Stem cell therapy for interstitial cystitis/bladder pain syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic disease with limited treatment options. Current multidisciplinary approach targeting bladder inflammation and urothelial dysfunction has limited durable effect that major surgery is ultimately required for both Hunner and non-Hunner type IC. Various investigational attempts are underway to avoid such operations and preserve the urinary bladder. Stem cell therapy is a fascinating option for treating chronic illnesses. Stem cells can self-renew, restore damaged tissue, and have paracrine effects. The therapeutic efficacy and safety of stem cell therapy have been demonstrated in numerous preclinical models, primarily chemically induced cystitis rat models. Only one clinical trial (phase 1 study) has investigated the safety of human embryonic stem cell-derived mesenchymal stem cells in three Hunner-type IC patients. Under general anesthesia, participants underwent cystoscopic submucosal stem cell injection (2.0 × 107 stem cells/5 mL). No safety issues were reported up to 12 months of follow-up and long-term follow-up (up to 3 years). Although there were variations in therapeutic response, all patients reported significant improvement in pain at 1 month postoperatively. One patient underwent fulguration of the Hunner lesion after the trial, but others reported an overall improvement in pain. The analysis on phase 1/2a trial which had several modifications in protocol is currently ongoing. Despite several limitations that need to be overcome, stem cell therapy could be a potential therapeutic option for treating IC/BPS. Clinical outcome on phase 1/2a trial is important and might provide more insight into the clinical application of stem cell therapy for IC/BPS.

Assessment of the Therapeutic Effectiveness of Glutathione-Enhanced Mesenchymal Stem Cells in Rat Models of Chronic Bladder Ischemia-Induced Overactive Bladder and Detrusor Underactivity.

Overactive bladder (OAB) and detrusor underactivity (DUA) are representative voiding dysfunctions with a chronic nature and limited treatment modalities, and are ideal targets for stem cell therapy. In the present study, we investigated the therapeutic efficacy of human mesenchymal stem cells (MSCs) with a high antioxidant capacity generated by the Primed Fresh OCT4 (PFO) procedure in chronic bladder ischemia (CBI)-induced OAB and DUA rat models. Sixteen-week-old male Sprague-Dawley rats were divided into three groups (sham, OAB or DUA, and stem cell groups; n=10, respectively). CBI was induced by bilateral iliac arterial injury (OAB, 10 times; DUA, 30 times) followed by a 1.25% cholesterol diet for 8 weeks. Seven weeks after injury, rats in the stem cell and other groups were injected with 1×106 PFO-MSCs and phosphate buffer, respectively. One week later, bladder function was analyzed by awake cystometry and bladders were harvested for histological analysis. CBI with a high-fat diet resulted in atrophy of smooth muscle and increased collagen deposits correlating with reduced detrusor contractility in both rat models. Arterial injury 10 and 30 times induced OAB (increased number of non-voiding contractions and shortened micturition interval) and DUA (prolonged micturition interval and increased residual volume), respectively. Injection of PFO-MSCs with the enhanced glutathione dynamics reversed both functional and histological changes; it restored the contractility, micturition interval, residual volume, and muscle layer, with reduced fibrosis. CBI followed by a high-fat diet with varying degrees of arterial injury induced OAB and DUA in rats. In addition, PFO-MSCs alleviated functional and histological changes in both rat models.

A Randomized, Double-Blind, Placebo-Controlled, Bridging Study to Evaluate the Efficacy and Safety of Vibegron in Treating Korean Patients With Overactive Bladder.

PURPOSE: Vibegron, a novel, potent ß3 agonist, has been approved for clinical use in overactive bladder (OAB) treatment in Japan and the Unites States. We performed a bridging study to investigate the efficacy and safety of a daily 50-mg vibegron (code name JLP-2002) dose in Korean patients with OAB. METHODS: A multicenter, randomized, double-blind, placebo-controlled study was conducted from September 2020 to August 2021. Adult patients with OAB with a symptom duration of more than 6 months entered a 2-week placebo run-in phase. Eligibility was assessed at the end of this phase and selected patients entered a double-blind treatment phase after 1:1 randomization to either the placebo or vibegron (50 mg) group. The study drug was administered once daily for 12 weeks and follow-up visits were scheduled at weeks 4, 8, and 12. The primary endpoint was the change in mean daily micturition at the end of treatment. The secondary endpoints included changes in OAB symptoms (daily micturition, nocturia, urgency, urgency incontinence, and incontinence episodes, and mean voided volume per micturition) and safety. A constrained longitudinal data model was used for statistical analysis. RESULTS: Patients who took daily vibegron had significant improvements over the placebo group in both primary and secondary endpoints, except for daily nocturia episodes. The proportions of patients with normalized micturition and resolution of urgency incontinence and incontinence episodes were significantly higher in vibegron group than in the placebo. Vibegron also improved the patients' quality of life with higher satisfaction rates. The incidence of adverse events in the vibegron and placebo groups was similar with no serious, unexpected adverse drug reactions. No abnormality in electrocardiographs was observed as well as no significant increase in postvoid residual volume. CONCLUSION: Once daily vibegron (50 mg) for 12 weeks was effective, safe, and well-tolerated in Korean patients with OAB.

