Urinary Incontinence,Overactive Bladder,and Other Lower Urinary Tract Symptoms: A Longitudinal Population-Based Survey in Men Aged 45–103 Years

Background

Lower urinary tract symptoms (LUTS) such as urinary incontinence (UI) and overactive bladder (OAB) are highly prevalent conditions, but there are few studies describing progression and remission of LUTS in men, especially over the long term.

Objective

To describe the prevalence of UI, OAB, and LUTS using current International Continence Society definitions in the same men studied longitudinally over time.

Design

Prospective, population-based, longitudinal study.

Setting and participants

In 1992, 10 458 men aged 45–99 yr, resident in the city of Gothenburg, were selected at random from the Population Register.

Measurements

The men received a postal questionnaire about the presence of LUTS, as well as questions on social, medical, health-related quality of life (HRQoL), and demographic data. Responders in 1992 were reassessed 11 yr later in 2003 using a similar questionnaire.

Results and limitations

In 2003, 4072 of the 7763 men who responded in 1992 were still available in the Population Register and 3257 men (80%) aged 56–103 yr, responded. Prevalence of UI and OAB had increased (p < 0.01) in the same men assessed in 1992 (4.5% and 15.6%, respectively) and 2003 (10.5% and 44.4%, respectively). The prevalence of nocturia, urgency, slow stream, hesitancy, incomplete emptying, postmicturition dribble, and the number of daytime micturitions had also increased (p < 0.01). Only a minority reported regression of symptoms. Men with UI or OAB reported a poorer (p < 0.001) HRQoL compared with men without UI or OAB.

Conclusions

There was a marked increase in the prevalence of UI, OAB, and other LUTS in the same men assessed longitudinally over this 11-yr period. UI and OAB had a negative influence on HRQoL, and men who developed UI or OAB had a greater deterioration in HRQoL than men who had no change in their UI/OAB status over time.     

A Longitudinal Population-based Survey of Urinary Incontinence,Overactive Bladder,and Other Lower Urinary Tract Symptoms in Women

Background

Female urinary incontinence (UI), overactive bladder (OAB), and other lower urinary tract symptoms (LUTS) are highly prevalent conditions with a profound influence on well-being and quality of life. There are a few studies describing progression as well as remission, in the short term, of UI in the general population as well as in selected groups; at present, there are very few population-based studies describing the natural course of other LUTS in the same women, and there are no long-term longitudinal studies.

Objective

To describe the prevalence of UI, OAB, and other LUTS in the same women studied prospectively over time and, thus, to assess possible progression or regression.

Design, setting, and participants

A longitudinal population-based study was performed in one primary health care district in the city of Gothenburg, Sweden. The participants were a sample of women aged ≥20 yr who were randomly selected from the Swedish National Population Register, assessed in 1991 (n = 2911), and available for reassessment in 2007 (n = 1408).

Methods

A self-administered postal questionnaire regarding UI, OAB, and other LUTS was returned by 77% of the contacted women in 1991. The same women who responded in 1991 and who were still alive and available in the Swedish National Population Register 16 yr later were reassessed using a similar self-administered postal questionnaire.

Results and limitations

In 2007, 1081 of the available 1408 women responded to the questionnaire (77%). The overall prevalence of UI, OAB, nocturia, and daytime micturition frequency of eight or more times per day increased by 13%, 9%, 20% (p < 0.001), and 3% (p < 0.05), respectively, from 1991 to 2007. The incidence of UI and OAB were 21% and 20%, respectively, and the corresponding remission rates were 34% and 43%, respectively. Women with OAB symptoms were classified as OAB dry or OAB wet, depending on the presence or absence of concomitant UI. The prevalence of OAB dry did not differ between the two assessment occasions (11% and 10%, respectively), but the prevalence of OAB wet increased from 6% to 16% (p < 0.001).

