Prognostic factors and treatment impact on overall survival in patients with renal neuroendocrine tumour.

Background: Renal neuroendocrine neoplasms (R-NEN) are exceptionally rare tumours characterized by high mortality rates. Objective: The objective of this study is to analyse prognostic factors and treatment impact on overall survival in patients with R-NEN. Design setting and participants: We identified all patients with R-NEN in the National Cancer Database (NCDB) from 2004 to 2019 and identified prognostic factors for improved survival. Results and limitations: Of 542 R-NEN cases, 166 (31%) were neuroendocrine tumour grade 1 (NET-G1), 14 (3%) were neuroendocrine tumour grade 2 (NET-G2), 169 (31%) were neuroendocrine carcinoma (NEC-NOS), 18 (3%) were large cell neuroendocrine carcinoma (LC-NEC) and 175 (32%) were small cell neuroendocrine carcinoma (SC-NEC). Median overall survival for all patients in the study was 44.88 months (SE, 4.265; 95% CI, 27.57-62.19). Median overall survival was 7.89 months (SE 0.67; 95% CI, 6.58-9.20) for patients without surgical intervention and 136.61 months (SE 16.44; 95% CI, 104.38-168.84, p < 0.001) for patients who underwent surgery. Increased age (HR, 1.05; 95% CI, 1.03-1.06; p < 0.001), T4 stage disease (HR, 3.17; 95% CI, 1.96-5.1; p < 0.001), NEC-NOS histology (HR, 2.82; 95% CI, 1.64-4.86; p < 0.001), LC-NEC histology (HR, 2.73; 95% CI, 1.04-7.17; p = 0.041) and SC-NEC histology (HR, 5.17; 95% CI, 2.95-9.05; p < 0.001) were all positive predictors of worsening overall survival. The main limitation of the study is its retrospective design. Conclusion: R-NEN is an aggressive tumour characterized by high mortality rates. Surgery continues to be the mainstay of treatment and has shown to provide a survival benefit for most patients. Patient Summary: R-NEN is composed of several tumour histologies that differ based on their aggressiveness with NEC-NOS and SC-NEC being the most lethal. Surgery, predominantly through minimally invasive approaches, is the mainstay of treatment and has a clear survival benefit.

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.

Development of a model to predict prostate cancer at the apex (PCAP model) in patients undergoing robot-assisted radical prostatectomy.

PURPOSE: To develop a model based on preoperative variables to predict apical prostate cancer. METHODS: We performed a retrospective analysis of 459 patients who underwent a robotic assisted radical prostatectomy (RALP) between January 2016 and September 2017. All patients had a preoperative biopsy and mpMRI of the prostate. Significant apical pathology (SAP) was defined as those patients who had a dominant nodule at the apex with a Gleason score > 6 and/or ECE at the apex. Binary logistic regression analyses were adopted to predict SAP. Variables included in the model were PSA, apical lesions prostate imaging reporting and data system (PI-RADS) score and apical biopsy Gleason score. The area under the curve (AUC) of the model was computed. RESULTS: A total of 121 (43.2%) patients had SAP. On univariable analysis, all apex-specific variables investigated emerged as predictors of SAP (all p < 0.05). On multivariable analysis PSA and apical PI-RADS score > 3 (all p < 0.05) emerged as significant predictors of SAP. The AUC of the model was 0.722. CONCLUSION: Patients with PI-RADS 3, 4 or 5 lesions at the apex were three times as more likely to have true SAP compared to those who have PI-RADS < 3 or negative mpMRI prior to undergoing RALP.

Defining Prostate Cancer at Favorable Intermediate Risk: The Potential Utility of Magnetic Resonance Imaging and Genomic Tests.

PURPOSE: We determined whether prostate multiparametric magnetic resonance imaging and genomic biomarkers might help further define patients with favorable intermediate risk prostate cancer which could safely be considered suitable for active surveillance. MATERIALS AND METHODS: From our institutional database we identified 509 patients who underwent radical prostatectomy with preoperative magnetic resonance imaging and a postoperative Decipher® prostate cancer test. According to the NCCN® (National Comprehensive Cancer Network®) risk stratification 125 men had favorable intermediate and 171 had unfavorable intermediate risk disease. Univariable and multivariable binary logistic regression analyses were done to test the utility of different variables in predicting adverse pathology, defined as Gleason Grade Group greater than 2, pT3b or pN1. RESULTS: On univariable analysis favorable intermediate risk, multiparametric magnetic resonance imaging and the prostate cancer test significantly predicted adverse pathology. On multivariable analysis favorable intermediate risk and the prostate cancer test maintained independent predictive value while multiparametric magnetic resonance imaging did not meet statistical significance (p = 0.059). The 19 patients at favorable intermediate risk with high genomic risk had an adverse pathology rate slightly higher than patients at unfavorable intermediate risk (42.1% vs 39.8%, p = 0.56). Those at low genomic risk had an adverse pathology rate slightly lower than patients at very low or low risk (7.5% vs 10.2%, p = 0.84). The 31 patients at favorable intermediate risk but at high multiparametric magnetic resonance imaging and genomic risk had an adverse pathology rate slightly lower than patients at unfavorable intermediate risk (25.8% vs 39.8%, p = 0.14). Those at low multiparametric magnetic resonance imaging and genomic risk had an adverse pathology rate slightly lower than patients at very low or low risk (8.5% vs 10.2%, p = 0.89). CONCLUSIONS: Multiparametric magnetic resonance imaging and the Decipher test allowed us to better define the risk of adverse pathology in patients at favorable intermediate risk who were diagnosed with prostate cancer.

