Complete Continence after Botulinum Neurotoxin Type A Injections for Refractory Idiopathic Detrusor Overactivity Incontinence: Patient-Reported Outcome at 4 Weeks

Background

Objective improvement following intradetrusor injections of botulinum neurotoxin type A (BoNTA) is well documented. Although patient-related outcome measures are highly recommended for monitoring overactive bladder symptoms, no study before has dealt with the question of patient-reported complete continence after BoNTA treatment using validated questionnaires.

Objective

To investigate the change in patient-reported continence rate after intradetrusor injections of BoNTA for treatment of refractory idiopathic detrusor overactivity (IDO) incontinence.

Design, setting, and participants

Seventy-four patients (51 women, 23 men) with refractory IDO incontinence treated for the first time with intradetrusor injections of 200 U BoNTA were evaluated in this nonrandomised, open-label, cohort study.

Measurements

Changes in patient-reported urinary frequency, urgency incontinence, and stress incontinence were assessed using the condition-specific validated short form of the Urogenital Distress Inventory (UDI 6) before and 4 wk after BoNTA treatment.

Results and limitations

The patient-reported outcome of complete continence (defined as a score of 0 in both the urgency and stress incontinence subscales of the UDI 6) was 51% (38 of 74) 4 wk after intradetrusor injections of BoNTA. In patients who were not completely continent, median urgency incontinence scores reduced significantly from 100 to 0 (p < 0.001), stress incontinence scores from 33 to 0 (p < 0.001), and median urinary frequency scores from 100 to 33 (p < 0.001), respectively. The inclusion of patients with mixed incontinence may have resulted in underestimation of the complete continence rate.

Conclusions

An excellent response with >50% of patients reporting complete continence 4 wk after BoNTA treatment reveals the efficacy of this emerging treatment for patients with refractory IDO incontinence. Furthermore, in those in whom complete continence was not achieved, there was a notable and significant reduction in reported urgency incontinence, stress incontinence, and urinary frequency.     

Suburothelial Myofibroblasts in the Human Overactive Bladder and the Effect of Botulinum Neurotoxin Type A Treatment

Background

An increasing body of evidence suggests a possible role of suburothelial myofibroblasts (MFs) in bladder mechanosensation and in the pathophysiology of detrusor overactivity (DO).

Objective

To determine whether markers of MFs, including gap junction protein connexin43 (Cx43) and c-kit have altered immunohistochemical expression in the suburothelium of patients with neurogenic DO (NDO) or idiopathic DO (IDO) and whether this is affected by successful treatment of DO with botulinum neurotoxin type A (BoNTA).

Design, setting, and participants

Patients with NDO (n = 10) or IDO (n = 11) were treated in a single-centre, open-label study of intradetrusor BoNTA injections. Control tissue was obtained from 10 patients undergoing pelvic-floor repair procedures who had no overactive bladder (OAB) symptoms. This study is registered with ClinicalTrials.gov, number NCT00662064.

Interventions

Bladder biopsies performed with flexible cystoscopes were obtained from control subjects and from NDO and IDO patients before BoNTA treatment and at 4 wk and 16 wk after treatment. They were studied with quantitative immunofluorescence using antibodies to connexin 43 (Cx43), vimentin, and c-kit.

Measurements

Differences in Cx43, vimentin, and c-kit immunoreactivity between control subjects and NDO or IDO patients (primary outcomes). Changes in NDO or IDO, Cx43 immunoreactivity, and c-kit immunoreactivity after BoNTA treatment (secondary outcomes).

Results and limitations

Cx43 immunoreactivity was increased in both IDO and NDO patients compared to controls, but remained unchanged after BoNTA treatment. C-kit immunoreactivity was similar in NDO/IDO patients and controls and remained unchanged after BoNTA treatment.

Conclusions

Increased gap junction formation in the suburothelium has been demonstrated in biopsies from humans with DO. It is hypothesised that this change could have a significant role in the pathogenesis of the detrusor abnormality. Successful treatment of NDO or IDO does not appear to be associated with changes in the expression of Cx43 or c-kit on suburothelial MFs.     

In the Human Urothelium and Suburothelium,Intradetrusor Botulinum Neurotoxin Type A Does Not Induce Apoptosis: Preliminary Results

Background

Intradetrusor injections of botulinum neurotoxin type A (BoNTA) are emerging as the preferred second-line treatment for neurogenic and idiopathic overactive bladder (OAB). In animal experiments, intradetrusor BoNTA injections have been shown to cause apoptosis in the bladder urothelium and suburothelium but not the detrusor.

Objective

To investigate BoNTA-induced apoptosis in patients with refractory neurogenic OAB.

Design, setting, and participants

Twelve refractory OAB patients with neurogenic detrusor overactivity resulting from multiple sclerosis (MS) and seven controls were included prospectively.

Measurements

The number of apoptotic cells before and 4 wk after first intradetrusor BoNTA (300 U of BOTOX [Allergan, Irvine, CA, USA]) injections were estimated using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) staining.

Results and limitations

Comparison of TUNEL-positive cells (yes vs no) in the bladder urothelium and suburothelium revealed no significant differences in OAB patients before (4 of 12, 33%) versus after (3 of 12, 25%) BoNTA treatment (p = 0.99). In addition, no significant differences (p = 0.99) were found in OAB patients versus controls. Because our findings are based on first intradetrusor BoNTA injections only, it is unclear whether the results could be extrapolated to repeat injections.

