N-803 Plus BCG Treatment for BCG-Naïve or -Unresponsive Non-Muscle Invasive Bladder Cancer: A Plain Language Review.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of two studies that looked at the safety and effectiveness of a potential new treatment, N-803 (Anktiva), in combination with a standard treatment bacillus Calmette-Guerin (BCG) for people with non-muscle invasive bladder cancer (NMIBC).One study was a Phase 1b study that tested increasing doses of N-803 in combination with the same dose of BCG in people with NMIBC who had never received BCG previously (BCG-naive). The other study is a Phase 2/3 study of N-803 and BCG in people with NMIBC whose cancer wasn't eliminated by BCG alone (BCGunresponsive). WHAT HAPPENED IN THE STUDIES?: In the Phase 1b study, the nine participants were split into three groups of 3 participants who received a dose of 100, 200, or 400 µg N-803 along with a standard 50 mg dose of BCG. In the Phase 2/3 study, one group (cohort A) of participants with carcinoma in situ (CIS) disease and another group (cohort B) with papillary disease were treated with 400 µg N-803 plus 50 mg BCG. There was also a cohort C that received only 400 µg N-803. Treatments were delivered directly into the bladder once a week for 6 weeks in a row. WHAT WERE THE KEY TAKEAWAYS?: N-803 plus BCG eliminated NMIBC in all nine BCG-naive participants and the effects were long-lasting, with participants remaining NMIBC-free for a range of 8.3 to 9.2 years.As reported in 2022, cancer was eliminated in 58 of 82 (71%) participants with BCG-unresponsive CIS disease and the effect was also long-lasting. Importantly, approximately 90% of the successfully treated participants avoided surgical removal of the bladder. In cohort B participants with papillary disease, 40 of 72 (55.4%) were cancer-free 12 months after treatment. N-803 used alone was only effective in 2 of 10 participants. In both studies, the combination of N-803 and BCG was found to be associated with very few adverse events.Based on results from the Phase 2/3 study, the U.S. Food and Drug Association (FDA) approved the use of N-803 plus BCG for the treatment of BCG-unresponsive bladder CIS with or without Ta/T1 papillary disease.Clinical Trial Registration: NCT02138734 (Phase 1b study), NCT03022825 (Phase 2/3 study).

Addition of the IL-15 superagonist N-803 to BCG therapy produces a high rate of success in eliminating non-muscle invasive bladder cancer in both BCG-naive and BCG-unresponsive patients, with long-lasting effects that allow patients to avoid surgical removal of the bladder.

Outcomes of Lymph Node Dissection in Nephroureterectomy in the Treatment of Upper Tract Urothelial Carcinoma: Analysis of the ROBUUST Registry.

PURPOSE: We sought to evaluate outcomes of lymph node dissection (LND) in patients with upper tract urothelial carcinoma. MATERIALS AND METHODS: We performed a multicenter retrospective analysis utilizing the ROBUUST (for RObotic surgery for Upper Tract Urothelial Cancer Study) registry for patients who did not undergo LND (pNx), LND with negative lymph nodes (pN0) and LND with positive nodes (pN+). Primary and secondary outcomes were overall survival (OS) and recurrence-free survival (RFS). Multivariable analyses evaluated predictors of outcomes and pathological node positivity. Kaplan-Meier analyses (KMAs) compared survival outcomes. RESULTS: A total of 877 patients were analyzed (LND performed in 358 [40.8%]/pN+ in 73 [8.3%]). Median nodes obtained were 10.2 for pN+ and 9.8 for pN0. Multivariable analyses noted increasing age (OR 1.1, p <0.001), pN+ (OR 3.1, p <0.001) and pathological stage pTis/3/4 (OR 3.4, p <0.001) as predictors for all-cause mortality. Clinical high-grade tumors (OR 11.74, p=0.015) and increasing tumor size (OR 1.14, p=0.001) were predictive for lymph node positivity. KMAs for pNx, pN0 and pN+ demonstrated 2-year OS of 80%, 86% and 42% (p <0.001) and 2-year RFS of 53%, 61% and 35% (p <0.001), respectively. KMAs comparing pNx, pN0 ≥10 nodes and pN0 <10 nodes showed no significant difference in 2-year OS (82% vs 85% vs 84%, p=0.6) but elicited significantly higher 2-year RFS in the pN0 ≥10 group (60% vs 74% vs 54%, p=0.043). CONCLUSIONS: LND during nephroureterectomy in patients with positive lymph nodes provides prognostic data, but is not associated with improved OS. LND yields ≥10 in patients with clinical node negative disease were associated with improved RFS. In high-grade and large tumors, lymphadenectomy should be considered.

