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There is a critical unmet need for safe and efficacious neoadjuvant treatment for cisplatin-ineligible patients with muscle-invasive bladder cancer. Here we launched a phase 1b study using the combination of intravesical cretostimogene grenadenorepvec (oncolytic serotype 5 adenovirus encoding granulocyte–macrophage colony-stimulating factor) with systemic nivolumab in cisplatin-ineligible patients with cT2-4aN0-1M0 muscle-invasive bladder cancer. The primary objective was to measure safety, and the secondary objective was to assess the anti-tumor efficacy as measured by pathologic complete response along with 1-year recurrence-free survival. No dose-limiting toxicity was encountered in 21 patients enrolled and treated. Combination treatment achieved a pathologic complete response rate of 42.1% and a 1-year recurrence-free survival rate of 70.4%. Pathologic response was associated with baseline free E2F activity and tumor mutational burden but not PD-L1 status. Although T cell infiltration was broadly induced after intravesical oncolytic immunotherapy, the formation, enlargement and maturation of tertiary lymphoid structures was specifically associated with complete response, supporting the importance of coordinated humoral and cellular immune responses. Together, these results highlight the potential of this combination regimen to enhance therapeutic efficacy in cisplatin-ineligible patients with muscle-invasive bladder cancer, warranting additional study as a neoadjuvant therapeutic option. ClinicalTrials.gov identifier: NCT04610671 . In a phase 1b trial, treatment of patients with muscle-invasive bladder cancer with intravesical oncolytic virus cretostimogene grenadenorepvec in combination with nivolumab was safe and led to encouraging preliminary clinical response rates.

BackgroundEpidural anesthesia has been associated with a decrease in cardiopulmonary complications and a decrease in blood loss in orthopedic procedures. Its influence on the outcomes of patients receiving radical cystectomies is unknown. We aim to use the large national database from the National Surgical Quality Improvement Project (NSQIP) to examine whether postoperative complications may be affected by the use of epidural anesthesia during radical cystectomy.MethodsData were collected from the 2014–2016 participant user files of the NSQIP database. Patients receiving radical cystectomy were identified by CPT code and further stratified by anesthesia type. Demographics, length of stay, and 30-day complications including death were collected and analyzed using univariable and multivariable analysis.ResultsA total of 6448 patients met the inclusion criteria for analysis. Between 2014 and 2016, 5064 patients received general anesthesia only (GA) and 1384 patients received general and epidural anesthesia (GEA). Statistical analysis showed an overall increase in major complications (17.8% vs 18.5%) in the GEA group (p = 0.0046). Subgroup analysis showed major complications to be more likely in patients older than 75 years receiving GEA instead of GA (p = 0.0301).ConclusionsElderly patients (age > 75) undergoing radical cystectomy may experience more major complications with the use of epidural anesthesia. This may be due to end-organ effects from the hemodynamic changes of epidural anesthesia which are poorly tolerated in the elderly population. Further single intervention epidural studies need to be performed to isolate the effects of epidural anesthesia on individual surgical procedures.

New therapeutics in development for bladder cancer need to address the recalcitrant nature of the disease. Intravesical adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) can potentially induce durable responses in bladder cancer while maximizing T cells at the tumor site. T cells infused into the bladder directly encounter immunosuppressive populations, such as myeloid derived suppressor cells (MDSCs), that can attenuate T cell responses. Intravesical instillation of gemcitabine can be used as a lymphodepleting agent to precondition the bladder microenvironment for infused T cell products. Urine samples from bladder cancer patients and healthy donors were analyzed by flow cytometry and cytometric bead array for immune profiling and cytokine quantification. MDSCs were isolated from the urine and cocultured with stimulated T cells to assess effects on proliferation. An orthotopic murine model of bladder cancer was established using the MB49-OVA cell line and immune profiling was performed. MDSCs from tumor-bearing mice were cocultured with OT-I splenocytes to assess T cell proliferation. Mice received intravesical instillation of gemcitabine and depletion of immune cells was measured via flow cytometry. Bladder tumor growth of mice treated with intravesical gemcitabine, OT-I transgenic T cells, or combination was monitored via ultrasound measurement. In comparison to healthy donors, urine specimen from bladder cancer patients show high levels of MDSCs and cytokines associated with myeloid chemotaxis, T cell chemotaxis, and inflammation. T cells isolated from healthy donors were less proliferative when cocultured with MDSCs from the urine. Orthotopic murine bladder tumors also presented with high levels of MDSCs along with enrichment of cytokines found in the patient urine samples. MDSCs isolated from spleens of tumor-bearing mice exerted suppressive effects on the proliferation of OT-I T cells. Intravesical instillation of gemcitabine reduced overall immune cells, MDSCs, and T cells in orthotopic bladder tumors. Combination treatment with gemcitabine and OT-I T cells resulted in sustained anti-tumor responses in comparison to monotherapy treatments. MDSCs are enriched within the microenvironment of bladder tumors and are suppressive to T cells. Gemcitabine can be used to lymphodeplete bladder tumors and precondition the microenvironment for intravesical ACT.

