Miguel Silva-Ramos

Prostate Cancer Prevention Trial and European Randomized Study of Screening for Prostate Cancer Risk Calculators: A Performance Comparison in a Contemporary Screened Cohort

BACKGROUND Several models can predict the risk of prostate cancer (PCa) on biopsy. OBJECTIVE To evaluate the performance of the Prostate Cancer Prevention Trial (PCPT) and European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculators in detecting PCa in a contemporary screened cohort. DESIGN, SETTING, AND PARTICIPANTS We analyzed prebiopsy characteristics of 525 consecutive screened patients submitted to biopsy, as required by the risk calculators, in one European center between 2006 and 2007. MEASUREMENTS Comparisons were done using tests of accuracy (area under the receiver operating characteristic curve [AUC-ROC]), calibration plots, and decision curve analysis. Biopsy predictors were identified by univariate and multivariate logistic regression. RESULTS AND LIMITATIONS PCa was detected in 35.2% of the subjects. Among predictors included in the calculators, the logarithmic transformations of prostate volume and prostate-specific antigen (PSA), digital rectal examination, previous biopsy status, and age were significantly associated with PCa; transrectal ultrasound abnormalities and family history were not. AUC-ROC for the ERSPC calculator was significantly higher than the PCPT calculator and PSA alone (80.1%, 74.4%, and 64.3%, respectively). Calibration plots showed better performance for the ERSPC calculator; nevertheless, ERSPC may underestimate risk, while PCPT tends to overestimate predictions. Decision curve analysis displayed higher net benefit for the ERSPC calculator; 9% and 23% unnecessary biopsies can be avoided if a threshold probability of 20% and 30%, respectively, is adopted. In contrast, the PCPT model displayed very limited benefit. Our findings apply to a screened European cohort submitted to extended biopsy schemes; consequently, caution should be exerted when considering different populations. CONCLUSIONS The ERSPC risk calculator, by incorporating several risks factors, can aid in the estimation of individual PCa risk and in the decision to perform biopsy. The ERSPC calculator outperformed the PCPT model, which is of very limited value, in a contemporary cohort of screened patients.

ATP released via pannexin-1 hemichannels mediates bladder overactivity triggered by urothelial P2Y6 receptors

In contrast to the well-known signaling role of urothelial ATP to control bladder function, the hypothesis that uracil nucleotides (UTP and/or UDP) also exert autocrine/paracrine actions only recently gained experimental support. Urothelial cells express UDP-sensitive P2Y6 receptors, yet their role in the control of bladder activity has been mostly neglected. This study was designed to investigate the ability of PSB0474, a stable UDP analogue which exhibits selectivity for P2Y6 receptors, to modulate urodynamic responses in the anaesthetized rat in vivo. Instillation of PSB0474 into the bladder increased the voiding frequency (VF) without affecting the amplitude (A) and the duration (Δt) of bladder contractions. PSB0474-induced bladder overactivity was prevented by the selective P2Y6 antagonist, MRS2578. The increase in the VF produced by PSB0474 was also blocked by inhibitors of pannexin-1 hemichannels, (10)Panx or carbenoxolone, when these drugs were applied inside the bladder lumen but not when they were administered intravenously. Reduction of hemichannels pore permeability with H1152 also prevented PSB0474-induced bladder overactivity, but the exocytosis inhibitor, Exo-1, was inactive. PSB0474 increased by 3-fold the urinary ATP content. Implication of hemichannels permeability on PSB0474-induced ATP release was demonstrated by real-time fluorescence video-microscopy measuring the uptake of propidium iodide by intact urothelial cells in the absence and in the presence of MRS2578 or carbenoxolone. Confocal microscopy studies confirmed the co-localization of pannexin-1 and P2Y6 receptors in the rat urothelium. Data indicate that activation of P2Y6 receptors causes bladder overactivity in the anaesthetized rat indirectly by releasing ATP from the urothelium via pannexin-1 hemichannels.

Urinary ATP May Be a Dynamic Biomarker of Detrusor Overactivity in Women with Overactive Bladder Syndrome

Background Nowadays, there is a considerable bulk of evidence showing that ATP has a prominent role in the regulation of human urinary bladder function and in the pathophysiology of detrusor overactivity. ATP mediates nonadrenergic-noncholinergic detrusor contractions in overactive bladders. In vitro studies have demonstrated that uroepithelial cells and cholinergic nerves from overactive human bladder samples (OAB) release more ATP than controls. Here, we compared the urinary ATP concentration in samples collected non-invasively from OAB women with detrusor overactivity and age-matched controls. Methods Patients with neurologic diseases, history of malignancy, urinary tract infections or renal impairment (creatinine clearance <70 ml/min) were excluded. All patients completed a 3-day voiding diary, a 24 h urine collection and blood sampling to evaluate creatinine clearance. Urine samples collected during voluntary voids were immediately freeze-preserved for ATP determination by the luciferin-luciferase bioluminescence assay; for comparison purposes, samples were also tested for urinary nerve growth factor (NGF) by ELISA. Results The urinary content of ATP, but not of NGF, normalized to patients’ urine creatinine levels (ATP/Cr) or urinary volume (ATP.Vol) were significantly (P<0.05) higher in OAB women with detrusor overactivity (n = 34) than in healthy controls (n = 30). Significant differences between the two groups were still observed by boosting urinary ATP/Cr content after water intake, but these were not detected for NGF/Cr. In OAB patients, urinary ATP/Cr levels correlated inversely with mean voided volumes determined in a 3-day voiding diary. Conclusion A high area under the receiver operator characteristics (ROC) curve (0.741; 95% CI 0.62–0.86; P<0.001) is consistent with urinary ATP/Cr being a highly sensitive dynamic biomarker for assessing detrusor overactivity in women with OAB syndrome.