Conclusions

In contrast to preliminary animal experiments, first intradetrusor BoNTA injections for treating refractory neurogenic OAB—a highly effective treatment—did not induce apoptosis in the bladder urothelium and suburothelium.     

Efficacy and Tolerability of Botulinum Toxin Type A in Patients with Neurogenic Detrusor Overactivity and Without Concomitant Anticholinergic Therapy: Comparison of Two Doses

Background

Botulinum toxin type A (BoNTA) has been reported to be effective for treatment of patients with neurogenic detrusor overactivity (NDO) refractory to anticholinergic agents. However, in most of the studies, the efficacy was associated with concomitant use of anticholinergics.

Objective

To evaluate the efficacy and tolerability of BoNTA and compare two different doses in patients with NDO without concomitant anticholinergics.

Design, setting, and participants

Between 2004 and 2006, adults with NDO refractory to anticholinergics or discontinued anticholinergics due to adverse events or contraindications from four different French clinical centres were included in a prospective, randomised, double-blind, comparative trial. Inclusion criteria were urinary incontinence (UI) resulting from NDO that could not be managed with anticholinergics. Patients with bladder cancer, lithiasis, or urinary infection were excluded.

Intervention

Patients were randomised to receive an intradetrusor injection of 500 U or 750 U of BoNTA.

Measurements

The initial evaluation (ie, clinical and urodynamic variables and quality of life [QoL]) was repeated at days 30, 90, 180, and 360. Primary outcome was complete continence rate at day 30. Secondary outcomes were cumulative incontinence rate, reappearance of leakages, pad usage, urodynamics, and QoL.

Results and limitations

Seventy-seven patients received 500 U (n = 39) or 750 U (n = 38) of BoNTA and were included in the full analysis set for efficacy analysis. Complete continence at day 30 was observed in 22 patients (56.4%) and 28 patients (73.7%) receiving 500 U or 750 U of BoNTA, respectively (p = 0.056; one-sided χ² test to compare to α = 0.025). The median delay in the reappearance of leakages was 168 d. Monotherapy of BoNTA significantly improved UI in patients with NDO. Although there was a trend towards a greater improvement with 750 U of BoNTA, no statistically significant differences in terms of clinical and urodynamic variables and QoL were found between the treatment groups. Tolerability was excellent and equivalent for both doses.

Conclusions

Monotherapy of BoNTA at Dysport (Ipsen, Brisbane, CA, USA) doses of 500 U or 750 U seems to be effective and well tolerated in patients with NDO.     

OnabotulinumtoxinA 100 U Significantly Improves All Idiopathic Overactive Bladder Symptoms and Quality of Life in Patients with Overactive Bladder and Urinary Incontinence: A Randomised,Double-Blind,Placebo-Controlled Trial

Background

Overactive bladder (OAB) syndrome with urinary incontinence (UI) is prevalent in the population and impairs health-related quality of life (HRQOL).

Objective

To assess the impact on efficacy, safety, and HRQOL of onabotulinumtoxinA (BOTOX^®, Allergan, Inc.) treatment in patients with OAB with UI.

Design, setting, and participants

This pivotal, multicentre, double-blind, randomised, placebo-controlled, phase 3 study enrolled patients with idiopathic OAB with ≥3 urgency UI episodes over 3 d and ≥8 micturitions per day who were inadequately managed by anticholinergics.

Intervention

OnabotulinumtoxinA at a 100 U dose (n = 277) or placebo (n = 271), administered as 20 intradetrusor injections of 0.5 ml.

Outcome measurements and statistical analysis

Co–primary end points were change from baseline in the number of UI episodes per day and proportion of patients reporting positive treatment response on the treatment benefit scale (TBS) at week 12. Additional end points included other OAB symptoms (episodes of urinary urgency incontinence, micturition, urgency, and nocturia) and HRQOL (Incontinence Quality of Life [I-QOL], King's Health Questionnaire [KHQ]). Safety assessments included adverse events (AEs), postvoid residual (PVR) urine volume, and initiation of clean intermittent catheterisation (CIC).

Results and limitations

OnabotulinumtoxinA significantly decreased UI episodes per day at week 12 (−2.95 for onabotulinumtoxinA versus −1.03 for placebo; p < 0.001). Reductions from baseline in all other OAB symptoms were also significantly greater following onabotulinumtoxinA compared with placebo (p ≤ 0.01). Patients perceived a significant improvement in their condition, as measured by patients with a positive treatment response on the TBS (62.8% for onabotulinumtoxinA versus 26.8% for placebo; p < 0.001). Clinically meaningful improvements from baseline in all I-QOL and KHQ multi-item domains (p < 0.001 versus placebo) indicated positive impact on HRQOL. AEs were mainly localised to the urinary tract. Mean PVR was higher in the onabotulinumtoxinA group (46.9 ml versus 10.1 ml at week 2; p < 0.001); 6.9% of onabotulinumtoxinA patients versus 0.7% of placebo patients initiated CIC.

Conclusions

OnabotulinumtoxinA 100 U was well tolerated and demonstrated significant and clinically relevant improvements in all OAB symptoms, patient-reported benefit, and HRQOL in patients inadequately managed by anticholinergics.

Trial registration

ClinicalTrials.gov: NCT00910520.     