Conclusions

UI and other LUTS constitute dynamic conditions. In this study, there was a marked overall increase in the prevalence of UI, OAB, and nocturia in the same women from 1991 to 2007. Both incidence and remission of most symptoms were considerable.     

Prevalence,Severity, and Symptom Bother of Lower Urinary Tract Symptoms among Men in the EPIC Study: Impact of Overactive Bladder

Background

Lower urinary tract symptoms (LUTS) are prevalent among men.

Objective

To describe the prevalence, severity, and symptom bother of LUTS in all men and men with overactive bladder (OAB) symptoms in the EPIC study.

Design, setting, and participants

A secondary analysis of data from EPIC, a multinational population-based survey of 19 165 adults, was performed. Current International Continence Society definitions were used for individual LUTS and OAB; OAB cases were defined as men reporting urgency.

Measurements

Participants were asked about the presence of individual LUTS and associated symptom bother. LUTS severity was measured using the International Prostate Symptom Score (IPSS).

Results and limitations

There was substantial overlap of storage, voiding, and postmicturition symptoms among all men (n = 7210) and in men with OAB symptoms (n = 502); men with OAB symptoms were more likely to experience multiple LUTS subtypes. Among both populations, nocturia was the most commonly reported symptom, except for urgency (the hallmark symptom) among men with OAB symptoms; terminal dribble and sensation of incomplete emptying were the most common voiding and postmicturition symptoms. The prevalence of all LUTS increased with age among the general population; only storage LUTS increased with age among men with OAB symptoms. Number of LUTS and mean IPSS increased with age in both populations but were higher among men with OAB symptoms at all ages; the proportion reporting moderate–severe LUTS was higher than the general population (30% vs 6%). The proportion of men with OAB symptoms reporting symptom bother increased with urgency severity and severity and number of LUTS. LUTS severity may have been underestimated by the IPSS, which does not assess incontinence.

Conclusions

Men with LUTS commonly experience coexisting storage, voiding, and postmicturition symptoms, emphasizing the need for comprehensive urologic assessments. Men with OAB symptoms reported more LUTS and greater severity than the general population. Symptom bother was related to number of LUTS and urgency severity.     

The Effect of Benign Lower Urinary Tract Symptoms on Subsequent Prostate Cancer Testing and Diagnosis

Background

Lower urinary tract symptoms (LUTS) are common and have been associated with the subsequent diagnosis of prostate cancer (PCa) in population cohorts.

Objective

To determine whether the association between LUTS and PCa is due to the intensity of PCa testing after LUTS diagnosis.

Design, setting, and participants

We prospectively followed a representative, population-based cohort of 1922 men, aged 40–79 yr, from 1990 until 2010 with interviews, questionnaires, and abstracting of medical records for prostate outcomes. Men were excluded if they had a previous prostate biopsy or PCa diagnosis. Self-reported LUTS was defined as an American Urological Association symptom index score >7 (n = 621). Men treated for LUTS (n = 168) were identified from review of medical records and/or self report. Median follow-up was 11.8 yr (interquartile range: 10.7–12.3).

Outcome measurements and statistical analysis

Associations between self-reported LUTS, or treatment for LUTS, and risk of subsequent prostate biopsy and PCa were estimated using Cox proportional hazard models.

Results and limitations

Fifty-five percent of eligible men enrolled in the study. Men treated for LUTS were more likely to undergo a prostate biopsy (hazard ratio [HR]: 2.4; 95% confidence interval [CI], 1.7–3.3). Men younger than 65 yr who were treated for LUTS were more likely to be diagnosed with PCa (HR: 2.3, 95% CI, 1.5–3.5), while men aged >65 yr were not (HR: 0.89, 95% CI, 0.35–1.9). Men with self-reported LUTS were not more likely to be biopsied or diagnosed with PCa. Neither definition of LUTS was associated with subsequent intermediate- to high-risk cancer. The study is limited by lack of histologic or prostate-specific antigen level data for the cohort.

