Urine scRNAseq reveals new insights into the bladder tumor immune microenvironment.

Due to bladder tumors' contact with urine, urine-derived cells (UDCs) may serve as a surrogate for monitoring the tumor microenvironment (TME) in bladder cancer (BC). However, the composition of UDCs and the extent to which they mirror the tumor remain poorly characterized. We generated the first single-cell RNA-sequencing of BC patient UDCs with matched tumor and peripheral blood mononuclear cells (PBMC). BC urine was more cellular than healthy donor (HD) urine, containing multiple immune populations including myeloid cells, CD4+ and CD8+ T cells, natural killer (NK) cells, B cells, and dendritic cells (DCs) in addition to tumor and stromal cells. Immune UDCs were transcriptionally more similar to tumor than blood. UDCs encompassed cytotoxic and activated CD4+ T cells, exhausted and tissue-resident memory CD8+ T cells, macrophages, germinal-center-like B cells, tissue-resident and adaptive NK cells, and regulatory DCs found in tumor but lacking or absent in blood. Our findings suggest BC UDCs may be surrogates for the TME and serve as therapeutic biomarkers.

Novel bladder-sparing approaches in patients with muscle-invasive bladder cancer.

The pursuit of surgeons and oncologists in fulfilling the inherent desire of patients to retain their urinary bladder despite having muscle-invasive bladder cancer (MIBC) has sparked years of research and multiple debates, given its aggressive nature and the high risk of fatal metastatic recurrence. Historically, several approaches to bladder-sparing treatment have been explored, ranging from radical transurethral resection to concurrent chemoradiation. A less well-established approach involves a risk-adapted approach with local therapy deferred based on the clinical response to transurethral resection followed by systemic therapy. Each approach is associated with potential risks, benefits, and trade-offs. In this review, we aim to understand, navigate, and suggest future perspectives on bladder-sparing approaches in patients with MIBC.

Natural Killer Cell Dysfunction In Human Bladder Cancer Is Caused By Tissue-Specific Suppression of SLAMF6 Signaling.

NK cells are innate lymphocytes critical for surveillance of viruses and tumors, however the mechanisms underlying NK cell dysfunction in cancer are incompletely understood. We assessed the effector function of NK cells from bladder cancer patients and found severe dysfunction in NK cells derived from tumors versus peripheral blood. While both peripheral and tumor-infiltrating NK cells exhibited conserved patterns of inhibitory receptor over-expression, this did not explain the observed defects in NK surveillance in bladder tumors. Rather, TME-specific TGF-ß and metabolic perturbations such as hypoxia directly suppressed NK cell function. Specifically, an oxygen-dependent reduction in signaling through SLAMF6 was mechanistically responsible for poor NK cell function, as tumor-infiltrating NK cells cultured ex vivo under normoxic conditions exhibited complete restoration of function, while deletion of SLAMF6 abrogated NK cell cytolytic function even under normoxic conditions. Collectively, this work highlights the role of tissue-specific factors in dictating NK cell function, and implicates SLAMF6 signaling as a rational target for immuno-modulation to improve NK cell function in bladder cancer.

Single-cell transcriptomic-informed deconvolution of bulk data identifies immune checkpoint blockade resistance in urothelial cancer.

Interactions within the tumor microenvironment (TME) significantly influence tumor progression and treatment responses. While single-cell RNA sequencing (scRNA-seq) and spatial genomics facilitate TME exploration, many clinical cohorts are assessed at the bulk tissue level. Integrating scRNA-seq and bulk tissue RNA-seq data through computational deconvolution is essential for obtaining clinically relevant insights. Our method, ProM, enables the examination of major and minor cell types. Through evaluation against existing methods using paired single-cell and bulk RNA sequencing of human urothelial cancer (UC) samples, ProM demonstrates superiority. Application to UC cohorts treated with immune checkpoint inhibitors reveals pre-treatment cellular features associated with poor outcomes, such as elevated SPP1 expression in macrophage/monocytes (MM). Our deconvolution method and paired single-cell and bulk tissue RNA-seq dataset contribute novel insights into TME heterogeneity and resistance to immune checkpoint blockade.

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.

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 (

BCG and Alternative Therapies to BCG Therapy for Non-Muscle-Invasive Bladder Cancer.