Therapeutic effects of axitinib, an anti-angiogenic tyrosine kinase inhibitor, on interstitial cystitis.

To investigate the therapeutic effects of axitinib, a tyrosine kinase inhibitor, in an interstitial cystitis (IC) rat model. IC patients with or without Hunner lesion and non-IC controls were enrolled (n = 5/group). Bladder tissues were stained with vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR-2), platelet-derived growth factor (PDGF), and PDGF receptor B (PDGFR-B). The IC group showed extensive VEGFR-2 and PDGFR-B staining compared with controls. Next, ten-week-old female Sprague Dawley rats were divided into three groups (n = 10/group): sham, hydrochloride (HCl), and axitinib groups. One week after HCl instillation (day 0), the axitinib group received oral axitinib (1 mg/kg) for five consecutive days and pain was evaluated daily. Bladder function, histology and genetics were evaluated on day 7. The pain threshold significantly improved 3 days after axitinib administration. Axitinib decreased non-voiding contraction and increased the micturition interval and micturition volume and alleviated urothelial denudation, angiogenesis, mast cell infiltration, and fibrosis. HCl instillation increased the expression of tyrosine kinase receptors, including VEGFR-2 and PDGFR-B; axitinib administration inhibited their expression. Oral administration of axitinib improved pain, voiding profiles, and urothelial integrity by inhibiting angiogenesis in IC rat model. Axitinib may have potential therapeutic efficacy in IC patients.

Safety of Human Embryonic Stem Cell-derived Mesenchymal Stem Cells for Treating Interstitial Cystitis: A Phase I Study.

There are still no definite treatment modalities for interstitial cystitis (IC). Meanwhile, stem cell therapy is rising as potential alternative for various chronic diseases. This study aimed to investigate the safety of the clinical-grade mesenchymal stem cells (MSCs) derived from human embryonic stem cells (hESCs), code name MR-MC-01 (SNU42-MMSCs), in IC patients. Three female IC patients with (1) symptom duration >6 months, (2) visual pain analog scale (VAS) ≥4, and (3) one or two Hunner lesions <2 cm in-office cystoscopy within 1 month were included. Under general anesthesia, participants received cystoscopic submucosal injection of SNU42-MMSCs (2.0 × 107/5 mL) at the center or margin of Hunner lesions and other parts of the bladder wall except trigone with each injection volume of 1 mL. Follow-up was 1, 3, 6, 9, and 12 months postoperatively. Patients underwent scheduled follow-ups, and symptoms were evaluated with validated questionnaires at each visit. No SNU42-MMSCs-related adverse events including immune reaction and abnormalities on laboratory tests and image examinations were reported up to 12-month follow-up. VAS pain was temporarily improved in all subjects. No de novo Hunner lesions were observed and one lesion of the first subject was not identifiable on 12-month cystoscopy. This study reports the first clinical application of transurethral hESC-derived MSC injection in three patients with IC. hESC-based therapeutics was safe and proved to have potential therapeutic efficacy in IC patients. Stem cell therapy could be a potential therapeutic option for treating IC.

Efficacy and Safety of DA-8010, a Novel M3 Antagonist, in Patients With Overactive Bladder: A Randomized, Double-Blind Phase 2 Study.

