Induction and maintenance of sequential intravesical gemcitabine/docetaxel for intermediate and high-risk non-muscle invasive bladder cancer with different dosage protocols.

INTRODUCTION: The combination of sequential intravesical gemcitabine and docetaxel (Gem/Doce) chemotherapy has been considered a feasible option for BCG (Bacillus Calmette-Guérin) treatment in non-muscle invasive bladder cancer (NMIBC), gaining popularity during BCG shortage period. We seek to determine the efficacy of the treatment by comparing Gem/Doce induction alone vs induction with maintenance, and to evaluate the treatment outcomes of two different dosage protocols. METHODS: A bi-center retrospective analysis of consecutive patients treated with Gem/Doce for NMIBC between 2018 and 2023 was performed. Baseline characteristics, risk group stratification (AUA 2020 guidelines), pathological, and surveillance reports were collected. Kaplan-Meier survival analysis was performed to detect Recurrence-free survival (RFS). RESULTS: Overall, 83 patients (68 males, 15 females) with a median age of 73 (IQR 66-79), and a median follow-up time of 18 months (IQR 9-25), were included. Forty-one had an intermediate-risk disease (49%) and 42 had a high-risk disease (51%). Thirty-seven patients (45%) had a recurrence; 19 (23%) had a high-grade recurrence. RFS of Gem/Doce induction-only vs induction + maintenance was at 6 months 88% vs 100%, at 12 months 71% vs 97%, at 18 months 57% vs 91%, and at 24 months 31% vs 87%, respectively (log-rank, p < 0.0001). Patients who received 2 g Gemcitabine with Docetaxel had better RFS for all-grade recurrences (log-rank, p = 0.017). However, no difference was found for high-grade recurrences. CONCLUSION: Gem/Doce induction with maintenance resulted in significantly better RFS than induction-only. Combining 2 g gemcitabine with docetaxel resulted in better RFS for all-grade but not for high-grade recurrences. Further prospective trials are necessary to validate our results.

Thromboembolic Events After Robotic Radical Cystectomy: A Comparative Analysis of Extended and Limited Prophylaxis.

OBJECTIVE: To compare limited (only inpatient) venous thromboembolism (VTE) prophylaxis after robot-assisted radical cystectomy (RARC) to limited plus extended prophylaxis. There is little consensus on postoperative VTE prophylaxis regimens after RARC with data mostly extrapolated from other cancers. METHODS: Retrospective review of all RARC patients at our center between 2014-2022, identifying two groups: patients after a prospectively implemented protocol (January 2018 to present) utilizing a prolonged 21-day postoperative course of either enoxaparin 40 mg daily or apixaban 2.5 mg twice daily after discharge, or patients prior to January 2018 receiving only limited VTE prophylaxis during their immediate postoperative inpatient stay. PRIMARY OUTCOME: incidence of symptomatic VTE confirmed with imaging within 90-days postoperatively. SECONDARY OUTCOMES: major hemorrhage, complications, readmission, and mortality within 30-days postoperatively. Descriptive statistics depicted baseline patient characteristics, operative information, and complications. Differences were compared between groups. Logistic regression was used to determine associations between variables and primary outcome. RESULTS: Eighty-six patients received limited prophylaxis and 364 received extended prophylaxis. Twelve (2.7%) patients experienced VTE within 90-day postoperatively: (10 [2.7%] extended vs 2 [2.3%] limited, P = .9). Upon stratification into EAU "low-risk" or "high +intermediate-risk" groups, no statistically significant difference in VTE rates was seen between the extended or limited groups. When controlling for prophylaxis regimen, intracorporeal approach was found to be predictive of a lower with a lower risk of VTE (P = .019). CONCLUSION: Limited and extended prophylaxis showed no significant differences in VTE rates among RARC patients. Further studies are necessary for RARC patients to improve guidelines.

Robotic-assisted radical cystectomy with cutaneous ureterostomies: a contemporary multicenter analysis.

