Steven A. Kaplan

Prostate Specific Antigen Density: A Means of Distinguishing Benign Prostatic Hypertrophy and Prostate Cancer

Isolated prostate specific antigen (PSA) determinations in asymptomatic individuals have not demonstrated sufficient sensitivity and specificity to be useful in the routine evaluation of prostate disease. To enhance the accuracy of serum PSA we have used a quotient of serum PSA and prostate volume, which we refer to as prostate specific antigen density (PSAD). Prostate volume in this study was calculated from magnetic resonance imaging determinations of benign prostatic hypertrophy (BPH) or from the dimensions of the surgical specimen of cancer using the formula, length x width x depth x 0.5 = volume. A total of 61 patients with prostatic disease clinically confined to the prostate glands (41 with prostate cancer undergoing radical prostatectomy and 20 with BPH) was evaluated. The mean PSAD for prostate cancer was 0.581 while that for BPH was 0.044 (p less than 0.002). No patient with BPH had a PSAD of greater than 0.117 and only 1 patient had a density of 0.1 or greater. Of 34 patients with a PSAD of 0.1 or greater 33 had prostate cancer. Only 2 of the 41 prostate cancer patients and 14 of the BPH patients had a PSAD of 0.05 or less. There were 11 patients with a PSAD of greater than 0.05 and less than 0.1, including 6 with prostate cancer (1 with P0 disease) and 5 with BPH. Of the 6 prostate cancer patients 5 had a PSA of 4.0 or less and among the 5 patients with BPH 4 had a serum PSA of greater than 4.0 and 1 had a PSA of greater than 10. These results suggest that PSAD may be useful in distinguishing BPH and prostate cancer.

Update on AUA Guideline on the Management of Benign Prostatic Hyperplasia

PURPOSE To revise the 2003 version of the American Urological Associations (AUA) Guideline on the management of benign prostatic hyperplasia (BPH). MATERIALS AND METHODS From MEDLINE® searches of English language publications (January 1999 through February 2008) using relevant MeSH terms, articles concerning the management of the index patient, a male ≥45 years of age who is consulting a healthcare provider for lower urinary tract symptoms (LUTS) were identified. Qualitative analysis of the evidence was performed. Selected studies were stratified by design, comparator, follow-up interval, and intensity of intervention, and meta-analyses (quantitative synthesis) of outcomes of randomized controlled trials were planned. Guideline statements were drafted by an appointed expert Panel based on the evidence. RESULTS The studies varied as to patient selection; randomization; blinding mechanism; run-in periods; patient demographics, comorbidities, prostate characteristics and symptoms; drug doses; other intervention characteristics; comparators; rigor and intervals of follow-up; trial duration and timing; suspected lack of applicability to current US practice; and techniques of outcomes measurement. These variations affected the quality of the evidence reviewed making formal meta-analysis impractical or futile. Instead, the Panel and extractors reviewed the data in a systematic fashion and without statistical rigor. Diagnosis and treatment algorithms were adopted from the 2005 International Consultation of Urologic Diseases. Guideline statements concerning pharmacotherapies, watchful waiting, surgical options and minimally invasive procedures were either updated or newly drafted, peer reviewed and approved by AUA Board of Directors. CONCLUSIONS New pharmacotherapies and technologies have emerged which have impacted treatment algorithms. The management of LUTS/BPH continues to evolve.

The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK and Sweden: results from the Epidemiology of LUTS (EpiLUTS) study

To estimate and compare the prevalence and associated bother of lower urinary tract symptoms (LUTS) in the general populations of the USA, UK and Sweden using current International Continence Society (ICS) definitions, as no previous population‐based studies evaluating the prevalence of LUTS in the USA, using the 2002 ICS definitions, have been conducted.

Meta-analysis of Functional Outcomes and Complications Following Transurethral Procedures for Lower Urinary Tract Symptoms Resulting from Benign Prostatic Enlargement

CONTEXT There is a continuous decline in the number of transurethral resections of the prostate (TURP) and an increase use of minimally invasive surgical therapy (MIST) for lower urinary tract symptoms resulting from benign prostatic enlargement. Current results from randomised controlled trials (RCT) and methodologically sound prospective studies suggest that some of the proposed procedures have the potential to replace TURP. OBJECTIVE To determine the contemporary status of TURP and of the currently most commonly applied transurethral MISTs: (1) bipolar TURP, (2) bipolar transurethral vaporisation of the prostate (bipolar TUVP), (3) holmium laser enucleation of the prostate (HoLEP), and (4) potassium-titanyl-phosphate (KTP) laser vaporisation of the prostate. EVIDENCE ACQUISITION This meta-analysis was based on a systematic Medline search assessing the period 1997-2009. All RCTs comparing TURP and the most commonly discussed ablative treatments were included. The end points of our analyses were functional outcomes and treatment-related adverse events. EVIDENCE SYNTHESIS Twenty-seven publications involving 23 different RCTs with a total of 2245 patients provided the highest level of evidence available (level 1b) and were fully assessed. Meta-analysis was conducted with SAS v.9.1.3 (SAS Institute, Cary, NC, USA). Forest plots were produced using the R software. Pooled odds ratios and 95% confidence intervals were calculated between various operative techniques versus TURP. Functional results between the specific transurethral procedures versus TURP were summarised as differences in means. CONCLUSIONS This meta-analysis demonstrates statistically comparable efficacy and overall morbidity for MISTs versus contemporary TURP. Type, category (minor vs major), and the number of complications (safety profile) vary specifically for each of the different transurethral techniques. We feel that the individual patients clinical profile should be carefully assessed to identify the most appropriate transurethral technique.

