Karl Pang

Prospective Implementation of Enhanced Recovery After Surgery Protocols to Radical Cystectomy

BACKGROUND Multimodal enhanced recovery after surgery (ERAS) regimens have improved outcomes from colorectal surgery. OBJECTIVE We report the application of ERAS to patients undergoing radical cystectomy (RC). DESIGN, SETTING, AND PARTICIPANTS Prospective collection of outcomes from consecutive patients undergoing RC at a single institution. INTERVENTION Twenty-six components including prehabilitation exercise, same day admission, carbohydrate fluid loading, targeted intraoperative fluid resuscitation, regional local anaesthesia, cessation of nasogastric tubes, omitting oral bowel preparation, avoiding drain use, early mobilisation, chewing gum use, and audit. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary outcomes were length of stay and readmission rate. Secondary outcomes included intraoperative blood loss, transfusion rates, survival, and histopathological findings. RESULTS AND LIMITATIONS Four hundred and fifty-three consecutive patients underwent RC, including 393 (87%) with ERAS. Length of stay was shorter with ERAS (median [interquartile range]: 8 [6-13] d) than without (18 [13-25], p<0.001). Patients with ERAS had lower blood loss (ERAS: 600 [383-969] ml vs 1050 [900-1575] ml for non-ERAS, p<0.001), lower transfusion rates (ERAS: 8.1% vs 25%, chi-square test, p<0.001), and fewer readmissions (ERAS: 15% vs 25%, chi-square test, p=0.04) than those without. Histopathological parameters (eg, tumour stage, node count, and margin state) and survival outcomes did not differ with ERAS use (all p>0.1). Multivariable analysis revealed ERAS use was (p=0.002) independently associated with length of stay. CONCLUSIONS The use of ERAS pathways was associated with lower intraoperative blood loss and faster discharge for patients undergoing RC. These changes did not increase readmission rates or alter oncological outcomes. PATIENT SUMMARY Recovery after major bladder surgery can be improved by using enhanced recovery pathways. Patients managed by these pathways have shorter length of stays, lower blood loss, and lower transfusion rates. Their adoption should be encouraged.

Identification and Diagnostic Performance of a Small RNA within the PCA3 and BMCC1 Gene Locus That Potentially Targets mRNA

Background: PCA3 is a long noncoding RNA (lncRNA) with unknown function, upregulated in prostate cancer. LncRNAs may be processed into smaller active species. We hypothesized this for PCA3. Methods: We computed feasible RNA hairpins within the BMCC1 gene (encompassing PCA3) and searched a prostate transcriptome for these. We measured expression using qRT-PCR in three cohorts of prostate cancer tissues (n = 60), exfoliated urinary cells (n = 484 with cancer and n = 166 controls), and in cell lines (n = 22). We used in silico predictions and RNA knockup to identify potential mRNA targets of short transcribed RNAs. Results: We predicted 13 hairpins, of which PCA3-shRNA2 was most abundant within the prostate transcriptome. PCA3-shRNA2 is located within intron 1 of PCA3 and appears regulated by androgens. Expression of PCA3-shRNA2 was upregulated in malignant prostatic tissues, exfoliated urinary cells from men with prostate cancer (13–273 fold change; t test P < 0.003), and closely correlated to PCA3 expression (r = 0.84–0.93; P < 0.001). Urinary PCA3-shRNA2 (C-index, 0.75–0.81) and PCA3 (C-index, 0.78) could predict the presence of cancer in most men. PCA3-shRNA2 knockup altered the expression of predicted target mRNAs, including COPS2, SOX11, WDR48, TEAD1, and Noggin. PCA3-shRNA2 expression was negatively correlated with COPS2 in patient samples (r = −0.32; P < 0.001). Conclusion: We identified a short RNA within PCA3, whose expression is correlated to PCA3, which may target mRNAs implicated in prostate biology. Impact: This short RNA is stable ex vivo, suggesting a role as a robust biomarker. We identify cytoplasmic enrichment of this RNA and potential targeting of mRNAs implicated in prostate carcinogenesis. Cancer Epidemiol Biomarkers Prev; 24(1); 268–75. ©2014 AACR.

MicroRNA and urothelial cell carcinoma

Predicting the behaviour of upper tract urothelial cancer (UTUC) is difficult but likely to be helped by measuring multiple variables. These variables may be clinical, radiological or pathological or, more excitingly, molecular biomarkers. Although to date no molecular markers have been used within the clinical setting for the prediction of UTUC [1], many people (across all urological cancers) are searching for robust and accurate biomarkers.