BACKGROUND: Robotic-assisted radical cystectomy (RARC) offers decreased blood loss during surgery, shorter hospital length of stay, and lower risk for thromboembolic events without hindering oncological outcomes. Cutaneous ureterostomies (UCS) are a seldom utilized diversion that can be a suitable alternative for a selected group of patients with competing co-morbidities and limited life expectancy. OBJECTIVE: To describe operative and perioperative characteristics as well as oncological outcomes for patients that underwent RARC + UCS. METHODS: Patients that underwent RARC + UCS during 2013-2023 in 3 centers (EU = 2, US = 1) were identified in a prospectively maintained database. Baseline characteristics, pathological, and oncological outcomes were analyzed. Descriptive statistics and survival analysis were performed using R language version 4.3.1. RESULTS: Sixty-nine patients were included. The median age was 77 years (IQR 70-80) and the median follow-up time was 11 months (IQR 4-20). Ten patients were ASA 4 (14.5%). Nine patients underwent palliative cystectomy (13%). The median operation time was 241 min (IQR 202-290), and the median hospital stay was 8 days (IQR 6-11). The 30-day complication rate was 55.1% (grade ≥ 3a was 14.4%), and the 30-day readmission rate was 17.4%. Eleven patients developed metastatic recurrence (15.9%), and 14 patients (20.2%) died during the follow-up period. Overall survival at 6, 12, and 24 months was 84%, 81%, and 73%, respectively. CONCLUSIONS: RARC + UCS may offer lower complication and readmission rates without the need to perform enteric anastomosis, it can be considered in a selected group of patients with competing co-morbidities, or limited life expectancy. Larger prospective studies are necessary to validate these results.

Longitudinal Tumor-informed Circulating Tumor DNA Status Predicts Disease Upstaging and Poor Prognosis for Patients Undergoing Radical Cystectomy.

BACKGROUND AND OBJECTIVE: Decision-making on the use of neoadjuvant and adjuvant treatment for patients with bladder cancer undergoing radical cystectomy (RC) currently depends on assessment of clinical and pathological features, which lack sensitivity. Circulating tumor DNA (ctDNA) has emerged as a possible novel prognostic biomarker in the field. Our aim was to assess whether ctDNA status before RC is predictive of pathological and oncological outcomes. We also evaluated the dynamic changes in ctDNA status after RC in relation to recurrence-free survival (RFS). METHODS: We analyzed data for patients who underwent RC during 2021-2023 for whom prospective tumor-informed ctDNA analyses were conducted before and after RC. RFS was evaluated using the Kaplan-Meier method. Predictors for disease recurrence were assessed using Cox proportional-hazards models. Pathological outcomes associated with detectable ctDNA before RC were assessed in univariable and multivariable regression analyses. KEY FINDINGS AND LIMITATIONS: We included 112 patients in the analysis. Median follow-up was 8 mo (interquartile range 4-13). ctDNA was detected before RC in 59 patients (53%) and was associated with poor RFS (log-rank p < 0.0001). Detectable ctDNA before RC was associated with poor outcomes regardless of clinical stage (

Contemporary outcomes of patients undergoing robotic-assisted radical cystectomy: A comparative analysis between intracorporeal ileal conduit and neobladder urinary diversions.

Objective: We aimed to compare perioperative and oncologic outcomes for patients undergoing robotic-assisted radical cystectomy (RARC) with intracorporeal ileal conduit (IC) and neobladder (NB) urinary diversion. Methods: Patients undergoing RARC with intracorporeal urinary diversion between January 2017 and January 2022 at the Icahn School of Medicine at Mount Sinai, New York, NY, USA were indexed. Baseline demographics, clinical characteristics, perioperative, and oncologic outcomes were analyzed. Survival was estimated with Kaplan-Meier plots. Results: Of 261 patients (206 [78.9%] male), 190 (72.8%) received IC while 71 (27.2%) received NB diversion. Median age was greater in the IC group (71 [interquartile range, IQR 65-78] years vs. 64 [IQR 59-67] years, p<0.001) and BMI was 26.6 (IQR 23.2-30.4) kg/m2. IC group was more likely to have prior abdominal or pelvic radiation (15.8% vs. 2.8%, p=0.014). American Association of Anesthesiologists scores were comparable between groups. The IC group had a higher proportion of patients with pathological tumor stage 2 (pT2) tumors (34 [17.9%] vs. 10 [14.1%], p=0.008) and pathological node stages pN2-N3 (28 [14.7%] vs. 3 [4.2%], p<0.001). The IC group had less median operative time (272 [IQR 246-306] min vs. 341 [IQR 303-378] min, p<0.001) and estimated blood loss (250 [150-500] mL vs. 325 [200-575] mL, p=0.002). Thirty- and 90-day complication rates were 44.4% and 50.2%, respectively, and comparable between groups. Clavien-Dindo grades 3-5 complications occurred in 27 (10.3%) and 34 (13.0%) patients within 30 and 90 days, respectively, with comparable rates between groups. Median follow-up was 324 (IQR 167-552) days, and comparable between groups. Kaplan-Meier estimate for overall survival at 24 months was 89% for the IC cohort and 93% for the NB cohort (hazard ratio 1.23, 95% confidence interval 1.05-2.42, p=0.02). Kaplan-Meier estimate for recurrence-free survival at 24 months was 74% for IC and 87% for NB (hazard ratio 1.81, 95% confidence interval 0.82-4.04, p=0.10). Conclusion: Patients undergoing intracorporeal IC urinary diversion had higher postoperative cancer stage, increased nodal involvement, similar complications outcomes, decreased overall survival, and similar recurrence-free survival compared to patients undergoing RARC with intracorporeal NB urinary diversion.