Prostate cancer upgrading and adverse pathology in Hispanic men undergoing radical prostatectomy.

PURPOSE: Radical prostatectomy (RP) outcomes in Hispanic men with prostate cancer are not well-described. Prior studies showed varying results regarding the rate of upgrading and upstaging, and these studies included limited pathologic data and lack of central pathology review. We characterized the rate of upgrading, adverse pathology, and oncologic outcomes in Hispanics after prostatectomy using a large institutional database. METHODS: We included Hispanic white (HW), non-Hispanic white (NHW), and black men who underwent (RP) between 2010 and 2021 at a single institution. We recorded differences in grade group between biopsy and prostatectomy and performed multivariable analyses for odds of upgrading and adverse pathologic findings. The primary outcome was rate of upgrading in HWs. Using a sub-cohort with follow-up data, we assessed race/ethnicity and upgrading as a predictor of biochemical recurrence (BCR)-free survival. RESULTS: Our cohort included 1877 men: 36.7% were NHW, 40.6% were HW, and 22.7% were black. Rates of upgrading were not different between NHW, NHW, and black men at 34.0, 33.8, and 37.3%, respectively (p = 0.4). In the multivariable analysis for upgrading, significant predictors for upgrading were older age (p = 0.002), higher PSA (p < 0.001), and lower prostate weight (p = 0.02), but race/ethnicity did not predict upgrading. In patients with available follow-up (1083, 58%), upgrading predicted worse BCR-free survival (HR 2.17, CI 1.46-3.22, p < 0.0001) but race/ethnicity did not. CONCLUSIONS: HW men undergoing RP had similar rates of upgrading and adverse pathologic outcomes as NHW men. Race/ethnicity does not independently predict upgrading or worse oncologic outcomes after RP.

Percentage of Gleason pattern 4 and tumor volume predict adverse pathological stage and margin status at radical prostatectomy in grade Group 2 and grade Group 3 prostate cancers.

BACKGROUND: Increasing percentages of Gleason pattern 4 (GP4%) in radical prostatectomy (RP) correlate with an increased likelihood of nonorgan-confined disease and earlier biochemical recurrence (BCR). However, there are no detailed RP studies assessing the impact of GP4% and corresponding tumor volume (TV) on extraprostatic extension (EPE), seminal vesicle (SV) invasion (SV+), and positive surgical margin (SM) status (SM+). METHODS: In 1301 consecutive RPs, we analyzed each tumor nodule (TN) for TV, Grade Group (GG), presence of focal versus nonfocal EPE, SV+ , and SM+. Using GG1 (GP4% = 0) TNs as a reference, we recorded GP4% for all GG2 or GG3 TNs. We performed a multivariable analysis (MVA) using a mixed effects logistic regression that tested significant variables for risk of EPE, SV+, and SM+, as well as a multinomial logistic regression model that tested significant variables for risks of nonorgan-confined disease (pT2+, pT3a, and pT3b) versus organ-confined disease (pT2). RESULTS: We identified 3231 discrete TNs ranging from 1 to 7 (median: 2.5) per RP. These included GG1 (n = 2115), GG2 (n = 818), GG3 (n = 274), and GG4 (n = 24) TNs. Increasing GP4% weakly paralleled increasing TV (tau = 0.07, p < .001). In MVA, increasing GP4% and TV predicted a greater likelihood of EPE (odds ratio [OR]: 1.03 and 4.41), SV+ (OR: 1.03 and 3.83), and SM+ (1.01, p = .01 and 2.83), all p < .001. Our multinomial logistic regression model demonstrated an association between GP4% and the risk of EPE (i.e., pT3a and pT3b disease), as well as an association between TV and risk of upstaging (all p < .001). CONCLUSIONS: Both GP4% and TV are independent predictors of adverse pathological stage and margin status at RP. However, the risks for adverse outcomes associated with GP4% are marginal, while those for TV are strong. The prognostic significance of GP4% on BCR-free survival has not been studied controlling for TV and other adverse RP findings. Whether adverse pathological stage and margin status associated with larger TV could decrease BCR-free survival to a greater extent than increasing RP GP4% remains to be studied.

Surveillance Intensity in Intermediate Risk, Nonmuscle Invasive Bladder Cancer: Revisiting the Optimal Timing and Frequency of Cystoscopy.