Conclusions

These results indicate that a possible cause of the association between LUTS and PCa is increased diagnostic intensity among men whose LUTS come to the attention of physicians. Increased symptoms themselves were not associated with intensity of testing or diagnosis.     

Genetic influences are important for most but not all lower urinary tract symptoms: a population-based survey in a cohort of adult Swedish twins

Background

The relative importance of genetic and environmental factors for the occurrence of lower urinary tract symptoms (LUTS) is poorly understood.

Objective

To (1) estimate the prevalence of urinary incontinence (UI), overactive bladder (OAB), and other LUTS and (2) to assess the heritability of these symptoms.

Design, setting, and participants

Cross-sectional survey of LUTS in a national population-based cohort of Swedish twins 20–46 yr of age (n = 42 582) from the Swedish Twin Registry.

Measurements

Prevalence rates were determined and heritability of LUTS (in female twins) was assessed using indicators of twin similarity.

Results and limitations

A total of 25 364 twins completed the questionnaire (response rate: 59.6%). LUTS were more common in women (UI: 7%; OAB: 9%; nocturia: 61%; micturition frequency: 18%) than in men (UI: 1%; OAB: 5%; nocturia: 40%; micturition frequency: 11%), and prevalence increased with age. The strongest genetic effects were observed for UI, frequency, and nocturia. The lowest estimate for genetic effects was observed for OAB where environmental effects dominated, and more specifically shared family environment accounted for a third or more of the total variation. For stress UI, a fifth of the total variation in susceptibility to the disorder could be attributed to shared environment. Nonshared environmental effects were seen in the range of 45–65% for the various LUTS. The prevalence of LUTS was low in the men, and there were too few male cases to compute measures of similarity or heritability estimates.

Conclusions

This study provides robust evidence of a genetic influence for susceptibility to UI, frequency, and nocturia in women. In contrast, shared environmental factors seem more important for the predisposition to develop OAB, which may reflect familial patterns such as learning from parental behaviours.     

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.     

TVT-O for the Treatment of Pure Urodynamic Stress Incontinence: Efficacy,Adverse Effects,and Prognostic Factors at 5-Year Follow-up

Background

Inside-out tension-free vaginal transobturator tape (TVT-O) is currently one of the most effective and popular procedures for the surgical treatment of female stress urinary incontinence (SUI), but data reporting long-term outcomes are scarce.

Objective

To evaluate the efficacy and safety of TVT-O 5-yr implantation for management of pure SUI in women.

Design, setting, and participants

A prospective observational study was conducted in four tertiary reference centers. Consecutive women presenting with urodynamically proven, pure SUI treated by TVT-O were included. Patients with mixed incontinence and/or anatomic evidence of pelvic organ prolapse were excluded.

Intervention

TVT-O implantation without any associated procedure.

Outcome measurements and statistical analysis

Data regarding subjective outcomes (International Consultation on Incontinence-Short Form [ICIQ-SF], Patient Global Impression of Improvement, patient satisfaction scores), objective cure (stress test) rates, and adverse events were collected during follow-up. Multivariable analyses were performed to investigate outcomes.

Results and limitations

Of the 191 women included, 21 (11.0%) had previously undergone a failed anti-incontinence surgical procedure. Six (3.1%) patients were lost to follow-up. The 5-yr subjective and objective cure rates were 90.3% and 90.8%, respectively. De novo overactive bladder (OAB) was reported by 24.3% of patients at 5-yr follow-up. Median ICIQ-SF score significantly improved from 17 (interquartile range [IQR]:16–17) preoperatively to 0 (IQR: 0–2) (p < 0.0001).Failure of a previous anti-incontinence procedure was the only independent predictor of subjective recurrence of SUI (hazard ratio [HR]: 4.4; p = 0.009) or objective (HR: 3.7; p = 0.02). No predictive factor of de novo OAB was identified.

