urinary incontinence. METHODS This was a phase III, randomized, double-blind, placebo-controlled trial in Japanese patients who were inadequately managed with overactive bladder medications (anticholinergics and/or β3 -adrenergic receptor agonists). Eligible patients were randomized 1:1 to receive a single dose of either onabotulinumtoxinA or placebo into the detrusor muscle (n = 124 each). The primary end-point was the change in the number of daily urinary incontinence episodes at week 12 from baseline. Secondary end-points included volume voided per micturition, other symptomatic measures (urinary urgency incontinence, micturition, urgency and nocturia) and patient-reported outcomes. RESULTS In the onabotulinumtoxinA group, there was a significantly greater decrease from baseline in the mean number of daily urinary incontinence episodes compared with the placebo group (2.16; P

The adipose stromal vascular fraction contains abundant mesenchymal stem cells and is utilized for cell therapy of male stress urinary incontinence. The purpose of this paper was to explore the effect of local transplantation of the stromal vascular fraction on improvement of damaged anal sphincter function.A rat model of vaginal distension was used as a model of damaged anal sphincter function. The adipose stromal vascular fraction was separated from the inguinal fat of syngeneic green fluorescent protein transgenic rats and delivered into the internal anal sphincter of vaginal distension rats. The maximum resting pressure was evaluated during insertion and withdrawal of the catheter at 4 or 10 days after vaginal distension treatment to estimate anal sphincter function. Green fluorescent protein-transfected human-adipose-derived mesenchymal stem cells were transplanted into the internal anal sphincter of nude rats. Hematoxylin-eosin and Masson trichrome staining were performed to evaluate tissue damage and collagen synthesis. Transplanted cells were identified using a green fluorescent protein antibody and a human-specific antibody. Activation of the transplanted human-ADSC was evaluated by quantitative RT-PCR RESULTS: The mean maximum resting pressure (during catheter withdrawal) of vaginal distension rats was significantly lower than that of control rats, and stromal vascular fraction injection normalized it 4 days after treatment (control: 5.66 ± 0.98, vaginal distension: 4.04 ± 1.28, vaginal distension + stromal vascular fraction: 5.92 ± 1.28 [mmHg, control versus vaginal distension: P = .039; vaginal distension versus vaginal distension + stromal vascular fraction: P = .007]). Histological examination showed that vaginal distension disrupted the internal anal sphincter, and the transplanted syngeneic stromal vascular fraction survived for 10 days. Transplanted xenogeneic human-adipose-derived mesenchymal stem cells survived in the internal anal sphincter of nude rats for 4 and 10 days. Genes related to extracellular remodeling were up-regulated in the transplanted human-adipose-derived mesenchymal stem cells CONCLUSION: Syngeneic and heterotopic transplanted adipose-derived mesenchymal stem cells engrafted in the internal anal sphincter and ameliorated damaged anal sphincter function in a rat model of vaginal distension.

To determine if the male responders with post-prostatectomy incontinence in the ADRESU study, which is a clinical trial of regenerative therapy by periurethral injection of adipose-derived regenerative cells, are influenced by any background characteristics.Briefly, autologous adipose-derived regenerative cells isolated from abdominal adipose tissue and a mixture of adipose-derived regenerative cells with fat tissue were transurethrally injected into the rhabdosphincter and submucosal space of the urethra, respectively. Sixteen out of 43 patients (37.2%) responded to treatment (responders) and exhibited improvement in the urine leakage volume, defined as50% reduction from baseline determined by the 24-hour pad test at 52 weeks of treatment (or last visit within 52 weeks). Background data such as age, body weight, method of prostatectomy, baseline frequency of leaks, number of leaks, number of pad changes, International Consultation on Incontinence Questionnaire-Short Form, King's Health Questionnaire, urodynamic urethral function including functional profile length and maximum urethral closure pressure, and abdominal leak point pressure were collected and compared between responders and nonresponders.None of the background factors influenced improvement in the responders as compared with the nonresponders. However, a significant between-group difference in the rates of decrease in urine leakage volume was noted in patients of younger age (70 years), compared with those of older age (≥70 years) from 2 to 26 weeks of treatment.A greater decrease in urine leakage volume was noted in the younger patient group than in the older patient group.

