Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial.

PURPOSE: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up. MATERIALS AND METHODS: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF). RESULTS: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease. CONCLUSIONS: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

Primary Chemoablation of Low-Grade Intermediate-Risk Nonmuscle-Invasive Bladder Cancer Using UGN-102, a Mitomycin-Containing Reverse Thermal Gel (Optima II): A Phase 2b, Open-Label, Single-Arm Trial.

PURPOSE: Low-grade intermediate-risk nonmuscle-invasive bladder cancer (LG IR NMIBC) is a recurrent disease, thus requiring repeated transurethral resection of bladder tumor under general anesthesia. We evaluated the efficacy and safety of UGN-102, a mitomycin-containing reverse thermal gel, as a primary chemoablative therapeutic alternative to transurethral resection of bladder tumor for patients with LG IR NMIBC. MATERIALS AND METHODS: This prospective, phase 2b, open-label, single-arm trial recruited patients with biopsy-proven LG IR NMIBC to receive 6 once-weekly instillations of UGN-102. The primary end point was complete response (CR) rate, defined as the proportion of patients with negative endoscopic examination, negative cytology and negative for-cause biopsy 3 months after treatment initiation. Patients with CR were followed quarterly up to 12 months to assess durability of treatment effect. Safety and adverse events were monitored throughout the trial. RESULTS: A total of 63 patients (38 males and 25 females 33-96 years old) enrolled and received ≥1 instillation of UGN-102. Among the patients 41 (65%) achieved CR at 3 months, of whom 39 (95%), 30 (73%) and 25 (61%) remained disease-free at 6, 9 and 12 months after treatment initiation, respectively. A total of 13 patients had documented recurrences. The probability of durable response 9 months after CR (12 months after treatment initiation) was estimated to be 73% by Kaplan-Meier analysis. Common adverse events (incidence ≥10%) included dysuria, urinary frequency, hematuria, micturition urgency, urinary tract infection and fatigue. CONCLUSIONS: Nonsurgical primary chemoablation of LG IR NMIBC using UGN-102 resulted in significant treatment response with sustained durability. UGN-102 may provide an alternative to repetitive surgery for patients with LG IR NMIBC.

Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.

BACKGROUND: BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer. METHODS: In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849. FINDINGS: Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths. INTERPRETATION: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. FUNDING: FKD Therapies Oy.

Finasteride Use and Risk of Bladder Cancer in a Multiethnic Population.

PURPOSE: Finasteride use has been associated with a reduced incidence of bladder cancer. However, the majority of studies have been conducted primarily in East Asian or White populations. Given differences in the incidence of bladder cancer among racial/ethnic groups, it is important to determine whether the effect of finasteride use on bladder cancer varies by race/ethnicity. MATERIALS AND METHODS: We identified all patients with a diagnosis of benign prostatic hyperplasia between 2000 and 2016 at our academic health center in Bronx, New York via an electronic medical record database. We then identified patients who were prescribed finasteride, and those who developed bladder cancer during followup. We used competing risk analysis to examine associations of finasteride use with risk of bladder cancer, adjusting for age, smoking and race/ethnicity. RESULTS: We identified 42,406 patients with benign prostatic hyperplasia (average±SD age 67±12.9 years), of whom 27.7% were Black and 14.8% were Hispanic. Finasteride was prescribed in 5,698 patients (13.4%). Bladder cancer was diagnosed in 84 of 5,698 finasteride users (1.5%), compared to 762 of 36,708 nonusers (2.1%, log-rank p=0.003). Finasteride was associated with a 36% reduction in risk of bladder cancer (HR: 0.64, 95% CI: 0.51-0.80; p <0.0001) among all patients. When data were stratified by race/ethnicity, finasteride use was associated with a reduction in risk of bladder cancer in White men (HR: 0.61, 95% CI: 0.43-0.86; p=0.005) and Hispanic men (HR: 0.44, 95% CI: 0.21-0.90; p=0.026), but there was no association among Black men (HR: 1.01, 95% CI: 0.67-1.51; p=0.964). CONCLUSIONS: Our study corroborates previous findings that men who are on finasteride have a lower bladder cancer incidence. However, the reduction in risk was seen only in White and Hispanic men, but not among Black men. Therefore, race/ethnicity represents an important stratification factor for future larger studies on finasteride as chemoprevention for bladder cancer.