Urodynamic Findings in Patients With Diabetic Cystopathy

To ascertain the relationship between voiding dysfunction associated with diabetes and bladder and sphincter behavior, the video urodynamic studies of 182 patients were retrospectively analyzed. Patients were classified based on urodynamic diagnosis and the presence or absence of signs of sacral cord involvement. Urodynamic findings were classified as either detrusor hyperreflexia, impaired detrusor contractility, detrusor areflexia, indeterminate and normal. The results indicate that mean bladder capacity was 485 +/- 89.3 ml. with a mean first sensation of filling of 298 +/- 67.4 ml. Of the 182 patients 100 (55%) had detrusor hyperreflexia, 42 (23%) had impaired detrusor contractility, 20 (11%) had indeterminate findings, 19 (10%) had detrusor areflexia and 1 (1%) was normal. Bladder outlet obstruction occurred in 66 patients (36%), all men (57%). The diagnosis was isolated in 24 patients (36%) or in combination with another diagnosis in 42 (74%). However, if one considers the presence of sacral cord signs (42 patients), the most common urodynamic diagnoses were either impaired detrusor contractility in 21 (50%) or detrusor areflexia in 10 (24%). These data suggest that classical diabetic cystopathy is not the most common urodynamic findings in patients with diabetes mellitus and voiding dysfunction, and in fact these patients present with variable pathophysiological findings. These findings demonstrate the importance of urodynamic studies in diagnosing voiding dysfunction in diabetics before initiation of therapy.

Safety and tolerability of tolterodine for the treatment of overactive bladder in men with bladder outlet obstruction.

PURPOSE Antimuscarinic therapy for men with OAB and BOO is perceived as a potential risk for urinary retention. Using pressure flow urodynamics, we evaluated the safety of tolterodine vs placebo in men with OAB and BOO. MATERIALS AND METHODS Men (older than 40 years) with BOO and confirmed detrusor overactivity were randomized to tolterodine (2 mg twice daily in 149) or placebo (in 72) for 12 weeks. Primary end points were Qmax and pdetQmax. RESULTS Median treatment differences in Qmax (-0.7 ml per second, 95% CI -1.6 to 0.4) and pdetQmax (-7 cm H2O, 95% CI -3 to 11) were comparable. Tolterodine significantly reduced the BOOI vs placebo (-9 vs 0, p < 0.02). There were significant treatment differences in volume to first detrusor contraction (+59 ml, 95% CI 19-100) and maximum cystometric capacity (+67 ml, 95% CI 35-103), favoring tolterodine over placebo (p < 0.003). Change in PVR was significantly greater among patients treated with tolterodine (+25 ml) than placebo (0 ml, p < 0.004). There were no significant between-group differences in the incidence of adverse events. Urinary retention was reported by 1 patient treated with placebo. CONCLUSIONS Tolterodine did not adversely affect urinary function in men with OAB and BOO. Urinary flow rate was unaltered, and there was no evidence of clinically meaningful changes in voiding pressure and PVR or urinary retention. Tolterodine was well tolerated. These results suggest that antimuscarinics can be safely administered in men with BOO.

Increased incidence of depressive symptoms in men with erectile dysfunction

OBJECTIVES To investigate the hypothesis that men with erectile dysfunction (ED) have a higher incidence of depressive symptoms compared with age-matched control subjects. We also hypothesized that depressive symptoms impact on the level of libido and on the success of treatment of ED. METHODS One hundred twenty men with ED or benign prostatic hyperplasia (BPH) were divided into three groups. Group 1 had ED only, group 2 had BPH only, and group 3 had both ED and BPH. Patients were screened for depressive symptoms using the Primary Care Evaluation of Mental Disorders and the Beck Depression Inventory. They were also surveyed for comorbidity, marital status, severity of ED, level of libido, prior ED treatment choice (if any), success of treatment, and others. RESULTS One hundred patients completed the questionnaires. Depressive symptoms were reported by 26 (54%) of 48 men with ED alone, 10 (56%) of 18 men with ED and BPH, and 7 (21 %) of 34 men with BPH alone. Patients with ED were 2.6 times more likely to report depressive symptoms than men with BPH alone (P < 0.005). Patients with depressive symptoms reported lower libido than other patients (P < 0.0001). Severity of comorbidities did not differ among the three groups. A total of 33 patients with ED had prior treatment for ED using penile injections or vacuum devices. All 15 (100%) patients with ED only continued treatment and were satisfied with its outcome, whereas only 7 (38.9%) of 18 patients with ED and depressive symptoms continued treatment (P < 0.00021). CONCLUSIONS ED is associated with high incidence of depressive symptoms, regardless of age, marital status, or comorbidities. Patients with ED have a decreased libido compared with control subjects. In addition, patients with depressive symptoms have a lower libido than patients without depressive symptoms. Patients with ED and depressive symptoms are more likely to discontinue treatment for ED than other patients with ED. These data emphasize the importance of a multidisciplinary approach to the treatment of erectile dysfunction.