This study was carried out to identify biomarkers that distinguish Hunner-type interstitial cystitis from non-Hunner-type interstitial cystitis patients.Total ribonucleic acid was purified from 212 punch biopsy specimens of 89 individuals who were diagnosed as interstitial cystitis/bladder pain syndrome. To examine the expression profile of patients' bladder specimens, 68 urothelial master transcription factors and nine known markers (E-cadherin, cytokeratins, uroplakins and sonic hedgehog) were selected. To classify the biopsy samples, principal component analysis was carried out. A decision tree algorithm was adopted to identify critical determinants, in which 102 and 116 bladder specimens were used for learning and validation, respectively.Principal component analysis segregated tissues from Hunner-type and non-Hunner-type interstitial cystitis specimens in principal component axes 2 and 4. Principal components 2 and 4 contained urothelial stem/progenitor transcription factors and cytokeratins, respectively. A decision tree identified KRT20, BATF and TP63 to classify non-Hunner-type and Hunner-type interstitial cystitis specimens. KRT20 was lower in tissues from Hunner-type compared with non-Hunner-type interstitial cystitis specimens (P 0.001). TP63 was lower in Hunner's lesions compared with adjacent mucosa from Hunner-type interstitial cystitis patients (P 0.001). Blinded validation using additional biopsy specimens verified that the decision tree showed fairly precise concordance with cystoscopic diagnosis.KRT20, BATF and TP63 were identified as biologically relevant biomarkers to classify tissues from interstitial cystitis/bladder pain syndrome specimens. The biologically explainable determinants could contribute to defining the elusive interstitial cystitis/bladder pain syndrome pathogenesis.

Objective To evaluate the efficacy and safety of intravesical KRP-116D, 50% dimethyl sulfoxide solution compared with placebo, in interstitial cystitis/bladder pain syndrome patients. Methods Japanese interstitial cystitis/bladder pain syndrome patients with an O'Leary-Sant Interstitial Cystitis Symptom Index score of ≥9, who exhibited the bladder-centric phenotype of interstitial cystitis/bladder pain syndrome diagnosed by cystoscopy and bladder-derived pain, were enrolled. Patients were allocated to receive either KRP-116D (n = 49) or placebo (n = 47). The study drug was intravesically administered every 2 weeks for 12 weeks. Results For the primary endpoint, the change in the mean O'Leary-Sant Interstitial Cystitis Symptom Index score from baseline to week 12 was -5.2 in the KRP-116D group and -3.4 in the placebo group. The estimated difference between the KRP-116D and placebo groups was -1.8 (95% confidence interval -3.3, -0.3; P = 0.0188). Statistically significant improvements for KRP-116D were also observed in the secondary endpoints including O'Leary-Sant Interstitial Cystitis Problem Index score, micturition episodes/24 h, voided volume/micturition, maximum voided volume/micturition, numerical rating scale score for bladder pain, and global response assessment score. The adverse drug reactions were mild to moderate, and manageable. Conclusions This first randomized, double-blind, placebo-controlled trial shows that KRP-116D improves symptoms, voiding parameters, and global response assessment, compared with placebo, and has a well-tolerated safety profile in interstitial cystitis/bladder pain syndrome patients with the bladder-centric phenotype.

Aim: To verify if the efficacy of the triple therapy with tamsulosin, dutasteride, and imidafenacin (TDI) is influenced by any background characteristics in patients with overactive bladder (OAB). Methods: A subanalysis of data from the DIrecT study was conducted. Superiority of TDI over tamsulosin and dutasteride in terms of efficacy based on the Overactive Bladder Symptom Score (OABSS), total International Prostate Symptom Score (IPSS), IPSS quality of life index, and postvoid residual (PVR) was evaluated in binary subgroups. Results: In the treatment groups, there was a significant interaction of total OABSS with testosterone level (≥4.8 vs. p = 0.043) and PVR (≥20 vs. p = 0.018). For the total IPSS, no significant interaction was found except for the IPSS QOL index. For the IPSS QOL index, a significant interaction was found with testosterone level (≥4.8 vs. p < 0.0001) as well as with total IPSS and total OABSS. For the PVR, no significant interaction was found except with total OABSS. Conclusions: Triple therapy with TDI is suggested to be a therapeutic option for benign prostatic hyperplasia in patients with residual OAB symptoms refractory to tamsulosin and in patients with various background characteristics regardless of severity of OAB symptoms. Trial Registry No. UMIN 000011980.