PURPOSE: DA-8010 is a novel muscarinic M3 receptor antagonist with significant selectivity for bladder over salivary gland in preclinical studies. We evaluated the clinical efficacy and safety of DA-8010 in overactive bladder (OAB) patients. METHODS: This phase 2, randomized, double-blind, parallel-group, active reference- and placebo-controlled trial was conducted at 12 centers in South Korea (NCT03566134). Patients aged ≥19 years with OAB symptoms for ≥3 months were enrolled. Three hundred six patients (30.07% male) were randomized to 12 weeks of treatment among 4 groups; 2 experimental groups (DA-8010 2.5 or 5 mg), an active reference group (solifenacin 5 mg), and a placebo group. The change from the baseline of (=∆) 24-hour frequency at 12 weeks (primary endpoint), episodes of urgency, overall/urgency urinary incontinence, average/ maximum voided volume, nocturia, and patients' subjective responses were analyzed. RESULTS: In the full analysis set, the mean (standard deviation) [median] values for ∆ 24-hour frequency at 12 weeks were -1.01 (2.44) [-1.33] for placebo, -1.22 (2.05) [-1.33] for DA-8010 2.5 mg, and -1.67 (2.25) [-1.67] for DA-8010 5 mg; DA-8010 5 mg showed a significant decrease compared with placebo (P=0.0413). At 4 and 8 weeks, both DA-8010 2.5 mg (P=0.0391 at 4 weeks, P=0.0335 at 8 weeks) and DA-8010 5 mg (P=0.0001 at 4 weeks, P=0.0210 at 8 weeks) showed significant decrease in ∆ 24-hour frequency compared with placebo. DA-8010 5 mg achieved a significant decrease in ∆ number of urgency episodes, compared with placebo at 4 (P=0.0278) and 8 (P=0.0092) weeks. Adverse drug reactions (ADRs) were observed in 3.95% of placebo, 6.67% of DA-8010 2.5 mg, 18.42% of DA-8010 5 mg, and 17.33% of solifenacin 5 mg groups. No serious ADRs were observed in any patient. CONCLUSION: Both DA-8010 2.5 mg and 5 mg showed therapeutic efficacy for OAB without serious ADRs. Therefore, both dosages of DA-8010 can advance to a subsequent large-scale phase 3 trial.

Effects of different types of hysterectomies on postoperative urodynamics and lower urinary tract symptoms.

PURPOSE: To evaluate the effects of different hysterectomies-simple hysterectomy (SH) and radical hysterectomy (RH) with or without radiation therapy (RT) on urodynamics and lower urinary tract symptoms (LUTS). MATERIALS AND METHODS: Among patients who underwent urodynamic study between 2009 and 2019, those with RH history due to cervical cancer and SH for uterine myoma were included. Clinical parameters were compared after adjusting clinically significant baseline variables with multivariate regression. RESULTS: A total of 289 patients (RH-only, n=57; RH+RT, n=72; SH, n=160) were included. Age at hysterectomy, gap between urodynamic study and hysterectomy, body mass index, hypertension and vaginal delivery history were adjusted. Stress urinary incontinence was more likely to occur in SH group (p<0.001), while urgency urinary incontinence was more prevalent in patients with history of RH (odds ratio [OR] 6.4, 95% confidence interval 2.171-18.855; p=0.001). There was no difference in OR of mixed urinary incontinence. Higher proportion of RH patients complained of recurrent urinary tract infection and voiding symptoms requiring intermittent catheterization. On urodynamic study, RH groups had lower maximal flow rate, larger post-void residual, decreased bladder sensation and impaired detrusor contractility (all p<0.001) than SH group. Adjuvant RT resulted in decreased compliance and decrease in volume of the first sense to void. CONCLUSIONS: Predominant LUTS differed among patients after different types of hysterectomy. RH resulted in inefficient bladder emptying, leading to recurrent urinary tract infection and voiding symptoms requiring intermittent catheterization. Adjuvant RT exacerbated bladder compliance and increased bladder sensation.

Intravital imaging and single cell transcriptomic analysis for engraftment of mesenchymal stem cells in an animal model of interstitial cystitis/bladder pain syndrome.

