Adjuvant Everolimus in Non-Clear Cell Renal Cell Carcinoma: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Clinical trial data on adjuvant therapy in patients with non-clear cell renal cell carcinoma (RCC) are scant. Objective: To evaluate the effect of adjuvant everolimus after nephrectomy on recurrence-free survival (RFS) and overall survival (OS) in patients with localized papillary and chromophobe RCC. Design, Setting, and Participants: This prespecified subgroup analysis of a phase 3 randomized clinical trial, EVEREST, included patients enrolled between April 1, 2011, and September 15, 2016. Eligible patients had fully resected RCC at intermediate-high risk (pT1 grade 3-4, N0 to pT3a grade 1-2, N0) or very-high risk (pT3a grade 3-4 to pT4 any grade or N+) for recurrence who had received radical or partial nephrectomy. Final analyses was completed in March 2022. Intervention: The intervention group received 54 weeks of everolimus (10 mg orally daily); the control group received a matching placebo. Main Outcomes and Measures: The main outcomes were RFS, OS, and rates of adverse events. For testing the hazard ratio (HR) for treatment effect, a Cox regression model was used for both OS and RFS. Results: Of 1545 adult patients with treatment-naive, nonmetastatic, fully resected RCC in EVEREST, 109 had papillary RCC (median [range] age, 60 [19-81] years; 82 [75%] male; 50 patients [46%] with very high-risk disease) and 99 had chromophobe RCC (median [range] age 51 [18-71] years; 53 [54%] male; 34 patients [34%] with very high-risk disease). Among 57 patients with papillary RCC in the intervention group, 26 (46%) completed 54 weeks of treatment, and among 53 patients with chromophobe RCC in the intervention group, 26 (49%) completed 54 weeks of treatment. With a median (IQR) follow-up of 76 (61-96) months, adjuvant everolimus did not improve RFS compared with placebo in either papillary RCC (5-year RFS: 62% vs 70%; HR, 1.19; 95% CI, 0.61-2.33; P = .61) or chromophobe RCC (5-year RFS: 79% vs 77%; HR, 0.89; 95% CI, 0.37-2.13; P = .79). In the combined non-clear RCC cohort, grade 3 or higher adverse events occurred in 48% of patients who received everolimus and 9% of patients who received placebo. Conclusions and Relevance: In this clinical trial assessing the use of adjuvant everolimus, postoperative everolimus did not show evidence of improved RFS among patients with papillary or chromophobe RCC, and results from the study do not support adjuvant everolimus for this cohort. However, since the lower bounds of the 95% CIs were 0.61 and 0.89, respectively, potential treatment benefit in these subgroups cannot be ruled out. Trial Registration: ClinicalTrials.gov Identifier: NCT01120249.

Pathological concordance rate and outcomes by subtype in advanced papillary renal cell carcinoma.

OBJECTIVE: To evaluate the clinical significance of subtyping (type 1 vs 2) of papillary renal cell carcinoma (PRCC) in patients treated with targeted therapy, as well as the concordance, sensitivity and positive predictive value (PPV) of local review pathology review. METHODS: Patients with advanced refractory PRCC were randomised to receive sunitinib or cabozantinib, crizotinib or savolitinib, stratified by PRCC subtype (type 1, type 2, or not otherwise specified [NOS]/mixed) by local review. Central review was retrospectively conducted by three expert genitourinary pathologists who independently reviewed cases. The sensitivity and PPV of local review were estimated and outcomes [objective response rate (ORR), progression-free survival (PFS)] were summarised for treatment groups stratified by subtypes by central review. RESULTS: Amongst the 147 patients reviewed, the prevalence of individual subtypes varied by local or central review (type 1: 17.7% vs 29.3%; type 2: 53.1% vs 45.6%; NOS/mixed: 29.3% vs 25.2%), respectively. Individual cases were frequently reclassified and local pathology review demonstrated low sensitivity (type 1: 48%, 95% confidence interval [CI] 33, 65; type 2: 67%, 95% CI 55, 78; NOS/mixed: 43%, 95% CI 27, 61). The PPVs of local review were 80%, 57.7% and 37% for type 1, 2 and NOS/mixed, respectively. Compared to sunitinib, cabozantinib demonstrated improved PFS for both type 1 and type 2 PRCC subgroups (7.4 vs 9.0 and 2.9 vs 5.6 months, respectfully) as well as higher ORR. CONCLUSIONS: The PRCC subtype assignment did not identify a subset of patients with greater clinical benefit from cabozantinib, with significant discordance between local and central review. Our findings confirm the limited clinical value of pathological subtyping of metastatic PRCC, in line with the recent World Health Organisation 2022 guidelines. PATIENT SUMMARY: In this study, categorising papillary renal cell carcinoma into type 1 or 2 subtypes showed limited concordance between central and local pathological review and did not enrich for patients more likely to benefit from cabozantinib in the S1500 PAPMET trial.