Conclusions

TVT-O implantation is a highly effective option for the treatment of women with pure SUI, showing a very high cure rate and a low incidence of complications after 5-yr follow-up.     

Anticholinergic medication use for female overactive bladder in the ambulatory setting in the United States

Introduction and hypothesis

Our objective was to estimate the prevalence and sociodemographic factors associated with anticholinergic medication use by adult women for overactive bladder (OAB) in the United States.

Methods

We conducted a cross-sectional study using the 2009 National Ambulatory Medical Care Survey database (NAMCS). We included women aged 18 years and older and identified visits for which anticholinergic medications for OAB were in active use. We evaluated the prevalence of medications used and estimated the use of short-acting versus long-acting drugs. We also assessed variables associated with anticholinergic use, (age, race/ethnicity, insurance, geographic location) using survey weights in the analysis to estimate national data.

Results

In 2009, adult women made 516.8 million outpatient office visits. Of these, 8.1 million (1.6 %) were associated with an OAB anticholinergic medication (annual rate 68 per 1,000 women). Women who used anticholinergics were predominantly insured by Medicare (61.0 %) and were older than those not using anticholinergic medications (70.0?±?1.1 vs. 53.0?±?0.5, p?<?0.001). No racial or ethnic differences were evident between the two groups. Tolterodine (33.8 %) and oxybutynin (33.1 %) were the most commonly reported medications, followed by solifenacin (19.5 %), darifenacin (9.3 %), and trospium (4.4 %). Long-acting anticholinergics were used more often than short-acting medications (53.8 % vs. 46.3 %, respectively, p?<?0.001).

Conclusions

Annually, more than 8 million outpatient visits occur in which adult women in the United States are using an OAB anticholinergic medication. Despite the abundance of newer-generation medications, tolterodine and oxybutynin remain the most commonly prescribed anticholinergic drugs for OAB. Solifenacin is the most popular newer-generation anticholinergic drug.     

Sex variability of fine-needle aspiration reliability in the diagnosis of malignancy in thyroid nodules ≥4 cm

Background

The effect of sex on fine-needle aspiration (FNA) diagnosis of thyroid cancer remains unknown. This study determines the reliability of FNA when evaluating thyroid nodules ≥4 cm in women and men.

Methods

Prospectively collected data of 1,068 patients who underwent FNA and thyroidectomy at a tertiary medical center were retrospectively reviewed. Data were stratified by sex and thyroid nodule size ≥4 cm.

Results

The FNA false-negative rate for thyroid malignancy in women and men was 17% and 0%, respectively. FNA was less predictive of malignancy in women (odd ratio = 31.7; 95% confidence interval, 19.2 to 52.5; P < .0001) compared with men (odds ratio = 51.7; 95% confidence interval, 11.8 to 225.1; P < .0001) with thyroid nodules ≥4 cm.

Conclusions

For the diagnosis of malignancy in large thyroid nodules, FNA may be less reliable in women compared with men. This study advocates using a more aggressive approach that includes surgical resection for definitive diagnosis in women with thyroid nodules ≥4 cm.     

Gender and Age Differences in the Perception of Bother and Health Care Seeking for Lower Urinary Tract Symptoms: Results from the Hospitalised and Outpatients’ Profile and Expectations Study

Background

Few comparisons have been made of health care seeking behaviour for lower urinary tract symptoms (LUTS) between men and women, as well as trends across age groups.

Objective

To investigate the bother from LUTS and effect on health care seeking in both men and women of different age groups and in comparison between the two genders.

Design, setting, and participants

A representative cross section of each of 13 clinics of a general academic hospital, with equal numbers of subjects recruited in each of six design cells that were defined by age (18–40, 41–60, 61–80 yr) and gender.

Intervention

A 2-h in-person interview, conducted by a trained psychologist/interviewer in a clinic office.