PURPOSE: We sought to determine the optimal cystoscopic interval for intermediate risk, nonmuscle invasive bladder cancer. MATERIALS AND METHODS: A retrospective analysis of patients with intermediate risk, nonmuscle invasive bladder cancer (2010-2017) was performed and 3 hypothetical models of surveillance intensity were applied: model 1: high (3 months), model 2: moderate (6 months) and model 3: low intensity (12 months) over a 2-year period. We compared timing of actual detection of recurrence and progression to proposed cystoscopy timing between each model. We calculated number of avoidable cystoscopies and associated costs. RESULTS: Of 107 patients with median followup of 37 months, 66/107 (77.6%) developed recurrence and 12/107(14.1%) had progression. Relative to model 1, there were 33 (50%) delayed detection of recurrences in model 2 and 41 (62%) in model 3. There was a 1.7-month mean delay in detection of recurrence for model 1 vs 3.2, and a 7.6-month delay for models 2 and 3 (p <0.001 model 1 vs 2; p <0.001 model 2 vs 3). Relative to model 1, there were 8 (67%) and 9 (75%) delayed detection of progression events in model 2 and 3. There were no progression-related bladder cancer deaths or radical cystectomies due to delayed detection. Mean number of avoidable cystoscopies was higher in model 1 (2) vs model 2 (1) and 3 (0). Model 1 had the highest aggregate cost of surveillance ($46,262.52). CONCLUSIONS: High intensity (3-month) surveillance intervals provide faster detection of recurrences but with increased cost and more avoidable cystoscopies without clear oncologic benefit. Moderate intensity (6-month) intervals in intermediate risk, nonmuscle invasive bladder cancer allows timely detection without oncologic compromise and is less costly with fewer cystoscopies.

Heterogeneity in Genomic Risk Assessment from Tissue Based Prognostic Signatures Used in the Biopsy Setting and the Impact of Magnetic Resonance Imaging Targeted Biopsy.

PURPOSE: Genomic prognostic signatures are used on prostate biopsy tissue for cancer risk assessment, but tumor heterogeneity and multifocality may be an issue. We evaluated the variability in genomic risk assessment from different biopsy cores within the prostate using 3 prognostic signatures (Decipher, CCP, GPS). MATERIALS AND METHODS: Men in this study came from 2 prospective prostate cancer trials of patients undergoing multiparametric magnetic resonance imaging and magnetic resonance imaging targeted biopsy with genomic profiling of positive biopsy cores. We explored the relationship among tumor grade, magnetic resonance imaging risk and genomic risk for each signature. We evaluated the variability in genomic risk assessment between different biopsy cores and assessed how often magnetic resonance imaging targeted biopsy or the current standard of care (profiling the core with the highest grade) resulted in the highest genomic risk level. RESULTS: In all, 224 positive biopsy cores from 78 men with prostate cancer were profiled. For each signature, higher biopsy grade (p <0.001) and magnetic resonance imaging risk level (p <0.001) were associated with higher genomic scores. Genomic scores from different biopsy cores varied with risk categories changing by 21% to 62% depending on which core or signature was used. Magnetic resonance imaging targeted biopsy and profiling the core with the highest grade resulted in the highest genomic risk level in 72% to 84% and 75% to 87% of cases, respectively, depending on the signature used. CONCLUSIONS: There is variation in genomic risk assessment from different biopsy cores regardless of the signature used. Magnetic resonance imaging directed biopsy or profiling the highest grade core resulted in the highest genomic risk level in most cases.

Risk Factors for Intravesical Recurrence after Minimally Invasive Nephroureterectomy for Upper Tract Urothelial Cancer (ROBUUST Collaboration).