An Updated Systematic Review and Statistical Comparison of Standardised Mean Outcomes for the Use of Botulinum Toxin in the Management of Lower Urinary Tract Disorders

Context

Botulinum toxin A (BoNTA) has received regulatory approval for use in neurogenic detrusor overactivity (NDO) and overactive bladder (OAB), but it remains unlicensed in other lower urinary tract symptoms (LUTS) indications such as nonneurogenic LUTS in men with benign prostatic enlargement (LUTS/BPE), bladder pain syndrome (BPS), and detrusor sphincter dyssynergia (DSD).

Objective

To compare statistically the outcomes of high level of evidence (LE) studies with placebo using BoNTA for LUTS indications; NDO, OAB, LUTS/BPE, BPS and DSD.

Evidence acquisition

We conducted a systematic review of the published literature on PubMed, Scopus, and Embase reporting on BoNTA use in LUTS dysfunction. Statistical comparison was made between high LE studies with placebo and low LE studies.

Evidence synthesis

In adult NDO, there are significantly greater improvements with BoNTA in daily incontinence and catheterisation episodes (−63% and −18%, respectively; p < 0.01), and the urodynamic parameters of maximum cystometric capacity (MCC), reflex volume, and maximum detrusor pressure (MDP) (68%, 61%, and −42%, respectively; all p < 0.01). In OAB, BoNTA leads to significant improvements in bladder diary parameters such as daily frequency (−29%), daily urgency (−38%), and daily incontinence (−59%) (all p < 0.02). The urodynamic parameters of MCC and MDP improved by 58% (p = 0.04) and −29% (p = 0.002), respectively. The risk of urinary tract infection was significantly increased from placebo at 21% versus 7% (p < 0.001), respectively; the risk of intermittent self-catherisation increased from 0% to 12% (p < 0.001). Men with LUTS/BPE showed no significant improvements in International Prostate Symptom Score, maximum flow rate, or prostate volume. There were insufficient data for statistical analysis in DSD, BPS, and paediatric studies. Low LE studies were found to overestimate the effects of BoNTA in all indications, but differences from high LE studies were significant in only a few parameters.

Conclusions

BoNTA significantly improves all symptoms and urodynamic parameters in NDO and OAB. The effect of BoNTA in treating LUTS dysfunction appears to be overestimated in lower as opposed to higher LE studies.     

Alvimopan Accelerates Gastrointestinal Recovery After Radical Cystectomy: A Multicenter Randomized Placebo-Controlled Trial

Background

Radical cystectomy (RC) for bladder cancer is frequently associated with delayed gastrointestinal (GI) recovery that prolongs hospital length of stay (LOS).

Objective

To assess the efficacy of alvimopan to accelerate GI recovery after RC.

Design, setting, and participants

We conducted a randomized double-blind placebo-controlled trial in patients undergoing RC and receiving postoperative intravenous patient-controlled opioid analgesics.

Intervention

Oral alvimopan 12 mg (maximum: 15 inpatient doses) versus placebo.

Outcome measurements and statistical analysis

The two-component primary end point was time to upper (first tolerance of solid food) and lower (first bowel movement) GI recovery (GI-2). Time to discharge order written, postoperative LOS, postoperative ileus (POI)-related morbidity, opioid consumption, and adverse events (AEs) were evaluated. An independent adjudication of cardiovascular AEs was performed.

Results and limitations

Patients were randomized to alvimopan (n = 143) or placebo (n = 137); 277 patients were included in the modified intention-to-treat population. The alvimopan cohort experienced quicker GI-2 recovery (5.5 vs 6.8 d; hazard ratio: 1.8; p < 0.0001), shorter mean LOS (7.4 vs 10.1 d; p = 0.0051), and fewer episodes of POI-related morbidity (8.4% vs 29.1%; p < 0.001). The incidence of opioid consumption and AEs or serious AEs (SAEs) was comparable except for POI, which was lower in the alvimopan group (AEs: 7% vs 26%; SAEs: 5% vs 20%, respectively). Cardiovascular AEs occurred in 8.4% (alvimopan) and 15.3% (placebo) of patients (p = 0.09). Generalizability may be limited due to the exclusion of epidural analgesia and the inclusion of mostly high-volume centers utilizing open laparotomy.

Conclusions

Alvimopan is a useful addition to a standardized care pathway in patients undergoing RC by accelerating GI recovery and shortening LOS, with a safety profile similar to placebo.

Patient summary

This study examined the effects of alvimopan on bowel recovery in patients undergoing radical cystectomy for bladder cancer. Patients receiving alvimopan experienced quicker bowel recovery and had a shorter hospital stay compared with those who received placebo, with comparable safety.

Trial registration

ClinicalTrials.gov identifier NCT00708201     

Four-Year Outcome of a Prospective Randomised Trial Comparing Bipolar Plasmakinetic and Monopolar Transurethral Resection of the Prostate

Background

No data have been published on the midterm efficacy of bipolar transurethral resection of the prostate (TURP).

Objective

To evaluate 4-yr results from a prospective randomised trial comparing bipolar TURP with standard monopolar TURP.

Design, setting, and participants

Seventy patients with symptomatic benign prostatic hyperplasia were enrolled in this prospective randomised controlled trial in a tertiary-care institution. Inclusion criteria were age >50 yr, good performance status, urinary retention, International Prostate Symptom Score (IPSS) ≥18, and maximal flow rate (Q_max) ≤15 ml/s. Exclusion criteria were prostate volume <30 cm³, documented or suspected prostate cancer, neurogenic bladder, bladder stone or diverticula, urethral stricture, and maximal bladder capacity >500 ml.