Re: Radical Cystectomy (Bladder Removal) Against Intravesical BCG Immunotherapy for High-risk Non-muscle Invasive Bladder Cancer (BRAVO): A Protocol for a Randomised Controlled Feasibility Study

Experts’ summary: The BRAVO group have summarised a protocol for their UK multicentre randomised controlled feasibility study to address potential barriers to a full randomised controlled trial (RCT). The group aim to randomise 60 patients with high-risk non– muscle-invasive bladder cancer (HRNMIBC) from six UK centres to maintenance bacillus Calmette-Guérin (mBCG) immunotherapy or radical cystectomy (RC) between October 2016 and March 2018. At least 12 mo of BCG therapy are required, including 6 wk of induction BCG after diagnosis. RC will include pelvic lymphadenectomy and the option of ileal conduit or neobladder urinary diversion. Preoperative, intraoperative, and postoperative care are to be carried out as per enhanced recovery after surgery (ERAS) protocols [1]. BRAVO is a feasibility study in advance of a main RCT and will assess eligibility and recruitment rates, acceptance of randomised treatment, mBCG compliance, and patient retention and withdrawal rates. Endpoints including quality of life (QoL) during and after treatment and cancer-specific survival will be analysed.

RE: “What factors influence British medical students’ career intentions?” Location and social relationships

We read with great interest the article by Ibrahim et al. (2014) regarding factors influencing British medical students’ in their future career intentions. The article highlighted that undergraduate experience and prestige, both significantly influenced British medical students’ future career aspirations. The Foundation Programme is the first 2-years of UK postgraduate medical training consisting of a training programme with six 4-monthly specialities. Recruitment for the 21 foundation schools is an annual national process in which applicants rank their choice of deanery and are accordingly given their rotations depending on the overall score they obtain on their online application. Recently our group assessed the factors influencing final-year medical students in their choice of their Foundation Programme. All 361 participants from 9 medical schools – Edinburgh, Swansea, Imperial, Peninsula, Leicester, Keele, Sheffield, Liverpool and Glasgow – had applied to the Foundation Programme. Twelve choices (year 1 specialities, year 2 specialities, undergraduate experience, prestige of foundation school, competitiveness, availability of academic post, location, family, partner, friends, finance and recommendations) were ranked in a 5-point Likert scale. Additionally, all respondents stated the single most important factor influencing their choice of foundation school. 67.6% of respondents either strongly agreed or agreed that undergraduate experience was an important factor for foundation school choice. When asked to give the single most important factor when embarking on their choice of foundation training school, 44% chose location with 26% choosing partner, family or friends. Only 3% and 1.6% of finalyear medical students stated that undergraduate experience and prestige was the most important factor in the choice of foundation school, respectively. Our study confirms that under-graduate experience is an important factor for the choice of future career intentions of British medical students. However, it appears that geographical and social factors are also important issues that shape early post-graduate training for British medical students. Saiful Miah, Suresh Venugopal & Karl Pang, Department of Urology, Royal Hallamshire Hospital, Sheffield, UK. E-mail: s.miah@sheffield.ac.uk

Reply to Mark C. Kendall's Letter to the Editor re: Karl H. Pang, Ruth Groves, Suresh Venugopal, Aidan P. Noon, James W.F. Catto. Prospective Implementation of Enhanced Recovery After Surgery Protocols to Radical Cystectomy. Eur Urol 2018;73:363–71

We value the important comments by Dr. Kendall and take this opportunity to clarify some points raised regarding our study on implementing enhanced recovery after surgery (ERAS) protocols for radical cystectomy [1]. As far as we are aware, our prospective study of 453 consecutive patients within a single institute represents the largest ERAS and radical cystectomy cohort to date [2]. Dr. Kendall raised some important issues.

Epidemiology of Bladder Cancer: A Systematic Review and Contemporary Update of Risk Factors in 2018

CONTEXT Bladder cancer (BC) is a significant health problem, and understanding the risk factors for this disease could improve prevention and early detection. OBJECTIVE To provide a systematic review and summary of novel developments in epidemiology and risk factors for BC. EVIDENCE ACQUISITION A systematic review of original articles was performed by two pairs of reviewers (M.G.C., I.J., F.E., and K.P.) using PubMed/Medline in December 2017, updated in April 2018. To address our primary objective of reporting contemporary studies, we restricted our search to include studies from the last 5yr. We subdivided our review according to specific risk factors (PICO [Population Intervention Comparator Outcome]). EVIDENCE SYNTHESIS Our search found 2191 articles, of which 279 full-text manuscripts were included. We separated our manuscripts by the specific risk factor they addressed (PICO). According to GLOBOCAN estimates, there were 430000 new BC cases and 165000 deaths worldwide in 2012. Tobacco smoking and occupational exposure to carcinogens remain the factors with the highest attributable risk. The literature was limited by heterogeneity of data. CONCLUSIONS Evidence is emerging regarding gene-environment interactions, particularly for tobacco and occupational exposures. In some populations, incidence rates are declining, which may reflect a decrease in smoking. Standardisation of reporting may help improve epidemiologic evaluation of risk. PATIENT SUMMARY Bladder cancer is common worldwide, and the main risk factors are tobacco smoking and exposure to certain chemicals in the working and general environments. There is ongoing research to identify and reduce risk factors, as well as to understand the impact of genetics on bladder cancer risk.