PURPOSE: Intravesical recurrence (IVR) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) has an incidence of approximately 20%-50%. Studies to date have been composed of mixed treatment cohorts-open, laparoscopic and robotic. The objective of this study is to assess clinicopathological risk factors for intravesical recurrence after RNU for UTUC in a completely minimally invasive cohort. MATERIALS AND METHODS: We performed a multicenter, retrospective analysis of 485 patients with UTUC without prior or concurrent bladder cancer who underwent robotic or laparoscopic RNU. Patients were selected from an international cohort of 17 institutions across the United States, Europe and Asia. Univariate and multiple Cox regression models were used to identify risk factors for bladder recurrence. RESULTS: A total of 485 (396 robotic, 89 laparoscopic) patients were included in analysis. Overall, 110 (22.7%) of patients developed IVR. The average time to recurrence was 15.2 months (SD 15.5 months). Hypertension was a significant risk factor on multiple regression (HR 1.99, CI 1.06; 3.71, p=0.030). Diagnostic ureteroscopic biopsy incurred a 50% higher chance of developing IVR (HR 1.49, CI 1.00; 2.20, p=0.048). Treatment specific risk factors included positive surgical margins (HR 3.36, CI 1.36; 8.33, p=0.009) and transurethral resection for bladder cuff management (HR 2.73, CI 1.10; 6.76, p=0.031). CONCLUSIONS: IVR after minimally invasive RNU for UTUC is a relatively common event. Risk factors include a ureteroscopic biopsy, transurethral resection of the bladder cuff, and positive surgical margins. When possible, avoidance of transurethral resection of the bladder cuff and alternative strategies for obtaining biopsy tissue sample should be considered.

Robotic intracorporeal orthotopic neobladder in the supine Trendelenburg position: a stepwise approach.

Robotic radical cystectomy with urinary diversion has become increasingly utilized for the surgical management of bladder cancer. Orthotopic neobladder reconstruction is still performed worldwide primarily via an extracorporeal approach because of the difficulty associated with robotic intracorporeal reconstruction. The objective of this article is to demonstrate a stepwise approach for robotic intracorporeal neobladder in a standardized manner that adheres to the principles of open surgery.

Prospective Evaluation of Focal High Intensity Focused Ultrasound for Localized Prostate Cancer.

PURPOSE: We report short-term outcomes of focal high intensity focused ultrasound use for primary treatment of localized prostate cancer. MATERIALS AND METHODS: Single-center prospectively collected data on patients with prostate cancer who underwent primary focal high intensity focused ultrasound from January 2016 to July 2018 were included. All patients underwent a 12-core biopsy with magnetic resonance imaging-ultrasound fusion biopsy depending on the presence of targetable lesions. Any Grade Group was allowed, however only patients with localized disease were included. The primary outcome was oncologic control, defined as negative followup in-field biopsy of treated cancer. Prostate specific antigen, Sexual Health Inventory for Men, International Prostate Symptom Score and Expanded Prostate Cancer Index Composite domain scores were assessed 3-monthly till 12 months. Biopsy was performed at 6 or 12 months for high or low/intermediate risk cancer, respectively. RESULTS: Fifty-two patients with minimum followup of 12 months were included in the study. The majority of patients (67%) had cancer Grade Group 2 or greater. Fifteen patients (28.8%) underwent complete transurethral prostate resection/holmium laser enucleation of prostate procedure for debulking large prostates to avoid postoperative urinary retention. Among 30 (58%) patients who underwent followup biopsies, 25 (83%) had negative in-field biopsy results and 4 (13%) had de-novo positive out-of-field biopsy. Only 5 major complications (all grade III) in 4 patients were noted. Urinary symptoms returned to near baseline questionnaire scores within 3-6 months. Sexual function returned to baseline at 12 months. CONCLUSIONS: Focal high intensity focused ultrasound is a safe and effective treatment for patients with localized clinically significant prostate cancer with acceptable short-term oncologic and functional outcomes. The complications are minimal and patient selection is essential. Short-term oncologic outcomes are promising but longer followup is required to establish long-term oncologic outcomes.

Use and Validation of the AUA/SUO Risk Grouping for Nonmuscle Invasive Bladder Cancer in a Contemporary Cohort.

PURPOSE: We applied nonmuscle invasive bladder cancer AUA (American Urological Association)/SUO (Society of Urologic Oncology) guidelines for risk stratification and analyzed predictors of recurrence and progression. MATERIALS AND METHODS: We retrospectively reviewed the records of 398 patients with nonmuscle invasive bladder cancer treated between 2001 and 2017. Descriptive statistics were used to compare AUA/SUO risk groups. Predictors of recurrence and progression were determined by multivariable regression. Kaplan-Meier analysis was done, a Cox proportional hazards regression model was created and time dependent AUCs were calculated to determine progression-free and recurrence-free survival by risk group. RESULTS: Median followup was 37 months (95% CI 35-42). Of the patients 92% underwent bacillus Calmette-Guérin induction and 46% received at least 1 course of maintenance treatment. Of the patients 11.5% were at low, 32.5% were at intermediate and 55.8% were at high risk. In patients at low, intermediate and high risk the 5-year progression-free survival rate was 93%, 74% and 54%, and the 5-year recurrence-free survival rate was 43%, 33% and 23%, respectively. Kaplan-Meier analysis was done to stratify high grade Ta 3 cm or less tumor recurrence-free and progression-free survival in the intermediate vs the high risk group. Relative to low risk, classification as intermediate and as high risk was an independent predictor of progression (HR 9.7, 95% CI 2.23-42.0, p <0.01, and HR 36, 95% CI 8.16-159, p <0.001, respectively). Recurrence was more likely in patients at high risk than in those at low risk (HR 2.03, 95% CI 1.11-3.71, p=0.022). For recurrence and progression the 1-year AUC was 0.60 (95% CI 0.546-0.656) and 0.68 (95% CI 0.622-0.732), respectively. CONCLUSIONS: The AUA/SUO nonmuscle invasive bladder cancer risk classification system appropriately stratifies patients based on the likelihood of recurrence and progression. It should be used at diagnosis to counsel patients and guide therapy.

