TCF21 Promotes Luminal-Like Differentiation and Suppresses Metastasis in Bladder Cancer.

Little is known regarding the subclone evolution process in advanced bladder cancer, particularly with respect to the genomic alterations that lead to the development of metastatic lesions. In this project, we identify gene expression signatures associated with metastatic bladder cancer through mRNA expression profiling of RNA isolated from 33 primary bladder cancer and corresponding lymph node (LN) metastasis samples. Gene expression profiling (GEP) was performed on RNA isolated using the Illumina DASL platform. We identified the developmental transcription factor TCF21 as being significantly higher in primary bladder cancer compared with LN metastasis samples. To elucidate its function in bladder cancer, loss- and gain-of-function experiments were conducted in bladder cancer cell lines with high and low expression of TCF21, respectively. We also performed GEP in bladder cancer cell lines following TCF21 overexpression. We identified 2,390 genes differentially expressed in primary bladder cancer and corresponding LN metastasis pairs at an FDR cutoff of 0.1 and a fold change of 1. Among those significantly altered, expression of TCF21 was higher in the primary tumor compared with LN metastasis. We validated this finding with qPCR and IHC on patient samples. Moreover, TCF21 expression was higher in luminal cell lines and knockdown of TCF21 increased invasion, tumor cell dissemination, and metastasis. In contrast, overexpression of TCF21 in highly metastatic basal bladder cancer cell lines decreased their invasive and metastatic potential. IMPLICATIONS: TCF21 is differentially overexpressed in primary bladder cancer compared with matched LN metastasis, with in vitro and in vivo studies demonstrating a metastasis suppressor function of this transcription factor.

Determining the optimal time for radical cystectomy after neoadjuvant chemotherapy.

OBJECTIVE: To determine whether the recovery window (RW) between neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) affects 90-day postoperative morbidity and incidence of lymph node metastasis. PATIENTS AND METHODS: We reviewed patients treated with NAC and RC from 1995 to 2013 for ≤cT4 N0 M0 bladder cancer. The association of the RW with 90-day perioperative morbidity and lymph node metastasis was determined. Generalised linear models were used to determine predictors of each endpoint. Patients were stratified into four RWs by 21-day intervals (18-42; 43-63; 64-84; and ≥85 days) from last day of NAC to RC. RESULTS: We evaluated 306 patients with RW information during the study period. The median (range) RW was 46 (18-199) days. There was no difference in overall morbidity, re-admission, or major complication rates amongst the four RWs. In the multivariable analysis extravesical disease was an independent predictor of overall morbidity (odds ratio [OR] 1.95, 95% confidence interval [CI] 1.16-3.26; P = 0.011). Age (OR 1.05, 95% CI: 1.02-1.09; P = 0.004), and surgical duration ≥7 h (OR 2.87, 95% CI: 1.52-5.42; P = 0.001) were independent predictors of major complications. Only surgical duration ≥7 h was a predictor of re-admission (OR 2.24; 95% CI: 1.26-3.98; P = 0.006). A RW of ≥85 days had the highest incidence of node-positive disease (pN+; 40%). In a separate multivariable model that included clinical predictors for pN+, a RW of ≥85 days was an independent predictor of nodal metastasis (OR 2.92, 95% CI: 1.20-7.09; P = 0.018). CONCLUSION: Patients treated with NAC for bladder cancer can undergo RC between 18 and 84 days (2.5-12 weeks) after NAC with no difference in the risk of perioperative morbidity. Delaying surgery beyond 12 weeks was associated with a significant risk of lymph node metastasis.

External validation of Global Evaluative Assessment of Robotic Skills (GEARS).

BACKGROUND: We demonstrate the construct validity, reliability, and utility of Global Evaluative Assessment of Robotic Skills (GEARS), a clinical assessment tool designed to measure robotic technical skills, in an independent cohort using an in vivo animal training model. METHODS: Using a cross-sectional observational study design, 47 voluntary participants were categorized as experts (>30 robotic cases completed as primary surgeon) or trainees. The trainee group was further divided into intermediates (≥5 but ≤30 cases) or novices (<5 cases). All participants completed a standardized in vivo robotic task in a porcine model. Task performance was evaluated by two expert robotic surgeons and self-assessed by the participants using the GEARS assessment tool. Kruskal-Wallis test was used to compare the GEARS performance scores to determine construct validity; Spearman's rank correlation measured interobserver reliability; and Cronbach's alpha was used to assess internal consistency. RESULTS: Performance evaluations were completed on nine experts and 38 trainees (14 intermediate, 24 novice). Experts demonstrated superior performance compared to intermediates and novices overall and in all individual domains (p < 0.0001). In comparing intermediates and novices, the overall performance difference trended toward significance (p = 0.0505), while the individual domains of efficiency and autonomy were significantly different between groups (p = 0.0280 and 0.0425, respectively). Interobserver reliability between expert ratings was confirmed with a strong correlation observed (r = 0.857, 95 % CI [0.691, 0.941]). Experts and participant scoring showed less agreement (r = 0.435, 95 % CI [0.121, 0.689] and r = 0.422, 95 % CI [0.081, 0.0672]). Internal consistency was excellent for experts and participants (α = 0.96, 0.98, 0.93). CONCLUSIONS: In an independent cohort, GEARS was able to differentiate between different robotic skill levels, demonstrating excellent construct validity. As a standardized assessment tool, GEARS maintained consistency and reliability for an in vivo robotic surgical task and may be applied for skills evaluation in a broad range of robotic procedures.