Intervention

Patients underwent standard or bipolar plasmakinetic TURP performed by the same surgeon using the same surgical technique.

Measurements

Treatment efficacy was evaluated at 1, 2, 3, and 4 yr by comparing urinary flow rates, IPSS, and estimated postvoid residual (PVR) urine volume. Midterm complications were also recorded.

Results and limitations

The number of dropouts was not statistically significantly different in the two groups (p = 0.2). The significant improvements in both groups were maintained at 4 yr for the IPSS, quality of life score, Q_max, and PVR versus baseline values. The main outcome variables at 4 yr for bipolar and monopolar TURP were mean IPSS 6.9 and 6.4 (p = 0.58); mean Q_max 19.8 ml/s and 21.2 ml/s (p = 0.44), and mean PVR volume 42 ml and 45 ml (p = 0.3). Overall, 2 of 32 (6.2%) and 3 of 31 (9.6%) patients required reoperation because of late complications (p = 0.15). The major study limitation was the small sample size.

Conclusions

This study represents the secondary, midterm analysis of a previously published trial. Our 4-yr data confirm our initial positive findings for the efficacy and safety of bipolar plasmakinetic TURP. Larger well-designed studies are needed to corroborate these findings.     

Pilot Study of Liposome-encapsulated OnabotulinumtoxinA for Patients with Overactive Bladder: A Single-center Study

Background

Intradetrusor onabotulinumtoxinA (BoNT-A) injection benefits overactive bladder (OAB) patients, but increased postvoid residual (PVR) urine volume and urinary tract infection (UTI) remain risks. Intravesical instillation of liposomal BoNT-A instead of injection could prevent such adverse events.

Objective

To evaluate instillation of liquid liposomal BoNT-A (Lipotoxin) for the treatment of OAB and to determine its mechanism of action.

Design, setting, and participants

A double-blind randomized parallel controlled pilot trial in 24 OAB patients at a single tertiary center.

Intervention

Patients were randomly assigned to intravesical instillation of Lipotoxin containing 80 mg liposomes and 200 U BoNT-A or normal saline (N/S). Patients were retreated with Lipotoxin 1 mo later if they failed the first treatment.

Outcome measurement and statistical analysis

Voiding diaries, OAB symptom scores, urodynamic studies, and adverse events were monitored. The primary end point was change of total urinary frequency per 3 d at 1 mo after treatment. Immunohistochemistry and Western blotting for synaptic vesicle glycoprotein 2A (SV2A) and synaptosomal-associated protein, 25 kDa (SNAP25) were performed at baseline and 3 mo after treatment. The Wilcoxon rank sum test and Wilcoxon signed rank test were used for statistical analysis.

Results and limitations

At 1 mo after treatment, the change of urinary frequency per 3 d significantly improved in the Lipotoxin group (n = 12; median: −6.50; interquartile range [IQR]: −18.3 to −0.25; p = 0.008) but not in the N/S group. (n = 12.0; IQR: −7.75 to 8.0; p = 0.792). Urgency episodes also showed a significant decrease in the Lipotoxin group (−12.0; IQR: −20.3 to −2.75; p = 0.012) but not in the N/S group (−1.0; IQR: −11.0 to 2.5; p = 0.196). SV2A and SNAP25 were expressed in urothelial cells and suburothelial tissues. However, the protein expression did not significantly differ between responders and nonresponders at 3 mo after treatment.

Conclusions

Intravesical Lipotoxin instillation effectively reduced frequency episodes 1 mo after treatment in OAB patients without any increase in PVR or risk of UTI.

Patient summary

We demonstrated that intravesical Lipotoxin instillation reduced frequency episodes at 1 mo in overactive bladder patients. This procedure is safe, without an increase in postvoid residual or the risk of urinary tract infection.     

Six-Year Follow-Up of Botulinum Toxin A Intradetrusorial Injections in Patients with Refractory Neurogenic Detrusor Overactivity: Clinical and Urodynamic Results

Background

Most reports in the literature on botulinum toxin A (BoNTA) therapy for neurogenic detrusor overactivity (NDO) are based on the results of a single injection. Because most patients may require retreatment, the efficacy and safety of multiple injections must be addressed clearly.

Objective

To investigate the effectiveness and safety of BoNTA intradetrusorial injections in a group of spinal cord–injured (SCI) patients with refractory detrusor overactivity (DO).

Design, setting, and participants

Seventeen SCI patients were prospectively included in the study and followed up to 6 yr.

Intervention

All patients received repeat intradetrusorial injections of BoNTA 300 units (Botox, Allergan, Irvine, CA) under cystoscopic control on an inpatient basis.

Measurements

The preliminary assessment included voiding diary, urodynamics, kidney and bladder ultrasound, and cystourethrography. Patients also completed a standardised quality-of-life (QoL) questionnaire. Clinical evaluation, urodynamics, urinary tract imaging, and QoL assessment were repeated every year throughout the follow-up.