Infections After Adoption of Antibiogram-directed Prophylaxis and Intracorporeal Urinary Diversion for Robot-assisted Radical Cystectomy.

BACKGROUND: Enhanced recovery after surgery (ERAS) has significantly decreased the morbidity associated with radical cystectomy. However, infectious complications including sepsis, urinary tract (UTIs), wound (WIs), and intra-abdominal (AIs) infections remain common. OBJECTIVE: To assess whether intracorporeal urinary diversion (ICUD) and antibiogram-directed antimicrobial prophylaxis would decrease infections after robotic-assisted radical cystectomy (RARC). DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was performed of a prospectively maintained database of patients undergoing RARC between 2014 and 2022 at a tertiary care institution, identifying two groups based on adherence to a prospectively implemented modified ERAS protocol for RARC: modified-ERAS-ICUD and antibiogram-directed ampicillin-sulbactam, gentamicin, and fluconazole prophylaxis were utilized (from January 2019 to present time), and unmodified-ERAS-extracorporeal urinary diversion (UD) and guideline-recommended cephalosporin-based prophylaxis regimen were utilized (from November 2014 to June 2018). Patients receiving other prophylaxis regimens were excluded. INTERVENTION: ICUD and antibiogram-directed infectious prophylaxis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was UTIs within 30 and 90 d postoperatively. The secondary outcomes were WIs, AIs, and sepsis within 30 and 90 d postoperatively, and Clostridioides difficile infection (CDI) within 90 d postoperatively. RESULTS AND LIMITATIONS: A total of 396 patients were studied (modified-ERAS: 258 [65.2%], unmodified-ERAS: 138 [34.8%]). UD via a neobladder was more common in the modified-ERAS cohort; all other intercohort demographic differences were not statistically different. Comparing cohorts, modified-ERAS had significantly reduced rates of 30-d (7.8% vs 15.9%, p = 0.027) and 90-d UTIs (11.2% vs 25.4%, p = 0.001), and 30-d WIs (1.2% vs. 8.7%, p < 0.001); neither group had a WI after 30 d. Rates of AIs, sepsis, and CDI did not differ between groups. On multivariate regression, the modified-ERAS protocol correlated with a reduced risk of UTIs and WIs (all p < 0.01). The primary limitation is the retrospective study design. CONCLUSIONS: Utilization of ICUD and antibiogram-based prophylaxis correlates with significantly decreased UTIs and WIs after RARC. PATIENT SUMMARY: In this study of infections after robotic radical cystectomy for bladder cancer, we found that intracorporeal (performed entirely inside the body) urinary diversion and an institution-specific antibiogram-directed antibiotic prophylaxis regimen led to fewer urinary tract infections and wound infections at our institution.

Eliminating the routine use of postoperative drain placement in patients undergoing robotic-assisted radical cystectomy with intracorporeal urinary diversion.

INTRODUCTION: Perioperative management of patients undergoing radical cystectomy and urinary diversion utilizing both open and minimally invasive techniques have routinely included the use of drains in the operative field. We herein demonstrate the safety of robotic-assisted radical cystectomy (RARC) without the routine use of postoperative drains. METHODS: Patients who underwent drainless RARC with intracorporeal urinary diversion between 2017 and 2022 at our institution were reviewed. Baseline and clinical characteristics as well as perioperative and postoperative outcomes were analyzed. The primary study outcome was incidence of postoperative urinary leak or intra-abdominal infectious collections within 90 days of RARC. A univariate and multivariable logistic regression analysis was performed to determine associations between study variables and the primary outcome. RESULTS: Of 381 patients, 298 (78.2%) were male and median age and BMI were 68 (63, 76) and 26.2 [23.0, 29.8], respectively. Overall 30 and 90-day complication rates were 39.6% and 50.4%, respectively. Twenty-one (5.5%) patients experienced a urine leak or intra-abdominal infectious collections. Sub-group analysis of patients who experienced the primary outcome demonstrated median postoperative day of presentation was day 19, and this group required 16 total additional procedures. On multivariable logistic regression analysis, only prior radiation therapy was associated with the development of the primary outcome of urinary leak or intra-abdominal infectious collection (odds ratio: 15.12, 95% confidence interval [1.52-156.8], p = 0.02). CONCLUSION: Drainless RARC with totally intracorporeal urinary diversion achieved competitive perioperative and complications outcomes compared to prior open and robotic series. In the context of a larger enhanced recovery after surgery protocol in RARC patients, the routine use of drains may be safely omitted.