Diabetes, Obesity, and Pathological Upstaging in Renal Cell Carcinoma: Results From a Large Multi-institutional Consortium.

PURPOSE: We sought to determine whether clinical risk factors and morphometric features on preoperative imaging can be utilized to identify those patients with cT1 tumors who are at higher risk of upstaging (pT3a). MATERIALS AND METHODS: We performed a retrospective international case-control study of consecutive patients treated surgically with radical or partial nephrectomy for nonmetastatic renal cell carcinoma (cT1 N0) conducted between January 2010 and December 2018. Multivariable logistic regression models were used to study associations of preoperative risk factors on pT3a pathological upstaging among all patients, as well as subsets with those with preoperative tumors ≤4 cm, renal nephrometry scores, tumors ≤4 cm with nephrometry scores, and clear cell histology. We also examined association with pT3a subsets (renal vein, sinus fat, perinephric fat). RESULTS: Among the 4,092 partial nephrectomy and 2,056 radical nephrectomy patients, pathological upstaging occurred in 4.9% and 23.3%, respectively. Among each group independent factors associated with pT3a upstaging were increasing preoperative tumor size, increasing age, and the presence of diabetes. Specifically, among partial nephrectomy subjects diabetes (OR=1.65; 95% CI 1.17, 2.29), male sex (OR=1.62; 95% CI 1.14, 2.33), and increasing BMI (OR=1.03; 95% CI 1.00, 1.05 per 1 unit BMI) were statistically associated with upstaging. Subset analyses identified hilar tumors as more likely to be upstaged (partial nephrectomy OR=1.91; 95% CI 1.12, 3.16; radical nephrectomy OR=2.16; 95% CI 1.44, 3.25). CONCLUSIONS: Diabetes and higher BMI were associated with pathological upstaging, as were preoperative tumor size, increased age, and male sex. Similarly, hilar tumors were frequently upstaged.

Volumetric Analysis of Renal Masses as Predictors of Partial Nephrectomy Outcomes.

Objective: To examine the role of endophytic tumor volume (TV) assessment (endophycity) on perioperative partial nephrectomy (PN) outcomes. Patients and Methods: Retrospective review of 212 consecutive laparoscopic and open partial nephrectomies from single institution using preoperative imaging and 1-year follow-up. Demographics, comorbidities, RENAL nephrometry scores, and all peri- and postoperative outcomes were recorded. Volumetric analysis performed using imaging software, independently assessed by two blinded radiologists. Univariate and multivariate statistical analysis were completed to assess predictive value of endophycity for all clinically meaningful outcomes. Results: Among those undergoing minimally invasive surgery (MIS), lower tumor endophycity was associated with higher likelihood of trifecta outcome (negative surgical margin, <10% decline in estimated glomerular filtration rate, the absence of complications) irrespective of max tumor size. For MIS, estimated blood loss increased with greater tumor endophycity regardless of tumor size. Among those who underwent open partial nephrectomy, lower tumor endophycity was associated with trifecta outcomes for tumors >4 cm only. On multivariate analysis with log-scaled odds ratios (OR), tumor endophycity and total kidney volume had the strongest correlation with tumor-related complications (OR = 3.23, 2.66). The analysis identified that tumor endophycity and TV on imaging were inversely correlated with of trifecta outcomes (OR = 0.53 for both covariates). Conclusions: Volumetric assessment of tumor endophycity performed well in identifying PN outcomes. As automated imaging software improves, volumetric analysis may prove to be a useful adjunct in preoperative planning and patient counseling.

Robot-assisted retroperitoneal lymph node dissection: a systematic review of perioperative outcomes.