Mesenchymal stem cell (MSC) therapy is a promising treatment for various intractable disorders including interstitial cystitis/bladder pain syndrome (IC/BPS). However, an analysis of fundamental characteristics driving in vivo behaviors of transplanted cells has not been performed, causing debates about rational use and efficacy of MSC therapy. Here, we implemented two-photon intravital imaging and single cell transcriptome analysis to evaluate the in vivo behaviors of engrafted multipotent MSCs (M-MSCs) derived from human embryonic stem cells (hESCs) in an acute IC/BPS animal model. Two-photon imaging analysis was performed to visualize the dynamic association between engrafted M-MSCs and bladder vasculature within live animals until 28 days after transplantation, demonstrating the progressive integration of transplanted M-MSCs into a perivascular-like structure. Single cell transcriptome analysis was performed in highly purified engrafted cells after a dual MACS-FACS sorting procedure and revealed expression changes in various pathways relating to pericyte cell adhesion and cellular stress. Particularly, FOS and cyclin dependent kinase-1 (CDK1) played a key role in modulating the migration, engraftment, and anti-inflammatory functions of M-MSCs, which determined their in vivo therapeutic potency. Collectively, this approach provides an overview of engrafted M-MSC behavior in vivo, which will advance our understanding of MSC therapeutic applications, efficacy, and safety.

A Multicenter, Open-Label, Observational Study Evaluating the Quality of Life After Using a Hydrophilic-Coated Catheter (SpeediCath) With Self-Intermittent Catheterization.

PURPOSE: We evaluated the change in patient quality of life after the use of a hydrophilic-coated catheter (SpeediCath) in adults requiring intermittent catheterization (IC). METHODS: This was a multicenter, open-label, observational study using the Patient Perception of Intermittent Catheterization (PPIC) questionnaire and the Intermittent Self-Catheterization questionnaire (ISC-Q) and safety at 12 and 24 weeks in adult patients who had already used other type of catheters prior to switching to SpeediCath or in patients undergoing self-IC for the first time for any reason. RESULTS: Among a total of 360 subjects, 215 (59.7%) were women, and the mean age was 62.0±13.2 years. At 24 weeks, the satisfaction rate after using SpeediCath was 84.1%, and 80% of patients responded that they could easily perform IC. In total, 81.6% of patients were willing to continue using SpeediCath. The mean ISC-Q score was 54.90±18.65 at 24 weeks. Men found less interference in their daily life by performing IC than women and found it easier to handle the catheter before it was inserted into the urethra. At week 12, the mean change in ISC-Q was significantly greater in patients <65 years (20.24±23.55) than in those ≥65 years (7.57±27.70, P=0.049), but there was no difference at 24 weeks. The most common adverse events were urinary tract infection in 9.72%, gross hematuria in 2.78%, and urethral pain in 1.39%. CONCLUSION: The use of a SpeediCath provided good quality of life for patients who needed self-IC regardless of age or sex.

A Preclinical Study of Human Embryonic Stem Cell-Derived Mesenchymal Stem Cells for Treating Detrusor Underactivity by Chronic Bladder Ischemia.

BACKGROUND: The therapeutic effects of human embryonic stem cell-derived multipotent mesenchymal stem cells (M-MSCs) were evaluated for detrusor underactivity (DUA) in a rat model with atherosclerosis-induced chronic bladder ischemia (CBI) and associated mechanisms. METHODS: Sixteen-week-old male Sprague-Dawley rats were divided into five groups (n = 10). The DUA groups underwent 30 bilateral repetitions of endothelial injury to the iliac arteries to induce CBI, while the sham control group underwent a sham operation. All rats used in this study received a 1.25% cholesterol diet for 8 weeks. M-MSCs at a density of 2.5, 5.0, or 10.0 × 105 cells (250 K, 500 K, or 1000 K; K = a thousand) were injected directly into the bladder 7 weeks post-injury, while the sham and DUA group were treated only with vehicle (phosphate buffer solution). One week after M-MSC injection, awake cystometry was performed on the rats. Then, the bladders were harvested, studied in an organ bath, and prepared for histological and gene expression analyses. RESULTS: CBI by iliac artery injury reproduced voiding defects characteristic of DUA with decreased micturition pressure, increased micturition interval, and a larger residual volume. The pathological DUA properties were improved by M-MSC treatment in a dose-dependent manner, with the 1000 K group producing the best efficacy. Histological analysis revealed that M-MSC therapy reduced CBI-induced injuries including bladder fibrosis, muscular loss, and apoptosis. Transplanted M-MSCs mainly engrafted as vimentin and NG2 positive pericytes rather than myocytes, leading to increased angiogenesis in the CBI bladder. Transcriptomes of the CBI-injured bladders were characterized by the complement system, inflammatory, and ion transport-related pathways, which were restored by M-MSC therapy. CONCLUSIONS: Single injection of M-MSCs directly into the bladder of a CBI-induced DUA rat model improved voiding profiles and repaired the bladder muscle atrophy in a dose-dependent manner.