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 β(3)-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 24h and three or more urgency episodes in a 3-d micturition diary were randomized 1:1:1 to once-daily mirabegron 50mg, mirabegron 100mg, 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 50mg, mirabegron 100mg, 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 -0.5mm Hg for mirabegron 50mg, 100mg, 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 systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with α-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia

CONTEXT Several randomized controlled trials (RCTs) on phosphodiesterase type 5 inhibitors (PDE5-Is) have showed significant improvements in both lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) in men affected by one or both conditions, without a significant increase in adverse events. However, the results are inconsistent. OBJECTIVE Perform a systematic review and meta-analysis of available prospective and cross-sectional studies on the use of PDE5-Is alone or in combination with α1-adrenergic blockers in patients with LUTS/benign prostatic hyperplasia (BPH). EVIDENCE ACQUISITION A systematic search was performed using the Medline, Embase, and Cochrane Library databases through September 2011 including the combination of the following terms: LUTS, BPH, PDE5-Is, sildenafil, tadalafil, vardenafil, udenafil, α-blockers, and α1-adrenergic blocker. The meta-analysis was conducted according to the guidelines for observational studies in epidemiology. EVIDENCE SYNTHESIS Of 107 retrieved articles, 12 were included in the present meta-analysis: 7 on PDE5-Is versus placebo, with 3214 men, and 5 on the combination of PDE5-Is with α1-adrenergic blockers versus α1-adrenergic blockers alone, with 216 men. Median follow-up of all RCTs was 12 wk. Combining the results of those trials, the use of PDE5-Is alone was associated with a significant improvement of the International Index of Erectile Function (IIEF) score (+5.5; p<0.0001) and International Prostate Symptom Score (IPSS) (-2.8; p<0.0001) but not the maximum flow rate (Q(max)) (-0.00; p=not significant) at the end of the study as compared with placebo. The association of PDE5-Is and α1-adrenergic blockers improved the IIEF score (+3.6; p<0.0001), IPSS score (-1.8; p = 0.05), and Q(max) (+1.5; p<0.0001) at the end of the study as compared with α-blockers alone. CONCLUSIONS The meta-analysis of the available cross-sectional data suggests that PDE5-Is can significantly improve LUTS and erectile function in men with BPH. PDE5-Is seem to be a promising treatment option for patients with LUTS secondary to BPH with or without ED.

TRANSURETHRAL ELECTROVAPORIZATION OF THE PROSTATE: A NOVEL METHOD FOR TREATING MEN WITH BENIGN PROSTATIC HYPERPLASIA

OBJECTIVES To determine the preliminary safety and efficacy of transurethral vaporization of the prostate (TVP) using the VaporTrode as a therapeutic alternative in the management of men with bladder outlet obstruction. METHODS Twenty-five men (mean age, 63.5 +/- 3.1 years) with mild to moderate symptoms of prostatism underwent TVP since August 1994. Patients were assessed at baseline for both safety and efficacy and in follow-up at 1 week and 1 and 3 months. Efficacy parameters evaluated included operative time (in minutes), change in hematocrit and serum sodium, postoperative catheterization time, American Urological Association symptom score, peak uroflow (Qmax) and postvoid residual urine. Safety parameters evaluated included incidence of side effects, changes in serum sodium and hematocrit, and evaluation of sexual function. RESULTS Symptoms decreased from 17.8 to 5.9 and 4.2 at 1 and 3 months, respectively (P < 0.01). Qmax increased from 7.4 to 15.3 and 17.3 mL/s at 1 and 3 months, respectively (P < 0.02). Mean operative time was 40.3 minutes; mean interval to catheter removal was 14.6 hours. Changes in serum parameters included a 0.9 mL/dL decrease in hematocrit and a 1.1 mEq/L change in sodium. Complications of the procedure included mild hematuria (n = 3) and distal bulbar urethral stricture (n = 1). There were no associated significant postprocedure irritative symptoms and no patient required recatheterization. CONCLUSIONS TVP is a new and potentially useful modification of performing transurethral resection of the prostate. In this preliminary study, there has been significant clinical improvement maintained with minimal morbidity. This early clinical experience highlights several potential advantages of TVP, including significantly lower cost and minimal postoperative irritative symptom score. Currently, a multicenter clinical trial is under way to determine the long-term efficacy and safety of TVP.