OBJECTIVE: To assess the safety and feasibility of robot-assisted retroperitoneal lymph node dissection (R-RPLND) and to compare the perioperative outcomes of R-RPLND with open RPLND (O-RPLND), as RPLND forms an integral part of the management of testis cancer and R-RPLND is a minimally invasive treatment option for this disease. MATERIALS AND METHODS: The PubMed® , Scopus® , Cochrane Central Register of Controlled Trials, and Web of Science™ databases were searched for studies reporting perioperative outcomes of primary and post-chemotherapy R-RPLND and studies comparing R-RPLND with O-RPLND. RESULTS: The search yielded 42 articles describing R-RPLND, including five comparative studies. The systematic review included 4222 patients (single-arm studies, n = 459; comparative studies, n = 3763). Of 459 patients in the single-arm studies, 271 underwent primary R-RPLND and 188 underwent post-chemotherapy R-RPLND. For primary R-RPLND, the operative time ranged from 175 to 540 min and the major complication rate was 4.1%. For post-chemotherapy R-RPLND, the operative time ranged from 134 to 550 min and the major complication rate was 8.5%. The conversion rate to open surgery was 2.2% in primary R-RPLND and 9.0% in post-chemotherapy R-RPLND. In comparison with O-RPLND, R-RPLND was associated with a lower transfusion rate (14.5% vs 0.9%, P < 0.001) and a lower complication rate (18.5% vs 7.8%, P = 0.002). CONCLUSION: Robot-assisted RPLND has acceptable perioperative outcomes in both the primary and post-chemotherapy settings but a notable rate of conversion to open surgery in the post-chemotherapy setting. Compared with O-RPLND, R-RPLND is associated with a lower transfusion rate and fewer overall complications. Given the potential impact of selection bias, the optimal patient selection criteria for R-RPLND remain to be elucidated.

Patency outcomes of primary inferior vena cava repair in radical nephrectomy and tumor thrombectomy.

OBJECTIVE: The reconstruction of inferior vena cava (IVC) during radical nephrectomy and venous tumor thrombectomy (RN-VTT) is mostly performed with primary repair or with a patch/graft. We sought to systematically evaluate the outcomes of IVC patency over short- to intermediate-term follow-up for patients undergoing primary repair of IVC and to assess the association with survival. METHODS: A retrospective review of patients undergoing RN-VTT between January 2013 and August 2018 was conducted. Patients were followed until death, last available follow-up, or March 2022. The patency outcomes and IVC diameters were studied using follow-up cross-sectional imaging. The χ2 test, Student t test, and Kaplan-Meier survival analysis were used. RESULTS: Seventy-seven patients were included. The mean age was 59.2 ± 12.2 years and 45.4% had Mayo classification level III thrombus or higher. At a median follow-up of 36.5 months (13.3-60.7 months), the 3-year overall survival (OS) was 64%. Sixty patients underwent primary repair of the IVC and 48 of these patients were assessed for IVC patency. Ten patients (20.8%) developed caval occlusion, either from recurrent tumor (8.3%), new-onset bland thrombus (8.3%), or stenosis (4.2). The IVC patency seemed to be a significant predictor of OS (hazard ratio, 2.85; P = .021). Although the IVC diameters decreased significantly at the 3-month postoperative scan at the infrarenal (P = .019), renal (P < .001), and suprarenal (P < .001) levels, they did not decrease further on long-term follow-up imaging. CONCLUSIONS: IVC reconstruction with primary repair results in an overall patency rate of 80.2% with only a 4.0% rate of stenosis. Recurrence of tumor thrombus (8.3%) or bland thrombus (8.3%) are the predominant reasons for IVC occlusion after RN-VTT, and this outcome is associated with poor OS.

Impact of Finasteride on Survival in Bladder Cancer: A Retrospective Multi-institutional Database Analysis.

INTRODUCTION: Androgen suppression therapy has been associated with a lower incidence of bladder cancer (BCa) or improved overall/cancer-specific survival. Results are ofent conflicting; therefore, we aim to assess the impact of use of finasteride on overall survival (OS) for BCa using multi-institutional database. METHODS: The South Texas Veterans Healthcare System from 5 medical centers was queried for patients with BCa with or without use of finasteride after diagnosis of BCa. The primary outcome was the impact of finasteride use after diagnosis on the OS in BCa and in the high-risk Non-muscle invasive BCa (NMIBC) cohort. RESULTS: A total of 1890 patients were included, amongst which 619 (32.8%) men were classified as finasteride users and 1271 (67.2%) men as controls. At a median (IQR) follow up of 53.8 (27.4, 90.9) months, death due to any cause was noted in 272 (43.9%) finasteride-treated, and 672 (49.3%) control groups (P = .028). The patients in the finasteride group had significantly better OS in overall cohort (112.1 months vs. 84.8 months, P < .001) as well as in the NMIBC cohort (129.3months vs. 103.2 months, P = .0046). The use of finasteride was independently associated with improved OS in both, overall cohort (HR 0.74, 95% CI 0.63-0.86; P < .001) and in the NMIBC cohort (HR = 0.71, 95% CI 0.55-0.93; P = .011). CONCLUSION: Finasteride use is associated with the improved overall survival in patients with BCa, specifically in patients with NMIBC. We, further, propose a randomized clinical trial to investigate the use of finasteride in BCa patients.

