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Purpose: The 6th International Consultation on New Developments in Prostate Cancer and Prostate Diseases met from June 24–28, 2005 in Paris, France to review new developments in benign prostatic disease. Materials and Methods: A series of committees were asked to produce recommendations on the evaluation and treatment of lower urinary tract symptoms in older men. Each committee was asked to base recommendations on a thorough assessment of the available literature according to the International Consultation on Incontinence level of evidence and grading system adapted from the Oxford system. Results: The Consultation endorsed the appropriate use of the current terminology lower urinary tract symptoms/benign prostatic hyperplasia/benign prostate enlargement and benign prostatic obstruction, and recommended that terms such as “clinical benign prostatic hyperplasia” or “the benign prostatic hyperplasia patient” be abandoned, and asked the authorities to endorse the new nomenclature. The diagnostic evaluation describes recommended and optional tests, and in general places the focus on the impact (bother) of lower urinary tract symptoms on the individual patient when determining investigation and treatment. The importance of symptom assessment, impact on quality of life, physical examination and urinalysis is emphasized. The frequency volume chart is recommended when nocturia is a bothersome symptom to exclude nocturnal polyuria. The recommendations are summarized in 2 algorithms, 1 for basic management and 1 for specialized management of persistent bothersome lower urinary tract symptoms. Conclusions: The use of urodynamics and transrectal ultrasound should be limited to situations in which the results are likely to benefit the patient such as in selection for surgery. It is emphasized that imaging and endoscopy of the urinary tract have specific indications such as dipstick hematuria. Treatment should be holistic, and may include conservative measures, lifestyle interventions and behavioral modifications as well as medication and surgery. Only treatments with a strong evidence base for their clinical effectiveness should be used. [Copyright &y& Elsevier]

Purpose: PLUS investigated the efficacy and safety of mirabegron add-on therapy in men with overactive bladder symptoms receiving tamsulosin for underlying lower urinary tract symptoms attributable to benign prostatic hyperplasia., Materials and Methods: In this phase 4 study a 4-week 0.4 mg tamsulosin run-in period was followed by a 12-week, randomized, double-blind, treatment period in which patients initially received 25 mg mirabegron or placebo add-on therapy. At 4 weeks doses were titrated to 50 mg mirabegron or placebo equivalent. Efficacy end points were changes from baseline to end of treatment in mean number of micturitions per day (primary), mean volume voided per micturition, number of urgency episodes per day, total urgency and frequency score, and total International Prostate Symptom Score (secondary). Safety assessments included treatment emergent adverse events, and post-void residual volume, and maximum urinary flow measurements., Results: Of the 676 men most were 65 years old or older (380, 56.2%). Tamsulosin plus mirabegron was statistically superior to tamsulosin plus placebo in reducing the mean number of micturitions per day (-2.00 vs -1.62; adjusted difference -0.39; 95% CI -0.76, -0.02). Statistically superior results were noted for tamsulosin plus mirabegron in mean volume voided per micturition, urgency episodes per day, and total urgency and frequency score (not International Prostate Symptom Score). Higher overall treatment emergent adverse event rates were observed with tamsulosin plus placebo, although higher rates of drug related treatment emergent adverse events were noted with tamsulosin plus mirabegron. Urinary retention rates were higher in the tamsulosin plus mirabegron group. Post-void residual volume and maximum urinary flow results were not clinically meaningful., Conclusions: The results of PLUS underscore the utility of mirabegron add-on therapy to treat men with overactive bladder symptoms receiving tamsulosin for benign prostatic hyperplasia.

