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

Randomized Comparison of Magnetic Resonance Imaging Versus Transurethral Resection for Staging New Bladder Cancers:Results From the Prospective BladderPath Trial

Purpose: Transurethral resection of bladder tumor (TURBT) is the initial staging procedure for new bladder cancers (BCs). For muscle-invasive bladder cancers (MIBCs), TURBT may delay definitive treatment. We investigated whether definitive treatment can be expedited for MIBC using flexible cystoscopic biopsy and multiparametric magnetic resonance imaging (mpMRI) for initial staging.Patients and Methods: We conducted a prospective open-label, randomized study conducted within 17 UK hospitals (registered as ISRCTN 35296862). Participants with suspected new BC were randomly assigned 1:1 to TURBT-staged or mpMRI-staged care, with minimization factors of sex, age, and clinician visual assessment of stage. Blinding was not possible. Patients unable/unwilling to undergo mpMRI or with previous BC were ineligible. The study had two stages with separate primary outcomes of feasibility and time to correct treatment (TTCT) for MIBC, respectively.Results: Between May 31, 2018, and December 31, 2021, 638 patients were screened, and 143 participants randomly assigned to TURBT (n = 72; 55 males, 15 MIBCs) or initial mpMRI (n = 71; 53 males, 14 MIBCs). For feasibility, 36 of 39 (92% [95% CI, 79 to 98]) participants with suspected MIBC underwent mpMRI. The median TTCT for participants with MIBC was significantly shorter with initial mpMRI (n = 12, 53 days [95% CI, 20 to 89] v n = 14, 98 days [95% CI, 72 to 125] for TURBT, log-rank P .02). There was no detriment for participants with non-MIBC (median TTCT: n = 30, 17 days [95% CI, 8 to 25] for mpMRI v n = 28, 14 days [95% CI, 10 to 29] for TURBT, log-rank P = .67). No serious adverse events were reported.Conclusion: The mpMRI-directed pathway led to a 45-day reduction in TTCT for MIBC. Incorporating mpMRI ahead of TURBT into the standard pathway was beneficial for all patients with suspected MIBC

Defining factors associated with high-quality surgery following radical cystectomy : analysis of the British Association of Urological Surgeons cystectomy audit

Background Radical cystectomy (RC) is associated with high morbidity. Objective To evaluate healthcare and surgical factors associated with high-quality RC surgery. Design, setting, and participants Patients within the prospective British Association of Urological Surgeons (BAUS) registry between 2014 and 2017 were included in this study. Outcome measurements and statistical analysis High-quality surgery was defined using pathological (absence of positive surgical margins and a minimum of a level I lymph node dissection template with a minimum yield of ten or more lymph nodes), recovery (length of stay ≤10 d), and technical (intraoperative blood loss <500 ml for open and <300 ml for minimally invasive RC) variables. A multilevel hierarchical mixed-effect logistic regression model was utilised to determine the factors associated with the receipt of high-quality surgery and index admission mortality. Results and limitations A total of 4654 patients with a median age of 70.0 yr underwent RC by 152 surgeons at 78 UK hospitals. The median surgeon and hospital operating volumes were 23.0 and 47.0 cases, respectively. A total of 914 patients (19.6%) received high-quality surgery. The minimum annual surgeon volume and hospital volume of ≥20 RCs/surgeon/yr and ≥68 RCs/hospital/yr, respectively, were the thresholds determined to achieve better rates of high-quality RC. The mixed-effect logistic regression model found that recent surgery (odds ratio [OR]: 1.22, 95% confidence interval [CI]: 1.11–1.34, p < 0.001), laparoscopic/robotic RC (OR: 1.85, 95% CI: 1.45–2.37, p < 0.001), and higher annual surgeon operating volume (23.1–33.0 cases [OR: 1.54, 95% CI: 1.16–2.05, p = 0.003]; ≥33.1 cases [OR: 1.64, 95% CI: 1.18–2.29, p = 0.003]) were independently associated with high-quality surgery. High-quality surgery was an independent predictor of lower index admission mortality (OR: 0.38, 95% CI: 0.16–0.87, p = 0.021). Conclusions We report that annual surgeon operating volume and use of minimally invasive RC were predictors of high-quality surgery. Patients receiving high-quality surgery were independently associated with lower index admission mortality. Our results support the role of centralisation of complex oncology and implementation of a quality assurance programme to improve the delivery of care. Patient summary In this registry study of patients treated with surgical excision of the urinary bladder for bladder cancer, we report that patients treated by a surgeon with a higher annual operative volume and a minimally invasive approach were associated with the receipt of high-quality surgery. Patients treated with high-quality surgery were more likely to be discharged alive following surgery

Pituitary insufficiency after operation of supratentorial intra- and extraaxial tumors outside of the sellar–parasellar region?

Recent studies investigating pituitary function after non-sellar brain tumor surgery showed that up to 38.2% of patients have pituitary insufficiency (PI). It has been assumed that the operation causes the PI, but preoperative hormone testing, which would have been necessary to prove this assumption, was not performed. The objective of this study is to answer the question if indeed microsurgery is the culprit of PI in patients with operatively treated non-sellar brain tumors. In this prospective trial, 54 patients with supratentorial non-sellar tumors were included. The basal levels of cortisol, prolactin, testosterone, estrogen, IGF-1, fT3, fT4, STH, TSH, ACTH, FSH, and LH were recorded preoperatively on days 1 and 7 after surgery. If basal hormone screening revealed an abnormality, a releasing hormone assay was performed. Before surgery, 24 of the 54 patients (44.4%) already had PI. Additional 25 patients showed either hypocortisolism or hypothyreoidism. As those patients had been pre-treated with dexamethasone and l-thyroxine, these findings were considered not to represent PI but drug effects. Hormone testing on days 1 and 7 after surgery revealed no changes. With 44.4% PI is a frequent finding in brain tumor patients already before surgery. The factors causing preoperative PI remain yet to be identified. The endocrine results after surgery are unchanged which rules out that surgery is the cause of PI

Does urinary cytology have a role in haematuria investigations?

