An individual participant meta-analysis of mirabegron in multiple sclerosis and spinal cord injury.

INTRODUCTION: Our objective was to conduct an individual patient data meta-analysis (IPDMA) of the two published randomized placebo-controlled trials of mirabegron in people with neurogenic lower urinary tract dysfunction (NLUTD) due to spinal cord injury (SCI) or multiple sclerosis (MS). METHODS: We identified two randomized, placebo-controlled trials. We extracted individual patient data from the trials and evaluated two primary outcomes: change in maximum cystometric capacity and change in the patient perception of bladder condition (PPBC). We also evaluated several secondary outcomes related to urodynamic function and quality of life. We conducted three exploratory analyses to test hypotheses based on our clinical experiences with mirabegron in NLUTD. Analysis of covariance with adjustment for baseline values was used for the statistical analysis. RESULTS: Our IPDMA included 98 patients from the two trials. The results showed that mirabegron was associated with a significant improvement in maximum cystometric capacity (+41 mL, p = 0.04) and in the PPBC (-0.8, p < 0.01) compared to placebo. Secondary outcomes including peak neurogenic detrusor overactivity pressure (-20 cm H2O, p < 0.01), incontinence-QOL score (+12, p < 0.01), and 24 h pad weights (-79 g, p = 0.04) also improved significantly compared to placebo. Exploratory analyses found similar improvements in people with MS and SCI; some outcomes improved to a greater degree among people with incomplete SCI, or SCIs that were below T7. CONCLUSIONS: Our IPDMA provides evidence supporting the use of mirabegron in patients with NLUTD due to SCI or MS. Further work evaluating differential responses in people with different SCI lesion characteristics may be warranted.

Toll-Like Receptor 3 Overexpression Induces Invasion of Prostate Cancer Cells, whereas Its Activation Triggers Apoptosis.

Toll-like receptor 3 (TLR3) is an endosomal receptor expressed in several immune and epithelial cells. Recent studies have highlighted its expression also in solid tumors, including prostate cancer (PCa), and have described its role primarily in the proinflammatory response and induction of apoptosis. It is up-regulated in some castration-resistant prostate cancers. However, the role of TLR3 in prostate cancer progression remains largely unknown. The current study experimentally demonstrated that exogenous TLR3 activation in PCa cell lines leads to a significant induction of secretion of the cytokines IL-6, IL-8, and interferon-ß, depending on the model and chemoresistance status. Transcriptomic analysis of TLR3-overexpressing cells revealed a functional program that is enriched for genes involved in the regulation of cell motility, migration, and tumor invasiveness. Increased motility, migration, and invasion in TLR3-overexpressing cell line were confirmed by several in vitro assays and using an orthotopic prostate xenograft model in vivo. Furthermore, TLR3-ligand induced apoptosis via cleavage of caspase-3/7 and poly (ADP-ribose) polymerase, predominantly in TLR3-overexpressing cells. These results indicate that TLR3 may be involved in prostate cancer progression and metastasis; however, it might also represent an Achilles heel of PCa, which can be exploited for targeted therapy.

Cardiovascular safety of mirabegron in individuals treated for spinal cord injury- or multiple sclerosis-induced neurogenic detrusor overactivity.

PURPOSE: To analyze cardiovascular safety of mirabegron in patients with spinal cord injury (SCI)- and multiple sclerosis (MS)-induced neurogenic detrusor overactivity (NDO) in a prospective, randomized, double-blind, placebo-controlled study. METHODS: Seventy-eight patients were enrolled into the study, and 66 of them were included into the final analysis. In 49 (74.2%), NDO developed due to suprasacral SCI, 17 (25.8%) suffered from NDO due to MS. Eleven patients were previously treated for hypertension and one for arrhythmia. All study participants received placebo for 2 weeks run-in period. Subsequently, eligible subjects were randomized for 4 weeks of active treatment with mirabegron 50 mg once daily (Group A; n = 32) or placebo (Group B; n = 34). Data from resting electrocardiography (ECG), 24-h ECG and blood pressure monitoring, and echocardiographic examination, were used for cardiovascular safety assessment. All reported variables were evaluated at time of randomization and at the end of the study. Longitudinal changes of variables within the groups and differences between the groups were assessed using nonparametric Kruskal-Wallis test, and p ≤ 0.05 was considered statistically significant. RESULTS: No statistically significant longitudinal changes were found in safety variables, except for prolongation of QT interval in placebo group (p = 0.0328) recorded by resting ECG. No significant difference between the Groups A and B, in any of the variables, was observed. A single cardiovascular study drug-related adverse event was recorded in a patient with cervical SCI (3.13%). CONCLUSIONS: Our results suggest that mirabegron can be safely used in the treatment of patients with SCI- and MS-induced NDO.