Methodology for triage of urologic surgical cases in the setting of a pandemic.

BACKGROUND: The first wave of the COVID-19 pandemic in March 2020 forced our healthcare system in the Bronx, New York to cancel nearly all scheduled surgeries. We developed a framework for prioritizing postponed urologic surgeries that was utilized once cases were permitted to be rescheduled. As many parts of our country experience first and second waves of this pandemic, our framework may serve as a resource for other centers experiencing restrictions on the scheduling of elective urologic surgeries. METHODS: As the COVID-19 pandemic started and peaked in New York, almost all of our scheduled urologic surgeries were cancelled. Each Urologist was asked to rank his/her cancelled surgeries by priority (Level 1-least urgent; Level 2-moderately urgent; Level 3-most urgent). A committee of Urologists assigned a subclass to Level 3 and 2 cases (3a-least urgent; 3b-moderately urgent; 3c-most urgent; 2a-lower priority; 2b-higher priority). The committee then reviewed cases by urgency to derive a final priority ranking. RESULTS: A total of 478 total urologic surgeries were canceled and categorized: 250 Level 1, 130 Level 2, 98 Level 3 (73 adult, 25 pediatric). Level 3c involved renal cell carcinoma ≥ T2b, high-grade bladder urothelial carcinoma, adrenal mass/cancer > 6 cm, testicular cancer requiring radical orchiectomy, and penile cancer. Level 3b involved T2a renal masses requiring nephrectomy, while high-risk prostate cancer and symptomatic nephrolithiasis were classified as 3a. Level 2 included testicular cancer requiring retroperitoneal lymph node dissection and complicated benign prostatic hyperplasia. Surgeries for urologic reconstruction, non-complicated nephrolithiasis, erectile dysfunction, and urinary incontinence were considered Level 1. CONCLUSIONS: Our disease-specific approach to surgical rescheduling offers appropriate guidance for triaging urologic surgeries. Our system can provide guidance to other institutions as COVID-19 cases surge in different regions and with the growing second wave.

SIU-ICUD consultation on bladder cancer: treatment of muscle-invasive bladder cancer.

PURPOSE: To provide a comprehensive overview and update of the Joint Société Internationale d'Urologie-International Consultation on Urological Diseases (SIU-ICUD) Consultation on Bladder Cancer for muscle-invasive presumably node-negative bladder cancer (MIBC). METHODS: Contemporary literature was analyzed for the latest evidence in treatment options, outcomes, including radical surgery, neoadjuvant and adjuvant treatment modalities, and bladder-sparing approaches. An international multi-disciplinary expert panel evaluated and graded the data according to guidelines from the Oxford Centre for Evidence-Based Medicine. RESULTS: Radical cystectomy (RC) is the standard of care for MIBC patients considered to be surgical candidates. While associated with substantial morbidity and mortality, this has been mitigated with improved technique, minimally invasive technology, and better perioperative care pathways (e.g., enhanced recovery after surgery). Neoadjuvant (NA) cisplatin-based combination chemotherapy improves overall survival and should be offered to eligible ≥ cT2N0 patients. Adjuvant (Adj) cisplatin-based combination chemotherapy may be considered, particularly for pT3-4 and/or pN+ disease without prior NA chemotherapy. Trimodal bladder-preserving treatment via maximum transurethral resection of bladder tumor followed by concurrent chemoradiation is safe and, when combined with early salvage RC for recurrence, offers long-term survival rates in selected patients comparable to RC. Immunotherapy is still experimental and is given either alone or in combination with chemotherapy and/or radiation. CONCLUSION: A multi-disciplinary approach is paramount to achieving optimal outcomes for MIBC patients, irrespective of their age, performance and nutritional status, fitness/frailty, renal and other organ function, or disease severity.

Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma.