Health Related Quality of Life of Patients with Bladder Cancer in the RAZOR Trial: A Multi-Institutional Randomized Trial Comparing Robot versus Open Radical Cystectomy.

PURPOSE: We evaluated health related quality of life following robotic and open radical cystectomy as a treatment for bladder cancer. MATERIALS AND METHODS: Using the Randomized Open versus Robotic Cystectomy (RAZOR) trial population we assessed health related quality of life by using the Functional Assessment of Cancer Therapy (FACT)-Vanderbilt Cystectomy Index and the Short Form 8 Health Survey (SF-8) at baseline, 3 and 6 months postoperatively. The primary objective was to assess the impact of surgical approach on health related quality of life. As an exploratory analysis we assessed the impact of urinary diversion type on health related quality of life. RESULTS: Analyses were performed in subsets of the per-protocol population of 302 patients. There was no statistically significant difference between the mean scores by surgical approach at any time point for any FACT-Vanderbilt Cystectomy Index subscale or composite score (p >0.05). The emotional well-being score increased over time in both surgical arms. Patients in the open arm showed significantly better SF-8 sores in the physical and mental summary scores at 6 months compared to baseline (p <0.05). Continent diversion (versus noncontinent) was associated with worse FACT-bladder-cystectomy score at 3 (p <0.01) but not at 6 months, and the SF-8 physical component was better in continent-diversion patients at 6 months (p=0.019). CONCLUSIONS: Our data suggests lack of significant differences in the health related quality of life in robotic and open cystectomies. As robotic procedures become more widespread it is important to discuss this finding during counseling.

Predictors of Recurrence, and Progression-Free and Overall Survival following Open versus Robotic Radical Cystectomy: Analysis from the RAZOR Trial with a 3-Year Followup.

PURPOSE: The RAZOR (Randomized Open versus Robotic Cystectomy) trial revealed noninferior 2-year progression-free survival for robotic radical cystectomy. This update was performed with extended followup for 3 years to determine potential differences between the approaches. We also report 3-year overall survival and sought to identify factors predicting recurrence, and progression-free and overall survival. MATERIALS AND METHODS: We analyzed the per protocol population of 302 patients from the RAZOR study. Cumulative recurrence was estimated using nonbladder cancer death as the competing risk event and the Gray test was applied to assess significance in differences. Progression-free survival and overall survival were estimated by the Kaplan-Meier method and compared with the log rank test. Predictors of outcomes were determined by Cox proportional hazard analysis. RESULTS: Estimated progression-free survival at 36 months was 68.4% (95% CI 60.1-75.3) and 65.4% (95% CI 56.8-72.7) in the robotic and open groups, respectively (p=0.600). At 36 months overall survival was 73.9% (95% CI 65.5-80.5) and 68.5% (95% CI 59.8-75.7) in the robotic and open groups, respectively (p=0.334). There was no significant difference in the cumulative incidence rates of recurrence (p=0.802). Patient age greater than 70 years, poor performance status and major complications were significant predictors of 36-month progression-free survival. Stage and positive margins were significant predictors of recurrence, and progression-free and overall survival. Surgical approach was not a significant predictor of any outcome. CONCLUSIONS: This analysis showed no difference in recurrence, 3-year progression-free survival or 3-year overall survival for robotic vs open radical cystectomy. It provides important prospective data on the oncologic efficacy of robotic radical cystectomy and high level data for patient counseling.

Complication rate after cystectomy following pelvic radiotherapy: an international, multicenter, retrospective series of 682 cases.