One-year follow-up after urethroplasty, with the focus on both lower urinary tract and erectile function.

Background: Urethral stricture disease (USD) represents a complex urological problem. Urethroplasty is considered the gold standard for the treatment of USD. Most available studies report outcome data obtained from retrograde urethrography and uroflowmetry. Only a limited number of papers describe the effect of urethroplasty on erectile function and their results are inconsistent. The goal of this prospective study was to evaluate the effect of urethroplasty on both lower urinary tract and erectile function using objective parameters and standardized patient-reported outcome measurement tools.Materials and Methods: A total of 55 consecutive patients with USD were enrolled into the study. Patients underwent ventral onlay urethroplasty, urethroplasty according to the Asopa technique, dorsal onlay urethroplasty, cutaneous flap urethroplasty using the Orandi technique or anastomotic repair. All patients were evaluated using uroflowmetry, urethrography, the PROM-USS questionnaire and the International Index of Erectile Function-5 questionnaire (IIEF-5) pre-operatively and consequently post-op, in 3-month intervals. This study presents the comparison of baseline pre-op parameters and parameters 12 months after the surgery using the Wilcoxon signed rank test, Wilcoxon rank sum test and the Kruskal-Wallis one-way analysis of variance.Results: A significant improvement in uroflowmetry parameters, all domains of the PROM-USS questionnaire, as well as the overall score of the IIEF-5 was observed. No statistically significant differences between sub-groups were found when comparing treatment results in patients with short versus long strictures and patients with penile urethra stricture versus bulbar or membranous urethra stricture.Conclusions: Urethroplasty yielded very good functional results with respect to both lower urinary tract and erectile functions.

Alpha-blockers for treating neurogenic lower urinary tract dysfunction in patients with multiple sclerosis: A systematic review and meta-analysis. A report from the Neuro-Urology Promotion Committee of the International Continence Society (ICS).

AIM: We aimed to systematically assess the evidence on the efficacy and safety of alpha-blockers in patients with multiple sclerosis (MS) suffering from neurogenic lower urinary tract dysfunction (NLUTD). METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used to perform this systematic review. An electronic search of Cochrane register, Embase, Medline, Scopus (last search 3 March 2018) and screening of reference lists as well as reviews were used to identify the studies. Articles were included if they reported on efficacy/safety of alpha-blockers for the treatment of NLUTD in patients with MS. RESULTS: After screening of 7'015 abstracts, three studies enrolling a total of 50 patients were included: one randomized, placebo-controlled, single-blind trial and two prospective cohort studies. Alpha-blocker treatment was successful in 50% to 96% of the patients. Pooling data from the three included studies, the relative risk for successful alpha-blocker treatment was 3.89 (95% confidence interval 2.7-7.0). The general safety profile of alpha-blockers was favorable with 8% of the patients reporting adverse events. CONCLUSIONS: Alpha-blockers may be effective and safe for treating NLUTD in female and male patients with MS but the studies were small and the overall quality of evidence was low. To make definitive conclusions, well designed randomized controlled trials are highly warranted.

Efficacy and safety of mirabegron for the treatment of neurogenic detrusor overactivity-Prospective, randomized, double-blind, placebo-controlled study.