Predictors of participants' retention-socioeconomic factors or nonadherence: insights from a urological clinical prospective study.

BACKGROUND: To investigate various patient-level variables, specifically socioeconomic status, as risk factors for withdrawal in a recently completed clinical study. We specifically investigated a non-interventional prospective study assessing the role of novel imaging as a biomarker for cancer upgradation in prostate cancer for this objective. METHODS: In this retrospective analysis, we assessed the association between various patient-level factors including clinic-demographic factors, socioeconomic status, and the number of non-adherences with the participants' retention or withdrawal from the study. For socioeconomic status (SES), we used the zip code-based Economic Innovation Group Distressed Community Index (DCI) which classifies into five even distress tiers: prosperous, comfortable, mid-tier, at-risk, or distressed. Low SES was defined as those with a DCI Distress tier of at-risk or distressed. We compared values between the two retention and withdrawal groups using t-test, chi-square test, and logistic regression analysis. RESULTS: Of 273 men screened, 123 men were enrolled. Among them, 86.2% (106/123) retained through the study whereas 13.8% (17/123) withdrew from the study. The mean (SD) age was 64 (6.4) years. Overall, 31.7% (39/123) were Hispanics and 24.3% (30/123) were African Americans. The median (IQR) DCI score was 34 (10.3, 68.1) and 30.8% (38/123) of patients belonged to low SES. The median DCI score in participants who retained in the study was statistically similar to those who withdrew from the study (p=0.4). Neither the DCI tiers (p=0.7) nor the low SES (p=0.9) were associated with participants' retention or withdrawal of the study. In terms of non-adherence, all participants in the withdrawn group had at least one non-adherent event compared to 48.1% in the retained group (p<0.001). Repetitive non-adherence was significantly higher in participants who withdrew from the study vs those who retained in the study [88.2% vs 16.9%, p <0.001]. On multivariate logistic regression analysis, the number of non-adherences (OR=12.5, p<0.001) and not DCI (OR=0.99, p=0.7) appeared to be an independent predictor for participants' retention or withdrawal from the study. CONCLUSIONS: Expanding diverse inclusion and limiting withdrawal with real-time non-adherence monitoring will lead to more efficient clinical research and greater generalizability of results.

The Latinx Disparity in Surgery for Kidney Cancer: Data from The South Texas Region.

The South Texas region, with a predominantly Latinx population, has a very high incidence of renal cell carcinoma (RCC), including those with tumor extending into the major blood vessels called venous tumor thrombus (VTT). There is currently no data on outcomes of Latinx patients with VTT as most published studies are from predominantly Caucasian population. Therefore, we performed this study to fill an urgent, unmet need. We reviewed patients who underwent radical nephrectomy with removal of VTT (called tumor thrombectomy) between 2015 and 2020. We collected data on demographics, clinical, pathological characteristics and outcomes of patients. Univariate and multivariate Cox regression analyses were used to evaluate the associations between ethnicity and disease progression or survival. We identified 112 patients, of which 67 (62%) were Latinx, and 41 (38%) were non-Latinx. Approximately 60% of patients had Level II-IV VTT; Latinx presented with a higher level of tumor thrombus (p=0.046). Latinx patients had a higher rate of no insurance (11% vs. 27%, p=0.04) and were more likely to lost to follow-up after surgery (22.4% vs. 13.3%, p=0.23) compared to non-Latinx. Fewer Latinx received systemic therapy (28% vs. 42%; p=0.13). Ninety-day mortality for the entire cohort was 3.8%. The Latinx population in the South Texas region present late, with advanced thrombus level, and do not have access to systemic therapy. Given symptomatic disease, surgical treatment, if feasible, is their only option. Our results highlight disparate treatment patterns which require further investigation and health-care policy changes.

A Decade of Robotic-Assisted Radical Nephrectomy with Inferior Vena Cava Thrombectomy: A Systematic Review and Meta-Analysis of Perioperative Outcomes.