PURPOSE: Conflicting evidence exists on the complication rates after cystectomy following previous radiation (pRTC) with only a few available series. We aim to assess the complication rate of pRTC for abdominal-pelvic malignancies. METHODS: Patients treated with radical cystectomy following any previous history of RT and with available information on complications for a minimum of 1 year were included. Univariable and multivariable logistic regression models were used to assess the relationship between the variable parameters and the risk of any complication. RESULTS: 682 patients underwent pRTC after a previous RT (80.5% EBRT) for prostate, bladder (BC), gynecological or other cancers in 49.1%, 27.4%, 9.8% and 12.9%, respectively. Overall, 512 (75.1%) had at least one post-surgical complication, classified as Clavien ≥ 3 in 29.6% and Clavien V in 2.9%. At least one surgical complication occurred in 350 (51.3%), including bowel leakage in 6.2% and ureteric stricture in 9.4%. A medical complication was observed in 359 (52.6%) patients, with UTI/pyelonephritis being the most common (19%), followed by renal failure (12%). The majority of patients (86%) received an incontinent urinary diversion. In multivariable analysis adjusted for age, gender and type of RT, patients treated with RT for bladder cancer had a 1.7 times increased relative risk of experiencing any complication after RC compared to those with RT for prostate cancer (p = 0.023). The type of diversion (continent vs non-continent) did not influence the risk of complications. CONCLUSION: pRTC carries a high rate of major complications that dramatically exceeds the rates reported in RT-naïve RCs.

Activation of hepatocyte growth factor/MET signaling initiates oncogenic transformation and enhances tumor aggressiveness in the murine prostate.

Emerging evidence has shown that the hepatocyte growth factor (HGF) and its receptor, MET proto-oncogene, receptor tyrosine kinase (MET), promote cell proliferation, motility, morphogenesis, and angiogenesis. Whereas up-regulation of MET expression has been observed in aggressive and metastatic prostate cancer, a clear understanding of MET function in prostate tumorigenesis remains elusive. Here, we developed a conditional Met transgenic mouse strain, H11Met/+:PB-Cre4, to mimic human prostate cancer cells with increased MET expression in the prostatic luminal epithelium. We found that these mice develop prostatic intraepithelial neoplasia after HGF administration. To further assess the biological role of MET in prostate cancer progression, we bred H11Met/+/PtenLoxP/LoxP:PBCre4 compound mice, in which transgenic Met expression and deletion of the tumor suppressor gene Pten occurred simultaneously only in prostatic epithelial cells. These compound mice exhibited accelerated prostate tumor formation and invasion as well as increased metastasis compared with PtenLoxP/LoxP:PB-Cre4 mice. Moreover, prostatic sarcomatoid carcinomas and lesions resembling the epithelial-to-mesenchymal transition developed in tumor lesions of the compound mice. RNA-Seq and qRT-PCR analyses revealed a robust enrichment of known tumor progression and metastasis-promoting genes in samples isolated from H11Met/+/PtenLoxP/LoxP:PB-Cre4 compound mice compared with those from PtenLoxP/LoxP:PB-Cre4 littermate controls. HGF-induced cell proliferation and migration also increased in mouse embryonic fibroblasts (MEFs) from animals with both Met transgene expression and Pten deletion compared with Pten-null MEFs. The results from these newly developed mouse models indicate a role for MET in hastening tumorigenesis and metastasis when combined with the loss of tumor suppressors.

Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial.