AIMS: To assess the efficacy and safety of mirabegron in the treatment of neurogenic detrusor overactivity. METHODS: This prospective, multicenter, randomized, double-blind, placebo-controlled study was conducted in three tertiary centers, and included 78 patients suffering from spinal cord injury or multiple sclerosis. Patients were randomized for Mirabegron 50 mg (Group A) or placebo (Group B). Urodynamic parameters, the 24 h pad-weight test, and patient-reported outcomes were assessed. Safety assessments included monitoring the incidence and severity of adverse events. Changes in time and differences between groups were assessed with nonparametric Kruskal-Wallis one-way analysis of variance; P ≤ 0.05 was considered statistically significant. RESULTS: In total, 66 patients were eligible for inclusion in the final analysis. There was a significant increase of volume at the first detrusor contraction (P = 0.00047) and an improvement in bladder compliance (P = 0.0041) in the mirabegron group compared with the placebo-treated group, whereas the increase in cystometric capacity did not reach statistical significance (P = 0.061). There was a clear tendency to reduced urine leakage (P = 0.056) in Group A. There were significant changes in all the patient-reported outcomes, favoring the mirabegron group. The incidence of drug-related adverse events was 3.13%. CONCLUSIONS: Mirabegron (50 mg) improved both urodynamic variables and patient-reported outcomes in patients with NDO. The treatment was tolerated well.

Evaluation of intra-individual test-re-test variability of uroflowmetry in healthy women and women suffering from stress, urge, and mixed urinary incontinence.

INTRODUCTION AND HYPOTHESIS: The objective was to evaluate the intra-individual variability of uroflowmetry (UFM) in healthy control subjects and women suffering from stress, urge, and mixed urinary incontinence. METHODS: A total of 35 healthy controls (group A) and 105 women suffering from urinary incontinence were enrolled in the study. Thirty-five women suffered from stress urinary incontinence (group B), 35 women suffered from mixed urinary incontinence (group C), and 35 women with overactive bladder both dry and wet (group D). All participants were asked to perform UFM measurement three times. The following parameters were analyzed: voided volume (VV), peak flow (Qmax), average flow (Qave), volume-corrected peak flow cQmax (cQmax = Qmax/2√ VV), volume-corrected average flow (cQave = Qave/2√ VV), and postvoid residual volume (PVR). Statistical analysis was performed using the analysis of variance on repeated measurements. Relative error was calculated using variation coefficients reported as a percentage of the average. All descriptive characteristics were reported as means ± standard deviation (SD). p values ≤0.05 were considered statistically significant. RESULTS: No statistically significant intra-individual difference in any of the recorded parameters was identified among the three UFM recordings in groups A, C, and D. The intra-individual variability of the following parameters reached statistical significance in patients suffering from stress urinary incontinence (group B): Qmax (p = 0.0016), Qave (p = 0.0005), and cQave (p = 0.0389). A significant difference was only observed in comparison between the first and second consecutive recordings. CONCLUSIONS: This study provides evidence supporting the high yield and good intra-individual reproducibility of UFM.

Intravesical instillation of onabotulinum toxin A embedded in inert hydrogel in the treatment of idiopathic overactive bladder: A double-blind randomized pilot study.

OBJECTIVE: It was hypothesized that increasing the time for which onabotulinum toxin A (OnabotA) is exposed to the urothelium following intravesical instillation will augment its effect. TC-3 is an inert heat-sensitive hydrogel, which creates an intravesical bulk providing a slow release of the embedded drug after instillation. The aim of this study was to evaluate the effect of OnabotA, embedded in inert TC-3 hydrogel, in patients with idiopathic overactive bladder (OAB). METHODS: In total, 39 female patients (age 30-65, average 53.8 years) with OAB symptoms were randomized for the study into four groups, each receiving 50 ml of the following intravesical instillations: Group A, 0.9% NaCl (placebo, n = 11); Group B, TC-3 gel + 200 U OnabotA (n = 9); Group C, TC-3 gel + 200 U OnabotA + dimethyl sulfoxide (DMSO) (n = 10); and Group D, DMSO (n = 9). The parameters were compared before and 1 month after treatment. RESULTS: When comparing parameters using conventional statistical methods (Kruskal-Wallis test), no statistically significant changes were observed within the groups. Comparison of the medians using an analysis based on the mathematical gnostics showed the superiority of the method used in Group B over the other groups in the following parameters: number of urgency grade 3 + 4 episodes/72 h, number of leakage episodes/72 h, Overactive Bladder Questionnaire total score and Patient Perception of Bladder Condition total score. Group D showed its superiority over the other groups in respect to the number of nocturia episodes/72 h. CONCLUSIONS: The results indicate that intravesical instillation of OnabotA, embedded in TC-3 gel, could become an alternative to intramural injection for a well-selected subgroup of patients.

Comparison between uroflowmetry and sonouroflowmetry in recording of urinary flow in healthy men.