Purpose of reviewThis review sought to define the emerging roles of urinary tumor DNA (utDNA) for diagnosis, monitoring, and treatment of bladder cancer. Building from early landmark studies the focus is on recent studies, highlighting how utDNA could aid personalized care.Recent findingsRecent research underscores the potential for utDNA to be the premiere biomarker in bladder cancer due to the constant interface between urine and tumor. Many studies find utDNA to be more informative than other biomarkers in bladder cancer, especially in early stages of disease. Points of emphasis include superior sensitivity over traditional urine cytology, broad genomic and epigenetic insights, and the potential for non-invasive, real-time analysis of tumor biology.SummaryutDNA shows promise for improving all phases of bladder cancer care, paving the way for personalized treatment strategies. Building from current research, future comprehensive clinical trials will validate utDNA's clinical utility, potentially revolutionizing bladder cancer management.

Tumor infiltrating lymphocytes (TIL) therapy was shown to provide durable objective response in patients with metastatic melanoma. As a fundamental first step to bring TIL therapy to clinical use, identification of patients whose tumors yield optimal numbers of reactive TIL is indispensable. We have previously shown that expansion of tumor reactive TIL from primary bladder tumors and lymph node metastases is feasible. Here, we performed TIL harvesting from additional surgical specimens (additional 31 primary tumors and 10 lymph nodes) to generate a heterogenous cohort of 53 patients with bladder cancer (BC) to evaluate the tumor characteristics that lead to tumor-reactive TIL expansion. Among a total of 53 patients, overall TIL growth from tumor samples were 37/53 (69.8%) and overall anti-tumor reactive TIL were 26/35 (74.3%). Mixed urothelial carcinoma is associated with higher anti-tumor reactivity of expanded TIL than pure urothelial carcinoma (89.5% vs. 56.3%, p=0.049). The anti-tumor reactivity of expanded TIL from primary tumors previously treated with BCG immunotherapy were lower (33.3% vs. 82.6%, p=0.027) although T-cell phenotype (CD3+, CD4+, CD8+, and CD56+) was similar regardless prior of BCG therapy. Addition of agonistic 4-1BB antibody in culture media with IL-2 improved the number of expanded TIL from primary tumors previously treated with BCG immunotherapy. There was no significant difference between basal and luminal subtype tumors in terms of viable and reactive TIL growth. Our study demonstrates that TIL expansion is feasible across all BC patients and BC subtypes, and we suggest that TIL therapy can be a reasonable treatment strategy for various manifestations of BC.