Surveillance for Nonmuscle Invasive Bladder Cancer: Identifying the Point of Diminishing Returns.

OBJECTIVE: To characterize first and second recurrence patterns using 26years of cohort-level follow-up and microsimulation modeling. METHODS: Patients diagnosed with nonmuscle-invasive bladder cancer in Stockholm County between 1995 and 1996 were included. Clinical, pathological, and longitudinal follow-up data were gathered. Logistic regressions, Kaplan Meier curves, and Cox proportional hazards models were run to generate assumptions for a microsimulation model, simulating first and second recurrence and progression for 10,000 patients. RESULTS: Three hundred eighty-six patients were included: 67.4% were male; >50% were TaLG; and 37.5% were American Urological Association high-risk. Median time to recurrence was 300days. Three patients had missing data. Cohort follow-up has been carried out for 26years. For simulated first-recurrences, low-risk patients recurred at 56.6% over 15years of follow-up, with 2.2% muscle-invasive (MI) progression; intermediate-risk patients recurred at 62.8%, with 4.3% MI progression; high-risk patients recurred at 48.7% over 15years, with MI progression at 14.3%. For second recurrences, 70.7%, 75.7%, and 84.7% of low, medium, and high-risk patients recurred. No patients were seen to have first recurrences after 9years, with low, but notable, rates beyond 5years. CONCLUSION: These data suggest that low-, intermediate-, and high-risk patients without recurrence at 5years may be potentially transitioned to less invasive monitoring.

Outcomes from a prospectively implemented protocol using apixaban after robot-assisted radical cystectomy.

OBJECTIVES: To compare the safety and efficacy of oral apixaban with that of injectable enoxaparin after robot-assisted radical cystectomy (RARC) for venous thromboembolism (VTE) thromboprophylaxis. MATERIALS AND METHODS: We conducted a retrospective review of prospectively collected data for all RARC patients treated at our tertiary care centre between 2018 and 2022. The study included two groups: patients who were subject to a prospectively implemented protocol from October 2021 to the present, comprising a 21-day postoperative course of apixaban 2.5 mg twice daily after discharge, and patients treated prior to October 2021 who received enoxaparin 40 mg daily. Baseline demographics and clinical characteristics, such as VTE (defined as deep vein thrombosis and pulmonary embolism), were analysed. The primary outcome was incidence of symptomatic VTE confirmed with definitive imaging within 90 days of RARC. Secondary outcomes included major bleeding, complications, readmission, and mortality within 30 days postoperatively. Descriptive statistics included baseline patient characteristics, operative information and complications. Differences in baseline characteristics and postoperative data were compared between groups. Multivariate logistic regression was used to determine associations between variables and the primary outcome. RESULTS: A total of 124 patients received apixaban and 250 patients received enoxaparin prophylaxis. Ten patients (2.7%) experienced a VTE within 90 days postoperatively (two [1.6%] apixaban group vs eight [3.2%] enoxaparin group; P = 0.5). After patient stratification into European Association of Urology risk groups, no statistically significant difference in VTE rates was seen between groups in the apixaban (2.7% high- + intermediate-risk group vs 1.1% low-risk group; P = 0.5) and enoxaparin cohorts (4.3% high- + intermediate-risk group vs 2.5% low-risk group; P = 0.5). On multivariate logistic regression, no variables were associated with the development of the primary outcome. CONCLUSION: Prophylaxis with apixaban and enoxaparin showed no statistically significant differences in VTE rates among RARC patients. Apixaban appears to be safe and effective for VTE prophylaxis after RARC.

Systemic Immunological Determinants of Oncological Outcomes After Surgery for Localized Renal Cell Carcinoma.