Bladder cancer is a heterogeneous disease. Treatment decisions are mostly decided based on disease stage (non-muscle invasive or muscle invasive). Patients with muscle-invasive disease will be offered a radical treatment combined with systemic therapy, while in those with non-muscle-invasive disease, an attempt to resect the tumor endoscopically will usually be followed by different intravesical instillations. The goal of intravesical therapy is to decrease the recurrence and/or progression of the tumor. In the current landscape of bladder cancer treatment, BCG is given intravesically to induce an inflammatory response and recruit immune cells to attack the malignant cells and induce immune memory. While the response to BCG treatment has changed the course of bladder cancer management and spared many "bladders", some patients may develop BCG-unresponsive disease, leaving radical surgery as the best choice of curative treatment. As a result, a lot of effort has been put into identifying novel therapies like systemic pembrolizumab and Nadofaragene-Firadenovac to continue sparing bladders if BCG is ineffective. Moreover, recent logistic issues with BCG production caused a worldwide BCG shortage, re-sparking interest in alternative BCG treatments including mitomycin C, sequential gemcitabine with docetaxel, and others. This review encompasses both the historic and current role of BCG in the treatment of non-muscle-invasive bladder cancer, revisiting BCG alternative therapies and reviewing the novel therapeutics that were approved for the BCG-unresponsive stage or are under active investigation.

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.

IL-15 synergizes with CD40 agonist antibodies to induce durable immunity against bladder cancer.

CD40 is a central costimulatory receptor implicated in productive antitumor immune responses across multiple cancers, including bladder cancer. Despite strong preclinical rationale, systemic administration of therapeutic agonistic antibodies targeting the CD40 pathway has demonstrated dose-limiting toxicities with minimal clinical activity, emphasizing an important need for optimized CD40-targeted approaches, including rational combination therapy strategies. Here, we describe a role for the endogenous IL-15 pathway in contributing to the therapeutic activity of CD40 agonism in orthotopic bladder tumors, with upregulation of transpresented IL-15/IL-15Rα surface complexes, particularly by cross-presenting conventional type 1 DCs (Dendritic Cells), and associated enrichment of activated CD8 T cells. In bladder cancer patient samples, we identify DCs as the primary source of IL-15, although they lack high levels of IL-15Rα at baseline. Using humanized immunocompetent orthotopic bladder tumor models, we demonstrate the ability to therapeutically augment this interaction through combined treatment with anti-CD40 agonist antibodies and exogenous IL-15, including the fully-human Fc-optimized antibody 2141-V11 currently in clinical development for the treatment of bladder cancer. Collectively, these data reveal an important role for IL-15 in mediating antitumor CD40 agonist responses in bladder cancer and provide key proof-of-concept for combined use of Fc-optimized anti-CD40 agonist antibodies and agents targeting the IL-15 pathway. These data support expansion of ongoing clinical studies evaluating anti-CD40 agonist antibodies and IL-15-based approaches to develop combinations of these promising therapeutics for the treatment of patients with bladder cancer.

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.

Development of a predictive model for recurrence-free survival in pTa low-grade bladder cancer.

BACKGROUND: Data on Ta low-grade (LG) non-muscle invasive bladder cancer (NMIBC) have shown that follow-up cystoscopies are normal in 82% and 67% of patients with single and multiple tumors, respectively. OBJECTIVE: To develop a predictive model associated with recurrence-free survival (RFS) at 6, 12, 18 and 24 months in TaLG cases that consider the patients' risk aversion. MATERIALS AND METHODS: Data from a prospectively maintained database of 202 newly diagnosed TaLG NMIBC patients treated at Scandinavian institutions were used for the analysis. To identify risk groups associated with recurrence, we performed a classification tree analysis. Association between risk groups and RFS was evaluated by Kaplan Meier analysis. A Cox proportional hazard model selected significant risk factors associated with RFS using the variables defining the risk groups. The reported C index for the Cox model was 0.7. The model was internally validated and calibrated using 1000 bootstrapped samples. A nomogram to estimate RFS at 6, 12, 18, and 24 months was generated. The performance of our model was compared to EUA/AUA stratification using a decision curve analysis (DCA). RESULTS: The tree classification found that tumor number, tumor size and age were the most relevant variables associated with recurrence. The patients with the worst RFS were those with multifocal or single, ≥ 4cm tumors. All the relevant variables identified by the classification tree were significantly associated with RFS in the Cox proportional hazard model. DCA analysis showed that our model outperformed EUA/AUA stratification and the treat all/none approaches. CONCLUSION: We developed a predictive model to identify TaLG patients that benefit from less frequent follow-up cystoscopy schedule based on the estimated RFS and personal recurrence risk aversion.