Measurements

Severity of LUTS was measured by the International Prostate Symptom Score (IPSS). Treatment seeking was measured by a single item. A bother question was modified to assess overall bother. Impact on quality of life (QoL) was measured by the IPSS QoL question.

Results and limitations

The final study sample comprised 415 patients. More women than men reported the presence of LUTS (85.5% vs 75.2%; p = 0.01). LUTS were more bothersome in women (25.4% of women vs 17.6% of men with bother “some” or “a lot”; p = 0.02). Severity of LUTS increased with age in both genders (men: p < 0.001; women: p = 0.03). Bother from LUTS increased as severity of symptoms increased in both genders (p < 0.001) but was associated with age only in men (p < 0.001). QoL showed similar results as bother. Although men and women had equal prevalence of treatment seeking (27.9% vs 23.7%; p = 0.40), men, but not women, were more likely to seek treatment as age (p < 0.01) and severity of LUTS (p < 0.001) increased. In multivariate logistic regressions, only bother from LUTS was associated with treatment seeking in women, compared with bother, age, and the presence of voiding symptoms in men.

Conclusions

In our hospital-based sample, differences in LUTS frequency, bother, and health care seeking profiles between men and women suggest a different perception and response to LUTS between the two genders.     

Adverse Events of Intravesical Botulinum Toxin A Injections for Idiopathic Detrusor Overactivity: Risk Factors and Influence on Treatment Outcome

Background

Intravesical injection of botulinum toxin type A (BoNTA) provides effective treatment for detrusor overactivity and overactive bladder (OAB). However, the high rates of treatment-related adverse events (AEs) prevent its more widespread use.

Objective

To investigate the risk factors of increasing AEs after BoNTA injection for idiopathic detrusor overactivity (IDO).

Design, setting, and participants

This study included a total of 217 patients receiving their first intravesical BoNTA injection for refractory IDO in a tertiary university hospital from 2004 to 2009.

Measurements

AE incidence was analyzed according to gender, age, comorbidities, prostate condition in men, OAB subtype, BoNTA dose, injection site, and baseline urodynamic parameters. Successful outcome was determined based on patient perception of improvement of bladder condition at 3 mo.

Results and limitations

Successful outcomes were reported by 144 (66.3%) patients. By multivariable analysis, male gender (p = 0.013) and baseline postvoid residual (PVR) ≥100 ml (p = 0.003) were independent predictors of acute urinary retention (AUR). Baseline PVR ≥100 ml (p = 0.007) and receiving >100 U BoNTA (p = 0.029) were predictors of straining to void. The incidence of large PVR after treatment was associated with comorbidity (p = 0.011). Urinary tract infection occurred more frequently in women (p = 0.003) and in men with retaining prostate (p = 0.008). No AUR developed after bladder base/trigonal injection. Nevertheless, the occurrence of AUR or large PVR did not affect therapeutic outcome. This study is limited by nonconsecutive enrollment of patients.

Conclusions

Male gender, baseline PVR ≥100 ml, comorbidity, and BoNTA dose >100 U are risk factors for increasing incidence of AEs after intravesical BoNTA injection for IDO.     

Randomized Double-blind,Active-controlled Phase 3 Study to Assess 12-Month Safety and Efficacy of Mirabegron,a β3-Adrenoceptor Agonist,in Overactive Bladder

Background

Despite several antimuscarinic treatment options for overactive bladder (OAB), there is still a need for distinct treatment approaches to manage this condition. Mirabegron, a β₃-adrenoceptor agonist, has demonstrated efficacy and tolerability for up to 12 wk in phase 3 trials.

Objective

To assess the 12-mo safety and efficacy of mirabegron.

Design, setting, and participants

Patients ≥18 yr of age with OAB symptoms for ≥3 mo.

Interventions

After a 2-wk single-blind placebo run-in, patients with eight or more micturitions per 24 h and three or more urgency episodes in a 3-d micturition diary were randomized 1:1:1 to once-daily mirabegron 50 mg, mirabegron 100 mg, or tolterodine extended release (ER) 4 mg for 12 mo.