Objective The urodynamics underlying lower urinary tract (LUT) dysfunction in frontotemporal lobar degeneration (FTLD) has not been reported. Herein, we investigated LUT function in FTLD patients by performing a urodynamics analysis. Patients and methods We recruited five FTLD patients with LUT symptoms: three men, two women; mean age, 70.4 years; mean disease duration, 3.8 years; mean Hoehn-Yahr grade 1.0. We administered a urinary symptom questionnaire and performed a urodynamics study in each patient. Results LUT symptoms were observed in all patients. Urinary urgency/frequency (also called overactive bladder, OAB) was noted in all; OAB wet in three (60%) and mild voiding difficulty in two (40%). The urodynamic abnormalities included detrusor overactivity in four (80%), increased bladder sensation in two, large post-void residual in one (comorbid spondylosis), and latent detrusor underactivity in two. None had apparent outlet obstruction or detrusor-sphincter dyssynergia. Sphincter electromyography was normal in the cases studied. Conclusion We observed detrusor overactivity in FTLD patients with LUT symptoms. Although a preliminary observation, this LUT feature, which might reflect the frontal/insular cortex pathology typically associated with FTLD, requires appropriate management and care.

Aims Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) causes long-standing pain and/or storage symptoms. This study aimed to evaluate the likelihood of deterioration of bladder sensation in a carrageenan-induced CP/CPPS model by direct measurement of the bladder mechanosensitive single-unit afferent nerve activity. Methods In this study, male adult Sprague-Dawley rats were used. They were injected 50 µL of 3% λ-carrageenan or its vehicle (saline) into both lobes of the ventral prostate. Seven days following injection, the pain behavior at the pelvic-perineal area (using von Frey filaments), prostatic blood flow (using a laser blood flowmeter), and histology were examined along with cystometry (under conscious free-moving condition) and mechanosensitive single-unit afferent nerve activity (under urethane anesthesia). Results The prostate showed increased tissue weight and decreased blood flow and inflammatory cell infiltration in the carrageenan group compared to the control group. Consequently, the threshold of the pain behavior was decreased, and the basal and threshold pressures of the bladder were increased in the carrageenan group. In contrast, no significant differences of bladder histology and other cystometric parameters were found between the groups. Regarding Aδ- or C-fibers, the mechanosensitive afferent nerve activities revealed no differences in either group. Conclusions The carrageenan-induced CP/CPPS rat model showed edema, ischemia, and inflammatory pain in the prostate, whereas a little change was detected in bladder sensation. These findings, which were evaluated using a direct measurement of the mechanosensitive single-unit afferent nerve activity, suggest that the bladder sensation is unlikely deteriorated in this model.

OBJECTIVE To examine the urodynamic effects of fesoterodine on neurogenic detrusor overactivity and/or low compliance bladder. METHODS A total of 77 patients (52 men, 25 women; aged 61.6 ± 20.3 years) were given fesoterodine 4-8 mg/day and prospectively followed for 12 weeks. The primary end-point variable was change in the maximum cystometric capacity on urodynamic study. The secondary end-point was to assess the number of patients whose neurogenic detrusor overactivity disappeared, and the changes in the urodynamic parameters, lower urinary tract symptoms questionnaires and the 3-day frequency volume chart parameters after the treatment. RESULTS A total of 13 patients (16.9%) withdrew because of adverse events (dry mouth or blurred vision), and four patients dropped out for unknown reasons. Finally, 60 patients completed the study. Bladder capacity at first desire to void, maximum cystometric capacity and bladder compliance increased by 29.2 mL, 79.9 mL and 22.2 mL/cm H2 O, respectively, showed statistical significance (P = 0.026, P

Objective The aim of this study was to examine the long-term efficacy of combination of tamsulosin 0.2 mg + dutasteride 0.5 mg + imidafenacin 0.2 mg (TDI) therapy compared with tamsulosin + dutasteride (TD) therapy for 52 weeks in benign prostatic hyperplasia (BPH) patients with a prostate volume (PV) ≥30 mL and remaining overactive bladder (OAB) symptoms after having received tamsulosin for ≥8 weeks. Previously, we reported that the improvement in OAB symptoms at 24 weeks was significantly greater in the TDI than TD group. Methods BPH patients with OAB symptoms after ≥8 weeks tamsulosin were randomly assigned to the TDI or TD group in a ratio of 1:1 ratio, and followed-up for 52 weeks. Changes in the OAB Symptom Score (OABSS), International Prostate Symptom Score (IPSS), and post-void residual (PVR) were evaluated. Results In all, 163 patients were randomized, and 125 patients (76.7%) completed 52 weeks of treatment. At Week 52, there were significant decreases in the OABSS and IPSS storage subscore compared with baseline in the TDI versus TD group, but the change in the total IPSS did not differ significantly between the two groups. There was no change in PVR from Week 24 to Week 52 in either group. Conclusions For BPH patients with PVR ≥30 mL and remaining storage symptoms despite tamsulosin monotherapy, TDI treatment showed better results in terms of improved OAB symptoms than TD treatment up to 52 weeks.

