Evaluation of magnetic resonance imaging for bladder cancer detection following transurethral resection of bladder tumour (TURBT).

PURPOSE: To evaluate the performance of MRI for detection of bladder cancer following transurethral resection of bladder tumour (TURBT). METHODS: This single-centre retrospective study included forty-one consecutive patients with bladder cancer who underwent bladder MRI after TURBT. Two uroradiologists retrospectively assessed the presence of tumour using bladder MRI with and without DWI (diffusion weighted imaging) using a five-point Likert scale. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated and inter-reader agreement was assessed. Histopathology was used as the reference standard. RESULTS: 24 out of 41 patients (58.5%) had no residual tumour or Tis (carcinoma in situ) after TURBT. Sensitivity, specificity, PPV and NPV for detection of tumour using T1WI (T1-weighted imaging) and T2WI (T2-weighted imaging) was 50.0%, 54.6%, 21.1%, and 81.8%, respectively and for T1WI, T2WI and DWI combined was 100%, 76.5%, 50.0% and 100%, respectively. Overestimation of tumour was more common than underestimation. MRI showed high accuracy for patients in whom there was no residual tumour (78.9%). Inter-reader agreement for tumour detection improved from fair (κ = 0.54) to moderate (κ = 0.70) when DWI was included. CONCLUSION: Non-contrast MRI with DWI showed high sensitivity and relatively high specificity for detection of residual tumour after TURBT. Inter-reader agreement improved from fair to moderate with the addition of DWI. MRI can be useful after TURBT in order to guide further management.

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.

Extensive heterogeneity in somatic mutation and selection in the human bladder.

The extent of somatic mutation and clonal selection in the human bladder remains unknown. We sequenced 2097 bladder microbiopsies from 20 individuals using targeted (n = 1914 microbiopsies), whole-exome (n = 655), and whole-genome (n = 88) sequencing. We found widespread positive selection in 17 genes. Chromatin remodeling genes were frequently mutated, whereas mutations were absent in several major bladder cancer genes. There was extensive interindividual variation in selection, with different driver genes dominating the clonal landscape across individuals. Mutational signatures were heterogeneous across clones and individuals, which suggests differential exposure to mutagens in the urine. Evidence of APOBEC mutagenesis was found in 22% of the microbiopsies. Sequencing multiple microbiopsies from five patients with bladder cancer enabled comparisons with cancer-free individuals and across histological features. This study reveals a rich landscape of mutational processes and selection in normal urothelium with large heterogeneity across clones and individuals.

Simulation in urology to train non-technical skills in ward rounds.

OBJECTIVE: To report our experience of an exercise designed to train newly appointed urology trainees in non-technical skills on ward rounds as a part of a simulation 'boot camp', through a qualitative analysis of participant feedback on the utility of this method of training. PATIENTS AND METHODS: The simulations took place in a high-fidelity simulated ward bay. Forty-eight doctors with formal urology training ranging between 2 and 60 months (mean 19.1 ± 11.6 months) took part. Thirty-one participants were on a formal urology specialty training pathway. The remaining participants were core (pre-specialty) surgical trainees. The entry requirement was that participants must be junior-level urologists, ideally at the beginning of specialty training. Participants individually led a simulated ward round, which was devised using actors to play patients and a simulated 'switchboard' for telephone conversations. Distractions were introduced deliberately for participants to manage an emergent urology-related scenario. 'Freeze-frames' were used to 'pause' the ward round, whereby observing consultants provided feedback on performance. After the simulated exercises, a whole-group structured debriefing took place. Non-Technical Skills for Surgeons (NOTSS) scores were generated for participants by seven consultant urologists. Participants completed a two-part feedback form. Part one involved nine questions scored on a Likert scale, and part two required free-text responses. RESULTS: The mean (±sd) itemized NOTSS scores for situational awareness, decision-making, communication and teamwork, and leadership were 3.01 (±0.15), 2.95 (±0.16), 3.05 (±0.19), and 2.98 (±0.15), respectively. From the thematic analysis, participants commented positively on the number of scenarios per participant, the use of actors as patients and real staff, and the use of freeze-frames for immediate feedback. Residents also provided suggestions for distractions to be considered in the future. CONCLUSIONS: This simulated ward round was generally well received by participants, and the obtained feedback provides an insight into how this can be adapted to maximize the benefits for new specialty residents. The mean NOTSS scores indicated that non-technical skills performances could be improved. This supports our rationale to train non-technical skills in a safe environment to bolster career transition into positions of greater decision-making autonomy.

Capsaicin: a novel radio-sensitizing agent for prostate cancer.

INTRODUCTION: Radio-sensitizing agents sensitize tumor cells to the lethal effects of radiotherapy (RT) allowing for use of lower doses of radiation to achieve equivalent cancer control, while minimizing adverse effects to normal tissues. Given their limited toxicity and ability to easily integrate into the diet, compounds occurring naturally in the diet make ideal potential radio-sensitizing agents. In this study, we have examined whether capsaicin, the active compound in chilli peppers, can modulate the response to RT in preclinical models of prostate cancer (PCa). METHODS: The effects of RT (1-8 Gy) and/or capsaicin (1-10 µM) on colony formation rates in human PCa cells were assessed using clonogenic assays. Mechanistic studies were performed by Western Blot, immunocytochemistry, and flow cytometry. Athymic mice (n = 40) were inoculated with human LNCaP cells. Once tumors reached 100 mm(3) , animals were randomized into four groups: control, capsaicin alone (5 mg/kg/d), RT alone (6 Gy), and capsaicin and RT. RESULTS: Capsaicin reduced colony formation rates and radio-sensitized human PCa cells (Sensitizer enhancement ratio = 1.3) which corresponded to the suppression of NFκB, independent of TRP-V1 receptor. Cell cycle modulation occurred following RT and capsaicin treatment independently. In vivo, oral administration of capsaicin with RT resulted in a 'greater than additive' growth delay and reduction in the tumor growth rate greater than capsaicin (P < 0.001) or RT (P < 0.03) alone. Immunohistochemical analysis revealed a reduction in proliferation and NFκB expression, and increase in DNA damage. DISCUSSION: Our findings suggest that capsaicin acts as a radio-sensitzing agent for PCa through the inhibition of NFκB signalling.