Purpose: These are the final results of the prospective, multicenter, long-term (3.5-year) study of the efficacy/safety of onabotulinumtoxinA for overactive bladder syndrome., Materials and Methods: Patients who completed either of 2, 24-week phase 3 trials could enter a 3-year extension and continue treatment with onabotulinumtoxinA 100 U as needed to control overactive bladder symptoms. Data were analyzed by the treatment(s) received (up to 6) and in discrete subgroups that received 1, 2, 3, 4, 5 or 6 treatments (to evaluate the consistency of the response after repeat treatments in the same patient groups). Assessments included the change from baseline in the number of urinary incontinence episodes per day and the proportion of patients who reported improvement/great improvement in urinary symptoms on the TBS (Treatment Benefit Scale) at week 12 as co-primary end points. Other end points were the change from baseline in I-QOL (Incontinence Quality of Life), the number of urgency and micturition episodes per day; duration of effect; the number of adverse events; and the initiation of intermittent catheterization., Results: Consistent mean reductions in urinary incontinence were observed following continued onabotulinumtoxinA treatment, ranging from -3.1 to -3.8 in the overall population and -2.9 to -4.5 in the discrete subgroups. Durable improvements were seen in overactive bladder symptoms and quality of life. A high proportion of patients rated their condition as improved/greatly improved. The median duration of effect was 7.6 months. The most common adverse event was urinary tract infection. The rate of de novo catheterization after the first treatment was 4.0% and it ranged from 0.6% to 1.7% after subsequent treatments., Conclusions: Long-term onabotulinumtoxinA treatment consistently decreased overactive bladder symptoms and improved quality of life with no new safety signals., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Tadalafil significantly improves lower urinary tract symptoms suggestive of benign prostatic hyperplasia. We post hoc characterized changes in the maximum urinary flow rate using integrated data from 4 international, placebo controlled studies of tadalafil once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia., Materials and Methods: After a 4-week placebo lead-in period 1,500 men were randomized to tadalafil 5 mg or placebo for 12 weeks. Data were analyzed using ANCOVA. Maximum urinary flow rate values were rank transformed for analysis., Results: Baseline maximum urinary flow rate data were available on 1,371 men with a mean age of 63.1 years and end point data were available on 1,197. Tadalafil 5 mg significantly increased maximum urinary flow vs placebo (median 1.1 vs 0.4 ml per second, p = 0.003). At a baseline voided volume of 125 to less than 250 ml the median change in the maximum urinary flow rate was 0.9 and 1.2 ml per second (p = 0.142) in 731 patients, at a baseline of 250 to 450 ml the change was -0.3 and 0.7 ml per second (p = 0.011) in 428, and at a baseline of greater than 450 ml the change was -0.2 and 2.0 ml per second (p = 0.186) in 38 for placebo and tadalafil, respectively. The difference was 0.3, 1.0 and 2.2 ml per second, respectively. At a baseline maximum urinary flow rate of greater than 15 ml per second in 128 patients the median flow rate change was -2.1 and -0.8 ml per second (p = 0.246), at a maximum of 10 to 15 ml per second in 522 the change was 0.2 and 0.8 ml per second (p = 0.044), and at a maximum of less than 10 ml per second in 547 the change was 1.2 and 1.8 ml per second (p = 0.189) for placebo and tadalafil, respectively. Tadalafil improved I-PSS (International Prostate Symptom Score) voiding subscores significantly vs placebo across all baseline maximum urinary flow subgroups (each p <0.001)., Conclusions: This integrated analysis revealed a small but statistically significant median maximum urinary flow rate improvement for tadalafil vs placebo. The numerical difference in the maximum urinary flow change from baseline between tadalafil and placebo increased with increased voided volume., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: We evaluated the efficacy, safety and tolerability of the EP1 receptor antagonist ONO-8539 in patients with overactive bladder syndrome., Materials and Methods: This was a 12-week, randomized, double-blind, placebo controlled, parallel group, multicenter study with a 2-week single blind placebo run-in phase. The 435 patients were randomized to receive twice daily ONO-8539 (30, 100 or 300 mg), placebo or once daily tolterodine (4 mg)., Results: At the end of the 12-week treatment no statistically significant difference was found between ONO-8539 and placebo in the change from baseline in the number of micturitions per 24 hours. The primary end points for 30, 100 and 300 mg ONO-8539, and placebo were -1.02, -1.53, -1.31 and -1.40, respectively. There was