BACKGROUND: The exonic single-nucleotide variant rs11762213 located in the MET oncogene has recently been identified as a prognostic marker in clear cell renal cell carcinoma (ccRCC). This finding was validated with The Cancer Genome Atlas (TCGA) cohort, and the biologic implications were explored. METHODS: The genotype status for rs11762213 was available for 272 patients. Paired tumor-normal data, genomic data, and clinical information were acquired from ccRCC TCGA data sets. Cancer-specific survival (CSS) was analyzed with the competing risk method, and Cox proportional hazards regression was used for the analysis of the time to recurrence (TTR). Multivariate competing risk models were fitted to adjust for the validated Mayo Clinic Stage, Size, Grade, and Necrosis (SSIGN) score. RESULTS: The variant allele of rs11762213 was detected in 10.3% of the cohort. After adjustments for the SSIGN score, the risk allele remained a significant predictor for adverse CSS (hazard ratio [HR], 3.88; 95% confidence interval [CI], 1.99-7.56; P < .0001) and for TTR (OR, 2.97; 95% CI, 1.43-6.2; P = .003). The mapping of rs11762213 to regulatory regions within the genome suggested that it might affect a DNA enhancer region. RNA and protein sequencing data for MET did not reveal differences in steady-state expression with stratification by risk allele. CONCLUSIONS: The exonic MET variant rs11762213 is an independent predictor of adverse CSS and TTR in ccRCC and should be integrated into clinical practice for prognostic stratification. Genomic analysis suggests that the single-nucleotide polymorphism may affect an enhancer region located in the coding region of MET. Further biological mechanistic interrogation is currently underway.

TCEB1-mutated renal cell carcinoma: a distinct genomic and morphological subtype.

Integrated sequencing analysis identified a group of tumors among clear cell renal cell carcinomas characterized by hotspot mutations in TCEB1 (a gene that contributes to the VHL complex to ubiquitinate hypoxia-inducible factor). We analyzed 11 tumors from two distinct cohorts with TCEB1 mutations along with an expanded cohort to assess whether these should be considered an entity distinct from clear cell renal cell carcinoma and clear cell papillary renal cell carcinoma. All tumors were characterized by hotspot mutations in TCEB1 Y79C/S/F/N or A100P. Morphological and immunohistochemical characteristics of the tumors were assessed by two experienced genitourinary pathologists. Clinical and pathological variables, copy number alterations, mutations, and expression signatures were compared with a cohort of TCEB1 wild-type tumors. All TCEB1-mutated tumors were VHL and PBRM1 wild type and contained distinct copy number profiles including loss of heterozygosity of chromosome 8, the location of TCEB1 (8q21.11). All tumors lacked the clear cell renal cell carcinoma signature 3p loss and contained distinct gene expression signatures. None of the clear cell papillary tumors harbored TCEB1 mutations. Pathologically, all TCEB1-mutated tumors shared characteristic features including thick fibromuscular bands transecting the tumor, pure clear cell cytology frequently with cells showing voluminous cytoplasm, and clear cell renal cell carcinoma-like acinar areas associated with infolding tubular and focally papillary architecture. The presence of voluminous cytoplasm, absence of luminal polarization of tumor nuclei, and lack of extensive cup-like distribution of carbonic anhydrase-IX expression distinguish it from clear cell papillary carcinoma. None of the patients developed metastases at last follow-up (median 48 months). In sum, TCEB1-mutated renal cell carcinoma is a distinct entity with recurrent hotspot mutations, specific copy number alterations, pathway activation, and characteristic morphological features. Further clinical follow-up is needed to determine whether these tumors are more indolent compared with the conventional clear cell renal cell carcinoma.

Pathological Stage T3a Significantly Increases Disease Recurrence across All Tumor Sizes in Renal Cell Carcinoma.

PURPOSE: Tumor size and stage are important prognostic parameters in renal cell carcinoma. While pathological stage T1 and T2 are defined by size alone, the presence of certain intrinsic features can up stage a tumor to pathological stage T3a regardless of size. We investigate the effect of pathological tumor stage on the relationship between tumor size and risk of disease recurrence. MATERIALS AND METHODS: Data were reviewed on patients who underwent nephrectomy at our institution between 2006 and 2013 to identify all those with pathological stage T1, T2 and T3a tumors. A proportional hazards Cox model was built with time to recurrence as outcome, and pathological stage and tumor size as covariates. An interaction term for stage and tumor size was included. RESULTS: The final cohort included 1,809 patients. On multivariable analysis, when adjusted for tumor size, patients with pT3a tumors had a greater risk of tumor recurrence compared to those with pT1/T2 tumors (HR 3.70; 95% CI 2.31, 5.92; p <0.0001). The risk of disease recurrence increased more rapidly as tumor size increased only with the presence of perinephric fat invasion (p=0.006). CONCLUSIONS: Using the AJCC 2010 staging criteria we validated pathological stage T3a as a poor prognostic factor in renal cell carcinoma regardless of tumor size. Our results also demonstrated an increased rate of risk of recurrence with perinephric fat invasion. Given this increased risk of recurrence, even in tumors less than 4 cm, closer surveillance is warranted in such cases and the role of perinephric involvement necessitates further investigation.