Opportunities of next-generation sequencing in non-muscle invasive bladder cancer outcome prediction

Bladder cancer (BC) is a common disease in both sexes and majority of cases present as non-muscle invasive BC (NMIBC). The percentage of NMIBC progressing to muscle invasive BC (MIBC) varies between 25% and 75% and currently there are no reliable biomarkers that may predict the outcome of high-risk (HR) NMIBC. Whilst The Cancer Genome Atlas (TCGA) project has identified genetic alteration in MIBC using next-generation sequencing (NGS), genetic data in HR-NMIBC outcome prediction using this new technology are limited. We reviewed data on NGS performed on DNA and RNA extracted from tissue, plasma and urinary samples obtained from patients with NMIBC. Analysis on different specimens revealed genetic alterations and microRNA alterations in common oncogenic pathways such as gene expression (TERT) and cell proliferation (PTEN, cyclin D). Validation of a 12-gene (CDC25B, KPNA2, BIRC5, COL18A1, MSN, UBE2C, COL4A1, FABP4, MBNL2, SKAP2, COL4A3BP, NEK1) progression score has shown significant association with progression. ARID1A mutations are associated with an increased risk of recurrence after Bacillus Calmette-Guerin (BCG) together with a high DNA damage repair (DDR) gene alterations in HR-NMIBC. Patients with progressive disease seem to have significantly higher levels of both plasma and urinary tumour DNA compared with patients with recurrence. Although experimental data appear promising, well-designed systematic studies are urgently needed to translate applicability to clinical practice.

Curing ‘PubMed fever’

The UK foundation programme (fi rst 2 years of UK postgraduate medical training) has an annual national process. Applicants (predominately medical students) who have up to two PubMed indexed publications score favourably. 2 As medical educators we have increasingly been informed by our students that their primary and often sole reason to participate in research is for a ‘PubMed publication’. The term ‘PubMed fever’ has now been coined because of the increasing pressure placed on medical students to publish work. 3 This ailment is described as the contagious nature of publicationrelated stress encountered by medical students. 3

Evaluation of a short RNA within Prostate Cancer Gene 3 in the predictive role for future cancer using non-malignant prostate biopsies

Background Prostate Cancer 3 (PCA3) is a long non-coding RNA (ncRNA) upregulated in prostate cancer (PCa). We recently identified a short ncRNA expressed from intron 1 of PCA3. Here we test the ability of this ncRNA to predict the presence of cancer in men with a biopsy without PCa. Methods We selected men whose initial biopsy did not identify PCa and selected matched cohorts whose subsequent biopsies revealed PCa or benign tissue. We extracted RNA from the initial biopsy and measured PCA3-shRNA2, PCA3 and PSA (qRT-PCR). Results We identified 116 men with and 94 men without an eventual diagnosis of PCa in 2–5 biopsies (mean 26 months), collected from 2002–2008. The cohorts were similar for age, PSA and surveillance period. We detected PSA and PCA3-shRNA2 RNA in all samples, and PCA3 RNA in 90% of biopsies. The expression of PCA3 and PCA3-shRNA2 were correlated (Pearson’s r = 0.37, p<0.01). There was upregulation of PCA3 (2.1-fold, t-test p = 0.02) and PCA3-shRNA2 (1.5-fold) in men with PCa on subsequent biopsy, although this was not significant for the latter RNA (p = 0.2). PCA3 was associated with the future detection of PCa (C-index 0.61, p = 0.01). This was not the case for PCA3-shRNA2 (C-index 0.55, p = 0.2). Conclusions PCA3 and PCA3-shRNA2 expression are detectable in historic biopsies and their expression is correlated suggesting co-expression. PCA3 expression was upregulated in men with PCa diagnosed at a future date, the same did not hold for PCA3-shRNA2. Futures studies should explore expression in urine and look at a time course between biopsy and PCa detection.