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To evaluate whether racial disparities in MRI-Bx usage persisted after correction for socioeconomic, demographic, and clinical factors.This is a retrospective cohort study of patients who received either MRI-Bx or systematic biopsy (SB) within a single academic medical center between January 2018 - June 2020. For each patient, socioeconomic variables including household income, education, percent below poverty, and unemployment were estimated using 2015 American Community Survey census-tract level data. Chi-square analysis was used to examine differences in clinical and demographic characteristics between the two groups. The Benjamini-Hochberg procedure was used to control false discovery rate (FDR) for multiple testing.Eighteen percent of Black men (53/295) received MRI-Bx while 41% (228/561) of white men received MRI-Bx. Patients coming from highly impoverished areas were less likely to receive MRI-Bx, 25% vs 75%, respectively. In multivariate analysis, race remained significantly different across MRI-Bx and SB groups. Clinical factors including family history, DRE, BMI, and prostate volume were not significantly different between patients receiving MRI-Bx and SB.Black men are less likely to receive MRI-Bx than white men, even after adjusting for clinical and socioeconomic characteristics. Further work is necessary to identify and study methods to increase equity in PCa diagnostic testing.

Objective To examine the performance of Leibovich score versus GRade, Age, Nodes, and Tumor score in predicting disease recurrence in renal cell carcinoma. Methods In total, 7653 patients diagnosed with renal cell carcinoma from 2010 to 2018 were captured in the nationwide DaRenCa database; 2652 underwent radical or partial nephrectomy and had full datasets regarding the GRade, Age, Nodes, and Tumor score and Leibovich score. Discrimination was assessed with a Cox regression model. The results were evaluated with concordance index analysis. Results Median follow-up was 40 months (interquartile range 24-56). Recurrence occurred in 17%, and 15% died. A significant proportion of patients (36%) had missing data for the calculation of the Leibovich score. Among 1957 clear cell renal cell carcinoma patients the distribution of GRade, Age, Nodes, and Tumor score of 0, 1, 2, or 3/4 was 21%, 56%, 21% and 1.4%, respectively, and for Leibovich score of low/intermediate/high this was 47%, 36% and 18%, respectively. A similar distribution was seen in 655 non-clear cell patients. Both Leibovich and GRade, Age, Nodes, and Tumor scores performed well in predicting outcomes for the favorable patient risk groups. The Leibovich score was better at predicting recurrence-free survival (concordance index 0.736 versus 0.643), but not overall survival (concordance index 0.657 versus 0.648). Similar results were obtained in non-clear cell renal cell carcinoma. Conclusion GRade, Age, Nodes, and Tumor and Leibovich scores were validated in clear cell and non-clear cell renal cell carcinoma. Leibovich score outperformed the GRade, Age, Nodes, and Tumor score in predicting recurrence-free survival and should remain the standard approach to risk stratify patients during follow-up when all data are available.

To study the effect of surgeon-administered Transversus Abdominis Plane block (sTAP) on opioid usage and length of stay (LOS).Starting in April 2018, two surgeons at our institution gradually introduced sTAP for radical cystectomy (RC) patients. We performed a retrospective observational cohort analysis of RC patients catalogued in a prospectively maintained database using the Enhanced Recovery After Surgery Interactive Auditing System. Two surgeons adopted the sTAP block technique in April 2018. We included patients undergoing RC for bladder malignancy under Enhanced Recovery After Surgery protocol between January 2017 and August 2020. Primary outcomes included LOS, and postoperative day (POD) 0-3 total opioids consumption measured by morphine milligram equivalents (MME). Multivariable linear or logistic models evaluated the association of TAP with outcomes while controlling for potential confounders.Among 178 patients included in analysis, 84 patients underwent sTAP block and 94 did not. Multivariable analysis demonstrated significantly lower POD 0-3 total opioid usage (106.4 vs 192.2 MME, P = .004), and mean LOS (5.6 vs 7.7 days, P.001) among the sTAP group.sTAP appears to be an effective adjunct to RC care associated with improved LOS, and POD 0-3 opioid consumption. Further studies are needed to optimize TAP block technique and anesthetic composition.

Supplemental Figures 1-5 with figure legends embedded.