no statistically significant difference between any ONO-8539 group and placebo in the change from baseline in the number of urgency or urinary urgency incontinence episodes per 24 hours, or the mean volume voided per micturition, which were secondary end points. Statistically significant differences for tolterodine vs placebo were observed in the change from baseline in the number of micturitions (p = 0.045), urgency episodes (p = 0.04) and mean volume voided per micturition (p <0.001). The incidence of adverse events was 54.1% in the placebo group, 43.0% to 54.0% in the ONO-8539 groups and 46.6% in the tolterodine group. The intensity of adverse events was similar among the treatment groups. Similar to other treatments, the most frequently reported adverse events after ONO-8539 were nasopharyngitis and diarrhea., Conclusions: The results of this study, which to our knowledge represents the first evaluation of ONO-8539 in patients with overactive bladder, suggest a minimal role for EP1 receptor antagonism in the management of overactive bladder syndrome., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Treatment options for patients with overactive bladder refractory to anticholinergics are limited. We assessed the dose response across a range of doses of onabotulinumtoxinA (BOTOX®) in patients with idiopathic overactive bladder and urinary urgency incontinence whose symptoms were not adequately managed with anticholinergics., Materials and Methods: In a phase 2, multicenter, randomized, double-blind study, 313 patients with idiopathic overactive bladder and urinary urgency incontinence experiencing 8 or more urinary urgency incontinence episodes a week and 8 or more micturitions daily at baseline received 50, 100, 150, 200 or 300 U intradetrusor onabotulinumtoxinA, or placebo. Symptoms were recorded using a 7-day bladder diary. The primary efficacy variable was weekly urinary urgency incontinence episodes and the primary end point was week 12., Results: Demographics and baseline characteristics were balanced across the treatment groups. Durable efficacy was observed for all onabotulinumtoxinA dose groups of 100 U or greater for primary and secondary efficacy measures, including the proportion of incontinence-free patients. When the dose response curves were analyzed, doses greater than 150 U contributed minimal additional or clinically relevant improvement in symptoms. This finding was also reflected in health related quality of life assessments. Dose dependent changes in post-void residual urine volume were observed and the use of clean intermittent catheterization was also dose dependent. The only adverse events significantly greater with onabotulinumtoxinA than with placebo were urinary tract infection and urinary retention., Conclusions: OnabotulinumtoxinA at doses of 100 U or greater demonstrated durable efficacy in the management of idiopathic overactive bladder and urinary urgency incontinence. A dose of 100 U may be the dose that appropriately balances the symptom benefits with the post-void residual urine volume related safety profile., (Copyright © 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: In this study we compared a polyvinyl chloride catheter with a new polyvinyl chloride-free catheter with the same hydrophilic coating, and determined whether patient perception of ease and comfort of clean intermittent catheterization was independent of the catheter material., Materials and Methods: This investigation was designed as a randomized, double-blind, parallel group, multicenter study. Eligible patients were experienced users of clean intermittent catheterization with a polyvinyl chloride catheter for a minimum of 1 month before randomization. They were randomized to continue to use the polyvinyl chloride catheter or switch to a polyvinyl chloride-free catheter for 4 weeks. Both catheters had a similar appearance. Patient perception of ease and comfort of clean intermittent catheterization was scored with questionnaires, and adverse events were documented., Results: A total of 195 patients were recruited from 6 countries and 13 centers for the intent to treat analysis, and 179 were used for the per protocol analysis. Before randomization 94% to 98% of the patients rated the polyvinyl chloride catheter as easy or manageable to handle during different phases of clean intermittent catheterization and overall 92% of patients were satisfied. Of the eligible patients satisfaction was reported by 89% randomized to continue using the polyvinyl chloride catheter and by 78% randomized to switch to the polyvinyl chloride-free catheter (not significant). The rate of adverse events was low and comparable between the 2 groups., Conclusions: The study confirms that clean intermittent catheterization is easy and safe. Conversion from a polyvinyl chloride to a polyvinyl chloride-free core catheter material does not alter patient perception of catheterization.