Comparing Oncological and Perioperative Outcomes of Open versus Laparoscopic versus Robotic Radical Nephroureterectomy for the Treatment of Upper Tract Urothelial Carcinoma: A Multicenter, Multinational, Propensity Score-Matched Analysis.

OBJECTIVES: To identify correlates of survival and perioperative outcomes of upper tract urothelial carcinoma (UTUC) patients undergoing open (ORNU), laparoscopic (LRNU), and robotic (RRNU) radical nephroureterectomy (RNU). METHODS: We conducted a retrospective, multicenter study that included non-metastatic UTUC patients who underwent RNU between 1990-2020. Multiple imputation by chained equations was used to impute missing data. Patients were divided into three groups based on their surgical treatment and were adjusted by 1:1:1 propensity score matching (PSM). Survival outcomes per group were estimated for recurrence-free survival (RFS), bladder recurrence-free survival (BRFS), cancer-specific survival (CSS), and overall survival (OS). Perioperative outcomes: Intraoperative blood loss, hospital length of stay (LOS), and overall (OPC) and major postoperative complications (MPCs; defined as Clavien-Dindo > 3) were assessed between groups. RESULTS: Of the 2434 patients included, 756 remained after PSM with 252 in each group. The three groups had similar baseline clinicopathological characteristics. The median follow-up was 32 months. Kaplan-Meier and log-rank tests demonstrated similar RFS, CSS, and OS between groups. BRFS was found to be superior with ORNU. Using multivariable regression analyses, LRNU and RRNU were independently associated with worse BRFS (HR 1.66, 95% CI 1.22-2.28, p = 0.001 and HR 1.73, 95%CI 1.22-2.47, p = 0.002, respectively). LRNU and RRNU were associated with a significantly shorter LOS (beta -1.1, 95% CI -2.2-0.02, p = 0.047 and beta -6.1, 95% CI -7.2-5.0, p < 0.001, respectively) and fewer MPCs (OR 0.5, 95% CI 0.31-0.79, p = 0.003 and OR 0.27, 95% CI 0.16-0.46, p < 0.001, respectively). CONCLUSIONS: In this large international cohort, we demonstrated similar RFS, CSS, and OS among ORNU, LRNU, and RRNU. However, LRNU and RRNU were associated with significantly worse BRFS, but a shorter LOS and fewer MPCs.

IL-15 synergizes with CD40 agonist antibodies to induce durable immunity against bladder cancer.

CD40 is a central co-stimulatory receptor implicated in the development of productive anti-tumor immune responses across multiple cancers, including bladder cancer. Despite strong preclinical rationale, systemic administration of therapeutic agonistic antibodies targeting the CD40 pathway have demonstrated dose limiting toxicities with minimal clinical activity to date, emphasizing an important need for optimized CD40-targeted approaches, including rational combination therapy strategies. Here, we describe an important role for the endogenous IL-15 pathway in contributing to the therapeutic activity of CD40 agonism in orthotopic bladder tumors, with upregulation of trans-presented IL-15/IL-15Rα surface complexes, particularly by cross-presenting cDC1s, and associated enrichment of activated CD8 T cells within the bladder tumor microenvironment. In bladder cancer patient samples, we identify DCs as the primary source of IL-15, however, they lack high levels of IL-15Rα at baseline. Using humanized immunocompetent orthotopic bladder tumor models, we demonstrate the ability to therapeutically augment this interaction through combined treatment with anti-CD40 agonist antibodies and exogenous IL-15, including the fully-human Fc-optimized antibody 2141-V11 currently in clinical development for the treatment of bladder cancer. Combination therapy enhances the crosstalk between Batf3-dependent cDC1s and CD8 T cells, driving robust primary anti-tumor activity and further stimulating long-term systemic anti-tumor memory responses associated with circulating memory-phenotype T and NK cell populations. Collectively, these data reveal an important role for IL-15 in mediating anti-tumor CD40 agonist responses in bladder cancer and provide key proof-of-concept for combined use of Fc-optimized anti-CD40 agonist antibodies and agents targeting the IL-15 pathway. These data support expansion of ongoing clinical studies evaluating anti-CD40 agonist antibodies and IL-15-based approaches to evaluate combinations of these promising therapeutics for the treatment of patients with bladder cancer.