BACKGROUND: Radical cystectomy is the surgical standard for invasive bladder cancer. Robot-assisted cystectomy has been proposed to provide similar oncological outcomes with lower morbidity. We aimed to compare progression-free survival in patients with bladder cancer treated with open cystectomy and robot-assisted cystectomy. METHODS: The RAZOR study is a randomised, open-label, non-inferiority, phase 3 trial done in 15 medical centres in the USA. Eligible participants (aged ≥18 years) had biopsy-proven clinical stage T1-T4, N0-N1, M0 bladder cancer or refractory carcinoma in situ. Individuals who had previously had open abdominal or pelvic surgery, or who had any pre-existing health conditions that would preclude safe initiation or maintenance of pneumoperitoneum were excluded. Patients were centrally assigned (1:1) via a web-based system, with block randomisation by institution, stratified by type of urinary diversion, clinical T stage, and Eastern Cooperative Oncology Group performance status, to receive robot-assisted radical cystectomy or open radical cystectomy with extracorporeal urinary diversion. Treatment allocation was only masked from pathologists. The primary endpoint was 2-year progression-free survival, with non-inferiority established if the lower bound of the one-sided 97·5% CI for the treatment difference (robotic cystectomy minus open cystectomy) was greater than -15 percentage points. The primary analysis was done in the per-protocol population. Safety was assessed in the same population. This trial is registered with ClinicalTrials.gov, number NCT01157676. FINDINGS: Between July 1, 2011, and Nov 18, 2014, 350 participants were randomly assigned to treatment. The intended treatment was robotic cystectomy in 176 patients and open cystectomy in 174 patients. 17 (10%) of 176 patients in the robotic cystectomy group did not have surgery and nine (5%) patients had a different surgery to that they were assigned. 21 (12%) of 174 patients in the open cystectomy group did not have surgery and one (1%) patient had robotic cystectomy instead of open cystectomy. Thus, 302 patients (150 in the robotic cystectomy group and 152 in the open cystectomy group) were included in the per-protocol analysis set. 2-year progression-free survival was 72·3% (95% CI 64·3 to 78·8) in the robotic cystectomy group and 71·6% (95% CI 63·6 to 78·2) in the open cystectomy group (difference 0·7%, 95% CI -9·6% to 10·9%; pnon-inferiority=0·001), indicating non-inferiority of robotic cystectomy. Adverse events occurred in 101 (67%) of 150 patients in the robotic cystectomy group and 105 (69%) of 152 patients in the open cystectomy group. The most common adverse events were urinary tract infection (53 [35%] in the robotic cystectomy group vs 39 [26%] in the open cystectomy group) and postoperative ileus (33 [22%] in the robotic cystectomy group vs 31 [20%] in the open cystectomy group). INTERPRETATION: In patients with bladder cancer, robotic cystectomy was non-inferior to open cystectomy for 2-year progression-free survival. Increased adoption of robotic surgery in clinical practice should lead to future randomised trials to assess the true value of this surgical approach in patients with other cancer types. FUNDING: National Institutes of Health National Cancer Institute.

Validation of dominant and secondary sequence utilization in PI-RADS v2 for classifying prostatic lesions.

INTRODUCTION: To assess the secondary sequence rule in The Prostate Imaging Reporting Data System (PI-RADS) version 2 by comparing the detection of Grade group 1+ (GG1+) and 2+ (GG2+) cancers in PI-RADS 3, an upgraded PI-RADS 4, and true (non-upgraded) PI-RADS 4 targets. MATERIALS AND METHODS: We analyzed a total of 589 lesions scored as PI-RADS 3 or 4 obtained from 434 men who underwent mpMRI-US fusion biopsy from September 2015 to November 2017 for evaluation of GG1+ and GG2+ prostate cancer. PI-RADS 4 lesions were differentiated into those that were 'upgraded' to PI-RADS 4 based on the secondary sequence and those that were 'true' PI-RADS 4 based on the dominant sequence. RESULTS: The odds of detecting a GG2+ cancer was significantly higher for an upgraded 4 (peripheral zone (PZ): OR 5.06, 95%CI 2.04-12.54, p < 0.001, transitional zone (TZ): OR 3.08, 95%CI 1.04-9.08, p = 0.042) and true 4 (PZ: OR 5.82, 95%CI 3.10-10.94, p < 0.0001, TZ: OR 2.43, 95%CI 1.14-5.18, p = 0.022) lesions compared to PI-RADS 3 lesions. Additionally, we found no difference in the odds of detecting a GG2+ prostate cancer between a true PI-RADS 4 (OR 1.15, 95%CI 0.49-2.71 p = 0.746) and upgraded 4 (referent) in the PZ. Similar non-significance was noted between true 4 (OR 0.79, 95%CI 0.26-2.38 p = 0.674) and upgraded 4 lesions in the TZ for detection of GG2+ cancers. CONCLUSIONS: Upgraded PI-RADS 4 and true 4 targets have a higher odds of detecting GG1+ and GG2+ compared to PI-RADS 3 in the PZ and TZ. Our findings validate the revised scoring system for PI-RADS.

Propensity matched comparative analysis of survival following chemoradiation or radical cystectomy for muscle-invasive bladder cancer.