Comet assay measures of DNA damage are predictive of bladder cancer cell treatment sensitivity in vitro and outcome in vivo.

Bladder cancer patients suffer significant treatment failure, including high rates of recurrence and poor outcomes for advanced disease. If mechanisms to improve tumour cell treatment sensitivity could be identified and/or if tumour response could be predicted, it should be possible to improve local-control and survival. Previously, we have shown that radiation-induced DNA damage, measured by alkaline Comet assay (ACA), correlates bladder cancer cell radiosensitivity in vitro. In this study we first show that modified-ACA measures of cisplatin and mitomycin-C-induced damage also correlate bladder cancer cell chemosensitivity in vitro, with essentially the same rank order for chemosensitivity as for radiosensitivity. Furthermore, ACA studies of radiation-induced damage in different cell-DNA substrates (nuclei, nucleoids and intact parent cells) suggest that it is a feature retained in the prepared nucleoids that is responsible for the relative damage sensitivity of bladder cancer cells, suggestive of differences in the organisation of DNA within resistant vs. sensitive cells. Second, we show that ACA analysis of biopsies from bladder tumours reveal that reduced DNA damage sensitivity associates with poorer treatment outcomes, notably that tumours with a reduced damage response show a significant association with local recurrence of non-invasive disease and that reduced damage response was a better predictor of recurrence than the presence of high-risk histology in this cohort. In conclusion, this study demonstrates that mechanisms governing treatment-induced DNA damage are both central to and predictive of bladder cancer cell treatment sensitivity and exemplifies a link between DNA damage resistance and both treatment response and tumour aggression.

Exercise does not counteract the effects of a "westernized" diet on prostate cancer xenografts.

BACKGROUND: The relationships between diet, exercise, and prostate cancer (PCa) remain unclear. We have previously reported that a "Western" diet promotes PCa tumor growth in vivo. Presently, we report the effects of sustained aerobic exercise on PCa progression in animals fed a high-fat diet versus a standard diet. METHODS: Athymic mice (n = 43) were inoculated subcutaneously with human PCa (LNCaP) cells, fed ad libitum with either a high-fat or a standard diet, and randomized into forced exercising and non-exercising groups. Body weight, tumor volume, and food consumption were recorded tri-weekly. Terminal serum samples and tumor biopsies were obtained for analysis. RESULTS: Body weight differences were not observed between the groups over time. The high-fat diet with exercise (HF-Ex) group showed significantly increased tumor growth rate compared to all other groups (P < 0.0007). Tumor growth rate of the standard diet with exercise (Std-Ex) group was reduced significantly compared to the high-fat diet without exercise (HF-No Ex) group (P = 0.0008). Significant differences (P ≤ 0.012) were observed in energy consumption (kcal) between the groups over time. Exercising mice consumed significantly more kcal than non-exercising mice, and the HF-Ex group consumed significantly more than each of the other three groups (P < 0.0007). The expression levels of p27 and p21 were increased in exercising animals, while AR expression was elevated in the HF-Ex group versus the Std-Ex and HF-No Ex groups. CONCLUSIONS: Sustained aerobic exercise did not counteract the tumor-promotional effect of increased consumption of a high-fat diet, suggesting that diet is more influential in PCa progression than exercise. Combining exercise with a healthy diet reduced the rate of PCa progression in this model. This study may have implications for PCa risk reduction in humans.

Improving and predicting radiosensitivity in muscle invasive bladder cancer.

PURPOSE: Muscle invasive bladder cancer is a common urological malignancy with a relatively poor prognosis and 5-year survival rates ranging from 20% to 90%. We review methods of improving the outcome of this condition, with particular emphasis on the principal bladder preserving treatment modality of radiation therapy. MATERIALS AND METHODS: We performed a literature search using MEDLINE and the ISI Web of Science using the keywords radiotherapy, radiosensitization and bladder neoplasia to ascertain the current status of radiation therapy and radiosensitizing agents in the treatment of muscle invasive bladder cancer. RESULTS: Several methods aimed at improving outcome following radiation therapy for muscle invasive bladder cancer are described. These methods range from modifications in the application of radiation therapy to use of conventional radiosensitizing agents, such as accelerated radiotherapy with carbon dioxide, oxygen and nicotinamide, and finally to use of more novel agents that interact with oncogenic products. The use of assays that predict tumor sensitivity on an individual basis represents an additional potential method to improve prognosis following radiation therapy. CONCLUSIONS: The ability to predict tumor radiosensitivity and the subsequent implementation of radiosensitizing techniques are likely to improve the results of treatment centered on radiation therapy, suggesting that bladder sparing approaches will remain a treatment option for muscle invasive bladder cancer.