Role of α- and ß-adrenergic signaling in phenotypic targeting: significance in benign and malignant urologic disease.

The urinary tract is highly innervated by autonomic nerves which are essential in urinary tract development, the production of growth factors, and the control of homeostasis. These neural signals may become dysregulated in several genitourinary (GU) disease states, both benign and malignant. Accordingly, the autonomic nervous system is a therapeutic target for several genitourinary pathologies including cancer, voiding dysfunction, and obstructing nephrolithiasis. Adrenergic receptors (adrenoceptors) are G-Protein coupled-receptors that are distributed throughout the body. The major function of α1-adrenoceptors is signaling smooth muscle contractions through GPCR and intracellular calcium influx. Pharmacologic intervention of α-and ß-adrenoceptors is routinely and successfully implemented in the treatment of benign urologic illnesses, through the use of α-adrenoceptor antagonists. Furthermore, cell-based evidence recently established the antitumor effect of α1-adrenoceptor antagonists in prostate, bladder and renal tumors by reducing neovascularity and impairing growth within the tumor microenvironment via regulation of the phenotypic epithelial-mesenchymal transition (EMT). There has been a significant focus on repurposing the routinely used, Food and Drug Administration-approved α1-adrenoceptor antagonists to inhibit GU tumor growth and angiogenesis in patients with advanced prostate, bladder, and renal cancer. In this review we discuss the current evidence on (a) the signaling events of the autonomic nervous system mediated by its cognate α- and ß-adrenoceptors in regulating the phenotypic landscape (EMT) of genitourinary organs; and (b) the therapeutic significance of targeting this signaling pathway in benign and malignant urologic disease. Video abstract.

Clash of the calculators: External validation of prostate cancer risk calculators in men undergoing mpMRI and transperineal biopsy.

Objective: To compare the accuracy of the European Randomized Study of Screening for Prostate Cancer (ERSPC) RC, MRI-ERSPC-RC, and Prostate Biopsy Collaborative Group (PBCG) RC in patients undergoing transperineal prostate biopsy. Patients and methods: We identified 392 patients who underwent mpMRI before transperineal prostate biopsy across multiple public and private institutions between January 2017 and August 2019. The estimated probabilities of detecting PCa and significant PCa were calculated using the MRI-ERSPC-RC, ERSPC-RC, and PBCG-RC. Receiver operating characteristic (ROC) curves for each calculator were generated and the area underneath the curve (AUC) was compared. Calibration and clinical utility were assessed with calibration plots and decision curve analysis, respectively. Results: PCa was detected in 285 patients (72.7%) with significant PCa found in 200 patients (51.1%). ROC curve analysis found the MRI-ERSPC-RC outperformed the ERSPC-RC and PBCG-RC. For the prediction of PCa, the AUC was 0.756, 0.696, and 0.675 for the MRI-ERSPC-RC, ERSPC-RC, and PBCG-RC, respectively. The AUC for the prediction of significant PCa was 0.803, 0.745, and 0.746 for the MRI-ERSPC-RC, ERSPC-RC, and PBCG-RC, respectively. Conclusions: Our study validated the ERSPC-RC, MRI-ERSPC-RC, and PBCG-RC in a cohort undergoing transperineal prostate biopsy with the MRI-ERSPC-RC performing the best. These RCs may enable improved shared decision making and help to guide patient selection for biopsy.

The prognostic utility of the transcription factor SRF in docetaxel-resistant prostate cancer: in-vitro discovery and in-vivo validation.