Subcentimeter pulmonary nodules are not associated with disease progression in patients with renal cell carcinoma.

PURPOSE: Renal cell carcinoma most commonly metastasizes to the lung. Indeterminate pulmonary nodules develop preoperatively in half of the patients with localized renal cell carcinoma but clinical significance remains poorly defined. We determined whether the presence of indeterminate pulmonary nodules, or nodule size or number is associated with renal cell carcinoma outcomes. MATERIALS AND METHODS: We reviewed data on 1,102 patients with renal cell carcinoma in whom chest computerized tomography was done within 6 months before nephrectomy from 2002 to 2012. Patients with metastatic disease at presentation, benign tumors, pulmonary nodules greater than 2 cm or concurrent pulmonary disease were excluded, leaving 748 available for analysis. Study outcomes included lung metastasis, any distant metastasis or death from renal cell carcinoma. Cox proportional hazards models were used to assess whether the presence of indeterminate pulmonary nodules, or nodule size or number was associated with outcomes. Models were evaluated by comparing discrimination using the Harrell c-index. RESULTS: Indeterminate pulmonary nodules were present in 382 of 748 patients (51%). Median followup was 4.1 years (IQR 2.2-6.1). The presence of indeterminate pulmonary nodules was not associated with distant metastasis or death from kidney cancer. However, compared to subcm indeterminate pulmonary nodules the nodules greater than 1 cm were associated with metastatic disease after adjusting for tumor histology, stage and size (HR 2.48, 95% CI 1.08-5.68, p = 0.031). The outcome c-index increased slightly after adding nodule size to a predictive model adjusted for tumor characteristics. CONCLUSIONS: No evidence in the current study suggested that indeterminate pulmonary nodules less than 1 cm are associated with renal cell carcinoma progression, although large nodules significantly predicted metastatic disease. Patients with subcm indeterminate pulmonary nodules would be unlikely to benefit from extensive postoperative chest imaging surveillance, which should be reserved for patients with nodules greater than 1 cm.

Performance of cognitive vs. image-guided fusion biopsy for detection of overall and clinically significant prostate cancer in a multiethnic population.

PURPOSE: Transrectal ultrasound-guided prostate biopsy remains the most used method for the detection of prostate cancer. We recently reported that detection of clinically significant prostate cancer (cs-CaP) using image-guided fusion biopsies (IGFB) varied by race/ethnicity, which calls for further comparison between cognitive fusion biopsy (CFB) and IGFB among non-Hispanic black and Hispanic populations. Therefore, the aim of our study is to compare the rates of detection of cs-CaP and overall CaP by CFB and IGFB in a multiethnic community. MATERIAL AND METHODS: We performed a retrospective, cross-sectional review of men who underwent MRI-transrectal ultrasound-guided prostate biopsy at our diverse, urban academic medical center. Agreement and discordance between fusion biopsies and systematic biopsies for detection of cs-CaP and overall CaP were determined using Kappa statistics. Univariate and multivariate mixed-effects logistic regression models were used to find associations between fusion modalities and prostate cancer detection. RESULTS: In total, 710 men underwent fusion prostate biopsies between December 2015 and June 2021. Upon univariate and multivariate logistic regression analysis, there was no significant association between IGFB vs. CFB and risk of overall CaP (OR = 0.66, 95% CI: 0.36-1.21, P = 0.18) or cs-CaP (OR = 0.57, 95% CI: 0.30-1.08, P = 0.09). We found moderate agreement between fusion and systematic biopsies for both CFB (κ = 0.56) and IGFB (κ = 0.52) in cs-CaP. CONCLUSIONS: CFB and IGFB offer similar detection rates of cs-CaP in a multiethnic population. CFB represents an effective and accessible means of accurately diagnosing prostate cancer.

Interruptions in bladder cancer care during the COVID-19 public health emergency.