OBJECTIVES: To evaluate the accuracy of sonouroflowmetry in recording urinary flow parameters and voided volume. METHODS: A total of 25 healthy male volunteers (age 18-63 years) were included in the study. All participants were asked to carry out uroflowmetry synchronous with recording of the sound generated by the urine stream hitting the water level in the urine collection receptacle, using a dedicated cell phone. From 188 recordings, 34 were excluded, because of voided volume <150 mL or technical problems during recording. Sonouroflowmetry recording was visualized in a form of a trace, representing sound intensity over time. Subsequently, the matching datasets of uroflowmetry and sonouroflowmetry were compared with respect to flow time, voided volume, maximum flow rate and average flow rate. Pearson's correlation coefficient was used to compare parameters recorded by uroflowmetry with those calculated based on sonouroflowmetry recordings. RESULTS: The flow pattern recorded by sonouroflowmetry showed a good correlation with the uroflowmetry trace. A strong correlation (Pearson's correlation coefficient 0.87) was documented between uroflowmetry-recorded flow time and duration of the sound signal recorded with sonouroflowmetry. A moderate correlation was observed in voided volume (Pearson's correlation coefficient 0.68) and average flow rate (Pearson's correlation coefficient 0.57). A weak correlation (Pearson's correlation coefficient 0.38) between maximum flow rate recorded using uroflowmetry and sonouroflowmetry-recorded peak sound intensity was documented. CONCLUSIONS: The present study shows that the basic concept utilizing sound analysis for estimation of urinary flow parameters and voided volume is valid. However, further development of this technology and standardization of recording algorithm are required.

Persistence with first line anticholinergic medication in treatment-naïve overactive bladder patients.

OBJECTIVE: The aim of this study was to evaluate the persistence of first line anticholinergic medication use by patients with overactive bladder (OAB). Data from a hospital outpatient database were matched with information obtained by a telephone survey of patients to determine which patients discontinued use of anticholinergic medication and to identify the reasons underlying discontinuation. MATERIAL AND METHODS: The study group included 377 OAB patients (52 men, 325 women) with a mean age of 60.29 ± 13.84 years. In total, 189 patients (50.1%) were treated with trospium (median dose 27.86 ± 12.73 mg), 41 patients (10.9%) with propiverine (28.17 ± 4.97 mg), nine patients (2.4%) with extended-release tolterodine (4.0 ± 0 mg), 48 patients (12.7%) with solifenacin (5.94 ± 1.97 mg) and 90 patients (23.9%) with fesoterodine (6.09 ± 2.01 mg). RESULTS: The median time for persistence with the first line anticholinergic treatment was 6.53 ± 3.84 months. Persistence was significantly higher in patients treated with anticholinergic medication with an extended-release formulation than in patients treated with immediate-release anticholinergics. The most common reasons for termination of treatment were healing/resolution of symptoms (35.9%), low effectiveness (30.9%) and side-effects (23.7%). CONCLUSIONS: More than half of the OAB patients were not satisfied with their first line treatment. Other treatment options should be sought, such as changing the medication or dosage, or possibly combining treatments.

Fistula between anterior rectum wall and seminal vesicles as a rare complication of low-anterior resection of the rectum.

Laparoscopic surgery has become a frequently used modality for rectal tumour surgery. A fistula between the rectum and lower urinary tract is one of the possible complications, with rectovesical fistulas occurring most frequently. This case report presents a 66-year-old man who underwent a laparoscopic low-anterior resection of the rectum due to the presence of a polyp with a high risk of malignant transformation. At the time of discharge on the eleventh postoperative day, the patient returned to the hospital with a fever, scrotal swelling and pain in the right hemiscrotum. These symptoms began four hours after discharge from the hospital. There was no sign of faecaluria. The presence of gas in the urinary bladder was confirmed after catheter insertion. The patient was diagnosed with a fistula between the anterior wall of the rectum and seminal vesicles. The diagnosis was based on cystoscopy findings, X-ray and computed tomography irrigography. The condition was treated conservatively by suprapubic insertion of a catheter and antibiotics. The total length of the treatment, including management of subsequent complications, was 4 months. Twelve months after the complication developed, the patient is symptom free, without urinary tract infection recurrence, and is under the care of both surgery and urology clinics. We describe the clinical symptoms, possibilities of treatment and the result of treatment of this rare complication of rectum low-anterior resection, which has never been described in the literature before.