In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).

Pituitary adenylate cyclase activating polypeptide (PACAP) peptides are expressed and regulated in sensory afferents of the micturition pathway. Although these studies have implicated PACAP in bladder control, the physiological significance of these observations has not been firmly established. To clarify these issues, the roles of PACAP and PACAP signaling in micturition and cystitis were examined in receptor characterization and physiological assays. PACAP receptors were identified in various tissues of the micturition pathway, including bladder detrusor smooth muscle and urothelium. Bladder smooth muscle expressed heterogeneously PAC 1null, PAC1HOP1, and VPAC2 receptors; the urothelium was more restricted in expressing preferentially the PAC 1 receptor subtype only. Immunocytochemical studies for PAC 1 receptors were consistent with these tissue distributions. Furthermore, the addition of 50 -100 nM PACAP27 or PACAP38 to isolated bladder strips elicited transient contractions and sustained increases in the amplitude of spontaneous phasic contractions. Treatment of the bladder strips with tetrodotoxin (1 M) did not alter the spontaneous phasic contractions suggesting direct PACAP effects on bladder smooth muscle. PACAP also increased the amplitude of nerve-evoked contractions. By contrast, vasoactive intestinal polypeptide had no direct effects on bladder smooth muscle. In a rat cyclophosphamide (CYP)-induced cystitis paradigm, intrathecal or intravesical administration of PAC 1 receptor antagonist, PACAP6 -38, reduced cystitis-induced bladder overactivity. In summary, these studies support roles for PACAP in micturition and suggest that inflammation-induced plasticity in PACAP expression in peripheral and central micturition pathways contribute to bladder dysfunction with cystitis.neuropeptides; urinary bladder; bladder overactivity; dorsal root ganglia; spinal cord; inflammation THE STORAGE AND PERIODIC ELIMINATION of urine requires a complex neural control system that coordinates the activities of the smooth muscle of the urinary bladder and the smooth and striated muscle of the urethral sphincters (13,32,33). Coordination between these organs is mediated by a complex neural control system located in the brain, spinal cord, and peripheral ganglia (12). Experiments with a chemically (cyclophosphamide, CYP)-induced bladder inflammation (11, 34,38) rodent model have demonstrated alterations in neurochemical (52, 53, 66, 69), electrophysiological (29, 72), organizational (65, 68), and functional properties of the micturition reflex (24, 38, 39), suggesting dramatic reorganization of the micturition reflex pathways. Alterations in peripheral bladder afferent (sensory)/ efferent (autonomic and motor) and central interneuronal pathway functions may underlie detrusor overactivity that accompany CYP-induced cystitis.Pituitary adenylate cyclase activating polypeptide (PACAP) peptides have diverse functions in the endocrine, nervous, gastrointestinal, and cardiovascular systems (1, 6) through PAC 1 , VPAC 1 and VPAC ...

a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e u r o p e a n u r o l o g y . c o m Article info AbstractBackground: Few randomised studies have compared antiandrogen intermittent hormonal therapy (IHT) with continuous maximal androgen blockade (MAB) therapy for advanced prostate cancer (PCa). Objective: To determine whether overall survival (OS) on IHT (cyproterone acetate; CPA) is noninferior to OS on continuous MAB. Design, setting, and participants: This phase 3 randomised trial compared IHT and continuous MAB in patients with locally advanced or metastatic PCa. Intervention: During induction, patients received CPA 200 mg/d for 2 wk and then monthly depot injections of a luteinising hormone-releasing hormone (LHRH; triptoreline 11.25 mg) analogue plus CPA 200 mg/d. Patients whose prostate-specific antigen (PSA) was <4 ng/ml after 3 mo of induction treatment were randomised to the IHT arm (stopped treatment and restarted on CPA 300 mg/d monotherapy if PSA rose to 20 ng/ml or they were symptomatic) or the continuous arm (CPA 200 mg/d plus monthly LHRH analogue). Outcome measurements and statistical analysis: Primary outcome measurement was OS. Secondary outcomes included cause-specific survival, time to subjective or objective progression, and quality of life. Time off therapy in the intermittent arm was recorded. Results and limitations: We recruited 1045 patients, of which 918 responded to induction therapy and were randomised (462 to IHT and 456 to continuous MAB). OS was similar between groups ( p = 0.25), and noninferiority of IHT was demonstrated (hazard ratio [HR]: 0.90; 95% confidence interval [CI], 0.76-1.07). There was a trend for an interaction between PSA and treatment ( p = 0.05), favouring IHT over continuous therapy in patients with PSA 1 ng/ml (HR: 0.79; 95% CI, 0.61-1.02). Men treated with IHT reported better sexual function. Among the 462 patients on IHT, 50% and 28% of patients were off therapy for 2.5 yr or >5 yr, respectively, after randomisation. The main limitation is that the length of time for the trial to mature means that other therapies are now available. A second limitation is that T3 patients may now profit from watchful waiting instead of androgen-deprivation therapy. Conclusions: Noninferiority of IHT in terms of survival and its association with better sexual activity than continuous therapy suggest that IHT should be considered for use in routine clinical practice.

Updated Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial findings show that radium-223 remained well tolerated during treatment and up to 3 yr after each patient's first injection.

RESULTSTransperineal injection resulted in tissue necrosis in all prostates and significant extraprostatic necrosis in two of three animals treated. With transurethral injection, the control groups showed minimal change, whereas the group injected with ethanol resulted in lesions with variable necrosis and location. CONCLUSIONSIntraprostatic chemoablation is possible with ethanol injection both transperineally and transurethrally. Transperineal ethanol injections were associated with more extraprostatic necrosis. Transurethral injections resulted in larger amounts of necrosis in the prostatic parenchyma with minimal extraprostatic effects. However, the extent of prostatic necrosis/ablation was inconsistent and further research is warranted.