Purpose: In the dome of the bladder of the pig muscarinic receptor stimulation has been shown to release a factor from the urothelium that exerts an inhibitory effect on the underlying smooth muscle. We examined whether the urothelium in the trigone of the bladder also releases this factor, identified which receptors stimulate its release and investigated possible cross-talk among these receptor systems in the trigone., Materials and Methods: Paired longitudinal strips of pig bladder were isolated, the urothelium was removed from 1 strip per pair and tissues were set up in gassed Krebs solution at 37C. Cumulative concentration-response curves to carbachol, phenylephrine or histamine were constructed. In some tissues a second phenylephrine curve was constructed in the presence of 1 microM. carbachol or 1 microM. histamine. In a further group of tissues the second phenylephrine curve was constructed in the presence of 1 microM. carbachol and 1 microM. atropine or 1 microM. histamine and 100 nM. mepyramine., Results: In the presence of an intact urothelium contractile responses to carbachol and histamine but not to phenylephrine were depressed. In the presence of 1 microM. carbachol or 1 microM. histamine the responses of intact urothelium strips to phenylephrine were significantly depressed. This effect was absent in the presence of atropine and mepyramine, respectively., Conclusions: Carbachol and histamine induce the release of a urothelium derived inhibitory factor in the bladder trigone. The factor appears to mediate cross-talk between these systems and the alpha-adrenoceptor system in this region of the bladder.

Purpose: We compared ambulatory urodynamics and conventional video cystometry findings in women with symptoms of bladder overactivity., Materials and Methods: In a prospective randomized crossover study 106 women with symptoms of urinary urgency with or without incontinence were comprehensively investigated by video cystometry and ambulatory urodynamics in random order. In addition, all women completed a validated symptoms questionnaire and voiding diary., Results: Involuntary detrusor activity was detected in 32 and 70 cases on video cystometry and ambulatory urodynamics, respectively (p <0.001). Video cystometry done according to International Continence Society standards diagnosed detrusor instability in 4 women with no involuntary detrusor activity on ambulatory urodynamics. Involuntary detrusor activity resulting in incontinence was observed in 39 cases on ambulatory urodynamics, including 20 (51%) with stable video cystometry results. Stress incontinence was diagnosed in 42 cases on video cystometry and in 34 on ambulatory urodynamics (p = 0.629). Increasingly severe urge and stress incontinence reported in the symptoms questionnaire correlated positively with the subsequent detection of detrusor overactivity and stress incontinence, respectively, on the 2 urodynamic tests., Conclusions: In contrast to video cystometry, ambulatory urodynamics provides objective evidence of clinically important bladder overactivity in the majority of women with symptoms suggestive of bladder overactivity. The correlation of symptoms with ambulatory urodynamic findings implies that greater reliance may be placed on symptomatic diagnosis of bladder overactivity. Improved objective assessment of detrusor function provided by ambulatory urodynamics has implications for the definition of bladder overactivity and relevance of conventional cystometry in this context. In women who complain of urgency stable conventional cystometrography findings should be interpreted with caution.

Purpose: We prospectively studied the potential contribution of ambulatory urodynamic monitoring in men with urinary symptoms unable to initiate a void on conventional video cystometrography., Materials and Methods: A total of 40 consecutive symptomatic men with a median International Prostate Symptom Score of 19 (range 1 to 29) and median age of 51.9 years (range 30 to 75) who were unable to void during video cystometrography underwent ambulatory urodynamic monitoring. Solid-state transducers mounted on silicone coated catheters were inserted urethrally and rectally, and connected to a portable recorder. Subjects voided in private into a specially designed flow meter, which they connected to the recording device., Results: Of the patients 2 (5%) failed to attend ambulatory urodynamic monitoring, despite multiple reminders, and in 1 (2.5%) the trace was uninterpretable. Pressure flow data were available for the remaining 37 patients with mean plus or minus standard deviation 2.72+/-0.1 storage void cycles recorded per patient. All 6 patients (15%) with obstruction were older than 40 years. In 6 cases (15%) obstruction was equivocal and the remainder were unobstructed. Transurethral prostatic resection in 2 and urethrotomy in 1 of 6 patients with obstruction resulted in subjective and objective improvement., Conclusions: The bashful bladder syndrome was not associated with any specific urodynamic diagnosis. Ambulatory urodynamic monitoring will yield a urodynamic diagnosis in more than 90% of cases after failure to record void data on video cystometrography. A surgically correctable cause of symptoms can be found in about 20% of men older than 40 years. The contribution of ambulatory urodynamic monitoring compared to more conventional evaluation in men younger than 40 years is negligible.

