Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Surgical management of vesicoureteral reflux in adults

Vesicoureteral reflux (VUR) is the retrograde flow of urine from the bladder into the upper urinary tract with or without upper-tract dilatation. This diagnosis is commonly made in childhood, affecting 1% of all births. In adults, its prevalence and incidence are not known. Presentation in adults could be with loin pain associated with voiding or a full bladder, recurrent urinary tract infections, a diagnosis carried over from childhood or an incidental finding. Most of the works on VUR have been done in the paediatric population. There are limited publications addressing VUR in adults. Unsurprisingly, the management of VUR in adults is extrapolated from the knowledge that we have gained from paediatric urology. Herein, we recap on the pathophysiology and review the surgical management of VUR in adults as published over the years. </jats:p

Management of recurrent urinary tract infections in women

Urinary tract infections are highly prevalent and result in significant patient morbidity as well as large financial costs to healthcare systems. Recurrent urinary tract infections can be challenging for many healthcare professionals, and the repeated use of antibiotics in this patient cohort inevitably contributes to the growing issue of antimicrobial resistance and superbugs. It is essential that these patients are appropriately diagnosed and managed to ensure rapid resolution of symptoms and the prevention of chronic or recurrent urinary tract infections. There are several antibiotic-based options available for the prophylaxis of recurrent urinary tract infections however, in the current era of rising antimicrobial resistance, an awareness of antibiotic stewardship and the use of non-antibiotic alternatives for the treatment and prevention of urinary tract infections is of critical importance. We present a case-based multidisciplinary team discussion to highlight how women with recurrent urinary tract infections should be managed, encouraging the use of non-antibiotic prophylactic measures when suitable. Level of evidence: Level 5 </jats:sec

Acute urinary retention in women due to urethral calculi: A rare case

We present a case of a 51-year-old woman with acute urinary retention caused by a urethral calculus. Urethral calculi in women are extremely rare and are usually formed in association with underlying genitourinary pathology. In this case, however, no pathology was detected via thorough urological evaluation. We discuss the pathogenesis, clinical presentation and treatment of urethral calculi. To our knowledge, this is the second reported case of a primary urethral calculus in a female with an anatomically normal urinary tract and the first in a middle-aged Caucasian female.</jats:p

British Association of Urological Surgeons (BAUS) consensus document on post-prostatectomy incontinence-stress urinary incontinence

The authors would like to acknowledge the time, expertise and input provided by our external peer reviewers Mr Nikesh Thiruchelvam (Consultant Urologist, Cambridge University Hospitals), Professor Paul Abrams (Consultant Urologist and Honorary Professor of Urology, Bristol) and Miss Suzie Venn (Consultant Urologist, University Hospitals Sussex).Peer reviewe

Prognostic phenotypes of early-stage lung adenocarcinoma

BackgroundSurvival after curative resection of early-stage lung adenocarcinoma (LUAD) varies and prognostic biomarkers are urgently needed.MethodsLarge-format tissue samples from a prospective cohort of 200 patients with resected LUAD were immunophenotyped for cancer hallmarks TP53, NF1, CD45, PD-1, PCNA, TUNEL and FVIII, and were followed for a median of 2.34 (95% CI 1.71–3.49) years.ResultsUnsupervised hierarchical clustering revealed two patient subgroups with similar clinicopathological features and genotype, but with markedly different survival: “proliferative” patients (60%) with elevated TP53, NF1, CD45 and PCNA expression had 50% 5-year overall survival, while “apoptotic” patients (40%) with high TUNEL had 70% 5-year survival (hazard ratio 2.23, 95% CI 1.33–3.80; p=0.0069). Cox regression and machine learning algorithms including random forests built clinically useful models: a score to predict overall survival and a formula and nomogram to predict tumour phenotype. The distinct LUAD phenotypes were validated in The Cancer Genome Atlas and KMplotter data, and showed prognostic power supplementary to International Association for the Study of Lung Cancer tumour–node–metastasis stage and World Health Organization histologic classification.ConclusionsTwo molecular subtypes of LUAD exist and their identification provides important prognostic information.</jats:sec

Current process and outcomes of the surgical management of LUTS due to benign prostatic enlargement: how consistent are we? – results from the multi-institutional audit of surgical management of BPE (AuSuM BPE) in the United Kingdom

Objective In view of changing landscape of surgical treatment for LUTS secondary to BPE, this audit was undertaken to assess key aspects of the processes and outcomes of the current interventional treatments for BPE, across different units in the UK. Materials and method A multi-institutional snapshot audit was conducted for patients undergoing interventions for LUTS/BPE over 8-week period. Using Delphi process two-part proforma was designed to capture data. Results 529 patients were included across 20 NHS trusts in England and Wales. Median age was 73 years. Indications for surgery were acute retention (47%) and LUTS (45%). 80% of patients had prior medical therapy. TURP formed the commonest procedure. 27% patients had &lt;23 hour hospital stay. Immediate (21%) and delayed (18%) complications were Clavien-Dindo &lt;2 category. High proportion of patients reported residual symptoms. Type and indication of surgery were significant predictor of complications, length of stay and failure of TWOC outcomes, on multivariate analyses. There were variations in departmental processes, 50% centres used PROMs. Conclusion Monopolar TURP still remains the commonest intervention for BPE. Most departments are adopting newer technologies. The audit identified opportunities for development of consistent, effective and patient centric practices as well as need for large-scale focused studies. </jats:sec