BACKGROUND: Docetaxel based therapy is one of the first line chemotherapeutic agents for the treatment of metastatic castrate-resistant prostate cancer. However, one of the major obstacles in the treatment of these patients is docetaxel-resistance. Defining the mechanisms of resistance so as to inform subsequent treatment options and combinations represents a challenge for clinicians and scientists. Previous work by our group has shown complex changes in pro and anti-apoptotic proteins in the development of resistance to docetaxel. Targeting these changes individually does not significantly impact on the resistant phenotype but understanding the central signalling pathways and transcription factors (TFs) which control these could represent a more appropriate therapeutic targeting approach. METHODS: Using a number of docetaxel-resistant sublines of PC-3 cells, we have undertaken a transcriptomic analysis by expression microarray using the Affymetrix Human Gene 1.0 ST Array and in conjunction with bioinformatic analyses undertook to predict dysregulated TFs in docetaxel resistant prostate cancer. The clinical significance of this prediction was ascertained by performing immunohistochemical (IHC) analysis of an identified TF (SRF) in the metastatic sites from men who died of advanced CRPC. Investigation of the functional role of SRF was examined by manipulating SRF using SiRNA in a docetaxel-resistant PC-3 cell line model. RESULTS: The transcription factors identified include serum response factor (SRF), nuclear factor kappa-B (NFκB), heat shock factor protein 1 (HSF1), testicular receptor 2 & 4 (TR2 &4), vitamin-D and retinoid x receptor (VDR-RXR) and oestrogen-receptor 1 (ESR1), which are predicted to be responsible for the differential gene expression observed in docetaxel-resistance. IHC analysis to quantify nuclear expression of the identified TF SRF correlates with both survival from date of bone metastasis (p = 0.003), survival from androgen independence (p = 0.00002), and overall survival from prostate cancer (p = 0.0044). Functional knockdown of SRF by siRNA demonstrated a reversal of apoptotic resistance to docetaxel treatment in the docetaxel-resistant PC-3 cell line model. CONCLUSIONS: Our results suggest that SRF could aid in treatment stratification of prostate cancer, and may also represent a therapeutic target in the treatment of men afflicted with advanced prostate cancer.

Dynamic sentinel node biopsy for penile cancer: an initial experience in an Irish Hospital.

BACKGROUND: The presence of nodal metastases is the single most important prognostic factor in penile cancer. However, reliable assessment of nodal status in clinically node-negative (cN0) patients poses a challenge. Approximately 20% of these patients harbour occult nodal metastases. Currently available non-invasive radiological investigations are unreliable in excluding micrometastatic disease. AIM: Dynamic sentinel node biopsy (DSNB) is a minimally invasive procedure for assessing lymph node involvement. We report our initial experience with DSNB in assessing the status of regional lymph nodes in cN0 penile cancer patients. METHODS: DSNB was performed in penile cancer patients with at least one cN0 groin. All patients undergoing DSNB at our institution were included. Lymphoscintigraphic images were obtained from all patients, after intradermal, peritumoral injection of a Technetium-99m nanocolloid. The sentinel nodes were defined as the nodes identified on lymphoscintigraphy, which were also radioactive intraoperatively using a gamma probe. RESULTS: In total, 18 groins from 11 patients underwent DSNB. Of these, 11 patients underwent bilateral DSNB and 4 had unilateral DSNB. The mean (range) age of patients at the time of presentation of their primary tumour was 63 (39-78) years. A mean of 1.2 nodes per groin was retrieved. One lymph node was positive in one patient, who subsequently underwent a bilateral inguinal lymph node dissection. Overall, the median (range) follow-up was 12.8 (2.7-31.3) months with no local or regional recurrences. CONCLUSION: Further cases and longer follow-up will define the accuracy of this technique in the Irish population.

Antibiotic resistance patterns of Escherichia coli urinary isolates and comparison with antibiotic consumption data over 10 years, 2005-2014.

INTRODUCTION: Escherichia coli is a common cause of urinary tract infections (UTI). Reviews of antibiotic resistance of this organism can inform choice of empiric treatment of UTI and other infections and strategies for combating antimicrobial resistance. We reviewed laboratory and hospital pharmacy records to assess trends in non-susceptibility rates and the effect of antimicrobial stewardship interventions. METHODS: A retrospective observational study of isolates of E. coli from MSU samples at a Dublin teaching hospital from inpatients and community, obtained from January 2005 to December 2014. Susceptibility to a panel of antibiotics was determined using the disc diffusion method, as well as extended-spectrum beta-lactamase (ESBL) production status. Trends in resistance were plotted graphically and analysed in a descriptive manner. RESULTS: Except for nitrofurantoin and gentamicin, non-susceptibility increased for all antimicrobials tested. Co-amoxiclav non-susceptibility reached 48% in hospital and 32.6% in the community by 2014. Piperacillin-tazobactam non-susceptibility increased from 6.8 to 23.8% in hospital and from <1 to 12.5% in community, with similar increases for ESBL producing isolates. Ciprofloxacin non-susceptibility peaked at 25.5% in hospital in 2012 and 11.44% in the community in 2014. CONCLUSION: Escherichia coli isolates from community MSU samples have high rates of non-susceptibility to trimethoprim and co-amoxiclav. Nitrofurantoin remains the best empiric therapy for cystitis. Increasing non-susceptibility to co-amoxiclav and piperacillin-tazobactam in hospital isolates is concerning. Ciprofloxacin non-susceptibility is increasing faster in the community than in hospital. A sharp reduction in hospital fluoroquinolone consumption did not result in a significant reduction in ciprofloxacin non-susceptibility of hospital E. coli isolates.

