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 0.1). 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

Hyperthermic intravesical chemotherapy with mitomycin‐C for the treatment of high‐risk non‐muscle‐invasive bladder cancer patients

Objectives The objectives of the study are to explore tolerability, acceptability and oncological outcomes for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) treated with hyperthermic intravesical chemotherapy (HIVEC) and mitomycin-C (MMC) at our institution. Patients and Methods Our single-institution, observational study consists of consecutive high-risk NMIBC patients treated with HIVEC and MMC. Our HIVEC protocol included six weekly instillations (induction), followed by two further cycles of three instillations (maintenance) (6 + 3 + 3) if there was cystoscopic response. Patient demographics, instillation dates and adverse events (AEs) were collected prospectively in our dedicated HIVEC clinic. Retrospective case-note review was performed to evaluate oncological outcomes. Primary outcomes were tolerability and acceptability of HIVEC protocol; secondary outcomes were 12-month recurrence-free, progression-free and overall survival. Results In total, 57 patients (median age 80.3 years) received HIVEC and MMC, with a median follow-up of 18 months. Of these, 40 (70.2%) had recurrent tumours, and 29 (50.9%) had received prior Bacillus Calmette–Guérin (BCG). HIVEC induction was completed by 47 (82.5%) patients, but only 19 (33.3%) completed the full protocol. Disease recurrence (28.9%) and AEs (28.9%) were the most common reasons for incompletion of protocol; five (13.2%) patients stopped treatment due to logistical challenges. AEs occurred in 20 (35.1%) patients; the most frequently documented were rash (10.5%), urinary tract infection (8.8%) and bladder spasm (8.8%). Progression during treatment occurred in 11 (19.3%) patients, 4 (7.0%) of whom had muscle invasion and 5 (8.8%) subsequently required radical treatment. Patients who had received prior BCG were significantly more likely to progress (p = 0.04). 12-month recurrence-free, progression-free and overall survival rates were 67.5%, 82.2%, and 94.7%, respectively. Conclusions Our single-institution experience suggests that HIVEC and MMC are tolerable and acceptable. Oncological outcomes in this predominantly elderly, pretreated cohort are promising; however, disease progression was higher in patients pretreated with BCG. Further randomised noninferiority trials comparing HIVEC versus BCG in high-risk NMIBC are required

Real-word outcomes for high-risk non-muscle-invasive bladder cancer: screened patients for the BRAVO trial

Objective To report real-world outcomes for high-risk non-muscle-invasive bladder cancer (HRNMIBC), including bacillus Calmette-Guérin (BCG) and radical cystectomy (RC), as randomised comparisons of these have not been possible. Methods We detail consecutive participants screened for the BRAVO randomised controlled trial comparing RC with BCG (International Standard Randomised Controlled Trial Number [ISRCTN]12509361). Patients were prospectively registered and case-note review used for outcomes. The primary outcome was overall survival. Secondary outcomes included recurrence, progression, metastasis, and bladder cancer-specific survival. Results and limitations A total of 193 patients were screened, including 106 (54.9%) who received BCG, 43 (22.3%) primary RC, 37 (19.2%) ‘other’ treatment and seven (3.6%) hyperthermic intravesical mitomycin C. All-cause death occurred in 55 (28.5%) patients at median (interquartile range [IQR]) of 29.0 (19.5–42.0) months. In multivariable analysis, overall mortality was more common in older patients (hazard ratio [HR] 2.63, 95% confidence interval [CI] 1.35–5.13; Cox P = 0.004 for age >70 years), those recruited from district hospitals (HR 0.53, 95% CI 0.3–0.95; P = 0.032) and those who did not undergo RC as their first treatment (HR 2.16, 95% CI 1.17–3.99; P = 0.014). In all, 17 (8.8%) patients died from bladder cancer (BC) at median (IQR) of 22.5 (19–36.25) months. In multivariable analysis, BC-specific mortality was more common in older patients (HR 4.87, 95% CI 1.1–21.6; P = 0.037) and those with Tis/T1 disease (HR 2.26, 95% CI 1.23–4.16; P = 0.008) but did not vary with initial treatment. Conclusions Patients with HRNMIBC are at high-risk of mortality. Those choosing RC as their initial treatment have lower risks of mortality than others, although this may reflect fitness and selection

Epidemiology, aetiology and screening of bladder cancer

Bladder cancer (BC) is a common, significant and expensive health condition. Understanding the risk factors for this disease is paramount to improving disease prevention and increasing public awareness. Historically BC has been a disease of industrialized regions and the most responsible carcinogens are tobacco smoke and occupational chemical exposure. BC incidence and mortality differ dramatically by region and reflect differences in risk factor exposure, healthcare behaviour, and population demographics. Screening studies have suggested a survival benefit amongst screened non-symptomatic populations with known risk factors, but this has not become standard practice

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

© Translational Andrology and Urology. Bladder cancer (BC) is a common disease in both sexes and majority of cases present as nonmuscle 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 highrisk (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

A complex gene regulatory architecture underlies the development and evolution of cuticle morphology in Drosophila

The cuticle of insects is decorated with non-sensory hairs called trichomes. A few Drosophila species independently lost most of the dorso-lateral trichomes on first instar larvae. Genetic experiments revealed that this naked cuticle phenotype was caused by the evolution of enhancer function at the ovo/shavenbaby (ovo/svb) locus. Here we explore how this discovery catalyzed major new insights into morphological evolution in different developmental contexts, enhancer pleiotropy in gene regulation and the functionality and evolution of the Svb gene regulatory network (GRN). Taken together this highlights the importance of understanding the architecture and evolution of gene regulatory networks in detail and the great potential for further study of the Svb GRN

Identification of differentially expressed long noncoding RNAs in bladder cancer

Purpose: Loss of epigenetic gene regulation through altered long non-coding RNA (lncRNA) expression appears important in human cancer. LncRNAs have diagnostic and therapeutic potential, and offer insights into the biology disease, but little is known of their expression in urothelial cancer (UC). Here we identify differentially expressed lncRNAs with potential regulatory functions in UC. Experimental Design: The expression of 17,112 lncRNAs and 22,074 mRNAs was determined using microarrays in 83 normal and malignant urothelial (discovery) samples and selected RNAs with qPCR in 138 samples for validation. Significantly differentially expressed RNAs were identified and stratified according to tumour phenotype. siRNA knock-down, functional assays and whole genome transcriptomic profiling were used to identify potential roles of selected lncRNAs. Results: We observed upregulation of many lncRNAs in UC that was distinct to corresponding, more balanced changes for mRNAs. In general, lncRNA expression reflected disease phenotype. We identified 32 lncRNAs with potential roles in disease progression. Focusing upon a promising candidate, we implicate upregulation of AB074278 in apoptosis avoidance and the maintenance of a pro-proliferative state in cancer through a potential interaction with EMP1, a tumour suppressor and a negative regulator of cell proliferation. Conclusions: We report differentially expression profiles for numerous lncRNA in UC. We identify phenotype-specific expression and a potential mechanistic target to explain this observation. Further studies are required to validate lncRNAs as prognostic biomarkers in this disease