Results and limitations

Before treatment, all patients complained of urinary incontinence and had DO. Bilateral and monolateral renal pelvis dilatation were detected in six and five patients, respectively, and a monolateral and third-grade vesicoureteral reflux was observed in three. At 6-yr follow-up, a significant decrease in the frequency of daily incontinence episodes (p < 0.01), a significant increase in first uninhibited detrusor contraction and in maximum bladder capacity (p < 0.001 for both), and a significant decrease in maximum pressure of these contractions (p < 0.01) were observed. Fifteen patients (88.2%) were completely continent. Renal pelvis dilatation and vesicoureteral reflux resolved in all cases, and the QoL index significantly increased. Limitations of the study are related to the small number of included patients.

Conclusions

In SCI patients with refractory NDO who do not want or are unfit for invasive reconstructive surgery, BoNTA intravesical treatment represents a valid alternative to control DO and urinary incontinence and to preserve upper urinary tract function over a long-term follow-up.     

A Randomized Double-blind Placebo-controlled Phase 2 Dose-ranging Study of OnabotulinumtoxinA in Men with Benign Prostatic Hyperplasia

Background

Botulinum toxin treatment has been investigated as a minimally invasive alternative to oral medications in men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (LUTS/BPH).

Objective

To explore the efficacy of onabotulinumtoxinA 100 U, 200 U, and 300 U versus placebo in men with LUTS/BPH in a phase 2 dose-ranging study.

Design, setting, and participants

A multicenter double-blind randomized, placebo-controlled 72-wk study enrolled men ≥50 yr of age with LUTS/BPH, International Prostate Symptom Score (IPSS) ≥12, total prostate volume (TPV) 30–100 ml, and maximum flow rate (Q_max) 5–15 ml/s.

Intervention

Single transperineal (n = 63) or transrectal (n = 311) administration of placebo (n = 94) or onabotulinumtoxinA 100 U (n = 95), 200 U (n = 94), or 300 U (n = 97) into the prostate transition zone.

Outcome measurements and statistical analysis

The primary efficacy end point was a change from baseline in IPSS at week 12. Secondary end points were Q_max, TPV, and transition zone volume (TZV). Analysis of covariance and the Cochran-Mantel-Haenszel method assessed the efficacy and proportion of IPSS responders. Adverse events (AEs) were assessed.

Results and limitations

Significant improvements from baseline in IPSS, Q_max, TPV, and TZV were observed for all groups, including placebo, at week 12 (p < 0.001), with no significant differences between onabotulinumtoxinA and placebo. However, in an exploratory post hoc analysis, a significant reduction in IPSS versus placebo was observed with onabotulinumtoxinA 200 U in prior α-blocker users (n = 180) at week 12. AEs were comparable across all groups.

Conclusions

Reductions in LUTS/BPH symptoms were seen in all groups, including placebo, with no significant between-group differences owing to a large placebo effect from the injectable therapy. The findings from the post hoc analysis in men previously treated with α-blockers will be further explored in an appropriately designed study.

Trial registration

http://www.Clinical Trials.gov; NCT00284518.     

In Vitro Release of Adenosine Triphosphate from the Urothelium of Human Bladders with Detrusor Overactivity,Both Neurogenic and Idiopathic

Background

There is increased evidence to suggest a role for nonadrenergic–noncholinergic neurotransmission in the pathogenesis of bladder dysfunction.

Objective

In this set of experiments, we have assessed the contribution of the urothelium to purinergic activity by quantifying the amount of adenosine triphosphate (ATP) released from the urothelium of patients with idiopathic detrusor overactivity (IDO) and with neurogenic detrusor overactivity (NDO) and comparing these releases to those of controls.

Design, setting, and participants

Bladder tissue with urodynamically and clinically proven NDO (n = 8) and IDO (n = 8) were included in this study. The carefully dissected urothelium was stimulated by mechanically stretching as well as electrically stimulating and the ATP; thus, release was quantified.

Measurements

We used a Lucy Anthos 1 luminometre (Anthos Labtec Instruments GmBH, Wals, Austria) to perform the assay. The results were analysed using Stingray software (Dazdaq Ltd, Brighton, UK).

Results and limitations

Both mechanical stretch and electric field stimulation (EFS) led to increased ATP release in both sets of tissues with overactivity compared to the controls; this rise was even more significant for the IDO urothelium (2416.7 ± 479.8 pmol/g [p < 0.005]) than for the NDO urothelium (133.1 ± 22.4 pmol/g [p < 0.01]); values for the controls were 77.6 ± 16.2 pmol/g. ATP release following mechanical stretch was more sensitive to tetrodotoxin in bladders with NDO compared to those with IDO as well as to the controls, with ATP levels falling from 233.5 ± 20.7 pmol/g to 107.2 ± 11.6 pmol/g, expressed as percentage of basal levels (p < 0.002). The experiments were performed in vitro, and the female patients were a mix of peri- and postmenopausal states.

Conclusions

These experiments suggested a significant rise in ATP release from the urothelium of bladders with NDO as well as those with IDO in comparison to controls. Most of the ATP released from bladders with NDO is primarily from neuronal sources.     

The primary determinants of radiation use during fixation of proximal femur fractures

Objectives

To establish the primary determinants of operative radiation use during fixation of proximal femur fractures.

Design

Retrospective cohort study.

Setting

Level I trauma centre.

Cohort

205 patients treated surgically for subtrochanteric and intertrochanteric femoral fractures.

Main outcome measures

Fluoroscopy time, dose-area-product (DAP).