BACKGROUND: Academic and community urology centers participating in a pragmatic clinical trial in non-muscle-invasive bladder cancer completed monthly surveys assessing restrictions in aspects of bladder cancer care due to the COVID-19 Public Health Emergency. Our objective was to describe pandemic-related restrictions on bladder cancer care. METHODS: We invited 32 sites participating in a multicenter pragmatic bladder cancer trial to complete monthly surveys distributed through REDCap beginning in May 2020. These surveys queried sites on whether they were experiencing restrictions in the use of elective surgery, transurethral resection of bladder tumors (TURBT), radical cystectomy, office cystoscopy, and intravesical bacillus Calmette-Guerin (BCG) availability. Responses were collated with descriptive statistics. RESULTS: Of 32 eligible sites, 21 sites had at least a 50% monthly response rate over the study period and were included in the analysis. Elective surgery was paused at 76% of sites in May 2020, 48% of sites in January 2021, and 52% of sites in January 2022. Over those same periods, coinciding with COVID-19 incidence waves, TURBT was restricted at 10%, 14%, and 14% of sites, respectively, radical cystectomy was restricted at 10%, 14%, and 19% of sites, respectively, and cystoscopy was restricted at 33%, 0%, and 10% of sites, respectively. CONCLUSIONS: Bladder cancer care was minimally restricted compared with more pronounced restrictions seen in general elective surgeries during the COVID-19 pandemic.

Concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab in patients with localized urothelial cancer of bladder: results from phase II study, BTCRC-GU15-023.

BACKGROUND: Patients with bladder cancer (BC) who are cisplatin ineligible or have unresectable disease have limited treatment options. Previously, we showed targeting programmed death-ligand 1 (PD-L1) with durvalumab (durva) and radiation therapy (RT) combination was safe in BC. We now report results from a phase II study evaluating the toxicity and efficacy of durva and RT in localized BC. METHODS: This is a single-arm, multi-institutional phase II study; N=26. Enrolled patients had pure or mixed urothelial BC (T2-4 N0-2 M0) with unresectable tumors and were unfit for surgery or cisplatin ineligible. Patients received durva concurrently with RT ×7 weeks, followed by adjuvant durva × 1 year. PRIMARY ENDPOINTS: (A) progression-free survival (PFS) at 1 year and (B) disease control rate (DCR) post adjuvant durva. Key secondary endpoints: (A) complete response (CR) post durvaRT (8 weeks), (B) overall survival (OS), (C) PFS and (D) toxicity. Correlative studies included evaluation of baseline tumor and blood (baseline, post durvaRT) for biomarkers. RESULTS: Median follow-up was 27 months. Evaluable patients: 24/26 post durvaRT, 22/26 for DCR post adjuvant durva, all patients for PFS and OS. Post adjuvant durva, DCR was seen in 72.7%, CR of 54.5%. 1-year PFS was 71.5%, median PFS was 21.8 months. 1-year OS was 83.8%, median OS was 30.8 months. CR at 8 weeks post durvaRT was 62.5%. Node positive (N+) patients had similar median PFS and OS. DurvaRT was well tolerated. Grade ≥3 treatment-related adverse events: anemia, high lipase/amylase, immune-nephritis, transaminitis, dyspnea (grade 4-COPD/immune), fatigue, rash, diarrhea and scleritis. No difference in outcome was observed with PD-L1 status of baseline tumor. Patients with CR/PR or SD had an increase in naïve CD4 T cells, a decrease in PD-1+CD4 T cells at baseline and an increase in cytokine-producing CD8 T cells, including interferon gamma (IFNγ) producing cells, in the peripheral blood. CONCLUSION: Durva with RT followed by adjuvant durva was safe with promising efficacy in localized BC patients with comorbidities, including N+ patients. Larger randomized studies, like S1806 and EA8185, are needed to evaluate the efficacy of combining immunotherapy and RT in BC. TRIAL REGISTRATION NUMBER: NCT02891161.

The Development of Non-Invasive Diagnostic Tools in Bladder Cancer.

Bladder cancer is a common urinary tract cancer with a difficult clinical course. With frequent recurrence, patients with a history of bladder cancer often undergo surveillance that involves invasive cystoscopies and biopsies. Not only is this financially burdensome for patients but it is also mentally and physically intensive. Given this predicament, the field has shifted towards the use of non-invasive urinary tests to detect bladder cancer earlier in the disease course and to avoid unnecessary procedures. The first non-invasive test developed was urine cytology; however, that was found to have a low sensitivity, especially for low-grade lesions. There are many tests that are available that utilize common protein biomarkers to enhance the sensitivity of detection. However, many of these tests lack the specificity seen with cytology. With recent technological and research advancements, there are newer detection systems such as RNA sequencing and microfluidics along with novel bladder cancer biomarkers including mRNAs, methylation patterns and exosomes, which have potential to be used in clinical practice. The aim of this review is to highlight established non-invasive bladder cancer diagnostic tests as well as innovative methodologies that are on the horizon for use in bladder cancer detection.