Features of Various Bladder Lesions and Their Impact on Clinical Symptoms and Recurrence in Interstitial Cystitis.

PURPOSE: We aimed to investigate the impact of various bladder lesions on the clinical symptoms and recurrence of interstitial cystitis (IC). MATERIALS AND METHODS: Patients with IC who underwent transurethral resection and cauterization for Hunner lesions (HLs) were enrolled. Features of HLs-noninflamed, inflamed, and gradually inflamed-and associated cystoscopic findings, including waterfall bleeding (none, focal or extensive), submucosal hemorrhage, and mucosal streak, were analyzed to investigate their association with preoperative symptoms and recurrence. RESULTS: We included 272 procedures from 141 patients (male:female ratio 37:104) with a mean±SD age of 61.4±10.5 years. Recurrence was observed in 160 procedures after a mean of 15.6 months (range 0.7-91.7); repeat transurethral resection and cauterization was performed in 131 cases. The number of HLs observed at each procedure was variable, and sufficient bladder filling revealed hidden lesions in 10.7% of cases. Waterfall bleeding was frequently accompanied with inflamed/gradually inflamed HLs. Inflammatory HLs were associated with smaller functional bladder capacity and preoperative urgency (p=0.007). Extensive waterfall bleeding was associated with smaller functional bladder capacity (p=0.006). On multivariate analysis, initially inflamed HLs (HR: 1.675, 95% CI: 1.022-2.746, p=0.041) and gradual inflammatory changes in HLs (HR: 1.893, 95% CI: 1.050-3.410, p=0.034) were found to be risk factors for recurrence. CONCLUSIONS: Sufficient bladder filling revealed hidden HLs. The features of HLs were not associated with subjective symptoms; inflamed changes were a predictive factor for IC recurrence, and associated with frequent urgency episodes and smaller bladder capacity.

Selective Detection of Nano-Sized Diagnostic Markers Using Au-ZnO Nanorod-Based Surface-Enhanced Raman Spectroscopy (SERS) in Ureteral Obstruction Models.

BACKGROUND: This study investigated the diagnosis of renal diseases using a biochip capable of detecting nano-sized biomarkers. Raman measurements from a kidney injury model were taken, and the feasibility of early diagnosis was assessed. MATERIALS AND METHODS: Rat models with mild and severe unilateral ureteral obstructions were created, with the injury to the kidney varying according to the tightness of the stricture. After generating the animal ureteral obstruction models, urine was collected from the kidney and bladder. RESULTS AND DISCUSSION: After confirming the presence of renal injury, urine drops were placed onto a Raman chip whose surface had been enhanced with Au-ZnO nanorods, allowing nano-sized biomarkers that diffused into the nanogaps to be selectively amplified. The Raman signals varied according to the severity of the renal damage, and these differences were statistically confirmed. CONCLUSION: These results confirm that ureteral stricture causes kidney injury and that signals in the urine from the release of nano-biomarkers can be monitored using surface-enhanced Raman spectroscopy.

Therapeutic Efficacy of Human Embryonic Stem Cell-Derived Multipotent Stem/Stromal Cells in Diabetic Detrusor Underactivity: A Preclinical Study.

Mesenchymal stem/stromal cell (MSC) therapy is a promising approach for treatment of as yet incurable detrusor underactivity (DUA), which is characterized by decreased detrusor contraction strength and/or duration, leading to prolonged bladder emptying. In the present study, we demonstrated the therapeutic potential of human embryonic stem cell (ESC)-derived multipotent MSCs (M-MSCs) in a diabetic rat model of DUA. Diabetes mellitus (DM) was induced by intraperitoneal injection of streptozotocin (STZ) (50 mg/kg) into 8-week-old female Sprague-Dawley rats. Three weeks later, various doses of M-MSCs (0.25, 0.5, and 1 × 106 cells) or an equivalent volume of PBS were injected into the outer layer of the bladder. Awake cystometry, organ bath, histological, and gene expression analyses were evaluated 1 week (short-term) or 2 and 4 weeks (long-term) after M-MSC transplantation. STZ-induced diabetic rats developed DUA, including phenotypes with significantly longer micturition intervals, increased residual urine amounts and bladder capacity, decreased micturition pressure on awake cystometry, and contractile responses to various stimuli in organ bath studies. Muscle degeneration, mast cell infiltration, fibrosis, and apoptosis were present in the bladders of DM animals. A single local transplantation of M-MSCs ameliorated DUA bladder pathology, including functional changes and histological evaluation, and caused few adverse outcomes. Immunostaining and gene expression analysis revealed that the transplanted M-MSCs supported myogenic restoration primarily by engrafting into bladder tissue via pericytes, and subsequently exerting paracrine effects to prevent apoptotic cell death in bladder tissue. The therapeutic efficacy of M-MSCs was superior to that of human umbilical cord-derived MSCs at the early time point (1 week). However, the difference in efficacy between M-MSCs and human umbilical cord-derived MSCs was statistically insignificant at the later time points (2 and 4 weeks). Collectively, the present study provides the first evidence for improved therapeutic efficacy of a human ESC derivative in a preclinical model of DM-associated DUA.