Results

Longer fluoroscopy time was correlated with higher body mass index (p = 0.04), subtrochanteric fracture (p < 0.001), attending surgeon (p = 0.001), and implant type (p < 0.001). Increased DAP was associated with higher body mass index (p < 0.001), subtrochanteric fracture (p = 0.002), attending surgeon (p = 0.003), lateral body position (p < 0.001), and implant type (p = 0.05).

Conclusion

The strongest determinants of radiation use during surgical fixation of intertrochanteric and subtrochanteric femur fractures were location of fracture, patient body position, patient body mass index, and the use of cephalomedullary devices. Surgeon style, presumably as it relates to teaching efforts, seems to strongly influence radiation use.     

Repeated botulinum toxin type A injections for refractory overactive bladder: medium-term outcomes, safety profile, and discontinuation rates

Background

Efficacy and safety of botulinum toxin type A (BoNTA) injection is supported by level 1 evidence, but data regarding repeated injections are limited in patients with refractory overactive bladder (OAB) and idiopathic detrusor overactivity (IDO).

Objectives

Describe medium-term outcomes and discontinuation rates for patients adopting repeated BoNTA as a management strategy for IDO.

Design, setting, and participants

Prospective data from a single centre were collected from the first 100 patients.

Intervention

Bladder injection of BoNTA (predominantly 200 U onabotulinumtoxinA; Allergan Ltd., Marlow, Buckinghamshire, UK) in an outpatient setting.

Measurements

OAB symptoms, quality of life, discontinuation rates, interinjection interval, and adverse events were recorded. Data comparisons were performed using a generalised linear model or a chi-square test where appropriate.

Results and limitations

Two hundred seven injections were performed in 100 patients. All patients had 1 injection, 53 had a total of 2, 20 had 3, 13 had 4, 10 had 5, 5 had 6, 3 had 7, 1 had 8, 1 had 9, and 1 had 10 injections. Statistics were applied up to five repeated injections. A statistically significant reduction in frequency, urgency, and urge urinary incontinence were seen following the first BoNTA injection compared to baseline. This improvement was maintained after repeated injections and was not statistically different when comparing differences between injections. Thirty-seven patients stopped treatment after the first two injections; thereafter, dropouts were rare. The most common reasons for discontinuing treatment were poor efficacy (13%) and clean intermittent self-catheterisation (CISC)–related issues (11%). The incidence of CISC after the first injection was 35%. Bacteriuria was detected in 21% of patients. The mean interinjection interval was 322 d. Limitations included the concurrent use of antimuscarinic drugs in some patients.

Conclusions

BoNTA can provide a safe and effective medium-term management option for patients with refractory IDO. The most common reasons cited for stopping treatment were poor efficacy and CISC-related issues.     

A Multicenter,Double-blind,Randomized, Placebo-controlled Trial of the β3-Adrenoceptor Agonist Solabegron for Overactive Bladder

Background

β-Adrenoceptor agonists are effective in animal models of bladder dysfunction, and the human bladder primarily expresses the β3 receptor subtype.

Objective

To evaluate the efficacy and tolerability of the highly selective and potent β3-adrenoceptor agonist solabegron in a clinical proof-of-concept study in incontinent women with overactive bladder (OAB).

Design, setting, and participants

This was a randomized, double-blind trial in adult women with OAB (one or more 24-h incontinence episodes and eight or more average 24-h micturitions).

Interventions

Solabegron 50 mg (n = 88), solabegron 125 mg (n = 85), or placebo (n = 85)—all twice daily—were administered.

Outcome measurements and statistical analysis

The primary efficacy end point was percentage change from baseline to week 8 in the number of incontinence episodes over 24 h. Secondary end points included actual change and percentage change from baseline to week 4 and week 8 in micturitions per 24 h, urgency episodes per 24 h, and volume voided per micturition. Adverse events (AEs) were assessed, as well.

Results and limitations

Solabegron 125 mg produced a statistically significant difference in percent change from baseline to week 8 in incontinence episodes over 24 h when compared with placebo (p = 0.025). Solabegron 125 mg treatment also showed statistically significant reductions from baseline to weeks 4 and 8 in micturitions over 24 h and a statistically significant increase from baseline to week 8 in urine volume voided. Solabegron was well tolerated, with a similar incidence of AEs in each treatment group. There were no significant treatment differences for mean changes from baseline to week 8 in systolic blood pressure (BP), diastolic BP, mean arterial pressure (MAP), or heart rate during the 24-h ambulatory measurement.

Conclusions

Solabegron significantly reduced the symptoms of OAB in women with moderate to severe OAB. Solabegron was safe, well tolerated, and did not demonstrate significant differences in AEs as compared to placebo. β3-Adrenoceptor agonists may represent a new therapeutic approach for treating OAB symptoms.     

Transvesical Robotic Simple Prostatectomy: Initial Clinical Experience

Background

Despite significant developments in transurethral surgery for benign prostatic hyperplasia (BPH), simple prostatectomy remains an excellent option for patients with large glands.

Objective

To describe our technique of transvesical robotic simple prostatectomy (RSP).

Design, setting, and participants

From May 2011 to April 2013, 25 patients underwent RSP.

Surgical procedure

We performed RSP using our technique.

Outcome measurements and statistical analysis

Baseline demographics, pathology data, perioperative complications, 90-d complications, and functional outcomes were assessed.