INTRODUCTION & OBJECTIVES: In systemic therapy trials, a decreasing neutrophil-to-lymphocyte ratio (NLR) after treatment for metastatic renal cell carcinoma (RCC) has been associated with improved oncologic outcomes. Paradoxically, for patients with localized RCC treated with upfront surgery the opposite effect has been reported. We thus aimed to evaluate NLR dynamics on localized RCC recurrence. MATERIALS AND METHODS: Treatment naïve patients with localized RCC managed surgically between 2005 and 2020 were included. Preoperative NLR was calculated within 6-weeks prior to surgery and postoperative NLR was calculated between 4 and twelve-weeks after surgery. Patients were followed for disease recurrence, noting metastatic sites and postoperative infections. Cox regression were used to determine whether the relative change in postoperative NLR was associated with metastasis-free survival (MFS) and cancer-specific survival (CSS), adjusted for preoperative NLR. RESULTS: In the cohort of 3310 patients, 996 (30%) had postoperative NLR available. These patients generally had more advanced disease, with 100 developing metastases and 38 dying from kidney cancer. Median MFS follow-up was 4.4 years. Decreasing 2-month postoperative NLR was associated with non-statistically significant worse MFS and CSS (HR 0.79, 95% 0.50, 1.24, P = .3; HR 0.83, 95% C.I. 0.40, 1.73; P = .6). On sensitivity analysis, across all NLR measurements, with NLR as a time-dependent covariate, results were similar, with a declining NLR associated with adverse MFS (HR 0.85, 95% CI 0.69, 1.30, P-value = .10), though not meeting conventional levels of significance. CONCLUSION: In higher-risk localized RCC patients, postoperative NLR is not suitable as a biomarker for predicting recurrences.

Radiogenomics in Clear Cell Renal Cell Carcinoma: A Review of the Current Status and Future Directions.

Radiogenomics is a field of translational radiology that aims to associate a disease's radiologic phenotype with its underlying genotype, thus offering a novel class of non-invasive biomarkers with diagnostic, prognostic, and therapeutic potential. We herein review current radiogenomics literature in clear cell renal cell carcinoma (ccRCC), the most common renal malignancy. A literature review was performed by querying PubMed, Medline, Cochrane Library, Google Scholar, and Web of Science databases, identifying all relevant articles using the following search terms: "radiogenomics", "renal cell carcinoma", and "clear cell renal cell carcinoma". Articles included were limited to the English language and published between 2009-2021. Of 141 retrieved articles, 16 fit our inclusion criteria. Most studies used computed tomography (CT) images from open-source and institutional databases to extract radiomic features that were then modeled against common genomic mutations in ccRCC using a variety of machine learning algorithms. In more recent studies, we noted a shift towards the prediction of transcriptomic and/or epigenetic disease profiles, as well as downstream clinical outcomes. Radiogenomics offers a platform for the development of non-invasive biomarkers for ccRCC, with promising results in small-scale retrospective studies. However, more research is needed to identify and validate robust radiogenomic biomarkers before integration into clinical practice.

Phase II Study of Neoadjuvant Nivolumab in Patients with Locally Advanced Clear Cell Renal Cell Carcinoma Undergoing Nephrectomy.

Immune checkpoint inhibitor therapy improves survival in patients with metastatic renal cell carcinoma (RCC) but has not been studied well preoperatively in patients with localized disease undergoing nephrectomy. We conducted a single-center study to evaluate the safety and feasibility of neoadjuvant nivolumab in patients undergoing nephrectomy for localized RCC. Eligible patients had a >20% risk of recurrence, as estimated by a preoperative nomogram. Patients received nivolumab every 2 wk for four treatments prior to surgery. The primary endpoints were feasibility, defined as completing at least three treatments without significant surgical delay, and safety, defined as the rate of surgical complications. Treatment effects were assessed by radiomics and immunohistochemistry. A total of 18 patients (11 men; median age 60 yr) with clear cell RCC were enrolled. All received at least one dose of nivolumab and proceeded to nephrectomy without delay; 16/18 patients completed all four doses. Two patients discontinued nivolumab for immune-related adverse events, and four had surgical complications as per the Clavien-Dindo classification. Integrated pathology plus radiomic analysis demonstrated an association between post-treatment immune infiltration and low entropy apparent diffusion coefficient on magnetic resonance imaging. Nivolumab prior to nephrectomy was safe and feasible, without significant surgical delays and with an expected rate of immune-related adverse events. PATIENT SUMMARY: We evaluated the outcomes for patients with localized kidney cancer who received immunotherapy prior to surgery to remove their kidney tumor. In a small group of patients who had cancer confined to the kidney, this approach appeared safe and feasible.

TIM-3 and TIGIT are possible immune checkpoint targets in patients with bladder cancer.

The resurgence of immunotherapy as an effective anticancer strategy has been coupled with more mature understandings of the underlying immune pathways and the development of novel immune checkpoint targets. The clinical development of antibodies first directed against cytotoxic T-lymphocyte-associated antigen 4, and later against program death 1, achieved durable disease control in a subset of patients across a large number of tumor types. Previous work demonstrates that targeting the programmed death 1 pathway alone does not result in complete restoration of T cell function and in some cancers, targeting this axis does not restore T cell function at all, suggesting a need to identify other molecules and inhibitory pathways that are involved in T cell exhaustion. In a comprehensive immune profiling study of patients with bladder cancer, we demonstrate T-cell immunoglobulin domain and mucin domain-containing molecule and T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain as possible targets as perhaps monotherapy or in combination with other immune checkpoint inhibitors.