Outcome measurements and statistical analysis

Primary variable: incidence and severity of treatment-emergent AEs (TEAEs). Secondary variables: change from baseline at months 1, 3, 6, 9, and 12 in key OAB symptoms.

Results and limitations

A total of 812, 820, and 812 patients received mirabegron 50 mg, mirabegron 100 mg, and tolterodine ER 4 mg, respectively. Baseline demographic and OAB characteristics were similar across groups. TEAEs were reported in 59.7%, 61.3%, and 62.6% of patients, respectively; most were mild or moderate. Serious TEAEs were reported in 5.2%, 6.2%, and 5.4% of patients, respectively. The most common TEAEs were similar across groups. Dry mouth was reported by 2.8%, 2.3%, and 8.6% of patients, respectively. Adjusted mean changes from baseline to final visit in morning systolic blood pressure were 0.2, 0.4, and −0.5 mm Hg for mirabegron 50 mg, 100 mg, and tolterodine ER 4 mg, respectively. Mirabegron and the active control, tolterodine, improved key OAB symptoms from the first measured time point of 4 wk, and efficacy was maintained throughout the 12-mo treatment period. The study was not placebo controlled, which was a limitation.

Conclusions

The safety and tolerability of mirabegron was established over 1 yr, with sustained efficacy observed over this treatment period.

Trial registration

ClinicalTrials.gov identifier: NCT00688688.     

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.     

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.     

The Effect of Age on the Efficacy of Maintenance Bacillus Calmette-Guérin Relative to Maintenance Epirubicin in Patients with Stage Ta T1 Urothelial Bladder Cancer: Results from EORTC Genito-Urinary Group Study 30911

Background

Although maintenance bacillus Calmette-Guérin (BCG) is the recommended treatment in high-risk non–muscle-invasive bladder cancer (NMIBC), its efficacy in older patients is controversial.

Objective

To determine the effect of age on prognosis and treatment outcome in patients with stage Ta T1 NMIBC treated with maintenance BCG.

Design, setting, and participants

A total of 957 patients with intermediate- or high-risk Ta T1 (without carcinoma in situ) NMIBC were randomized in European Organization for Research and Treatment of Cancer (EORTC) trial 30911 comparing six weekly instillations of epirubicin, BCG, and BCG plus isoniazid followed by three weekly maintenance instillations over 3 yr.

Outcome measurements and statistical analysis

Cox multivariate proportional hazards regression models were used to assess the relative importance of age for recurrence, progression, overall survival, and NMIBC-specific survival with adjustment for EORTC risk scores.

Results and limitations

Overall, 822 eligible patients were included: 546 patients in the BCG with or without INH arms and 276 in the epirubicin arm. In patients treated with BCG with or without INH, 34.1% were >70 yr of age and 3.7% were >80 yr. With a median follow-up of 9.2 yr, patients >70 yr had a shorter time to progression (p = 0.028), overall survival (p < 0.001), and NMIBC-specific survival (p = 0.049) after adjustment for EORTC risk scores in the multivariate analysis. The time to recurrence was similar compared with the younger patients. BCG was more effective than epirubicin for all four end points considered, and there was no evidence that BCG was any less effective compared with epirubicin in patients >70 yr.

Conclusions

In intermediate- and high-risk Ta T1 urothelial bladder cancer patients treated with BCG, patients >70 yr of age have a worse long-term prognosis; however, BCG is more effective than epirubicin independent of patient age.

Patient summary

Intravesical bacillus Calmette-Guérin for non–muscle-invasive bladder cancer is less effective in patients >70 yr of age, but it is still more effective than epirubicin.

Trial registration

This study was registered with the US National Cancer Institute clinical trials database (protocol ID: EORTC 30911; http://www.cancer.gov/clinicaltrials/search/view?cdrid=77075&version=HealthProfessional&protocolsearchid=12442243#StudyIdInfo_CDR0000077075).     