Objectives To show the efficacy of propiverine hydrochloride in the management of symptoms of stress urinary incontinence in female patients with mixed-type urinary incontinence. Methods The study was carried out as a multicenter single-arm clinical trial at 64 institutions in Japan. The participants were female patients aged ≥20 years with mixed-type urinary incontinence. The frequency of stress urinary incontinence and urgency urinary incontinence was evaluated at baseline and 4, 8 and 12 weeks after treatment with propiverine hydrochloride. Subjective symptoms were evaluated using the Overactive Bladder Symptom Score and the International Consultation on Incontinence Questionnaire-Short Form. Functional urethral length and maximum urethral closing pressure were also measured at baseline and 12 weeks after treatment at the institutions where the urethral pressure profile was taken. Results In total, 49 mixed-type urinary incontinence patients were enrolled in the present study. The number of cases of urgency urinary incontinence was reduced time-dependently, which showed statistically significant differences between baseline and 4, 8 and 12 weeks after treatment. A similar statistically different reduction was also observed for stress urinary incontinence. The mean reduction rates of urgency urinary incontinence and stress urinary incontinence at 12 weeks after treatment were 63.9% and 44.3%, respectively. The total scores of International Consultation on Incontinence Questionnaire-Short Form and Overactive Bladder Symptom Score were gradually reduced, and the differences were statistically significant. Functional urethral length and maximum urethral closing pressure at 12 weeks after treatment did not show any statistical differences compared with those at baseline. Conclusions Propiverine hydrochloride can be an effective therapeutic option for stress urinary incontinence in patients with mixed-type urinary incontinence.

Parkinson’s disease (PD) and multiple system atrophy (MSA) are major neurogenerative diseases characterized pathologically by abnormal alpha-synuclein aggregation. PD and MSA are clinically characterized by motor disorder and bladder dysfunction (mainly urinary urgency and frequency, also called overactive bladder). However, few literatures are available concerning bladder dysfunction in PD or MSA. A systematic review. The bladder dysfunction in MSA is more severe than that in PD for large post-void residual or urinary retention. These bladder dysfunctions presumably reflect the different nervous system pathologies. Overactive bladder in PD reflects lesions in the brain, e.g., in the prefrontal-nigrostriatal D1 dopaminergic bladder-inhibitory pathway. Overactive bladder in MSA reflects lesions similar to PD and the cerebellum (bladder-inhibitory), and the urinary retention in MSA presumably reflects lesions in the pontine micturition center and the sacral intermediolateral nucleus of the spinal cord (bladder-facilitatory). Bladder dysfunction not only impairs an individual’s quality of life, it can also cause emergency hospitalizations due to acute retention and early institutionalization. Anticholinergics are the first-line treatment for bladder dysfunction in PD and MSA patients, but care should be taken for the management of bladder dysfunction—particularly in MSA patients due to the high prevalence of difficult emptying, which needs clean, intermittent catheterization. This review summarizes the epidemiology, pathophysiology, and management of bladder dysfunction in individuals with PD or MSA.