Purpose: All urethral reconstruction that involves substitution has an inherent ongoing incidence of restenosis with time. Anastomotic restoration of urethral continuity naturally obviates these complications but to achieve its potential of a long-term stricture-free success rate that approaches 100% circumstances must be ideal and the reconstructive surgical technique must be meticulous. If the critical indications for anastomotic reconstruction are overextended, complications inevitably increase. Considerable additional urethral length is required to overcome the terminal atretic deficiency associated with hypospadias and create a tension-free anastomotic neomeatoplasty. Mobilization and advancement of the penile urethra alone are rarely sufficient to achieve this without causing penile chordee. We describe the details of bulbar elongation anastomotic meatoplasty (BEAM) that we have been using for approximately the last 8 years., Materials and Methods: The only part of the urethra that can be mobilized to provide extra length for anastomotic urethroplasty without creating penile curvature chordee is the bulbar urethra. Full length mobilization of the whole length of the bulbar urethra through a perineal incision provides 2 to 2.5 cm. of tension-free lengthening in children and 4 to 5 cm. in adults. Thus, many subterminal urethral deficiencies can be resolved by bulbar elongation anastomotic meatoplasty when the total extent of the urethral deficiency is not disproportionally long. We performed bulbar elongation anastomotic meatoplasty in 12 patients 2 to 25 years old., Results: At a followup of 2 to 7 years the neomeatus is functionally and cosmetically satisfactory in all cases with no long-term complications or chordee., Conclusions: When circumstances are appropriate, bulbar elongation anastomotic meatoplasty is a preferable alternative to some of the current substitution procedures. Once established, anastomotic reconstructions are generally stable in the long term.

There were 54 patients entered into this study of the UroLume permanent prostatic stent, most of whom were unfit for conventional prostatic surgery. The stents were inserted with the patient under local or regional anesthesia. Of the patients 34 presented in acute retention, 12 had chronic retention, 4 had severe and worsening symptoms, and 4 had symptoms and urodynamic evidence of obstruction occurring in the presence of Parkinson's disease. Following stent insertion 50 patients were able to void satisfactorily, while the remaining 4 presented with chronic retention and detrusor failure. The 40 patients who had no or minimal remaining symptoms were satisfied with the stent. Most patients experienced frequency and urgency of micturition for 1 to 3 months, which resolved in all but 9 patients with persistent severe detrusor instability. Symptom scores decreased to 6.5 (total) at 1 year for nonretention patients and 6.0 for retention patients. Stents were covered with epithelium within 6 to 9 months. However, when the stent was positioned with any part of the proximal end within the bladder or when the stent could not be epithelialized incrustation occurred (14 cases, all of which were asymptomatic). No serious urosepsis was noted in any patient in this study. Six stents were removed endoscopically without difficulty or damage to the urethra at up to 18 months. The implications of these findings to the potential role of the UroLume stent in the management of a wider range of patients with prostatic obstruction are discussed.

Different regions of the prostate gland, namely prostatic capsule, peripheral prostate and central prostate (subdivided into proximal (near the bladder neck), distal (near the verumontanum) and midway between these areas) were obtained from 32 obstructed (stable obstructed, n = 8; unstable obstructed, n = 13; acute retention, n = 11) and five control patients. The innervation of these tissues was studied both histochemically to localise acetylcholinesterase activity and immunohistochemically for dopamine-beta-hydroxylase, 5-hydroxytryptamine, vasoactive intestinal polypeptide, neuropeptide Y, leu- and met-enkephalin, calcitonin gene-related peptide, substance P and somatostatin. In control patients the greatest density of nerves was found in the proximal central prostate, followed by the anterior capsule and distal central prostate, with the least density in the peripheral prostate. The greatest density of nerves were acetylcholinesterase positive and immunoreactive to neuropeptide Y followed (in decreasing order) by nerves immunoreactive to: vasoactive intestinal polypeptide and dopamine beta-hydroxylase; leu-enkephalin and 5-hydroxytryptamine; calcitonin gene-related peptide; met-enkephalin; substance P; somatostatin. In addition a group of periacinar 5-hydroxytryptamine-immunoreactive cells and ganglia containing acetylcholinesterase, dopamine beta-hydroxylase and all of the peptides studied except somatostatin were identified. In the prostate gland from obstructed patients there was a significant reduction in the density of acetylcholinesterase-positive nerves (p less than 0.001) when compared with the controls. A similar trend was found for dopamine beta-hydroxylase, 5-hydroxytryptamine and all of the putative neuropeptides in most areas of the prostate, the most notable exceptions being in the peripheral prostate, with an increase in dopamine beta-hydroxylase- and leu-enkephalin-immunoreactive nerves in all three groups of obstructed patients an an increase in vasoactive intestinal polypeptide- and calcitonin gene-related peptide-immunoreactive nerves in those presenting in urinary retention. The functional significance of these findings is discussed.