Treatment outcomes and overactive bladder symptoms after midurethral sling in female patients with or without various neurological diseases.

AIMS: We investigated surgical outcomes and changes of overactive bladder (OAB) symptoms after midurethral sling in female stress urinary incontinence (SUI) patients with or without neurological disease (ND) without spinal cord injury. METHODS: Patients who underwent midurethral sling for SUI between January 2009 and December 2018 were reviewed. Postoperative changes in OAB symptoms (de novo occurrence or resolution) within 1 year were compared in each preoperative symptom subset with a 1:1 matched analysis between non-neurological disease (NND) and ND group. RESULTS: A total of 855 patients (median follow-up: 49.8 months; mean age: 57.9 ± 9.3 years) were included. Successful SUI correction was achieved in 95.0% of NND and 93.7% of ND patients (p = .440). Among 797 patients (711 NND and 86 ND) without remnant SUI, 227 had SUI only, 198 had SUI with urgency, and 372 had mixed urinary incontinence (MUI) preoperatively. The ND patients tended to be older (62.8 ± 9.2 vs. 57.2 ± 9.0 years) and had higher proportions of diabetes (24.4% vs. 8.0%), hypertension (47.7% vs. 26.7%), and MUI (64.0% vs. 44.6%) than NND patients (p < .001, respectively). After matching age, diabetes, and hypertension, the incidence of de novo OAB was higher in ND patients (SUI only; 21.1% vs. 5.3%; p < .001) while resolution rates of urgency urinary incontinence (UUI) were similar (MUI; 57.7% vs. 53.9%; p = .414). CONCLUSIONS: Success rates of midurethral sling and resolution of UUI were comparable between NND and ND patients. In patients with neurological conditions, de novo OAB symptoms were more likely to develop.

A multicenter prospective study for overactive bladder patient treatment satisfaction with mirabegron after being unsatisfied with antimuscarinic therapy (FAVOR study).

AIM: We investigated the satisfaction and efficacy of mirabegron in patients with overactive bladder (OAB) symptoms who were unsatisfied with previous antimuscarinic treatment. METHODS: This was a 12-week, open-label study of adults with OAB who had been treated with antimuscarinics within 2 years of screening and expressed dissatisfaction over poor efficacy or adverse events of antimuscarinics. All enrolled patients have received mirabegron 50 mg once daily for 12 weeks. The primary outcome was the percentage of patients reporting treatment satisfaction questions (TSQ) at week 12 ("very satisfied" or "somewhat satisfied"). Patients completed voiding diaries, Overactive Bladder Questionnaire short form (OAB-q-SF), Overactive Bladder Symptom Score (OABSS), and the global response assessment (GRA) at baseline, Week 4, and Week 12. At 12-weeks, patients were assessed for willingness to continue treatment. RESULTS: The response rate of treatment satisfaction at 12 weeks was 69.3% (275/397) (95% confidence interval 64.7-73.8). Significant improvements from baseline to weeks 4 and 12 were observed in the frequency, urgency due to urinary incontinence, and urgency episodes per 24 h (all p < .0001). Both OAB-q-SF and OABSS were significantly improved compared to baseline. At 4 and 12 weeks, 27.5% and 41.8% of patients, respectively, responded to the GRA as being moderately or markedly improved. At 12 weeks, 80.8% of patients were willing to continue mirabegron. CONCLUSIONS: Mirabegron improved the rates of treatment satisfaction and symptoms in patients with OAB who were unsatisfied with prior antimuscarinic treatment.