Multiparametric Magnetic Resonance Imaging Features Identify Aggressive Prostate Cancer at the Phenotypic and Transcriptomic Level.

PURPOSE: Multiparametric magnetic resonance imaging is a diagnostic tool for prostate cancer with limited data on prognostic use. We sought to determine whether multiparametric magnetic resonance could predict aggressive prostate cancer features. MATERIALS AND METHODS: We retrospectively analyzed the records of 206 patients who underwent radical prostatectomy between 2013 and 2017. All patients had available RNA expression data on the final pathology specimen obtained from a location corresponding to a lesion location on multiparametric magnetic resonance imaging. The association between the PIRADS™ (Prostate Imaging Reporting and Data System) score and adverse pathology features were analyzed. We also performed differential transcriptomic analysis between the PIRADS groups. Factors associated with adverse pathology were analyzed using a multivariable logistic regression model. RESULTS: Lesion size (p = 0.03), PIRADS score (p = 0.02) and extraprostatic extension (p = 0.01) associated significantly with the Decipher® score. Multivariable analysis showed that the PIRADS score (referent PIRADS 3, OR 8.1, 95% CI 1.2-57.5, p = 0.04), the Gleason Grade Group (referent 3, OR 5.6, 95% CI 1.5-21.1, p = 0.01) and prostate specific antigen (OR 1.103, 95% CI 1.011-1.203) were risk factors for adverse pathology findings. The difference between PIRADS 4 and 5 did not reach significance (OR 1.9, 95% CI 0.8-4.5, p = 0.12). However, the PI3K-AKT-mTOR, WNT-ß and E2F signaling pathways were more active in PIRADS 5 than in PIRADS 4 cases. CONCLUSIONS: The PIRADS score is associated with adverse pathology results, increased metastatic risk and differential genomic pathway activation.

An evaluation of race, ethnicity, age, and sex-based representation in phase I to II renal cell carcinoma clinical trials in the United States.

INTRODUCTION: Enrollment of a representative study population permits generalizable and reliable results for clinical trials. We sought to evaluate whether patients enrolled in trials for advanced renal cell carcinoma (RCC) are representative of the overall population of advanced RCC patients in the United States. MATERIALS AND METHODS: The clinicaltrials.gov results database was queried for interventional clinical trials directed at clinically advanced (stage III/IV) RCC that enrolled patients from the US only. We identified 375 patients from 18 phase I to II trials that met eligibility criteria. The American College of Surgeons' National Cancer Database (NCDB) which includes data on approximately 70% of all US cancer diagnoses was queried and we identified 75,308 patients with advanced (stage III/IV) RCC. Demographic characteristics were summarized and compared between the 2 populations. RESULTS: Compared to the US population of advanced RCC (NCDB), significant under-representation in clinical trials was observed for patients aged 65+ (26.3% vs. 50.4%; P<0.001) and among those with Hispanic ethnicity (2.7% vs. 7.2%; P = 0.005). A trend toward under-representation was observed for black patients (7.0% vs. 9.8%, P = 0.076) but not for white patients (89.9% vs. 87.0%, P = 0.107) or other racial groups (P>0.05 for all). Female patients made up 30.3% of trial enrollees and 33.3% of the US advanced RCC population (P = 0.221). CONCLUSION: Significant under-representation was observed for elderly and Hispanic patients with a trend toward under-representation for black and female patients in phase I to II RCC clinical trials. Greater efforts to include underrepresented populations are necessary to improve the effectiveness and generalizability of clinical trials in kidney cancer.

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.

Factors associated with regional recurrence after lymph node dissection for penile squamous cell carcinoma.