Results and limitations

Mean patient age was 72.9 yr (range: 54–88), baseline International Prostate Symptom Score (IPSS) was 23.9 (range: 9–35), prostate volume was 149.6 ml (range: 91–260), postvoid residual (PVR) was 208.1 ml (range: 72–800), maximum flow rate (Q_max) was 11.3 ml/s, and preoperative prostate-specific antigen was 9.4 ng/ml (range: 1.9–56.3). Eight patients were catheter dependent before surgery. Mean operative time was 214 min (range: 165–345), estimated blood loss was 143 ml (range: 50–350), and the hospital stay was 4 d (range: 2–8). There were no intraoperative complications and no conversions to open surgery. Five patients had a concomitant robotic procedure performed. Early functional outcomes demonstrated significant improvement from baseline with an 85% reduction in mean IPSS (p < 0.0001), an 82.2% reduction in mean PVR (p = 0.014), and a 77% increase in mean Q_max (p = 0.20). This study is limited by small sample size and short follow-up period. One patient had a urinary tract infection; two had recurrent hematuria, one requiring transfusion; one patient had clot retention and extravasation, requiring reoperation.

Conclusions

Our technique of RSP is safe and effective. Good functional outcomes suggest it is a viable option for BPH and larger glands and can be used for patients requiring concomitant procedures.

Patient summary

We describe the technique and report the initial results of a series of cases of transvesical robotic simple prostatectomy. The procedure is both feasible and safe and a good option for benign prostatic hyperplasia with larger glands.     

Botulinum Neurotoxin Serotype A Suppresses Neurotransmitter Release from Afferent as Well as Efferent Nerves in the Urinary Bladder

Background

Botulinum neurotoxin A (BoNTA), which alleviates overactive bladder symptoms, is thought to act predominantly via the inhibition of transmitter release from parasympathetic nerves. However, actions at other sites such as afferent nerve terminals are possible.

Objective

To evaluate the effects of BoNTA on bladder afferent neuropeptide release and firing.

Design, setting, and participants

One side of the bladder of control and chronic (1–2 wk) spinal cord transected (SCT; T₈-T₉) adult female mice was injected with BoNTA (0.5 U/5 μl saline). After 48 h, bladders with L₆-S₂ spinal nerves were prepared for in vitro recordings.

Outcome measurements and statistical analysis

In bladder preparations, tension and optical mapping of Ca²⁺ transients were used to measure intrinsic contractions, those evoked by capsaicin or the electrical stimulation of spinal nerves. Afferent firing was evoked by stretch or intrinsic bladder contractions. The numbers of responding units and firing rates were measured. Animal numbers were used to detect moderate to large between-group differences based on Cohen's criteria. Two-way analysis of variance was used to test spatial/temporal differences in Ca²⁺ signals as mean plus or minus standard deviation. Differences between data sets were tested with the student t test and skewed data sets with a Mann-Whitney U test (significant when p < 0.05).

Results and limitations

In control and SCT bladders, BoNTA treatment decreased the contractions evoked by electrical stimulation of spinal nerves without altering intrinsic contractions. Afferent firing on untreated sides in response to stretch/intrinsic contractions was increased in SCTs versus controls. On BoNTA-treated sides, afferent firing rates were greatly attenuated in response to mechanical stimulation as were the capsaicin-evoked optical signals mediated by neuropeptide release.

Conclusions

SCT caused an increased sensitivity of afferent nerves to mechanical stimulation that was reduced by BoNTA treatment. Increased intrinsic activity after SCT was unaffected by the toxin. Thus BoNTA suppresses neurogenic detrusor overactivity by targeting afferent as well as efferent pathways in the bladder.     

A Multicentre Year-long Randomised Controlled Trial of Exercise Training Targeting Physical Functioning in Men with Prostate Cancer Previously Treated with Androgen Suppression and Radiation from TROG 03.04 RADAR

Background

Long-term prostate cancer (PCa) survivors are at increased risk for comorbidities and physical deconditioning.

Objective

To determine the effectiveness of a year-long randomised controlled trial of exercise training in PCa survivors >5 yr postdiagnosis on physical functioning.

Design, setting, and participants

Between 2010 and 2011, 100 long-term PCa survivors from Trans-Tasman Radiation Oncology Group 03.04 Randomised Androgen Deprivation and Radiotherapy previously treated with androgen-deprivation therapy and radiation therapy were randomly assigned to 6 mo of supervised exercise followed by 6 mo of a home-based maintenance programme (n = 50) or printed educational material about physical activity (n = 50) for 12 mo across 13 university-affiliated exercise clinics in Australia and New Zealand.

Intervention

Supervised resistance and aerobic exercise or printed educational material about physical activity.

Outcome measurements and statistical analysis

The primary end point was a 400-m walk as a measure of cardiovascular fitness. Secondary end points were physical function, patient-reported outcomes, muscle strength, body composition, and biomarkers. Analysis of covariance was used to compare outcomes for groups at 6 and 12 mo adjusted for baseline values.

Results and limitations

Participants undergoing supervised exercise showed improvement in cardiorespiratory fitness performance at 6 mo (−19 s [p = 0.029]) and 12 mo (−13 s [p = 0.028]) and better lower-body physical function across the 12-mo period (p < 0.01). Supervised exercise also improved self-reported physical functioning at 6 (p = .006) and 12 mo (p = 0.002), appendicular skeletal muscle at 6 mo (p = 0.019), and objective measures of muscle strength at 6 and 12 mo (p < 0.050). Limitations included the restricted number of participants undertaking body composition assessment, no blinding to group assignment for physical functioning measures, and inclusion of well-functioning individuals.