Male stress urinary incontinence is a prevalent condition after radical prostatectomy. While the standard recommendation for the management of urine leakage is pelvic floor muscle training, its efficacy is still unsatisfactory. Therefore, we have focused on regenerative therapy, which consists of administering a periurethral injection of autologous regenerative cells from adipose tissue, separated using the Celution® system. Based on an interim data analysis of our exploratory study, we confirmed the efficacy and acceptable safety profile of this treatment. Accordingly, we began discussions with Japanese regulatory authorities regarding the development of this therapy in Japan. The Ministry of Health, Labour and Welfare suggested that we implement a clinical trial of a new medical device based on the Pharmaceutical Affaires Act in Japan. Next, we discussed the design of this investigator-initiated clinical trial (the ADRESU study) aimed at evaluating the efficacy and safety of this therapy, in a consultation meeting with the Pharmaceuticals and Medical Device Agency. The ADRESU study is an open-label, multi-center, single-arm study involving a total of 45 male stress urinary incontinence patients with mild-to-moderate urine leakage persisting more than 1 year after prostatectomy, in spite of behavioral and pharmacological therapies. The primary endpoint is the rate of patients at 52 weeks with improvement of urine leakage volume defined as a reduction from baseline greater than 50% by 24-h pad test. Our specific hypothesis is that the primary endpoint result will be higher than a pre-specified threshold of 10%. The ADRESU study is the first clinical trial of regenerative treatment for stress urinary incontinence by adipose-derived regenerative cells using the Celution® system based on the Japanese Pharmaceutical Affaires Act. We will evaluate the efficacy and safety in this trial to provide an adequate basis for marketing approval with the final objective of making this novel therapy widely available for Japanese patients. This trial was registered at the University Hospital Medical information Network Clinical Trial Registry (UMIN-CTR Unique ID: UMIN000017901 ; Registered July 1, 2015) and at ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT02529865 ; Registered August 18, 2015).

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.

Objectives To characterize interstitial cystitis pathology based on the expression profile of urothelial tissue-specific master transcription factors. Methods Bladder carcinoma cell lines derived from the urothelial stem cells (epithelial or mesenchymal) were used to identify candidate urothelial master transcription factors. Gene expression was measured with quantitative reverse transcription polymerase chain reaction. From the initial screening of 170 transcription factors (human homologs of Drosophila segmentation genes and known master transcription factors from a database), 28 transcription factors were selected. Subsequently, messenger ribonucleic acid from bladder biopsies of interstitial cystitis patients was purified, and gene expression levels of known urothelial marker genes and candidate master transcription factors were measured. Multivariate expression data were analyzed with spss software. Results Factor analysis decomposed the expression profile into four axes: principal axis 1 included retinoic acid receptors and 17 candidate master transcription factors. Principal axis 2 included KRT5 and five candidates. Principal axis 3 included transcription factor TP63 and two candidates. Principal axis 4 included SHH and two candidates. Principal component analysis segregated biopsies from Hunner's lesion in the principal component 1 (retinoic acid)/principal component 2 (SOX13)/principal component 3 (TP63) space. Conclusions Urothelial master transcription factors could serve as novel diagnostic markers and potentially explain the molecular pathology of interstitial cystitis.

Objectives To evaluate the efficacy and safety of a combination therapy with dutasteride and imidafenacin in patients with benign prostatic hyperplasia and persistent overactive bladder symptoms. Methods A total of 163 patients presenting an enlarged prostate (volume >30 mL) and persistent overactive bladder symptoms despite at least 8 weeks of tamsulosin were randomized to receive tamsulosin and dutasteride, or tamsulosin, dutasteride and imidafenacin at a 1:1 ratio. The primary end-point was the mean change from baseline to week 24 in total overactive bladder symptom score. Results The mean change in total overactive bladder symptom score from baseline at week 24 was −1.99 (95% confidence interval −2.57 to −1.41) in the tamsulosin and dutasteride group, and −3.12 (95% confidence interval −3.72 to −2.52) in the tamsulosin, dutasteride and imidafenacin group. The tamsulosin, dutasteride and imidafenacin group significantly improved total overactive bladder symptom score at week 24 as compared with the tamsulosin and dutasteride group; the mean difference was −1.18 (−2.02 to −0.34). The between-group difference was statistically significant as early as week 4. The total International Prostate Symptom Score, storage subscore, quality of life index, and benign prostatic hyperplasia impact index also significantly improved in the tamsulosin, dutasteride and imidafenacin group. Conclusions Tamsulosin, dutasteride and imidafenacin combination therapy improves overactive bladder symptoms and quality of life without causing serious adverse drug reactions in patients with enlarged prostate not responding to tamsulosin. This combination therapy seems to represent a promising therapeutic option in these patients.