Predicting prostate cancer: analysing the clinical efficacy of prostate cancer risk calculators in a referral population.

BACKGROUND: The decision to proceed to biopsy for the diagnosis of prostate cancer in clinical practice is a difficult one. Prostate cancer risk calculators allow for a systematic approach to the use of patient information to predict a patient's likelihood of prostate cancer. AIMS: In this paper, we validate the two leading prostate cancer risk calculators, the prostate cancer prevention trial (PCPT) and the European Randomized Study of Screening for Prostate Cancer (ERSPC) in an Irish population. METHODS: Data were collected for 337 men referred to one tertiary referral center in Ireland. Calibration analysis, ROC analysis and decision curve analysis were undertaken to ascertain the performance of the PCPT and the ERSPC risk calculators in this cohort. RESULTS: Of 337 consecutive biopsies, cancer was subsequently diagnosed in 146 men (43 %), 98 (67 %) of which were high grade. The AUC for the PCPT and ERSPC risk calculators were 0.68 and 0.66, respectively for the prediction of prostate cancer. Each calculator was sufficiently calibrated in this cohort. Decision curve analysis demonstrated a net benefit via the use of the PCPT and ERSPC risk calculators in the diagnosis of prostate cancer. CONCLUSIONS: The PCPT and ERSPC risk calculators achieve a statistically significant prediction of prostate cancer in this Irish population. This study provides external validation for these calculators, and therefore these tools can be used to aid in clinical decision making.

Prostate cancer risk assessment tools in an unscreened population.

OBJECTIVE: To compare the prostate cancer prevention trial risk calculator (PCPT-RC) and European randomized study of screening for prostate cancer risk calculator (ERSPC-RC) in a unique unscreened population from the West of Ireland. PATIENTS AND METHODS: Data was prospectively recorded for all 556 consecutive men who underwent prostate biopsy at our institution as part of the Rapid Access Prostate Assessment Clinic program in Ireland. The estimated probabilities of detecting prostate cancer and high-grade disease were calculated using the PCPT and ERSPC risk calculators. For each calculator the discriminative ability, calibration and clinical utility was assessed. RESULTS: Prostate cancer was detected in 49% and high-grade prostate cancer in 34% of men. Receiver operating characteristic curve analysis demonstrated that the PCPT-RCs outperformed the ERSPC-RCs for the prediction of prostate cancer areas underneath the ROC curve (AUC 0.628 vs. 0.588, p = 0.0034) and for the prediction of high-grade prostate cancer (AUC 0.792 vs. 0.690, p = 0.0029). Both risk calculators generally over-predicted the risk of prostate cancer and high-grade disease across a wide range of predicted probabilities. Decision curve analysis suggested greater net benefit using the PCPT-RCs in this population. CONCLUSIONS: Multivariable nomograms can further aid patient counselling for early prostate cancer detection. In unscreened men from Western Ireland, the PCPT-RCs provided better discrimination for overall prostate cancer and high-grade disease compared to the ERSPC-RC. However, both tools overpredicted the risk of cancer detection on biopsy, and it is possible that a different set of predictive variables may be more useful in this population.

Methylphenidate-induced erections in a prepubertal child.

Methylphenidate is a medication used routinely in the management of attention deficit hyperactivity disorder. We report a case of a prepubertal child who developed unwanted erections after commencing a response-adjusted dosing regimen of sustained release methylphenidate. Despite priapism being a rare adverse reaction associated with methylphenidate, physicians and parents need to be aware as it can have significant long-term complications.