PURPOSE: Open radical nephrectomy with inferior vena cava thrombectomy (O-CT) is standard management for renal cell carcinoma with inferior vena cava thrombus. First reported a decade ago, robotic-assisted radical nephrectomy with inferior vena cava thrombectomy (R-CT) is a minimally invasive option for this disease. We aimed to perform a systematic review to assess the safety and feasibility of R-CT in terms of perioperative outcomes and compare the outcomes between R-CT and O-CT. MATERIALS AND METHODS: The PubMed®, Scopus®, Cochrane Central Register of Controlled Trials and Web of ScienceTM databases were searched using the free-text and MeSH terms "renal cell carcinoma," "inferior vena cava," "thrombosis" or "thrombus," "robot" and "thrombectomy." Studies reporting perioperative outcomes of R-CT and studies comparing R-CT with O-CT were included. The review was done in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: The search retrieved 28 articles describing R-CT, including 7 comparative studies. This systematic review included 1,375 patients, out of which 329 patients were in single-arm studies and 1,046 patients were in comparative studies. Of the 329 patients who underwent R-CT, 14.7% were level I, 60.9% level II, 20.4% level III and 2.5% level IV thrombus. Operative time ranged from 150 to 530 minutes; blood transfusion was administered in 38.2% (126). The overall complication rate was 30.3% (99). R-CT, in comparison to O-CT, was associated with a lower blood transfusion rate (18.4% vs 64.3%, p=0.002) and a lower complication rate (14.5% vs 36.7%, p=0.005). Major complication and 30-day mortality rates were similar in both groups. CONCLUSIONS: R-CT has acceptable perioperative outcomes in carefully selected patients. Compared with O-CT, R-CT is associated with a lower blood transfusion rate and fewer overall complications. In experienced hands with carefully selected patients, R-CT is feasible and safe, with acceptable outcomes; however, selection bias limits definitive inference of these results, and optimal patient selection criteria remain to be described.

Absolute Prostate Specific Antigen after 6 Months of Androgen Deprivation Therapy Is a Predictor of Overall and Cancer-Specific Mortality in Men with Hormone-Sensitive Prostate Cancer.

PURPOSE: We sought to determine if absolute prostate specific antigen (PSA) value after 6 months of androgen deprivation therapy (ADT) is predictive of subsequent survival in patients with prostate adenocarcinoma. MATERIALS AND METHODS: We performed a retrospective review of men receiving care within the Veterans Health Administration who initiated ADT for prostate adenocarcinoma. We used low- (≤0.2 ng/ml), intermediate- (>0.2 to 4 ng/ml) and high-risk (>4 ng/ml) absolute PSA values after 6-9 months of ADT, previously described in Southwest Oncology Group trial 9346. The primary endpoints were all-cause mortality and prostate cancer-specific mortality (PCSM). Kaplan-Meier survival curves for each PSA category were estimated and log-rank test was conducted. We employed Cox regression analysis adjusted for covariates and inverse propensity score weights associated with PSA categories to estimate the PSA category association with PCSM and all-cause mortality. RESULTS: We identified 9,170 patients in our cohort. Following ADT induction, 3,508 patients had low, 3,419 had intermediate and 2,243 had high PSA values. Two- and 5-year survival rates for low, intermediate and high PSA groups were 93.9% and 85.2% vs 88.6% and 71.2% vs 63.6% and 38.6%, respectively (p <0.0001). Patients in the high and intermediate PSA categories had a 15-fold and 3-fold higher risk of PCSM compared to those with PSA <0.2 ng/ml (p <0.0001). CONCLUSIONS: Absolute PSA in hormone-sensitive prostate cancer after 6-9 months of ADT is a predictor of overall mortality and PCSM. This measure can rapidly assess the efficacy of new interventions in phase 2 clinical trials.

Chronic kidney damage pathology score for systematic assessment of the non-neoplastic kidney tissue and prediction of post-operative renal function outcomes.

To establish a systematic histological assessment of non-neoplastic kidney (NNK) tissue at the time of nephrectomy to evaluate a patient's risk of developing post-operative renal dysfunction, a combined prospective pathologic assessment of the NNK and a retrospective clinical chart review was conducted. A blinded nephropathologist performed standardized assessment of glomerular sclerosis, tubulointerstitial fibrosis, arteriosclerosis, and hyaline arteriolosclerosis. Combined these formulated the chronic kidney damage pathology score (CKDPS). Multivariate logistic regression models were developed to assess the effect of CKDPS and other clinical factors on renal function up to 24 months following nephrectomy (partial or radical). 156 patients were included in the analysis with a median age of 60 years. 70% patients underwent radical nephrectomy. A history of hypertension and/or diabetes was present in 55.8% and 22.1%, respectively. Higher CKDPS (particularly glomerular global sclerosis and arteriosclerosis scores), radical nephrectomy, and reduced baseline estimated glomerular filtration rate (eGFR) were associated with worsening post-operative renal function outcomes. The systematic assessment of non-neoplastic kidney tissue at the time of renal surgery can help identify patients at risk of post-operative renal dysfunction. CKDPS represents a standardized and prognostically relevant histologic reporting system for non-neoplastic kidney tissue.

