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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.

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.

PurposeTo describe the perioperative safety, functional and immediate post-operative oncological outcomes of minimally invasive RPLND (miRPLND) for testis cancer.MethodsWe performed a retrospective multi-centre cohort study on testis cancer patients treated with miRPLND from 16 institutions in eight countries. We measured clinician-reported outcomes stratified by indication. We performed logistic regression to identify predictors for maintained postoperative ejaculatory function.ResultsData for 457 men undergoing miRPLND were studied. miRPLND comprised laparoscopic (n = 56) or robotic (n = 401) miRPLND. Indications included pre-chemotherapy in 305 and post-chemotherapy in 152 men. The median retroperitoneal mass size was 32 mm and operative time 270 min. Intraoperative complications occurred in 20 (4%) and postoperative complications in 26 (6%). In multivariable regression, nerve sparing, and template resection improved ejaculatory function significantly (template vs bilateral resection [odds ratio (OR) 19.4, 95% confidence interval (CI) 6.5–75.6], nerve sparing vs non-nerve sparing [OR 5.9, 95% CI 2.3–16.1]). In 91 men treated with primary RPLND, nerve sparing and template resection, normal postoperative ejaculation was reported in 96%. During a median follow-up of 33 months, relapse was detected in 39 (9%) of which one with port site (< 1%), one with peritoneal recurrence and 10 (2%) with retroperitoneum recurrences.ConclusionThe low proportion of complications or peritoneal recurrences and high proportion of men with normal postoperative ejaculatory function supports further miRPLND studies.

Objectives: Accurate pathologic interpretation of testicular germ cell tumors (GCTs) can be problematic due to low incidence and variation in histologic patterns. By analyzing changes in the diagnosis of testicular specimens after secondary review, we hoped to determine how these can affect prognosis and treatment. Methods: From 1999 to 2013, a total of 235 patients underwent radical orchiectomy at a referring facility and had pathology specimens reanalyzed by our center’s pathologists with expertise in genitourinary malignancies. We identified discrepancies in pathologic reporting. Results: Fifty (21.3%) patients had variations in interpretation of their orchiectomy specimens. A clinically significant alteration was identified in 16 (6.8%) patients, most commonly due to recognition (or misrecognition) of lymphovascular invasion (LVI) associated with nonseminomatous germ cell tumors (NSGCTs). Changes in LVI status resulted in upstaging or downstaging from clinical stage 1A to stage 1B or vice versa in six patients with NSGCTs, with a subsequent change in therapeutic strategy. In addition, one patient with stage 1 pure seminoma had been misclassified with nonseminoma. Conclusions: Inaccurate interpretation of orchiectomy specimens is not uncommon and may lead to incorrect tumor staging, imprecise assignment of progression risk, and inappropriate management recommendations. Secondary opinions of primary GCT orchiectomy specimens potentially facilitate appropriate counseling and therapeutic strategies.

Understanding tumor-resident T cells is important for cancer prognosis and treatment options. Conventional, solid tumor specimen exome files can be searched directly for recombined T cell receptor (TcR)-α segments; RNASeq files can include TcR-β VDJ recombinations. To learn whether there are medically relevant uses of exome-based detection of TcR V(D)J recombinations in the tumor microenvironment, we searched cancer genome atlas and Moffitt Cancer Center, tumor specimen exome files for TcR-β, TcR-γ, and TcR-δ recombinations, for bladder and stomach cancer. We found that bladder cancer exomes with productive TcR-β recombinations had a significant association with No Subsequent Tumors and a positive response to drug treatments, with p  < 0.004, p  < 0.05, and p  < 0.004, depending on the sample sets examined. We also discovered the opportunity to detect productive TcR-γ and TcR-δ recombinations in the tumor microenvironment, via the tumor specimen exome files.

Tumor immunoscoring is rapidly becoming a universal parameter of prognosis, and T-cells isolated from tumor masses are used for ex vivo amplification and readministration to patients to facilitate an antitumor immune response. We recently exploited the cancer genome atlas (TCGA) RNASeq data to assess T-cell receptor (TcR) expression and, in particular, discovered strong correlations between major histocompatibility class II (MHCII) and TcR-α constant region expression levels. In this article, we describe the results of searching TCGA exome files for TcR-α V-regions, followed by searching the V-region datasets for TcR-α-J regions. Both primary and metastatic breast cancer sample files contained recombined TcR-α V-J regions, ranging in read counts from 16–39, at the higher level. Among four such V-J rearrangements, three were productive rearrangements. Rearranged TcR-α V–J regions were also detected in TCGA–bladder cancer, -lung cancer, and -ovarian cancer datasets, as well as exome files representing bladder cancer, in Moffitt Cancer Center patients. These results suggest that a direct search of commonly available, conventional exome files for rearranged TcR segments could play a role in more sophisticated immunoscoring or in identifying particular T-cell clones and TcRs directed against tumor antigens.