Dynamic Progression of Overactive Bladder and Urinary Incontinence Symptoms: A Systematic Review

Context

Overactive bladder (OAB) and urinary incontinence (UI) are worldwide public health problems. Longitudinal epidemiologic studies that assess the natural history of OAB and UI are valuable in making accurate prognoses, determining causes and consequences, and predicting resource utilization.

Objective

Our aim was to assess whether the severity of OAB and UI symptoms progress dynamically over time, with the secondary aim of assessing factors that may be associated with symptom progression and regression.

Evidence acquisition

A systematic review of English articles published between January 1, 1990, and September 20, 2009, was conducted using PubMed and Embase. Search terms included longitudinal, natural history, overactive bladder, incontinence, progression, remission, and regression. Eligibility was assessed by Dr. Irwin with editorial assistance. Studies were required to be longitudinal and population based; meeting abstracts and conference proceedings were excluded. Results were assessed qualitatively.

Evidence synthesis

Overall, the 7 longitudinal studies of OAB and 14 longitudinal studies of UI reviewed reported an increase in the incidence and remission/regression of both OAB and UI symptoms over time that varied across studies (eg, OAB incidence, 3.7–8.8%; UI incidence, 0.8–19%). The studies provide evidence for a dynamic progression of OAB and UI symptoms (eg, among women with OAB without urge urinary incontinence [UUI], 28% reported OAB with UUI 16 yr later) and also show that although symptom severity progresses dynamically, for many individuals symptoms also persist over long time periods.

Conclusions

The results support the hypothesis that OAB and UI symptom severity progress dynamically and are also sustained over time. However, the variations in symptom definitions and methods used across studies prevent statistical determinations of overall incidence rates. The recognition of OAB and UI as progressive conditions allows for a shift from the current treatment paradigm of symptom control alone to one of symptom management.     

Natural History of Early,Localized Prostate Cancer: A Final Report from Three Decades of Follow-up

Background

Most localized prostate cancers are believed to have an indolent course. Within 15 yr of diagnosis, most deaths among men with prostate cancer (PCa) can be attributed to other competing causes. However, data from studies with extended follow-up are insufficient to determine appropriate treatment for men with localized disease.

Objective

To investigate the long-term natural history of untreated, early-stage PCa.

Design, setting, and participants

We conducted a population-based, prospective-cohort study using a consecutive sample of 223 patients with untreated, localized PCa from a regionally well-defined catchment area in central Sweden. All subjects were initially managed with observation. Androgen deprivation therapy was administered when symptomatic tumor progression occurred.

Outcome measurements and statistical analysis

Based on >30 yr of follow-up, the main outcome measures were: progression-free, cause-specific, and overall survival, and rates of progression and mortality per 1000 person-years.

Results and limitations

After 32 yr of follow-up, all but 3 (1%) of the 223 men had died. We observed 90 (41.4%) local progression events and 41 (18.4%) cases of progression to distant metastasis. In total, 38 (17%) men died of PCa. Cause-specific survival decreased between 15 and 20 yr, but stabilized with further follow-up. All nine men with Gleason grade 8–10 disease died within the first 10 yr of follow-up, five (55%) from PCa. Survival for men with well-differentiated, nonpalpable tumors declined slowly through 20 yr, and more rapidly between 20 and 25 yr (from 75.2% [95% confidence interval, 48.4–89.3] to 25% [95% confidence interval, 22.0–72.5]). It is unclear whether these data are relevant for tumors detected by elevated prostate-specific antigen levels.

Conclusions

Although localized PCa most often has an indolent course, local progression and distant metastasis can develop over the long term, even among patients considered low risk at diagnosis.     

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.     