Prevalence and Landscape of Actionable Genomic Alterations in Renal Cell Carcinoma.

PURPOSE: We report our experience with next-generation sequencing to characterize the landscape of actionable genomic alterations in renal cell carcinoma (RCC). EXPERIMENTAL DESIGN: A query of our institutional clinical sequencing database (MSK-IMPACT) was performed that included tumor samples from 38,468 individuals across all cancer types. Somatic variations were annotated using a precision knowledge database (OncoKB) and the available clinical data stratified by level of evidence. Alterations associated with response to immune-checkpoint blockade (ICB) were analyzed separately; these included DNA mismatch repair (MMR) gene alterations, tumor mutational burden (TMB), and microsatellite instability (MSI). Data from The Cancer Genome Atlas (TCGA) consortium as well as public data from several clinical trials in metastatic RCC were used for validation purposes. Multiregional sequencing data from the TRAcking Cancer Evolution through Therapy (TRACERx) RENAL cohort were used to assess the clonality of somatic mutations. RESULTS: Of the 753 individuals with RCC identified in the MSK-IMPACT cohort, 115 showed evidence of targetable alterations, which represented a prevalence of 15.3% [95% confidence interval (CI), 12.7%-17.8%). When stratified by levels of evidence, the alterations identified corresponded to levels 2 (11.3%), 3A (5.2%), and 3B (83.5%). A low prevalence was recapitulated in the TCGA cohort at 9.1% (95% CI, 6.9%-11.2%). Copy-number variations predominated in papillary RCC tumors, largely due to amplifications in the MET gene. Notably, higher rates of actionability were found in individuals with metastatic disease (stage IV) compared with those with localized disease (OR, 2.50; 95% CI, 1.16-6.16; Fisher's P = 0.01). On the other hand, the prevalence of alterations associated with response to ICB therapy was found to be approximately 5% in both the MSK-IMPACT and TCGA cohorts and no associations with disease stage were identified (OR, 1.35; 95% CI, 0.46-5.40; P = 0.8). Finally, multiregional sequencing revealed that the vast majority of actionable mutations occurred later during tumor evolution and were only present subclonally in RCC tumors. CONCLUSIONS: RCC harbors a low prevalence of clinically actionable alterations compared with other tumors and the evidence supporting their clinical use is limited. These aberrations were found to be more common in advanced disease and seem to occur later during tumor evolution. Our study provides new insights on the role of targeted therapies for RCC and highlights the need for additional research to improve treatment selection using genomic profiling.

Evolving biological associations of upfront cytoreductive nephrectomy in metastatic renal cell carcinoma.

BACKGROUND: Systemic responses to cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) are variable and difficult to anticipate. The authors aimed to determine the association of CN with modifiable International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors and oncological outcomes. METHODS: Consecutive patients with mRCC referred for potential CN (2009-2019) were reviewed. The primary outcome was overall survival (OS); variables of interest included undergoing CN and the baseline number of modifiable IMDC risk factors (anemia, hypercalcemia, neutrophilia, thrombocytosis, and reduced performance status). For operative cases, the authors evaluated the effects of IMDC risk factor dynamics, measured 6 weeks and 6 months after CN, on OS and postoperative treatment disposition. RESULTS: Of 245 treatment-naive patients with mRCC referred for CN, 177 (72%) proceeded to surgery. The CN cases had fewer modifiable IMDC risk factors (P = .003), including none in 71 of 177 patients (40.1%); fewer metastases (P = .011); and higher proportions of clear cell histology (P = .012). In a multivariable analysis, surgical selection, number of IMDC risk factors, metastatic focality, and histology were associated with OS. Total risk factors changed for 53.8% and 57.2% of the patients from the preoperative period to 6 weeks and 6 months after CN, respectively. Adjusted for preoperative IMDC risk scores, an increase in IMDC risk factors at 6 weeks and 6 months was associated with adverse OS (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.13-2.19; P = .007; HR, 2.52; 95% CI, 1.74-3.65; P < .001). CONCLUSIONS: IMDC risk factors are dynamic clinical variables that can improve after upfront CN in select patients, and this suggests a systemic benefit of cytoreduction, which may confer clinically meaningful prognostic implications.

Single-cell sequencing links multiregional immune landscapes and tissue-resident T cells in ccRCC to tumor topology and therapy efficacy.