OBJECTIVE: To compare survival outcome between chemoradiation therapy (CRT) and radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). PATIENTS AND METHODS: We conducted a retrospective analysis of patients with MIBC (≥cT2, N0, M0) in the National Cancer Database (2004-2013). CRT was defined as a radiation dose of ≥40 Gy and chemotherapy within 90 days of radiation. Descriptive statistics were used to compare groups. RC and CRT patients were propensity matched. Kaplan-Meier analysis was used to compare overall survival (OS). Multivariable Cox regression was used to determine predictors of survival. RESULTS: In all, 8 379 (6 606 RC and 1 773 CRT) patients met the inclusion criteria and 1 683 patients in each group were propensity matched. On multivariable extended Cox analysis, significant predictors of decreased OS were age, Charlson-Deyo Comorbidity score of 1, Charlson-Deyo Comorbidity score of 2, stage cT3-4, and urothelial histology. CRT was associated with decreased mortality at year 1 (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.74-0.96; P = 0.01), but at 2 years (HR 1.4, 95% CI 1.2-1.6; P < 0.001) and 3 years onward (HR 1.5, 95% CI 1.2-1.8; P < 0.001) CRT was associated with increased mortality. The 5-year OS was greater for RC than for CRT (38% vs 30%, P = 0.004). CONCLUSIONS: Initially after treatment for MIBC the risk of mortality is lower with CRT compared to RC. However, at ≥2 years after treatment the mortality risk favours RC. Patients who are suitable surgical candidates, with a low risk of morbidity, may be better served by RC.

Racial disparity and survival outcomes between African-American and Caucasian American men with penile cancer.

OBJECTIVE: To determine whether there is a survival difference for African-American men (AAM) versus Caucasian American men (CM) with penile squamous cell carcinoma (pSCC), particularly in locally advanced and metastatic cases where disease mortality is highest. PATIENTS AND METHODS: Using the Florida Cancer Data System, we identified men with pSCC from 2005 to 2013. We compared age, follow-up, stage, race, and treatment type between AAM and CM. We performed Kaplan-Meier analysis for overall survival (OS) between AAM and CM for all stages, and for those with locally advanced and metastatic disease. A multivariable model was developed to determine significant predictors of OS. RESULTS: In all, 653 men (94 AAM and 559 CM) had pSCC and 198 (30%) had locally advanced and/or metastatic disease. A higher proportion of AAM had locally advanced and/or metastatic disease compared to CM (38 [40%] vs 160 [29%], P = 0.03). The median (interquartile range) follow-up for the entire cohort was 12.6 (5.4-32.0) months. For all stages, AAM had a significantly lower median OS compared to CM (26 vs 36 months, P = 0.03). For locally advanced and metastatic disease, there was a consistent trend toward disparity in median OS between AAM and CM (17 vs 22 months, P = 0.06). After adjusting for age, stage, grade, and treatment type, AAM with pSCC had a greater likelihood of death compared to CM (hazard ratio 1.64, P = 0.014). CONCLUSIONS: AAM have worse OS compared to CM with pSCC and this may partly be due to advanced stage at presentation. Treatment disparity may also contribute to lessened survival in AAM, but we were unable to demonstrate a significant difference in treatment utilisation between the groups.

Comparison of readmission and short-term mortality rates between different types of urinary diversion in patients undergoing radical cystectomy.

PURPOSE: To analyze the impact of urinary diversion type following radical cystectomy (RC) on readmission and short-term mortality rates. METHODS: Patients who underwent RC for bladder cancer in the National Cancer Data Base were grouped based on the type of urinary diversion performed: non-continent [ileal conduit (IC)] or two continent techniques [continent pouch (CP) and orthotopic neobladder (NB)]. We used propensity score matching and multivariable logistic regression models to compare 30-day readmission and 30- and 90-day mortality between the different types of urinary diversion. RESULTS: Among 11,933 patients who underwent RC, we identified 10,197 (85.5%) IC, 1044 (8.7%) CP, and 692 (5.8%) NB. Patients who received IC were significantly older and had more comorbidities (p < 0.0001). Continent diversions were more likely to be performed at an academic center (p < 0.0001). Surgery performed at a non-academic center was an independent predictor of 30-day readmission (OR 1.19, p = 0.010) and 30-day mortality (OR 1.27, p = 0.043). Patients undergoing NB had an increased likelihood of being readmitted (OR 1.41, p = 0.010). There was no significant difference in short-term mortality between groups. CONCLUSIONS: Patients undergoing NB had marginally increased rates of readmission compared to IC. Surgery performed at a non-academic center was associated with higher readmission and 30-day mortality. Similar short-term mortality rates were observed among the different types of urinary diversion.