Conclusions

Supervised exercise training in long-term PCa survivors is more effective than physical activity educational material for increasing cardiorespiratory fitness, physical function, muscle strength, and self-reported physical functioning at 6 mo. Importantly, these benefits were maintained in the long term with a home-based programme with follow-up at 12 mo.

Clinical trial registry

The effect of an exercise intervention on cardiovascular and metabolic risk factors in prostate cancer patients from the RADAR study, ACTRN: ACTRN12609000729224.     

A Randomized,Double-Blind,Dose-Finding,Multicenter, Phase 2 Study of Radium Chloride (Ra 223) in Patients with Bone Metastases and Castration-Resistant Prostate Cancer

Background

Patients with castration-resistant prostate cancer (CRPC) and bone metastases have an unmet clinical need for effective treatments that improve quality of life and survival with a favorable safety profile.

Objective

To prospectively evaluate the efficacy and safety of three different doses of radium chloride (Ra 223) in patients with CRPC and bone metastases.

Design, setting, and participants

In this phase 2 double-blind multicenter study, 122 patients were randomized to receive three injections of Ra 223 at 6-wk intervals, at doses of 25 kBq/kg (n = 41), 50 kBq/kg (n = 39), or 80 kBq/kg (n = 42). The study compared the proportion of patients in each dose group who had a confirmed decrease of ≥50% in baseline prostate-specific antigen (PSA) levels.

Outcome measurements and statistical analysis

Efficacy was evaluated using blood samples to measure PSA and other tumor markers, recorded skeletal-related events, and pain assessments. Safety was evaluated using adverse events (AEs), physical examination, and clinical laboratory tests. The Jonckheere-Terpstra test assessed trends between groups.

Results and limitations

The study met its primary end point with a statistically significant dose–response relationship in confirmed ≥50% PSA declines for no patients (0%) in the 25-kBq/kg dose group, two patients (6%) in the 50-kBq/kg dose group, and five patients (13%) in the 80-kBq/kg dose group (p = 0.0297). A ≥50% decrease in bone alkaline phosphatase levels was identified in six patients (16%), 24 patients (67%), and 25 patients (66%) in the 25-, 50-, and 80-kBq/kg dose groups, respectively (p < 0.0001). The most common treatment-related AEs (≥10%) occurring up to week 24 across all dose groups were diarrhea (21%), nausea (16%), and anemia (14%). No difference in incidence of hematologic events was seen among dose groups. Potential limitations include small patient numbers and differences among dose groups at baseline.

Conclusions

Ra 223 had a dose-dependent effect on serum markers of CRPC activity, suggesting that control of bone disease with Ra 223 may affect cancer-related outcomes. Ra 223 was well tolerated at all doses.

Trial registration

ClinicalTrials.gov: NCT00337155.     

Robotic Partial Nephrectomy with Superselective Versus Main Artery Clamping: A Retrospective Comparison

Background

Concerns have been raised regarding partial nephrectomy (PN) techniques that do not occlude the main renal artery.

Objective

Compare the perioperative outcomes of superselective versus main renal artery control during robotic PN.

Design, setting, and participants

A retrospective analysis of 121 consecutive patients undergoing robotic PN using superselective control (group 1, n = 58) or main artery clamping (group 2, n = 63).

Intervention

Group 1 underwent tumor-specific devascularization, maintaining ongoing arterial perfusion to the renal remnant at all times. Group 2 underwent main renal artery clamping, creating global renal ischemia.

Outcome measurements and statistical analysis

Perioperative and functional data were evaluated. The Pearson chi-square or Fisher exact and Wilcoxon rank sum tests were used.

Results and limitations

All robotic procedures were successful, all surgical margins were negative, and no kidneys were lost. Compared with group 2 tumors, group 1 tumors were larger (3.4 vs 2.6 cm, p = 0.004), more commonly hilar (24% vs 6%, p = 0.009), and more complex (PADUA 10 vs 8, p = 0.009). Group 1 patients had longer median operative time (p < 0.001) and transfusion rates (24% vs 6%, p < 0.01) but similar estimated blood loss (200 vs 150 ml), perioperative complications (15% vs 13%), and hospital stay. Group 1 patients had less decrease in estimated glomerular filtration rate at discharge (0% vs 11%, p = 0.01) and at last follow-up (11% vs 17%, p = 0.03). On computed tomography volumetrics, group 1 patients trended toward greater parenchymal preservation (95% vs 90%, p = 0.07) despite larger tumor size and volume (19 vs 8 ml, p = 0.002). Main limitations are the retrospective study design, small cohort, and short follow-up.

Conclusions

Robotic PN with superselective vascular control enables tumor excision without any global renal ischemia. Blood loss, complications, and positive margin rates were low and similar to main artery clamping. In this initial developmental phase, limitations included more perioperative transfusions and longer operative time. The advantage of superselective clamping for better renal function preservation requires validation by prospective randomized studies.

Patient summary

Preserving global blood flow to the kidney during robotic partial nephrectomy (PN) does not lead to a higher complication rate and may lead to better postoperative renal function compared with clamped PN techniques.