Clear cell renal cell carcinomas (ccRCCs) are highly immune infiltrated, but the effect of immune heterogeneity on clinical outcome in ccRCC has not been fully characterized. Here we perform paired single-cell RNA (scRNA) and T cell receptor (TCR) sequencing of 167,283 cells from multiple tumor regions, lymph node, normal kidney, and peripheral blood of two immune checkpoint blockade (ICB)-naïve and four ICB-treated patients to map the ccRCC immune landscape. We detect extensive heterogeneity within and between patients, with enrichment of CD8A+ tissue-resident T cells in a patient responsive to ICB and tumor-associated macrophages (TAMs) in a resistant patient. A TCR trajectory framework suggests distinct T cell differentiation pathways between patients responding and resistant to ICB. Finally, scRNA-derived signatures of tissue-resident T cells and TAMs are associated with response to ICB and targeted therapies across multiple independent cohorts. Our study establishes a multimodal interrogation of the cellular programs underlying therapeutic efficacy in ccRCC.

A qualitative framework of non-selection factors for cytoreductive nephrectomy.

PURPOSE: Cytoreductive nephrectomy (CN) benefits a subset of patients with metastatic renal cell carcinoma (mRCC), however proper patient selection remains complex and controversial. We aim to characterize urologists' reasons for not undertaking a CN at a quaternary cancer center. METHODS: Consecutive patients with mRCC referred to MSKCC urologists for consideration of CN between 2009 and 2019 were included. Baseline clinicopathologic characteristics were used to compare patients selected or rejected for CN. The reasons cited for not operating and the alternative management strategies recommended were extrapolated. Using an iterative thematic analysis, a framework of reasons for rejecting CN was designed. Kaplan-Meier estimates tested for associations between the reasons for not undertaking a CN and overall survival (OS). RESULTS: Of 297 patients with biopsy-proven mRCC, 217 (73%) underwent CN and 80 (27%) did not. Median follow-up of patients alive at data cut-off was 27.3 months. Non-operative patients were older (p = 0.014), had more sites of metastases (p = 0.008), harbored non-clear cell histology (p = 0.014) and reduced performance status (p < 0.001). The framework comprised seven distinct themes for recommending non-operative management: two patient-fitness considerations and five oncological considerations. These considerations were associated with OS; four of the oncological factors conferred a median OS of less than 12 months (p < 0.001). CONCLUSION: We developed a framework of criteria by which patients were deemed unsuitable candidates for CN. These new insights provide a novel perspective on surgical selection, could potentially be applicable to other malignancies and possibly have prognostic implications.

The spinal distribution of metastatic renal cell carcinoma: Support for locoregional rather than arterial hematogenous mode of early bony dissemination.

BACKGROUND: Quantifying the degree to which spinal involvement of metastatic renal cell carcinoma (mRCC) is a locoregional phenomenon vs. a hematogenous, bone-specific affinity has implications for prognosis and antimetastatic therapy. OBJECTIVE: To investigate the distribution of spinal metastasis in mRCC and to explore relationships between clinical factors and patterns of spinal spread. METHODS: Patients with mRCC and spinal involvement from June 2005 to November 2018 were identified. Clinical and biologic features including primary tumor size and degree of spinal and nonbony metastatic involvement were collected. Spinal distributions were evaluated by the permutation test, with the null hypothesis that metastases are distributed uniformly across levels. RESULTS: One hundred patients with 685 spinal levels involved by mRCC were evaluated. A nonuniform spatial distribution was observed across the cohort (P < 0.001); a preponderance of thoracolumbar involvement was noted with the mode at L3. No significant deviation in metastatic distribution from uniform was observed in right- or left-sided tumors, subgroups of distant or local metastases, or histology. Patients with smaller tumors (<4 cm) and local spread had distribution of spinal metastases not significantly different from uniform (P = 0.292 and P = 0.126, respectively). CONCLUSIONS: These data support a dominant locoregional as opposed to arterial hematogenous mechanism for early spinal dissemination of mRCC. Characterizations of the biologic molecular features contributing to osseous tropism and aggressive tumor biology (as seen in the subset of outlier patients with small tumors who appear to have more uniform spread), have implications for surveillance and are an area of active investigation.

Putative Drivers of Aggressiveness in TCEB1-mutant Renal Cell Carcinoma: An Emerging Entity with Variable Clinical Course.