The association between sarcopenia and bladder cancer-specific mortality and all-cause mortality after radical cystectomy: A systematic review and meta-analysis.

Objective: To compare cancer-specific mortality (CSM) and all-cause mortality (ACM) between patients with and without sarcopenia who underwent radical cystectomy for bladder cancer. Materials and methods: We performed a systematic review and meta-analysis of original articles published from October 2010 to March 2019 evaluating the effect of sarcopenia on CSM and ACM. We extracted hazard ratios (HRs) and 95% confidence intervals (CIs) for CSM and ACM from the included studies. Heterogeneity amongst studies was measured using the Q-statistic and the I 2 index. Meta-analysis was performed using a random-effects model if heterogeneity was high and fixed-effects models if heterogeneity was low. Results: We identified 145 publications, of which five were included in the meta-analysis. These five studies represented 1447 patients of which 453 were classified as sarcopenic and 534 were non-sarcopenic. CSM and ACM were increased in sarcopenic vs non-sarcopenic patients (HR 1.64, 95% CI 1.30-2.08, P < 0.01 and HR 1.41, 95% CI 1.22-1.62, P < 0.01, respectively). Conclusions: Sarcopenia is significantly associated with increased CSM and ACM in bladder cancer. Identifying patients with sarcopenia will augment preoperative counselling and planning. Further studies are required to evaluate targeted interventions in patients with sarcopenia to improve clinical outcomes. Abbreviations: ACM: all-cause mortality; ASA: American Association of Anesthesiologists; BMI: body mass index; CCI: Charlson Comorbidity Index; CSM: cancer-specific mortality; CSS: cancer-specific survival; ECOG: Eastern Cooperative Oncology Group; HR: hazard ratio; NAC: neoadjuvant chemotherapy; NIH: National Institutes of Health; OS: overall survival; RC: radical cystectomy; RCT: randomised controlled trial; SMI: Skeletal Muscle Index.

Correlates of refusal of radical cystectomy in patients with muscle-invasive bladder cancer.

PURPOSE: To evaluate factors associated with radical cystectomy (RC) refusal, subsequent treatment decisions, and their influence on overall survival (OS). MATERIALS AND METHODS: We queried the National Cancer Database for patients with non-metastatic muscle-invasive bladder cancer (MIBC), cT2-T4M0. Patients who refused recommended RC were further stratified by treatment into chemotherapy, radiation therapy, chemoradiotherapy, and no treatment groups. Patients were excluded from the analysis if surgery was not planned, not recommended; or if survival data were unknown. Multivariate logistic regression modeling was utilized to identify independent predictors of refusing RC. Cox proportional hazards model with propensity score overlap weighting was utilized to identify survival predictors. Kaplan-Meier analysis was utilized to evaluate survival according to treatment. RESULTS: A total of 74,159 MIBC patients were identified. Among patients with documented reasons for no surgery, 5.4% refused RC despite physician recommendation. Predictors of refusal on multivariate analysis included female gender (P = 0.016), advancing age ≥80 (vs. <60, P < 0.001), African American race (vs. white, P < 0.001) Medicaid (vs. private insurance, P < 0.001) and advancing T stage (T4 vs. T2, P < 0.001). Patients treated at academic centers were less likely to decline RC (vs. community centers, P < 0.001). Median survival after RC was 40.44 months vs. 12.52 months in refusal group. Undergoing chemoradiation had significantly improved survival in those patients compared to monotherapy or no treatment (hazard ratio 0.25, P < 0.001). Overlap weighted model Identified RC refusal as an independent predictor of poor OS (P < 0.001). CONCLUSIONS: Several sociodemographic and clinical factors are associated with refusing radical cystectomy. Such refusal is associated with poor survival outcomes.

Oncologic and Functional Outcomes of Radical and Partial Nephrectomy in pT3a Pathologically Upstaged Renal Cell Carcinoma: A Multi-institutional Analysis.