Specimens of the detrusor muscle of the bladder from four patients with lower motor neurone lesion and three patients with carcinoma of the bladder used as "controls", were studied immunohistochemically for vasoactive intestinal polypeptide, neuropeptide Y, calcitonin-gene related peptide, substance P and somatostatin. The greatest density of nerves in the bladder from "control" patients contained neuropeptide Y, followed in a decreasing order by vasoactive intestinal polypeptide, calcitonin gene-related peptide, substance P and somatostatin. Neuropeptide Y- and vasoactive intestinal polypeptide-immunoreactive nerves were found throughout the smooth muscle and the base of the mucosa, while calcitonin gene-related peptide-, substance P- and somatostatin-immunoreactive nerves were found predominantly in nerve bundles with a few single fibres at the base of the mucosa. Vasoactive intestinal polypeptide-, neuropeptide Y- and calcitonin gene-related peptide-immunoreactive nerves were also located around blood vessels. In patients with lower motor neurone lesion, there was a decrease in the density of vasoactive intestinal polypeptide-, calcitonin gene-related peptide- and substance P-immunoreactive nerves, but there was little change in neuropeptide Y- or somatostatin-immunoreactive nerves. Urinary retention, bladder areflexia and deficient sensation may be directly linked to neuropeptide neuropathy in patients with lower motor neurone lesion.

Radioligand receptor binding and autoradiography were used to characterize, localize and compare alpha-1 and alpha-2 adrenoceptors and muscarinic cholinergic receptor populations in human benign prostatic hyperplastic tissue. The binding of selective alpha-1 and alpha-2 ligands, [3H]-prazosin and [3H]-UK 14,304, to homogenates of human central and peripheral prostate was saturable and of high affinity. Scatchard analysis produced an equilibrium dissociation constant (KD) of 0.51 +/- 0.10 nM for alpha-1 adrenoceptors, and 2.34 +/- 0.40 nM for alpha-2 adrenoceptors. The mean densities, Bmax, of alpha-1 and alpha-2 adrenoceptors identified in the human adenomatous prostate were 65.9 +/- 12.9 and 36.1 +/- 7.0 fmoles/mg. protein respectively. Receptor autoradiography was used to examine the distribution of muscarinic cholinergic receptors [( 3H]-QNB), alpha-1 adrenoceptors [( 3H]-prazosin]), and alpha-2 adrenoceptors [( 3H]-rauwolscine) on consecutive sections of benign hyperplastic prostatic tissue. Although both subtypes of adrenoceptor were seen in the stromal component of the hyperplastic prostate, there was a substantial predominance of alpha-1 adrenoceptors. A densitometric computer-assisted analysis was performed on the autoradiographic slides to determine the mean ratio of specific alpha-1: alpha-2 adrenoceptors in the stromal compartment of the hyperplastic tissue. The ratio, expressed as % grain occupancy/unit area, was 3.9 +/- 0.75, which is in agreement with a functional alpha-1 adrenoceptor predominance shown in previous studies. Although sparsely distributed in the stroma, a dense alpha-2 adrenoceptor population was seen in association with blood vessels, and in close proximity to the base of some of the [3H]-QNB-labelled prostatic glandular epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)