Risk based neoadjuvant chemotherapy in muscle invasive bladder cancer.

Muscle invasive bladder cancer (MIBC) is an aggressive disease that frequently requires radical cystectomy (RC) to achieve durable cure rates. Surgery is most effective when performed in organ-confined disease, with the best outcomes for those patients with a pT0 result. The goals of neoadjuvant chemotherapy (NC) are to optimize surgical outcomes for a malignancy with limited adjuvant therapies and a lack of effective salvage treatments. Despite level 1 evidence demonstrating a survival benefit, the utilization of NC has been hampered by several issues, including, the inability to predict responders and the perception that NC may delay curative surgery. In this article, we review the current efforts to identify patients that are most likely to derive a benefit from NC, in order to create a risk-adapted paradigm that reserves NC for those who need it.

Clinicopathologic characteristics and outcomes of penile cancer treated at tertiary care centers in the Western United States.

BACKGROUND: This article reports on the experience with penile squamous cell carcinoma (PSCC) in a unique multiethnic patient population from Los Angeles, California, with regard to treatments rendered and clinical outcomes. PATIENTS AND METHODS: Available clinical, pathologic, and treatment information for PSCC patients treated at 3 hospitals associated with the University of Southern California from 1991 to 2011 was retrospectively reviewed. Associations of patient variables with prognosis were assessed using univariable and multivariable analyses. RESULTS: Of the 95 PSCC patients identified, clinicopathologic and outcome information was available on 89 men (median age, 53 years; median follow-up, 23 months). National minorities comprised 76.4% of the cohort with 57.3% Hispanics accounting for all patients. Presence of poorly differentiated tumors was associated with higher tumor stage (P = .020), nodal metastasis (P = .016), distant metastasis (P = .004), and advanced AJCC disease stage (P = .001). Univariate analysis showed that tumor (P = .008), nodal (P = .033), and metastasis (P < .001) stage, and tumor differentiation (P = .010) were associated with survival. When categorized according to the AJCC classification, patients with ≥ stage III disease had worse outcomes (P = .006). Type of primary therapy delivered did not affect outcomes. AJCC disease stage was independently prognostic in multivariable analysis (P = .035). CONCLUSION: These results confirm associations of several clinicopathologic factors with PSCC outcomes, although the presented population differs from others previously described from the United States with a relatively higher proportion of Hispanic men. This highlights the need for studies on the effects of race, cultural, health, and behavioral patterns on PSCC outcomes in multiethnic populations.

Comparative assessment of three standardized robotic surgery training methods.

OBJECTIVES: To evaluate three standardized robotic surgery training methods, inanimate, virtual reality and in vivo, for their construct validity. To explore the concept of cross-method validity, where the relative performance of each method is compared. MATERIALS AND METHODS: Robotic surgical skills were prospectively assessed in 49 participating surgeons who were classified as follows: 'novice/trainee': urology residents, previous experience <30 cases (n = 38) and 'experts': faculty surgeons, previous experience ≥30 cases (n = 11). Three standardized, validated training methods were used: (i) structured inanimate tasks; (ii) virtual reality exercises on the da Vinci Skills Simulator (Intuitive Surgical, Sunnyvale, CA, USA); and (iii) a standardized robotic surgical task in a live porcine model with performance graded by the Global Evaluative Assessment of Robotic Skills (GEARS) tool. A Kruskal-Wallis test was used to evaluate performance differences between novices and experts (construct validity). Spearman's correlation coefficient (ρ) was used to measure the association of performance across inanimate, simulation and in vivo methods (cross-method validity). RESULTS: Novice and expert surgeons had previously performed a median (range) of 0 (0-20) and 300 (30-2000) robotic cases, respectively (P < 0.001). Construct validity: experts consistently outperformed residents with all three methods (P < 0.001). Cross-method validity: overall performance of inanimate tasks significantly correlated with virtual reality robotic performance (ρ = -0.7, P < 0.001) and in vivo robotic performance based on GEARS (ρ = -0.8, P < 0.0001). Virtual reality performance and in vivo tissue performance were also found to be strongly correlated (ρ = 0.6, P < 0.001). CONCLUSIONS: We propose the novel concept of cross-method validity, which may provide a method of evaluating the relative value of various forms of skills education and assessment. We externally confirmed the construct validity of each featured training tool.