Urine supernatant reveals a signature that predicts survival in clear-cell renal cell carcinoma.

OBJECTIVE: To profile the cell-free urine supernatant and plasma of a small cohort of clear-cell renal cell carcinoma (ccRCC) patients by measuring the relative concentrations of 92 proteins related to inflammation. Using The Cancer Genome Atlas (TCGA), we then performed a targeted mRNA analysis of genes encoding the above proteins and defined their effects on overall survival (OS). SUBJECTS/PATIENTS AND METHODS: Samples were collected prospectively from ccRCC patients. A multiplex proximity extension assay was used to measure the concentrations of 92 inflammation-related proteins in cell-free urine supernatants and plasma. Transcriptomic and clinical information from ccRCC patients was obtained from TCGA. Unsupervised clustering and differential protein expression analyses were performed on protein concentration data. Targeted mRNA analysis on genes encoding significant differentially expressed proteins was performed using TCGA. Backward stepwise regression analyses were used to build a nomogram. The performance of the nomogram and clinical benefit was assessed by discrimination and calibration, and a decision curve analysis, respectively. RESULTS: Unsupervised clustering analysis revealed inflammatory signatures in the cell-free urine supernatant of ccRCC patients. Backward stepwise regressions using TCGA data identified transcriptomic risk factors and risk groups associated with OS. A nomogram to predict 2-year and 5-year OS was developed using these risk factors. The decision curve analysis showed that our model was associated with a net benefit improvement compared to the treat-all/none strategies. CONCLUSION: We defined four novel biomarkers using proteomic and transcriptomic data that distinguish severity of prognosis in ccRCC. We showed that these biomarkers can be used in a model to predict 2-year and 5-year OS in ccRCC across different tumour stages. This type of analysis, if validated in the future, provides non-invasive prognostic information that could inform either management or surveillance strategies for patients.

Characteristics Contributing to Survival Differences Between Black and White Patients Following Cystectomy.

PURPOSE: Examine patient, tumor, and treatment characteristics effect on the disparity between black and white patients with muscle-invasive bladder cancer (MIBC) who undergo radical cystectomy (RC). METHODS: 1,286 black patients in the 2004 to 2016 National Cancer Database fit inclusion criteria. A tapered match was performed from 17,374 white patients sequentially matched to the black cohort on demographics (age, gender, insurance, income, education, county, diagnosis year), presentation (demographic variables, stage, grade, tumor size, Charlson score), and treatment (demographic and presentation variables, lymph node count, hospital volume, neoadjuvant chemotherapy [NAC], treatment delay), creating 3 matched cohorts. Chi-square and Kruskal-Wallis tests were used to compare cohorts. Kaplan-Meier analysis was used to compare 5-year overall survival (OS). RESULTS: 5-year OS rate was 40.4% and 35.6% for unmatched white and black cohorts (P < 0.001), respectively. Following demographics and presentation match, 5-year OS rate for white patients decreased to 39.2% (P = 0.003) and 39.10% (P = 0.019), respectively. After treatment match, 5-year OS rate decreased to 36.7% for white patient (P = 0.32). Following presentation match, 7.2% of black patients vs. 5.8% of white patients had treatment delay, and 10.1% of black patients vs. 11.2% of white patients received NAC. The treatment match resulted in a 0.3% difference between groups for treatment delay and NAC. CONCLUSIONS: Our analysis demonstrates that disparity between black and white patients with muscle-invasive bladder cancer exists in demographic-, presentation-, and treatment-related variables. Treatment variables may be a large contributing factor to survival disparities. Further research is needed to identify social, biological, and organizational inputs that contribute to these disparities.