BACKGROUND: The efficacy of partial nephrectomy (PN) in setting of pT3a pathologic-upstaged renal cell carcinoma (RCC) is controversial. We compared oncologic and functional outcomes of radical nephrectomy (RN) and PN in patients with upstaged pT3a RCC. PATIENTS AND METHODS: This was a multicenter retrospective analysis of patients with cT1-2N0M0 RCC upstaged to pT3a postoperatively. The primary outcome was recurrence-free survival, with secondary outcomes of overall survival and de novo estimated glomular filtration rate (eGFR) < 60. Multivariable analysis was performed to identify predictive factors for oncologic outcomes. Kaplan-Meier analyses (KMA) were obtained to elucidate survival outcomes. RESULTS: A total of 929 patients had pT3a upstaging (686 [72.6%] RN; 243 [25.7%] PN; mean follow-up, 48 months). Tumor size was similar (RN 7.7 cm vs. PN 7.3 cm; P = .083). PN had decreased ΔeGFR (6.1 vs. RN 19.4 mL/min/1.73m2; P < .001) and de novo eGFR < 60 (9.5% vs. 21%; P = .008). Multivariable analysis for recurrence showed increasing RENAL score (hazard ratio [HR], 3.8; P < .001), clinical T stage (HR, 1.8; P < .001), positive margin (HR, 1.57; P = .009), and high grade (HR, 1.21; P = .01) to be independent predictors, whereas surgery was not (P = .076). KMA revealed 5-year recurrence-free survival for cT1-upstaged PN, cT1-upstaged RN, cT2-upstaged PN, and cT2-upstaged RN of 79%, 74%, 70%, and 51%, respectively (P < .001). KMA revealed 5-year overall survival for cT1-upstaged PN, cT1-upstaged RN, cT2-upstaged PN, and cT2-upstaged RN of 64%, 65.2%, 56.4%, and 55.2%, respectively (P = .059). CONCLUSIONS: In pathologically upstaged pT3a RCC, PN did not adversely affect risk of recurrence and provided functional benefit. Surgical decision-making in patients at risk for T3a upstaging should be individualized and driven by tumor as well as functional risks.

Nuclear NADPH oxidase-4 associated with disease progression in renal cell carcinoma.

Nuclear NADPH oxidase-4 (Nox4) is a key component of metabolic reprogramming and is often overexpressed in renal cell carcinoma (RCC). However, its prognostic role in RCC remains unclear. Here we examined the significance of nuclear Nox4 on disease progression and development of drug resistance in advanced RCC. We analyzed human RCC tissue from multiple regions in the primary index tumor, cancer-associated normal adjacent parenchyma, intravascular tumor in locally advanced cancer patients. We found that the higher nuclear Nox4 expression was significantly associated with progression and death. These findings were consistent after controlling for other competing clinical variables. In contrast, patients with lower nuclear Nox4, even in higher stage RCC had better prognosis. We identified a subset of patients with high nuclear Nox4 who had rapid disease progression or died within 6 months of surgery. In addition, higher nuclear Nox4 level correlated with resistance to targeted therapy and immunotherapy. Western blotting performed on fresh human RCC tissue as well as cell-lines revealed increased nuclear Nox4 expression. Our data support an important prognostic role of Nox4 mediated regulation of RCC independent of other competing variables. Nox4 localizes to the nucleus in high-grade, high-stage RCC. Higher nuclear Nox4 has prognostic significance for disease progression, poor survival, and development of drug resistance in RCC.

Microbiome within Primary Tumor Tissue from Renal Cell Carcinoma May Be Associated with PD-L1 Expression of the Venous Tumor Thrombus.

OBJECTIVE: To perform a proof of concept microbiome evaluation and PD-L1 expression profiling in clear-cell renal cell carcinoma (cc-RCC) with associated tumor thrombus (TT). METHODS: After IRB approval, six patients underwent radical nephrectomy (RN) with venous tumor thrombectomy (VTT). We collected fresh tissue specimens from normal adjacent, tumor, and thrombus tissues. We utilized RNA sequencing to obtain PD-L1 expression profiles and perform microbiome analysis. Statistical assessment was performed using Student's t-test, chi-square, and spearman rank correlations using SPSS v25. RESULTS: We noted the tumor thrombus to be mostly devoid of diverse microbiota. A large proportion of Staphylococcus epidermidus was detected and unknown if this is a surgical or postsurgical contaminant; however, it was noted more in the thrombus than other tissues. Microbiome diversity profiles were most abundant in the primary tumor compared to the thrombus or normal adjacent tissue. Differential expression of PD-L1 was examined in the tumor thrombus to the normal background tissue and noted three of the six subjects had a threshold above 2-fold. These three similar subjects had foreign microbiota that are typical residents of the oral microbiome. CONCLUSION: Renal tumors have more diverse microbiomes than normal adjacent tissue. Identification of resident oral microbiome profiles in clear-cell renal cancer with tumor thrombus provides a potential biomarker for thrombus response to PD-L1 inhibition.