The present article is an abridged English translation of the Japanese clinical guidelines for the diagnosis and treatment of lower urinary tract dysfunction in patients with spinal cord injury updated as of July 2019. The patients are adult spinal cord injured patients with lower urinary tract dysfunction; special consideration of pediatric and elderly populations is presented separately. The target audience is healthcare providers who are engaged in the medical care of patients with spinal cord injury. The mandatory assessment includes medical history, physical examination, frequency-volume chart, urinalysis, blood chemistry, transabdominal ultrasonography, measurement of post-void residual urine, uroflowmetry and video-urodynamic study. Optional assessments include questionnaires on the quality of life, renal scintigraphy and cystourethroscopy. The presence or absence of risk factors for renal damage and symptomatic urinary tract infection affects urinary management, as well as pharmacological treatments. Further treatment is recommended if the maximum conservative treatment fails to improve or prevent renal damage and symptomatic urinary tract infection. In addition, management of urinary incontinence should be considered individually in patients with risk factors for urinary incontinence and decreased quality of life.

Aim To evaluate the effects of early (≤6 months after starting any medical treatment [baseline] for benign prostatic hyperplasia [BPH]), intermediate (between >6 months and 2 years from baseline) and late (2 years after baseline) initiation of add-on dutasteride therapy on the incidence of acute urinary retention (AUR) and BPH-related surgery in Japanese patients with moderate-to-severe BPH. Methods This multicentre, observational, retrospective chart review study used anonymised data from Japanese medical records. Eligible patients (≥50 years) were followed from baseline until first AUR, BPH-related surgery or Year 4. Results Overall, 1206 patients were included (early initiation: n = 793; intermediate: n = 233; late: n = 180). Early dutasteride initiation was not superior to late initiation in reducing the risk of first AUR or BPH-related surgery from baseline (hazard ratio [HR] 0.733; 95% confidence interval [CI] 0.468-1.150) but was superior in reducing the risk of first AUR alone (HR 3.449; 95% CI 1.796-6.623). One year after initiation, the cumulative incidence of first AUR rose rapidly in the late vs early and intermediate initiation groups. Incidences of all parameters (first AUR/BPH-related surgery, first AUR alone and BPH-related surgery alone) in patients undergoing BPH-related surgery in low incidence sites (ie clinical sites with ≤ 16% incidence of first AUR or BPH-related surgery) were significantly lower in the early vs late initiation groups. Conclusion Early dutasteride initiation reduced the risk of AUR in a Japanese real-world setting. A randomised controlled trial is warranted to evaluate the benefit of early initiation in preventing BPH-related surgery in Japanese patients.

We report a rare case of extravasation of urine, which may be associated with bilateral complete ureteral duplication, vesicoureteral reflux (VUR), and benign prostatic hyperplasia (BPH). A 71-year-old male presented with a complaint of right abdominal pain. An extravasation of urine was noted, and was improved by indwelling urethral catheterization. Transurethral resection of the prostate and the endoscopic subureteral injection of dextanomer/hyaluronic acid were performed for the treatment of BPH and VUR, respectively. The post-surgery recovery was successful.

To investigate gastrointestinal function in dementia with Lewy bodies and Parkinson disease. We examined gastric emptying and colonic transit time in 19 dementia with Lewy bodies and 46 Parkinson disease patients. Gastric emptying was longer in dementia with Lewy bodies than in Parkinson disease (p = 0.014). Colonic transit time tended to be longer in dementia with Lewy bodies than in Parkinson disease. There was no relationship between gastric emptying and colonic transit time, nor between gastric emptying, colonic transit time and age. Gastric emptying was prolonged in dementia with Lewy bodies compared to Parkinson disease.

In order to investigate lower urinary tract function in hereditary spastic paraplegia (HSP), we recruited 12 HSP patients: 8 men, 4 women; mean age, 64.6 years; mean disease duration, 18.9 years; walk without cane, 2, walk with cane, 6, wheelchair bound, 3. We performed urinary symptom questionnaires and a urodynamic testing in all patients. As a result, urinary symptoms were observed in all but 3, including urinary urgency/frequency (also called overactive bladder) in 9 and hesitancy/poor stream in 6. Urodynamic abnormalities included detrusor overactivity during bladder filling in 10, underactive detrusor on voiding in 8 (detrusor hyperactivity with impaired contraction [DHIC] in 5), detrusor-sphincter dyssynergia (DSD) on voiding in 3, and post-void residual in 5. Sphincter electromyography showed neurogenic motor unit potential in 4. In conclusion, we observed high frequency of urinary symptoms in HSP. Urodynamics indicated that the main mechanism is DHIC with/without DSD for their urinary symptom, and sacral cord involvement in some cases. These findings facilitate patients’ care including clean, intermittent catheterization.