Tumor acidosis is a hallmark of cancer that leads to abrogation of T cell function and cancer progression. Oral sodium bicarbonate therapy for alkalization of the extracellular tumor pH has shown moderate positive effects in tumor models. However, its applicability in the clinic is very limited due to the unreasonably high dosage required and gastrointestinal disturbances that arise. In this study, we assessed the functional effects of acidity on T cells. We show that acidity alters T cell proliferation, migration and effector functions as well as transcriptional programming using in vitro culture techniques and RNA sequencing. We then tested the potency of a proprietary transdermal formulation, DYV800, containing sodium bicarbonate to increase the extracellular tumor pH (pHe) and augment anti-tumor immune responses in a murine model of bladder cancer. The tumor pH was assessed using Chemical Exchange Saturation Transfer Magnetic Resonance Imaging (CEST-MRI) and antitumor immune responses via flow cytometry. We found that transdermal DYV800 significantly reduced tumor burden and improved antigen-specific CD8 T cell responses. Chemical Exchange Saturation Transfer Magnetic Resonance Imaging (CEST-MRI) of treated tumors showed an increase in intra-tumoral pH of bladder tumors, and this therapy also alkalizes the urine. The transdermal delivery of DYV800 led to durable anti-tumor immune responses and is more clinically applicable to combat acidity in bladder cancer than oral bicarbonate. Targeting acidosis in the bladder tumor microenvironment has the potential to enhance T cell responses and improve anti-tumor immunity.

Background The perioperative period can be a critical period with long-term implications on cancer-related outcomes. In this study, we evaluate the influence of regional anesthesia on cancer-specific outcomes in a radical cystectomy (RC) cohort of patients. Methods We performed a retrospective analysis of patients with clinically-nonmetastatic urothelial carcinoma of the bladder who underwent RC at our institution from 2008 to 2012. Patients were retrospectively registered and stratified based on two anesthetic techniques: perioperative epidural analgesia with general anesthesia (epidural) versus general anesthesia alone (GA). Epidural patients received a sufentanil-based regimen (median intraoperative sufentanil dose 50 mcg (45,85). Propensity-score was used to make 1:1 case-control matching. Cumulative risk of recurrence with competing risks was calculated based on anesthetic technique. Kaplan-Meier curves were used to compare recurrence-free (RFS) and cancer-specific survival (CSS). Univariable and multivariable analyses were performed with Cox proportional hazard regression models for RFS and CSS. Results Only patients with complete data on anesthetic technique were included. Out of 439 patients, 215-pair samples with complete follow-up were included in the analysis. Median follow-up was 41.4 months (range: 0.20–101). Patients with epidurals received higher median total intravenous morphine equivalents (ivMEQ) versus those in the GA group (75 (11–235) vs. 50 ivMEQ (7–277), p  < 0.0001). Cumulative risk of recurrence at two years was 25.2% (19.6, 31.2) for epidural patients vs. 20.0% (15.0, 25.7) for GA patients (Gray test p  = 0.0508). Epidural analgesic technique was a significant predictor of worse RFS (adjusted HR = 1.67, 1.14–2.45; p  = 0.009) and CSS (HR = 1.53, 1.04–2.25; p  = 0.030) on multivariable analyses. Conclusions Epidural anesthesia using sufentanil was associated with worse recurrence and disease-free survival in bladder cancer patients treated with surgery. This may be due use of epidural sufentanil or due to the increased total morphine equivalents patient received as a consequence of this drug.

Introduction Although enhanced recovery after surgery (ERAS) components include both anesthesia and surgical care processes, it is unclear whether a multidisciplinary approach to implementing ERAS care processes improves clinical outcomes. The addition of multidisciplinary care with anesthesiology-related components to an existing ERAS protocol for radical cystectomy at a US comprehensive cancer center provided an opportunity to compare short- and long-term outcomes. Methods We retrospectively compared the outcomes of 116 consecutive patients who underwent cystectomy after implementation of a multidisciplinary ERAS protocol with those of a historical control group of 143 consecutive patients who had been treated with a surgical ERAS protocol. Length of stay, return of bowel function, rate of blood transfusion, nausea, pain, and readmission rates were examined. Results Implementation of a multidisciplinary ERAS protocol was associated with better postsurgical symptom control, as indicated by lower rates of patient-reported nausea ( P  < .05). Multivariate Poisson regression analysis showed a decrease in estimated intraoperative transfusions ( P  ≤ .001) after adjusting for the effects of potential confounding variables. There were no statistically significant differences noted in length of stay, return of bowel function, 30- and 90-day complications, or readmissions. Conclusion This is the first study to investigate the effects of adding anesthesia ERAS components to an existing surgical ERAS protocol for radical cystectomy. We found that with the addition of anesthesia-related interventions, there was a decrease in transfusions and nausea.