BACKGROUND: TCEB1-mutant renal cell carcinoma (RCC) is a rare variant of RCC with clear-cell features. Owing to its unique morphological and molecular features it has recently been proposed as a separate entity. Initial series suggested an indolent, early-stage phenotype. Here we expand our clinical cohort and describe a more detailed genomic analysis looking for potential drivers of aggressiveness. DESIGN, SETTING, AND PARTICIPANTS: We identified five new cases in our institutional sequencing cohort, four of whom were found to have high-stage disease (American Joint Committee on Cancer stage III/IV). Twelve previously reported cases were pooled for comparison purposes (Sato, The Cancer Genome Atlas, TRACERx Renal). OUTCOME MEASURES AND STATISTICAL ANALYSIS: We used our previously validated pipeline to analyze somatic mutations and copy number alterations (CNAs) in seven tumor samples with available data and estimated the number of cancer cells bearing each somatic mutation. The oncogenic potential of mutations was assessed using OncoKB and two other algorithms. Mann-Whitney U tests were used to evaluate differences in genomic markers between stage groups. RESULTS AND LIMITATIONS: All tumors showed biallelic inactivation of the TCEB1 gene according to a combination of somatic mutation and CNA analyses. Mutations were always found in residues involved in hydrophobic interactions with VHL. We found that high-stage tumors had additional oncogenic mutations (median 1, interquartile range [IQR] 1-1 vs 2, IQR 2-2; median difference 1, 95% confidence interval [CI] 1-1; p= 0.002) and showed whole-genome doubling events. They also seemed to have a higher burden of somatic CNAs (median fraction CNA genome 0.10, IQR 0.10-0.15 vs 0.63, IQR 0.58-0.68), however, this finding did not reach statistical significance (median difference 0.49, 95% CI 0.33-0.63; p=0.052). CONCLUSIONS: TCEB1-mutant RCC can show variable behavior ranging from very indolent to aggressive. Specific molecular events leading to high genomic instability seem to be associated with aggressiveness. This study expands the clinical spectrum of TCEB1-mutant RCC. PATIENT SUMMARY: We present four cases of aggressive TCEB1-mutant renal cell carcinoma, a rare type of kidney cancer. In-depth analysis of the genomes of these tumors revealed certain abnormalities that might explain this aggressive behavior.

The Clinicopathologic and Molecular Landscape of Clear Cell Papillary Renal Cell Carcinoma: Implications in Diagnosis and Management.

BACKGROUND: Clear cell papillary renal cell carcinoma (CCPRCC) is a recently described tumor entity. Several questions remain about its epidemiology, molecular features, and clinical behavior. OBJECTIVE: To comprehensively evaluate clinicopathologic and molecular features of CCPRCC, and compare it with more common kidney cancer subtypes. DESIGN, SETTING, AND PARTICIPANTS: We identified 89 CCPRCC patients and compared their clinicopathologic features with 1120 localized clear cell renal cell carcinoma (ccRCC) and 129 type 1 papillary renal cell carcinoma (pRCC) patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Nonparametric statistical testing was used to compare relevant features between tumor types. Overall, cancer-specific survival (CSS) and metastasis-free survival estimates were calculated from initial diagnosis using the Kaplan-Meier method. Patients with ipsilateral multifocal disease were explored further. A subset of CCPRCC tumors underwent genomic analysis and were compared with other RCC subtypes. RESULTS AND LIMITATIONS: A higher proportion of female (45% vs 32%) and African-American (19% vs 3%) patients were observed in the CCPRCC cohort than in the ccRCC and pRCC cohorts. CCPRCC tumors also had increased odds of presenting with additional ipsilateral masses (odds ratio [OR]: 4.41 [confidence interval {CI}: 2.34, 8.15], p < 0.001) and bilateral disease (OR: 4.80 [CI: 2.40, 9.59], p < 0.001) compared with ccRCC tumors. On molecular analysis, CCPRCC tumors showed fewer somatic aberrations and a greater degree of mitochondrial DNA depletion. In multifocal CCPRCC tumors, histologic concordance among the different renal cell carcinoma masses was estimated at 44% (7/16), and none of the individuals presenting exclusively with CCPRCC tumors developed metastatic disease after 5 yr. In contrast, multifocal tumors with CCPRCC and other nonconcordant histologies were more likely to experience adverse outcomes (CSS, log rank p = 0.034). CONCLUSIONS: CCPRCC is characterized by distinct molecular and epidemiologic features that could be used to refine current diagnostic approaches. Although their clinical course is generally indolent, multifocal CCPRCC tumors represent a unique diagnostic challenge. In this context, single-mass biopsies could miss concomitant aggressive disease, with a potential negative impact on patient outcomes. Furthermore, high discordance rates in multifocal CCPRCC tumors have important clinical implications in management. PATIENT SUMMARY: We explored the molecular and clinical features of clear cell papillary renal cell carcinoma (CCPRCC) relative to other kidney cancer subtypes. While CCPRCC generally conveys a good prognosis, additional caution should be taken when it is diagnosed using biopsy if multiple kidney masses are present.