Interstitial cystitis (IC), also known as bladder pain syndrome, is a chronic inflammatory disease that affects the bladder. The symptoms of IC vary, including feeling an urgent need for immediate urination and of needing to urinate often, as well as bladder or pelvic pain. Despite its high incidence, no molecular diagnostic methods are available for IC, and the molecular pathogenesis is unknown. microRNAs (miRNA) can regulate expression of RNA transcripts in cells and aberrant expression of miRNAs is associated with several human diseases. Here, we investigated the molecular pathogenesis of IC based on miRNA expression signatures. RNA sequencing of miRNA levels in IC tissues and comparison with levels in normal bladder tissue and bladder cancer revealed dysregulated expression of 366 miRNAs (203 and 163 down- and upregulated miRNAs, respectively). In particular, miR-320 family miRNAs(miR-320a, miR-320b, miR-320c, miR-320d and miR-320e) had downregulated expression in IC tissues. Genome-wide gene expression analyses and in silico database analyses showed that three transcription factors, E2F-1, E2F-2 and TUB, are regulated by miR-320 family miRNAs. Immunostaining of IC tissues confirmed that these transcription factors are overexpressed in IC tissues. Novel approaches that identify aberrantly expressed miRNA regulatory networks in IC could provide new prognostic markers and therapeutic targets for this disease.

The "Japanese Clinical Guideline for Female Lower Urinary Tract Symptoms," published in Japan in November 2013, contains two algorithms (a primary and a specialized treatment algorithm) that are novel worldwide as they cover female lower urinary tract symptoms other than urinary incontinence. For primary treatment, necessary types of evaluation include querying the patient regarding symptoms and medical history, examining physical findings, and performing urinalysis. The types of evaluations that should be performed for select cases include evaluation with symptom/quality of life (QOL) questionnaires, urination records, residual urine measurement, urine cytology, urine culture, serum creatinine measurement, and ultrasonography. If the main symptoms are voiding/post-voiding, specialized treatment should be considered because multiple conditions may be involved. When storage difficulties are the main symptoms, the patient should be assessed using the primary algorithm. When conditions such as overactive bladder or stress incontinence are diagnosed and treatment is administered, but sufficient improvement is not achieved, the specialized algorithm should be considered. In case of specialized treatment, physiological re-evaluation, urinary tract/pelvic imaging evaluation, and urodynamic testing are conducted for conditions such as refractory overactive bladder and stress incontinence. There are two causes of voiding/post-voiding symptoms: lower urinary tract obstruction and detrusor underactivity. Lower urinary tract obstruction caused by pelvic organ prolapse may be improved by surgery.

Objectives To conduct histopathological studies on various organs in three different groups of female rats for adverse effects of pulsed magnetic stimulation (MS). Blood tests and body and organ weights were also studied. Methods A high-frequency continuous magnetic stimulator was used (SMN-X, Nihon Kohden, Tokyo). Thirty-four female Sprague-Dawley rats (SPF) were randomly divided into three groups: treatment (MS) groups with 12 and 36 stimulations (seven rats in each); sham groups exposed only to sounds of stimulation for 12 and 36 times; (seven rats in each); and control groups with no stimulation or sound during the same periods of 12 and 36 stimulations (five rats in each). The MS group received magnetic stimulation at the maximum output level (560 mT peak) at 10 Hz for 25 min once daily for 5 days a week. After treatment various organs including genital organs were removed for histological and endocrinological examinations. Results No changes were seen in body and organ weights and daily behaviors among the three groups. No adverse influence of magnetic stimulation was noted on histopathological examinations of liver, spleen, kidney, lung, heart, thymus, urinary bladder, skeletal muscle and bone marrow. No intragroup changes were seen among the three groups with regard to endocrinological findings including blood cell counts, adrenocorticotropic hormone (ACTH), estrogen and progesterone levels. Conclusions Pulsed magnetic stimulation exerted no apparent adverse effect on the various organs, hormone levels, body weight, and daily behaviors in female rats.