Outcome Following Active Surveillance of Men with Screen-detected Prostate Cancer. Results from the Göteborg Randomised Population-based Prostate Cancer Screening Trial

Background

Active surveillance (AS) has emerged as a treatment strategy for reducing overtreatment of screen-detected, low-risk prostate cancer (PCa).

Objective

To assess outcomes following AS of men with screen-detected PCa.

Design, setting, and participants

Of the 968 men who were diagnosed with screen-detected PCa between 1995 and 2010 in the Göteborg randomised, population-based PCa screening trial, 439 were managed with AS and were included in this study. Median age at diagnosis was 65.4 yr of age, and median follow-up was 6.0 yr from diagnosis.

Intervention

The study participants were followed at intervals of 3–12 mo and were recommended to switch to deferred active treatment in case of a progression in prostate-specific antigen, grade, or stage.

Outcome measurements and statistical analysis

The end points—overall survival (OS), treatment-free survival, failure-free (no relapse after radical treatment) survival, and cancer-specific survival—were calculated for various risk groups (very low, low, intermediate, and high) with Kaplan-Meier estimates. A Cox proportional hazards model as well as a competing risk analysis were used to assess whether risk group or age at diagnosis was associated with failure after AS.

Results and limitations

Forty-five per cent of all screen-detected PCa were managed with AS, and very low-risk and low-risk PCa constituted 60% of all screen-detected PCa. Thirty-seven per cent (162 of 439) switched from surveillance to deferred active treatment, and 39 men failed AS. The 10-yr OS, treatment-free survival, and failure-free survival were 81.1%, 45.4%, and 86.4%, respectively (Kaplan-Meier estimates). Men with low-, intermediate-, and high-risk tumours had a hazard ratio for failure of 2.1 (p = 0.09), 3.6 (p = 0.002), and 4.6 (p = 0.15), respectively, compared to very low-risk tumours (Cox regression). Only one PCa death occurred, and one patient developed metastasis (both in the intermediate-risk group). The main limitation of this study is the relatively short follow-up.

Conclusions

A large proportion of men with screen-detected PCa can be managed with AS. AS appears safe for men with low-risk PCa.     

Does Primary Androgen-Deprivation Therapy Delay the Receipt of Secondary Cancer Therapy for Localized Prostate Cancer?

Background

Despite evidence that shows no survival advantage, many older patients receive primary androgen-deprivation therapy (PADT) shortly after the diagnosis of localized prostate cancer (PCa).

Objective

This study evaluates whether the early use of PADT affects the subsequent receipt of additional palliative cancer treatments such as chemotherapy, palliative radiation therapy, or intervention for spinal cord compression or bladder outlet obstruction.

Design, setting, and participants

This longitudinal population-based cohort study consists of Medicare patients aged ≥66 yr diagnosed with localized PCa from 1992 to 2006 in areas covered by the Surveillance Epidemiology and End Results (SEER) program. SEER-Medicare linked data through 2009 were used to identify the use of PADT and palliative cancer therapy.

Outcome measurements and statistical analysis

Instrumental variable analysis methods were used to minimize confounding effects. Confidence intervals were derived from the bootstrap estimates.

Results and limitations

This study includes 29 775 men who did not receive local therapy for T1–T2 PCa within the first year of cancer diagnosis. Among low-risk patients (Gleason score 2–7 in 1992–2002 and Gleason score 2–6 in 2003–2006) with a median age of 78 yr and a median follow-up of 10.3 yr, PADT was associated with a 25% higher use of chemotherapy (hazard ratio [HR]: 1.25; 95% confidence interval [CI], 1.08–1.44) and a borderline higher use of any palliative cancer treatment (HR: 1.07; 95% CI, 0.97–1.19) within 10 yr of diagnosis in regions with high PADT use compared with regions with low PADT use. Because this study was limited to men >65 yr, the results may not be applicable to younger patients.

Conclusions

Early treatment of low-risk, localized PCa with PADT does not delay the receipt of subsequent palliative therapies and is associated with an increased use of chemotherapy.