Purpose Lymphadenectomy (LND) is part of the surgical management of penile cancer but causes significant perioperative morbidity. We determined whether sarcopenia, a novel marker of nutritional status, is a predictor of postoperative complications after LND. Materials and methods Seventy-nine patients underwent LND for penile cancer from 1999 to 2014, and 43 had available preoperative abdominal imaging. Skeletal muscle index (SMI) was calculated on axial computed tomography images at the third lumbar vertebrae, and an SMI of 55 cm 2 /m 2 was used to classify patients as sarcopenic versus not. This classification was then correlated with postoperative complications and survival. Results Median lumbar SMI was 54.7 cm 2 /m 2 with 22 (51.2 %) patients categorized as sarcopenic versus 21 (48.8 %) who were not. Twenty-seven postoperative complications occurred in 20 patients within 30 days, of which 11 (40.7 %) were major (Clavien score ≥IIIa) and 16 (59.3 %) were minor. The most common complications were wound dehiscence (25.9 %), wound infection (18.5 %), lymphocele (18.5 %), and flap necrosis (14.8 %). On univariate analysis, the presence of sarcopenia, nodal disease, and lymphovascular invasion were predictors of postoperative complications. On multivariate analysis, only sarcopenia was an independent predictor of 30-day complications [ p  = 0.038; 95 % confidence interval (CI) 1.1–21.1]. Although sarcopenia was not statistically associated with worse overall survival (OS), there was a trend toward poorer outcomes in these patients. Conclusions Sarcopenia can be a useful prognostic tool to predict the likelihood of postoperative complications after LND for penile cancer. Preoperative nutritional supplementation may help reduce complication rates in the future.

BackgroundMuscle-invasive urothelial cancer (UC) has a high risk of recurrence after definitive treatment. Nivolumab adjuvant to radical surgery improves disease-free survival in patients with UC with a high risk of recurrence; however, its role adjuvant to chemoradiation therapy (CRT) is unknown.MethodsThe NEXT trial is a single-arm, phase-2 study evaluating the efficacy and tolerability of nivolumab adjuvant to CRT in patients with localized or locoregional UC. The primary endpoint is failure-free survival (FFS) at 2 years. Secondary endpoints include patterns of recurrence, toxicity and quality of life (QoL). Plasma cell-free DNA (cfDNA) was subjected to shallow whole-genome sequencing to correlate with outcomes.Results28 patients were enrolled and received 480 mg of nivolumab intravenously every 4 weeks for up to 12 cycles adjuvant to CRT. The FFS at 2 years was 33.2% (95% CI 18.5% to 59.6%). Nine (32%) patients had localized progression, and eight (29%) had distant progression. 25 (89%) had one or more high-risk features (ie, plasmacytoid differentiation, T4, N+, multiple tumors, tumors >5 cm, residual disease before CRT, carcinoma in situ, and hydronephrosis). Patients with ≤2 high-risk features had a median FFS of 45.2 months (95% CI 14.56 to not reached (NR)) compared with 8.2 months (95% CI 7.1 to NR) in those with three or more risk features (p=0.0024). Nivolumab-associated treatment-related adverse events occurred in 18 (64.3%) patients, only 3 had grade 3 TRAEs, with significant changes in QoL. Plasma cfDNA copy number instability (CNI) scores ≤25 before the first dose of adjuvant nivolumab and at cycle 4 were associated with better overall survival compared with CNI scores ≥26 (49.6 months vs 20.5 months, p=0.0024). Genome copy number changes indicated chromatin remodeling and tyrosine kinase pathways, among others, as oncogenic drivers implicated in progression.ConclusionNivolumab adjuvant to CRT in localized or locally advanced UC is well tolerated. Stratification by risk factors and correlation with plasma cfDNA analyses generate hypotheses for potential patient selection and putative therapeutic targets for future study.Trial registration numberNCT03171025.