Activation of P2Y6 receptors increases the voiding frequency in anaesthetized rats by releasing ATP from the bladder urothelium

Despite the abundant expression of the UDP‐sensitive P2Y6 receptor in urothelial cells and sub‐urothelial myofibroblasts its role in the control of bladder function is not well understood.

The quality of reporting of randomized controlled trials in pelvic organ prolapse

Introduction and hypothesisRandomized controlled trials (RCTs) must comply with the strict rules of design and conduct and their reporting should reflect it. Our aim was to evaluate how the quality of RCT reporting in pelvic organ prolapse (POP) has evolved.MethodsRCTs in POP published between 1997 and 2010 were retrieved through a PubMed search. The quality of reporting was assessed by applying the 2010 revised Consolidated Standards of Reporting Trials (CONSORT) statement. Appropriate statistical analysis was performed.ResultsForty-one RCTs were identified for review. The implementation of randomization, recruitment, blinding, outcomes with effect size and precision, trial registration, and full protocol availability were reported in less than half of the trials. Comparing two periods (1997–2006 and 2007–2010), there was no improvement in the quality of reporting for any of the CONSORT criteria.ConclusionsRCTs in POP are scarce. The quality of reporting is suboptimal in many aspects and has not improved in recent years.

Increased urinary adenosine triphosphate in patients with bladder outlet obstruction due to benign prostate hyperplasia

Diagnosis of bladder outflow obstruction (BOO) in patients with lower urinary tract (LUT) symptoms is challenging without using invasive urodynamic tests. Recently, we showed in vitro that urothelial strips from patients with benign prostatic hyperplasia (BPH) release more ATP than controls. Here, we tested whether urinary ATP can be used as a wall tension transducer non‐invasive biomarker to detect BOO in patients with BPH.

Inhibition of cholinergic neurotransmission by β3-adrenoceptors depends on adenosine release and A1-receptor activation in human and rat urinary bladders

The direct detrusor relaxant effect of β3-adrenoceptor agonists as a primary mechanism to improve overactive bladder symptoms has been questioned. Among other targets, activation of β3-adrenoceptors downmodulate nerve-evoked acetylcholine (ACh) release, but there is insufficient evidence for the presence of these receptors on bladder cholinergic nerve terminals. Our hypothesis is that adenosine formed from the catabolism of cyclic AMP in the detrusor may act as a retrograde messenger via prejunctional A1 receptors to explain inhibition of cholinergic activity by β3-adrenoceptors. Isoprenaline (1 µM) decreased [3H]ACh release from stimulated (10 Hz, 200 pulses) human (-47 ± 5%) and rat (-38 ± 1%) detrusor strips. Mirabegron (0.1 µM, -53 ± 8%) and CL316,243 (1 µM, -37 ± 7%) mimicked isoprenaline (1 µM) inhibition, and their effects were prevented by blocking β3-adrenoceptors with L748,337 (30 nM) and SR59230A (100 nM), respectively, in human and rat detrusor. Mirabegron and isoprenaline increased extracellular adenosine in the detrusor. Blockage of A1 receptors with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 100 nM) or the equilibrative nucleoside transporters (ENT) with dipyridamole (0.5 µM) prevented mirabegron and isoprenaline inhibitory effects. Dipyridamole prevented isoprenaline-induced adenosine outflow from the rat detrusor, and this effect was mimicked by the ENT1 inhibitor, S-(4-nitrobenzyl)-6-thioinosine (NBTI, 30 µM). Cystometry recordings in anesthetized rats demonstrated that SR59230A, DPCPX, dipyridamole, and NBTI reversed the decrease in the voiding frequency caused by isoprenaline (0.1-1,000 nM). Data suggest that inhibition of cholinergic neurotransmission by β3-adrenoceptors results from adenosine release via equilibrative nucleoside transporters and prejunctional A1-receptor stimulation in human and rat urinary bladder.

Does 3D Ultrasound Enhance the Diagnosis of Bladder Tumours in Patients with Haematuria

Purpose. Bladder cancer is a frequent cause of haematuria in elderly patients, and bladder ultrasound (US) is a valuable tool in diagnosing these malignancies. We examined the accuracy of 3D bladder US in diagnosing bladder tumors in patients with haematuria. Patients and Methods. Twenty-one patients observed in the emergency department for haematuria underwent a kidney and bladder US. Patients with normal or uncertain bladder US findings underwent a 3D US and a cystoscopy. Results. In 5 (23.8%) patients, the 3D US detected bladder tumours not seen in 2D US. All these patients were found to have bladder tumours on cystoscopy. Another 5 (23.8%) patients with uncertain findings on 2D US had normal 3D US and cystoscopy. 3D US showed a sensitivity of 83.3% and a specificity of 100% with a positive predicted value and negative predictive values of 100% and 93.8%, respectively. Conclusion. 3D US was more sensitive than 2D US in diagnosing bladder tumours in patients with haematuria.