Antiadenovirus Antibodies Predict Response Durability to Nadofaragene Firadenovec Therapy in BCG-unresponsive Non-muscle-invasive Bladder Cancer: Secondary Analysis of a Phase 3 Clinical Trial.

A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.

Rate of renal cell carcinoma subtypes in different races.

PURPOSE: We sought to identify racial differences among histological subtypes of renal cell carcinoma (RCC) between black and non-black patients in an equal-access health care system. MATERIALS AND METHODS: We established a multi-institutional, prospective database of patients undergoing partial or radical nephrectomy between January 1, 2000 and Sept 31, 2009. For the purposes of this study, data captured included age at diagnosis, race, tumor size, presence of lymphovascular invasion, presence of capsular invasion, margin status, and tumor histology. RESULTS: 204 kidney tumors were identified (Table-1). Of these, 117 (57.4%) were in black patients and 87 (42.6%) were in non-black patients. Age at surgery ranged from 37 to 87 with a median of 62. Tumor size ranged from 1.0 to 22.0 cm with a median of 5.0 cm. Overall, tumors were composed of clear cell RCC in 97 cases (47.5%), papillary RCC in 65 cases (31.9%), chromophobe RCC in 13 cases (6.4%), collecting duct/medullary RCC in 2 cases (1.0%), RCC with multiple histological subtypes in 8 cases (3.9%), malignant tumors of other origin in 6 cases (2.9%), and benign histology in 13 cases (6.4%). Among black patients, papillary RCC was seen in 56 cases (47.9%), compared to 9 cases (10.3%) among non-black patients (p < 0.001) (Table-2). Clear cell RCC was present in 38 (32.5%) of black patients and in 59 (67.8%) of non-blacks (p < 0.001). CONCLUSIONS: In our study, papillary RCC had a much higher occurrence among black patients compared to non-black patients. This is the first study to document such a great racial disparity among RCC subtypes.

OUTCOMES OF INTRAVESICAL BACILLUS CALMETTE-GUERIN IN A MULTIRACIAL COHORT WITH NON-MUSCLE-INVASIVE BLADDER CANCER.

INTRODUCTION: We sought to determine if outcomes of Bacillus Calmette-Guerin (BCG) therapy in patients with non-muscle-invasive bladder cancer (NMIBC) vary by race. METHODS: A retrospective chart review was conducted on 149 patients treated with BCG for intermediate- and high-risk NMIBC between 2001 and 2018, and who were followed up for cancer recurrence through March 2019.The primary outcomes were disease-free survival (DFS), low-grade disease-free survival (LGDFS), high-grade disease-free survival (HGDFS), and progression-free survival (PFS) at five years. Kaplan-Meier survival curves stratified by race (African American vs non-African American) were analyzed for all the above outcomes and multivariate Cox regression analyses were also performed to compare recurrence differences by race, after adjusting for age, sex, initial stage and grade. RESULTS: Of the 149 patients, 37.6% were Caucasian, 24.8% were African American, 26.8% were Hispanic, and 10.7% were of other/unknown race. Disease stage at initial presentation was 65.1% Ta, 34.9% T1, and 18.1% CIS. African American patients (N=37) did not have evidence for worse outcomes compared to non-African American patients when considering DFS (54.1% vs. 65.7%, p = 0.202), HGDFS (58.8% vs. 71.7%, p = 0.158), and PFS (83.8% vs. 92.6%, p = 0.117) at five years. Multivariate analysis did not reveal statistically significant racial differences in recurrence or progression. CONCLUSIONS: African Americans with NMIBC did not have worse disease recurrence and progression after receiving intravesical BCG treatment. Although there did appear to be a trend towards worse oncologic outcomes in African Americans, larger studies are needed to validate this finding.

Native kidney small renal masses in patients with kidney transplants: Does chronic immunosuppression affect tumor biology?