Efficacy and Safety of Naftopidil in Patients With Neurogenic Lower Urinary Tract Dysfunction: An 8-Week, Active-Controlled, Stratified-Randomized, Double-Blind, Double-Dummy, Parallel Group, Noninferiority, Multicenter Design.

PURPOSE: The aim of this study was to evaluate the efficacy and safety of naftopidil compared with tamsulosin in patients with neurogenic lower urinary tract dysfunction (LUTD). METHODS: This study was conducted as an 8-week, active-controlled, stratified-randomized, double-blind, double-dummy, parallel group, noninferiority, and multicenter clinical trial. After 2 weeks of screening, eligible subjects were randomly assigned to receive naftopidil (25 mg for 1 week followed by 75 mg for 7 weeks) or tamsulosin (0.2 mg for 8 weeks). Primary endpoint was a change of International Prostatic Symptom Score (IPSS) total score after 8 weeks of treatment. RESULTS: One hundred ninety-four subjects with neurogenic LUTD were included into this trial. There were no differences between the 2 groups in baseline characteristics, including urodynamic study results, subtype of LUTD, pretreatment and concomitant medication, and causes of neurogenic bladder. The medication compliance rate was 94.0% (naftopidil, 93.6%; tamsulosin, 94.4%). There was a statistically significant decrease of IPSS total score at 8 weeks versus baseline in both the naftopidil (-5.64±0.66) and tamsulosin (-6.53±0.65) groups (P<0.0001 each). The mean difference between both groups was 0.89 (upper limit of 95% confidential interval, 2.72), which was lower than the noninferiority limit of 3 points. A subgroup analysis of neurologic lesions and sex found no mean difference of IPSS total score in each group. There was also no difference in safety profiles, including treatment emergent adverse events. CONCLUSION: Naftopidil was not inferior to tamsulosin as a therapeutic drug for patients with neurogenic LUTD and had a similar safety profile.

Current and Future Directions of Stem Cell Therapy for Bladder Dysfunction.

Stem cells are capable of self-renewal and differentiation into a range of cell types and promote the release of chemokines and progenitor cells necessary for tissue regeneration. Mesenchymal stem cells are multipotent progenitor cells with enhanced proliferation and differentiation capabilities and less tumorigenicity than conventional adult stem cells; these cells are also easier to acquire. Bladder dysfunction is often chronic in nature with limited treatment modalities due to its undetermined pathophysiology. Most treatments focus on symptom alleviation rather than pathognomonic changes repair. The potential of stem cell therapy for bladder dysfunction has been reported in preclinical models for stress urinary incontinence, overactive bladder, detrusor underactivity, and interstitial cystitis/bladder pain syndrome. Despite these findings, however, stem cell therapy is not yet available for clinical use. Only one pilot study on detrusor underactivity and a handful of clinical trials on stress urinary incontinence have reported the effects of stem cell treatment. This limitation may be due to stem cell function loss following ex vivo expansion, poor in vivo engraftment or survival after transplantation, or a lack of understanding of the precise mechanisms of action underlying therapeutic outcomes and in vivo behavior of stem cells administered to target organs. Efficacy comparisons with existing treatment modalities are also needed for the successful clinical application of stem cell therapies. This review describes the current status of stem cell research on treating bladder dysfunction and suggests future directions to facilitate clinical applications of this promising treatment modality, particularly for bladder dysfunction.

Longitudinal micro-endoscopic monitoring of high-success intramucosal xenografts for mouse models of colorectal cancer.

Colorectal cancer (CRC) is one of the most frequently lethal forms of cancer. Intramucosal injection allows development of better mouse models of CRC, as orthotopic xenografts allow development of adenocarcinoma in the submucosa of the mouse colon wall. In this paper, a method of orthotopic injection is monitored longitudinally using cellular-resolution real-time in vivo fluorescence microendoscopy, following the injection of three different cell lines: 3T3-GFP to confirm immunosuppression and HCT116-RFP cells to model CRC. Adenoma formation is first observable after 7 to 10 days, and by use of 33 G needles a tumor induction rate of greater than 85% is documented. An additional experiment on the injection of rapamycin reveals drug efficacy and localization between 24 and 48 hours, and suggests the promise of real-time cellular-resolution fluorescence micro-endoscopy for developing longitudinal therapy regimes in mural models of CRC.