OBJECTIVE: To identify factors associated with regional recurrence after lymph node dissection (LND) for squamous cell carcinoma (SCC) to determine which patients might benefit from adjuvant therapy. PATIENTS AND METHODS: Men who underwent LND for penile SCC from 1977 to 2014 were identified from an institutional database. Kaplan-Meier curves estimated recurrence-free survival (RFS) calculated from the date of LND. Cox regression models evaluated the association between RFS and patient and tumour characteristics. RESULTS: In all, 182 men who underwent LND for penile SCC were identified. The median patient age was 62 years and the median follow-up was 4.2 years. After LND 34 men had regional recurrence, of which 24 developed isolated regional recurrences without distant metastasis. The median RFS was 5.7 months, and the 3-year RFS rate was 70%. On univariate analysis, lymphovascular invasion, clinical and pathological nodal stage, pathological inguinal laterality, pelvic nodal involvement, lymph node density ≥5.2%, ≥3 pathologically involved lymph nodes, and extranodal extension (ENE) were associated with worse RFS (all P < 0.05). On multivariate analysis, clinical N3 disease [adjusted hazard ratio (AHR)] 3.53, 95% confidence interval (CI) 1.68-7.45; P = 0.001), ≥3 pathologically involved lymph nodes (AHR 3.78, 95% CI 2.12-6.65; P < 0.001), and ENE (AHR 3.32, 95% CI 1.93-5.76; P < 0.001) were associated with worse RFS. The 3-year RFS for patients with cN0, cN1, cN2, and cN3 disease was 91.7%, 64.5%, 54.7%, and 38.3%, respectively. For men with ≥3 involved nodes, the 3-year RFS was 17% vs 82.4% in men with <3 involved nodes. The 3-year RFS was 29.7% in men with ENE and 85.7% in men without ENE. CONCLUSION: The presence of clinical N3 disease, ≥3 pathologically involved lymph nodes, and ENE was associated with worse RFS. As regional recurrence portends a dismal prognosis with few salvage options, adjuvant therapies should be developed for men with the aforementioned adverse factors.

Employing an orthotopic model to study the role of epithelial-mesenchymal transition in bladder cancer metastasis.

Epithelial-to-mesenchymal transition (EMT) has been implicated in the progression of bladder cancer. To study its contribution to bladder cancer metastasis, we established new xenograft models derived from human bladder cancer cell lines utilizing an orthotopic "recycling" technique that allowed us to isolate and examine the primary tumor and its corresponding circulating tumor cells (CTC's) and metastatic lesions. Using whole genome mRNA expression profiling, we found that a reversible epithelial-to-mesenchymal transition (EMT) characterized by TGFß pathway activation and SNAIL expression was associated with the accumulation of CTCs. Finally, we observed that conditional silencing of SNAIL completely blocked CTC production and regional/distant metastasis. Using this unique bladder cancer xenograft model, we conclude that metastasis is dependent on a reversible EMT mediated by SNAIL.

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.

Near-infrared fluorescence imaging to facilitate super-selective arterial clamping during zero-ischaemia robotic partial nephrectomy.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: There is concern that warm ischaemia time during partial nephrectomy may have an adverse impact on postoperative renal function. As a result, there is increased interest in developing a safe and effective method for performing non-ischaemic partial nephrectomy. Several novel approaches have recently been described. We present our initial experience performing zero-ischaemia partial nephrectomy using near-infrared fluorescence imaging to facilitate super-selective arterial clamping. We report the operative and early postoperative outcomes from such cases as compared with a matched cohort of patients undergoing traditional partial nephrectomy with clamping of the main renal artery. We show that this technique is both safe and effective and may lead to improved renal preservation at short-term follow-up. OBJECTIVE: To describe a novel technique of eliminating renal ischaemia during robotic partial nephrectomy (RPN) using near-infrared fluorescence (NIRF) imaging. PATIENTS AND METHODS: Over an 8-month period (March 2011 to November 2011), 34 patients were considered for zero-ischaemia RPN using the da Vinci NIRF system. Targeted tertiary/higher-order tumour-specific branches were controlled with robotic bulldog(s) or neurosurgical aneurysm micro-bulldog(s). Indocyanine green dye was given, and NIRF imaging used to confirm super-selective ischaemia, defined as darkened tumour/peri-tumour area with green fluorescence of remaining kidney. Matched pair analysis was performed by matching each patient undergoing zero-ischaemia RPN (n = 27) to a previous conventional RPN (n = 27) performed by the same surgeon. RESULTS: Of 34 patients, 27 (79.4%) underwent successful zero-ischaemia RPN; seven (20.6%) required conversion to main renal artery clamping (ischaemia time <30 min) for the following reasons: persistent tumour fluorescence after clamping indicating inadequate tumoral devascularization (n = 5), and parenchymal bleeding during RPN (n = 2). Matched-pair analysis showed comparable outcomes between cohorts, except for longer operating time (256 vs 212 min, P = 0.02) and superior kidney function (reduction of estimated glomerular filtration rate (-1.8% vs -14.9%, P = 0.03) in the zero-ischaemia cohort. All surgical margins were negative. CONCLUSIONS: In this pilot study, we show that zero-ischaemia RPN with NIRF is a safe alternative to conventional RPN with main renal artery clamping. Eliminating global ischaemia may improve functional outcomes at short-term follow-up.

Paraneoplastic hypertension associated with renal oncocytoma: management with cryoablation.

Paraneoplastic hypertension associated with a renal oncocytoma is an unreported syndrome. We report a unique case of a patient with multidrug-resistant hypertension who was found to have a solitary renal mass. Cryoablation was performed and resulted in an immediate and dramatic decrease in blood pressure. Histologic review of intraoperative biopsy specimens revealed findings consistent with renal oncocytoma. To our knowledge, this is the first report of hypertension in the setting of a renal oncocytoma, with subsequent improvement of this paraneoplastic syndrome after cryoablation.