OBJECTIVES: To determine the diagnostic accuracy of urinary cytology to diagnose bladder cancer and upper tract urothelial cancer (UTUC) as well as the outcome of patients with a positive urine cytology and normal haematuria investigations in patients in a multicentre prospective observational study of patients investigated for haematuria. PATIENT AND METHODS: The DETECT I study (clinicaltrials. gov NCT02676180) recruited patients presenting with haematuria following referral to secondary case at 40 hospitals. All patients had a cystoscopy and upper tract imaging (renal bladder ultrasound [RBUS] and/ or CT urogram [CTU]). Patients where urine cytology were performed were sub-analysed. The reference standard for the diagnosis of bladder cancer and UTUC was histological confirmation of cancer. A positive urine cytology was defined as a urine cytology suspicious for neoplastic cells or atypical cells. RESULTS: Of the 3556 patients recruited, urine cytology was performed in 567 (15.9%) patients from 9 hospitals. Median time between positive urine cytology and endoscopic tumour resection was 27 (IQR: 21.3-33.8) days. Bladder cancer was diagnosed in 39 (6.9%) patients and UTUC in 8 (1.4%) patients. The accuracy of urinary cytology for the diagnosis of bladder cancer and UTUC was: sensitivity 43.5%, specificity 95.7%, positive predictive value (PPV) 47.6% and negative predictive value (NPV) 94.9%. A total of 21 bladder cancers and 5 UTUC were missed. Bladder cancers missed according to grade and stage were: 4 (19%) were ≥ pT2, 2 (9.5%) were G3 pT1, 10 (47.6%) were G3/2 pTa and 5 (23.8%) were G1 pTa. High risk cancer was confirmed in 8 (38%) patients. There was a marginal improvement in sensitivity (57.7%) for high risk cancers. When urine cytology was combined with imaging, the diagnostic performance improved with CTU (sensitivity 90.2%, specificity 94.9%) superior to RBUS (sensitivity 66.7%, specificity 96.7%). False positive cytology results were confirmed in 22 patients, of which 12 (54.5%) had further invasive tests and 5 (22.7%) had a repeat cytology. No cancer was identified in these patients during follow-up. CONCLUSIONS: Urine cytology will miss a significant number of muscle invasive bladder cancer and high risk disease. Our results suggest that urine cytology should not be routinely performed as part of haematuria investigations. The role of urine cytology in select cases should be considered in the context of the impact of a false positive result leading to further potentially invasive tests conducted under general anaesthesia. This article is protected by copyright. All rights reserved

Healthcare practice placements: back to the drawing board?

YesBackground: Sourcing healthcare practice placements continues to present a challenge for higher education institutions. Equally, the provision of clinical placements by healthcare providers is not at the forefront of their agenda. In view of this, the historic and traditional models of clinical placements is becoming more difficult to provide. In light of this, new models of clinical placements are being explored. Aims: This literature review explores the differing models of clinical placements in use and examines the merits and limitation of each. Methods: A mixed-methods literature review with a pragmatic approach has been used. Findings: Several placement models were described, including the traditional 1:1 model as well as 2:1, 3:1. The hub and spoke, capacity development facilitator, collaborative learning in practice and role emerging placement models were also discussed. Conclusion: There is a considerable paucity of high-quality evidence evaluating differing placement modules. Further research is required to evaluate the differing placement models from a students, clinical educators and service user’s perspective

Perioperative management and anaesthetic considerations in pelvic exenterations using Delphi methodology: Results from the PelvEx Collaborative

Background: The multidisciplinary perioperative and anaesthetic management of patients undergoing pelvic exenteration is essential for good surgical outcomes. No clear guidelines have been established, and there is wide variation in clinical practice internationally. This consensus statement consolidates clinical experience and best practice collectively, and systematically addresses key domains in the perioperative and anaesthetic management. Methods: The modified Delphi methodology was used to achieve consensus from the PelvEx Collaborative. The process included one round of online questionnaire involving controlled feedback and structured participant response, two rounds of editing, and one round of web-based voting. It was held from December 2019 to February 2020. Consensus was defined as more than 80 per cent agreement, whereas less than 80 per cent agreement indicated low consensus. Results: The final consensus document contained 47 voted statements, across six key domains of perioperative and anaesthetic management in pelvic exenteration, comprising preoperative assessment and preparation, anaesthetic considerations, perioperative management, anticipating possible massive haemorrhage, stress response and postoperative critical care, and pain management. Consensus recommendations were developed, based on consensus agreement achieved on 34 statements. Conclusion: The perioperative and anaesthetic management of patients undergoing pelvic exenteration is best accomplished by a dedicated multidisciplinary team with relevant domain expertise in the setting of a specialized tertiary unit. This consensus statement has addressed key domains within the framework of current perioperative and anaesthetic management among patients undergoing pelvic exenteration, with an international perspective, to guide clinical practice, and has outlined areas for future clinical research