PurposeFollowing radical orchiectomy, surveillance and primary retroperitoneal lymph node dissection (RPLND) are acceptable options for the management of early stage pure testicular teratoma in adult patients; however, there is no uniform consensus. The aim of this study was to investigate survival outcomes of adults with early stage pure testicular teratoma based on management strategy.MethodsData was extracted from the National Cancer Database (NCDB) from testicular cancer patients diagnosed with clinical stage (CS) I pure teratoma (pT1-4N0M0S0) between 2004 and 2014. Kaplan-Meier and Cox regression analyses were used to assess clinical outcomes based on management strategy.ResultsOf the 61,167 patients diagnosed with testicular cancer, 692 (1.1%) had pure teratoma. Only individuals with CS I disease were considered (n = 237). The median age was 28 (23–35) years. Overall, 43 (18%) patients underwent RPLND and 194 (82%) patients were managed with surveillance. There was an increase in surveillance for CS I teratoma during the study period. Increasing distance from residence to treatment facility was an unadjusted predictor for undergoing primary RPLND (p < 0.001). Median follow-up was 54 months and there was no significant difference in overall survival between CS I teratoma patients managed with RPLND and those managed with surveillance (p = 0.13).ConclusionsThere has been a trend toward increasing adoption of surveillance for the management of early stage pure testicular teratoma in adults. Our findings suggest that surveillance provides comparable survival outcomes to primary retroperitoneal lymph node dissection in this setting.

Approximately 10%‐20% of patients with clinically localized clear cell renal cell carcinoma (ccRCC) at time of surgery will subsequently experience metastatic progression. Although considerable progression was seen in the systemic treatment of metastatic ccRCC in last 20 years, once ccRCC spreads beyond the confines of the kidney, 5‐year survival is less than 10%. Therefore, significant clinical advances are urgently needed to improve overall survival and patient care to manage the growing number of patients with localized ccRCC. We comprehensively evaluated expression of 388 candidate genes related with survival of ccRCC by using TCGA RNAseq (n = 515), Total Cancer Care (TCC) expression array data (n = 298), and a well characterized Moffitt RCC cohort (n = 248). We initially evaluated all 388 genes for association with overall survival using TCGA and TCC data. Eighty‐one genes were selected for further analysis and tested on Moffitt RCC cohort using NanoString expression analysis. Expression of nine genes (AURKA, AURKB, BIRC5, CCNE1, MK167, MMP9, PLOD2, SAA1, and TOP2A) was validated as being associated with poor survival. Survival prognostic models showed that expression of the nine genes and clinical factors predicted the survival in ccRCC patients with AUC value: 0.776, 0.821 and 0.873 for TCGA, TCC and Moffitt data set, respectively. Some of these genes have not been previously implicated in ccRCC survival and thus potentially offer insight into novel therapeutic targets. Future studies are warranted to validate these identified genes, determine their biological mechanisms and evaluate their therapeutic potential in preclinical studies. Our study identified nine genes as prognostic biomarkers of ccRCC survival. Some of these genes have not been previously implicated in ccRCC survival and thus potentially offer insight into novel therapeutic targets.

Introduction Solid testis tumors in post‐pubertal males usually represent germ cell malignancies; however, other uncommon or rare histologies must be considered. Case presentation We present a case of an 18‐year‐old male undergoing attempted bilateral partial orchiectomies for suspected germ cell tumors. Tumor pathology, laboratory results, radiographic studies, and post‐surgical elevated adrenocorticotropic hormone levels supported the diagnosis of testicular adrenal rest tumors secondary to previously undiagnosed nonclassical congenital adrenal hyperplasia. Conclusion Testicular adrenal rest tumors are rare in patients with nonclassical congenital adrenal hyperplasia and may be accompanied by adrenal insufficiency and hypogonadism, which can be treated with glucocorticoid therapy and testosterone replacement. Differential diagnosis of tumors is challenging but necessary for proper symptom‐based management.

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.