Objectives To investigate the factors for continuation or withdrawal as an extension of a prospective study of silodosin monotherapy for the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia for more than 6 years. Methods A total of 104 patients (age 71.5 ± 8.2 years) were enrolled in the present study. The mean prostate volume was 44.1 ± 23.9 mL. International Prostate Symptom Score, quality of life index, maximum flow rate, and postvoid residual urine volume were determined at baseline, and at 1, 3, 6 and 12–72 months after treatment. Results Adverse events were noted in 14 patients (13.5%), and the most frequent adverse event was ejaculatory dysfunction (5.8%). Withdrawal was noted in 78 patients, and 26 patients (25.0%) were still taking silodosin at 72 months (continuing group). The reasons for withdrawals were: unknown in 27 patients (26.0%), adverse events in nine patients (8.7%), unsatisfactory effects in 30 patients (28.8%) and satisfied with the current condition for six patients (5.8%). In 30 patients who withdrew because of unsatisfactory effects, surgery was carried out in 21 patients (surgery group). The baseline total International Prostate Symptom Score did not differ between the continuing group and the surgery group. However, patients with the continuing group had significantly smaller baseline prostate volume, and lower baseline quality of life index and prostate-specific antigen, than in the surgery group. The mean total International Prostate Symptom Score, quality of life index and maximum flow rate improved significantly at 1 month, and remained stable up to 72 months. Conclusions The withdrawal rate was higher in patients with a larger prostate. The effects of silodosin for lower urinary tract symptoms was immediate and stable up to 72 months.

Background:Amantadine is a drug used for patients with Parkinson's disease (PD) and vascular parkinsonism (VP). These patients often have lower urinary tract symptoms (LUTS) and nocturnal polyuria (NP). Thus, we investigated the effect of amantadine on these in parkinsonian patients.Methods:Twenty-two patients with LUTS, including 13 with PD and nine with VP, were recruited. We performed a urinary questionnaire, frequency-volume chart, and residual urine (RU) measurement before and after daily administration of 150 mg and 300 mg amantadine.Results:Before amantadine administration, mean daytime urinary frequency was 9.07(standard error [SE], 0.64), nighttime urinary frequency 2.89 (0.24), urinary urgency per week 24.2 (6.69), urge incontinence per month 15.1( 9.94), urine volume per void 145.6( 12.6) mL, and residual urine volume 12.5( 6.30) mL. After daily 150 mg amantadine administration, mean daytime and nighttime urinary frequency, urinary urgency, and urge incontinence decreased to 6.9( 0.42), 1.97( 0.21), 13.0( 3.58), and 14.2( 10.2), respectively, and urine volume per void increased to 174.1( 11.3) mL. NP( N=8) was ameliorated in six patients. No patient had side effects. After daily 300 mg amantadine administration( N=8), mean daytime and nighttimeurinary frequency, urinary urgency, and urge incontinence decreased to 6.90 (0.33), 1.69 (0.10), 5.88 (1.61), and 2.31 (0.61), respectively, and urine volume per void increased to180.2 (15.0) mL. NP (N=4) was ameliorated in two patients. One patient developed hallucination, and two patients developed flashing sensation.Conclusion:Amantadine has beneficial effects on LUTS and NP in patients with VP and PD.

Objectives To investigate the efficacy of a once-daily oxybutynin patch for nocturia, and its influence on sleep quality in patients with overactive bladder. Methods We carried out post-hoc analysis of a phase III, randomized, double-blind, comparative study in which an oxybutynin patch was administered once daily for 12 weeks to Japanese patients with overactive bladder. Patients with a baseline mean of one or more episodes of nocturia per night (data from voiding diaries) were analyzed. The mean number of micturitions, mean voided volume per micturition, mean first voided volume at night, mean sleep duration, and hours of undisturbed sleep were compared between the once-daily oxybutynin patch group and the placebo group. All parameters were expressed as the least squares mean values. Results The analysis included 576 patients. The number of nocturia episodes decreased by 0.66 in the oxybutynin patch group versus 0.51 in the placebo group (P = 0.0249). Also, the voided volume per nocturnal micturition and the first voided volume at night showed a significant increase in the oxybutynin patch group compared with the placebo group (P = 0.0073 and P = 0.0005, respectively). The hours of undisturbed sleep showed significant prolongation by 76.14 min in the oxybutynin patch group versus 56.07 min in the placebo group (P = 0.0257). Conclusions Oxybutynin patch treatment reduces the number of nocturia episodes and prolongs the hours of undisturbed sleep, thus improving sleep quality and sleep-related quality of life in patients with overactive bladder.