Urinary Diversion Disparity Following Radical Cystectomy for Bladder Cancer in the Hispanic Population.

OBJECTIVE: To determine if disparities in quality of surgical care exist between Hispanics and non-Hispanics undergoing radical cystectomy for bladder cancer. MATERIALS AND METHODS: An observational cohort study was conducted retrospectively on patients who underwent radical cystectomy for urothelial carcinoma of the bladder at our institution between January 2005 and July 2018. Data was collected on demographic, clinical, and pathological characteristics of patients, including self-reported ethnicity. Univariable and multivariable logistic or linear regression analyses were used to evaluate the association of ethnicity with receipt of neoadjuvant chemotherapy, utilization of laparoscopic surgery, number of lymph nodes removed, and continent urinary diversion. RESULTS: We identified 507 patients in our database out of which, 136 (27%) were Hispanic and 371 (73%) were non-Hispanic. Compared to non-Hispanics, Hispanics had a higher body mass index (26.9 kg/m2 vs 28.2 kg/m2, P = .006) and lived further away from site of surgery (34 vs 96 miles, P = .02). No significant differences were observed in receipt of neoadjuvant chemotherapy, laparoscopic surgery, or number of lymph nodes removed during cystectomy between ethnicity groups. However, Hispanics were less likely than non-Hispanics to receive a continent urinary diversion on multivariable analysis (odds ratio 0.30, 95% confidence interval 0.10 - 0.92, P = .03). CONCLUSION: Disparity exists in the delivery of continent urinary diversions for Hispanic patients undergoing radical cystectomy for bladder cancer. Further investigation is needed to determine the potential causes for this disparity in care delivered.

Risk Factors for Upstaging, Recurrence, and Mortality in Clinical T1-2 Renal Cell Carcinoma Patients Upstaged to pT3a Disease: An International Analysis Utilizing the 8th Edition of the Tumor-Node-Metastasis Staging Criteria.

OBJECTIVE: To investigate risk factors for and outcomes in pathological T3a-upstaging in Renal Cell Carcinoma (RCC), as Tumor-Node-Metastasis staging for T3a RCC was recently revised. METHODS: Multicenter retrospective analysis of patients with clinical T1-T2 RCC, stratified by occurrence of pathologic T3a-upstaging. Primary outcome was recurrence-free survival (RFS). Multivariable analyses (MVA) were conducted for upstaging and recurrence. Kaplan-Meier analysis (KMA) was utilized for RFS and overall survival (OS). RESULTS: We analyzed 2573 patients (1223 RN/1350 PN). Upstaging occurred in 360 (14.0%). On MVA, higher clinical stage was associated with increasing risk of upstaging [cT1a (referent), odds ratio for cT1b, cT2a, and cT2b was 2.6, 6.5, and 14.1, P < .001]. Higher clinical stage at presentation correlated with increasing risk of recurrence in pT3a-upstaged RCC (cT1a upstaged-pT3a [referent], hazard ratio [HR] for cT1b, cT2a, and cT2b upstaged pT3a was 1.16 [P = .729], 3.02 [P = .013], and 4.5 [P = .003]). Perirenal fat (HR 1.6, P = .038) and renal vein (HR 2.2, P = .006) invasion were associated with increased risk of recurrence; type of surgery was not (P = .157). KMA for RFS and OS in pT3a-upstaged patients demonstrated differences based on initial clinical stage (5-year PFS for cT1a/b, and cT2 upstaged was 84.5%/72.8%, and 44.7%, P < .001; 5-year OS for cT1 and cT2 upstaged was 83.8% and 63.2%, P < .001). CONCLUSION: Risk of pT3a-upstaging and recurrence in pT3a-upstaged RCC correlates with clinical stage at presentation. Renal vein and perinephric fat invasion were associated with increased risk of recurrence. PN did not increase risk of recurrence and potential of pT3a-upstaging should not deter consideration of PN.