Dara Lundon

European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculators significantly outperform the Prostate Cancer Prevention Trial (PCPT) 2.0 in the prediction of prostate cancer: a multi-institutional study.

To analyse the performance of the Prostate Cancer Prevention Trial Risk Calculator (PCPT‐RC) and two iterations of the European Randomised Study of Screening for Prostate Cancer (ERSPC) Risk Calculator, one of which incorporates prostate volume (ERSPC‐RC) and the other of which incorporates prostate volume and the prostate health index (PHI) in a referral population (ERSPC‐PHI).

Improving multivariable prostate cancer risk assessment using the Prostate Health Index.

To analyse the clinical utility of a prediction model incorporating both clinical information and a novel biomarker, p2PSA, in order to inform the decision for prostate biopsy in an Irish cohort of men referred for prostate cancer assessment.

The analysis of serum response factor expression in bone and soft tissue prostate cancer metastases

Castration‐resistant prostate cancer (CRPC) represents a challenge to treat with no effective treatment options available. We recently identified serum response factor (SRF) as a key transcription factor in an in vitro model of castration resistance where we showed that SRF inhibition resulted in reduced cellular proliferation. We also demonstrated an association between SRF protein expression and CRPC in a cohort of castrate‐resistant transurethral resections of the prostate (TURPS). The mechanisms regulating the growth of CRPC bone and visceral metastases have not been explored in depth due to the paucity of patient‐related material available for analysis. In this study, we aim to evaluate SRF protein expression in prostate cancer (PCa) metastases, which has not previously been reported.

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

IntroductionEscherichia 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.MethodsA 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.ResultsExcept 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.ConclusionEscherichia 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.

A Prospective Study of Total Glans Resurfacing for Localized Penile Cancer to Maximize Oncologic and Functional Outcomes in a Tertiary Referral Network

Purpose: Penile cancer is a rare malignancy worldwide, representing only 1% of all cancers affecting men. There are little data outlining the comparative effectiveness of penile preservation techniques and to our knowledge no guidelines regarding their use currently exist. Outcomes data reporting is nonstandardized and followup is not measured consistently. The aim of this study was to analyze the outcomes of total glans resurfacing in terms of oncologic control, form and function in localized penile cancer. Materials and Methods: From 2013 to 2015, 19 prospectively enrolled patients underwent total glans resurfacing. Demographics, cosmesis, patient satisfaction and disease recurrence were assessed at followup to quantify oncologic and functional outcomes. At 3 months of followup patients completed the IIEF (International Index of Erectile Function) questionnaire detailing erectile and sexual function, and general satisfaction using a visual analog scale. All statistical analysis was performed with Prism® 6. Results: No perioperative complications were experienced. Of the patients 94.7% had complete graft take with a median cosmesis score of 5 of 5 on the visual analog scale. There was 1 local and no regional nodal recurrence at a mean followup of 23 months. One‐year progression‐free and overall survival rates were 100% and the 1‐year recurrence‐free survival rate was 95%. Of the patients 81% reported an improved sex life postoperatively. Conclusions: Total glans resurfacing is a viable and acceptable option for glans preservation in patients with localized penile cancer. It demonstrates acceptable functional and oncologic outcomes. We believe that total glans resurfacing should be considered in all cases of localized penile cancer.

External Evaluation of a Novel Prostate Cancer Risk Calculator (ProstateCheck) Based on Data from the Swiss Arm of the ERSPC

PURPOSE We externally validated a novel prostate cancer risk calculator based on data from the Swiss arm of the ERSPC and assessed whether the risk calculator (ProstateCheck) is superior to the PCPT-RC and SWOP-RC in an independent Swiss cohort. MATERIALS AND METHODS Data from all men who underwent prostate biopsy at an academic tertiary care center between 2004 and 2012 were retrospectively analyzed. The probability of having any prostate cancer or high grade prostate cancer (Gleason score 7 or greater) on prostate biopsy was calculated using the ProstateCheck. Risk calculator performance was assessed using calibration and discrimination, and additionally compared with the PCPT-RC and SWOP-RC by decision curve analyses. RESULTS Of 1,615 men 401 (25%) were diagnosed with any prostate cancer and 196 (12%) with high grade prostate cancer. Our analyses of the ProstateCheck-RC revealed good calibration in the low risk range (0 to 0.4) and moderate overestimation in the higher risk range (0.4 to 1) for any and high grade prostate cancer. The AUC for the discrimination of any prostate cancer and high grade prostate cancer was 0.69 and 0.72, respectively, which was slightly but significantly higher compared to the PCPT-RC (0.66 and 0.69, respectively) and SWOP-RC (0.64 and 0.70, respectively). Decision analysis, taking into account the harms of transrectal ultrasound measurement of prostate volume, showed little benefit for ProstateCheck-RC, with properties inferior to those of the PCPT-RC and SWOP-RC. CONCLUSIONS Our independent external evaluation revealed moderate performance of the ProstateCheck-RC. Its clinical benefit is limited, and inferior to that of the PCPT-RC and SWOP-RC.

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

BackgroundDocetaxel 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.MethodsUsing 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.ResultsThe 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.ConclusionsOur 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.

Water-enhanced antegrade MR pyelography in pregnancy: a novel radiation-free approach

Our aim was to determine if water-enhanced antegrade magnetic resonance (MR) pyelography can be an alternative to conventional antegrade pyelography in pregnant patients who require percutaneous nephrostomy placement for urosepsis and/or obstructive uropathy. The pregnant patient was placed supine in a 1.5-T MRI scanner seven days after percutaneous nephrostomy placement using ultrasound. Serial axial and coronal T2-weighted echo-planar fast spin-echo sequences were performed before and after injection of the catheter. The right nephrostomy catheter hub was sterilised using chlorhexidine. Sixty millilitres of sterile water were slowly injected. No Gd-based contrast agent was utilised due to safety concerns for the foetus. MR antegrade pyelography demonstrated the level of ureteric obstruction and the absence of renal calculi using sterile water as a contrast medium injected through a percutaneous nephrostomy followed by T2-weighted imaging. Air bubbles in the injected solution were differentiated from calculi due to their mobility on serial scans and their anti-dependent position. Water-enhanced antegrade MR pyelography was a safe and effective method of imaging the pregnant patient. It served as an alternative to conventional antegrade pyelography and minimised potential risks to the foetus.

Extramammary Paget’s Disease

Extramammary Paget’s disease (EMPD) is a rare intraepithelial malignancy that has only been a few hundred times in the literature with level 4 evidence. The precise incidence is unknown. However, little is known regarding optimal treatment and prognostic factors. Due to poor understanding of the condition, it can remain undiagnosed for a number of years prior to treatment, and with individual patient numbers remaining small across centers, it becomes difficult to build up a true understanding of the disease process.

Prostate cancer risk prediction and the persistence of uncertainty.

Supplementary analysis by the authors evaluated the performance of previous versions of the PCPT-RC, specifically v1.0 and PCPT-RC v1.0 with prostate volume. The inclusion of prostate volume demonstrated an improved predictive ability of this RC. The AUC for the prediction of significant prostate cancer using the PCPT-RC v1.0 with prostate volume was 0.74. This contrasts with the ERSPC risk tool: AUC of 0.73 (which includes a trichotomised estimation of prostate volume), and the novel PCPT-RC v2.0; AUC of 0.70 (which does not include prostate volume as a factor).