INTRODUCTION: We compared clinicopathological characteristics and outcomes of radical nephrectomy (RN) for small renal masses (SRM) in patients with end-stage renal disease (ESRD) before or after transplant at a high-volume urologic and transplant center. METHODS: We performed a retrospective review of patients with ESRD (glomerular filtration rate [GFR] <15 mL/min) who underwent RN for suspected malignant SRM from 2000-2018. Group 1 consisted of patients who underwent RN after transplant; group 2 underwent RN prior to transplant, and group 3 underwent RN without subsequent transplant. Dominant tumor size and histopathological characteristics, recurrence, and survival outcomes were compared between groups. Chi-squared and Mann-Whitney U tests were used to compare categorical and continuous baseline and histopathologic characteristics, respectively. Univariate analysis and log rank test were used to compare RCC recurrence rates. RESULTS: We identified 34 nephrectomies in group 1, 27 nephrectomies in group 2, and 70 nephrectomies in group 3. Median time from transplant to SRM radiological diagnosis in group 1 was 87 months, and three months from diagnosis to nephrectomy for all groups. There were no statistically significant differences between pathological dominant mass size, histological subtype breakdown, grade, or stage between the groups. Rates of benign histology were similar between the groups. Univariate analysis did not reveal a statistically significant difference in recurrence-free survival between the groups (p=0.9). CONCLUSIONS: Patients undergoing nephrectomy before or after transplant for SRM have similar indolent clinicopathological characteristics and low recurrence rates. Our results suggest that chronic immunosuppression does not adversely affect SRM biology.

Resource-efficient pooled sequencing expands translational impact in solid tumors.

Intratumoral genetic heterogeneity (ITH) poses a significant challenge to utilizing sequencing for decision making in the management of cancer. Although sequencing of multiple tumor regions can address the pitfalls of ITH, it does so at a significant increase in cost and resource utilization. We propose a pooled multiregional sequencing strategy, whereby DNA aliquots from multiple tumor regions are mixed prior to sequencing, as a cost-effective strategy to boost translational value by addressing ITH while preserving valuable residual tissue for secondary analysis. Focusing on kidney cancer, we demonstrate that DNA pooling from as few as two regions significantly increases mutation detection while reducing clonality misattribution. This leads to an increased fraction of patients identified with therapeutically actionable mutations, improved patient risk stratification, and improved inference of evolutionary trajectories with an accuracy comparable to bona fide multiregional sequencing. The same approach applied to non-small-cell lung cancer data substantially improves tumor mutational burden (TMB) detection. Our findings demonstrate that pooled DNA sequencing strategies are a cost-effective alternative to address intrinsic genetic heterogeneity in clinical settings.

Human urothelial bladder cancer generates a clonal immune response: The results of T-cell receptor sequencing.

BACKGROUND: High T-cell receptor (TCR) repertoire clonality is associated with clinical response to immune checkpoint blockade in bladder cancer. OBJECTIVE: To determine if TCR repertoire is more clonal in tumors than in benign inflammation. METHODS: We prospectively identified 12 patients with bladder lesions undergoing transurethral resection. Specimens were collected at time of transurethral resection and stored at -80C. DNA was extracted and high throughput DNA sequencing of the CDR3 region of the TCR beta chain using the immunoSEQ assay (Adaptive Biotechnologies) was performed. T-cell fraction, clonal dominance, and maximum frequency of TCR clone were assessed. RESULTS: Of the 12 bladder lesions resected, 3 of 12 were cT0, 3 of 12 were cTa, 3 of 12 were cT1, and 3 of 12 were cT2 or greater. The median number of T cells in urothelial carcinoma specimens (UC+) and benign (UC-) specimens was 5,569 and 25,872, respectively. The number of unique TCRs sequenced in UC+ and UC- specimens was 3,069 and 9,680, respectively. The median tumor infiltrating lymphocyte percentage in UC+ and UC- specimens was 2% and 12%, respectively. The UC+ specimens demonstrated clonality as evidenced by identification of a specific T-cell clone being present in up to 17% of the total tumor infiltrating lymphocyte pool, in contrast to 2% among UC- specimens. CONCLUSIONS: Primary urothelial tumors contain clonally expanded T-cell populations. These data support the hypothesis that bladder tumors induce an antigen-driven immunogenic host response, in contrast to the benign inflammatory response, which does not appear to demonstrate any T-cell clonal dominance.