Castration-resistant prostate cancer can be treated with the antiandrogen enzalutamide, but responses and duration of response are variable. To identify genes that support enzalutamide resistance, we performed a short hairpin RNA (shRNA) screen in the bone-homing, castration-resistant prostate cancer cell line, C4-2B. We identified 11 genes (TFAP2C, CAD, SPDEF, EIF6, GABRG2, CDC37, PSMD12, COL5A2, AR, MAP3K11, and ACAT1) whose loss resulted in decreased cell survival in response to enzalutamide. To validate our screen, we performed transient knockdowns in C4-2B and 22Rv1 cells and evaluated cell survival in response to enzalutamide. Through these studies, we validated three genes (ACAT1, MAP3K11, and PSMD12) as supporters of enzalutamide resistance in vitro. Although ACAT1 expression is lower in metastatic castration-resistant prostate cancer samples versus primary prostate cancer samples, knockdown of ACAT1 was sufficient to reduce cell survival in C4-2B and 22Rv1 cells. MAP3K11 expression increases with Gleason grade, and the highest expression is observed in metastatic castration-resistant disease. Knockdown of MAP3K11 reduced cell survival, and pharmacologic inhibition of MAP3K11 with CEP-1347 in combination with enzalutamide resulted in a dramatic increase in cell death. This was associated with decreased phosphorylation of AR-Serine650, which is required for maximal AR activation. Finally, although PSMD12 expression did not change during disease progression, knockdown of PSMD12 resulted in decreased AR and AR splice variant expression, likely contributing to the C4-2B and 22Rv1 decrease in cell survival. Our study has therefore identified at least three new supporters of enzalutamide resistance in castration-resistant prostate cancer cells in vitro.

In many patients with prostate cancer, the cancer will be recurrent and eventually progress to lethal metastatic disease after primary treatment, such as surgery or radiation therapy. Therefore, it would be beneficial to better predict which patients with early-stage prostate cancer would progress or recur after primary definitive treatment. In addition, many studies indicate that activation of NF-κB signaling correlates with prostate cancer progression; however, the precise underlying mechanism is not fully understood. Our studies show that activation of NF-κB signaling via deletion of one allele of its inhibitor, IκBα, did not induce prostatic tumorigenesis in our mouse model. However, activation of NF-κB signaling did increase the rate of tumor progression in the Hi-Myc mouse prostate cancer model when compared with Hi-Myc alone. Using the nonmalignant NF-κB–activated androgen-depleted mouse prostate, a NF-κB–activated recurrence predictor 21 (NARP21) gene signature was generated. The NARP21 signature successfully predicted disease-specific survival and distant metastases-free survival in patients with prostate cancer. This transgenic mouse model–derived gene signature provides a useful and unique molecular profile for human prostate cancer prognosis, which could be used on a prostatic biopsy to predict indolent versus aggressive behavior of the cancer after surgery. Cancer Res; 74(10); 2763–72. ©2014 AACR.

PDF file - 453KB, Supplementary Figure 1. NF-kappaB signaling is continuously activated in the prostate of IkappaBalpha+/- mouse. Supplementary Figure 2. NF-kappaB signaling activated in the prostate of Myc/IkappaBalpha bigenic mouse. Supplementary Figure 3. Continuous activation of NF-kappaB signaling promotes PCa progression in the Hi-Myc transgenic mouse. Supplementary Figure 4. The NF24 gene signature predicts significant differences in the overall cancer-specific survival of the PCa patients. Supplemental Figure 5. Molecular network analysis using Ingenuity Pathway Analysis (IPA). Supplemental Figure 6. NF-kappaB signaling is activated/inactivated in PCa cells by infecting with IKK2-EE or IKK2-KD retroviral vectors. Supplemental Figure 7. Activation of NF-kappaB signaling increases JNK phosphorylation in PCa cells. Supplemental Figure 8. Blocking JNK signaling inhibits NF-kappaB induced invasive ability efficiently in PCa cells. Tables 1 and 2. Matched human homolog genes. Supplementary Table 3. Stratification of 77 PCa patients.

Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility.Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry.Design, setting, and participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry.Outcome measurements and statistical analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness.Results and limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10-4).Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry.Patient summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

To elucidate regional trends of infectious complications following transrectal ultrasound prostate biopsy (TRUS-PB) from a national, privately-insured database.Using Market Scan, we identified all men who underwent TRUS-PB from 2010 to 2015. Infectious complications (UTI, prostatitis, sepsis) occurring 30 days after the prostate biopsy from emergency room (ER) visits or hospital admissions constituted the primary outcomes. We analyzed unadjusted and adjusted rates of infectious complications from ER visits and hospital admissions per 100 prostate biopsies by state. Multivariable logistic regression analyses were used to identify patient covariates associated with infectious complications.During the study interval, we identified 193,490 patients who underwent TRUS-PB. The mean age was 57.6 years (SD: 5.0). Over time the unadjusted national rates of infectious complications remained similar from 0.4 ER visits per 100 prostate biopsies in 2010 -0.2 in 2015 (P = 0.83), and 1.2 hospital admissions per 100 prostate biopsies in 2010 to 1.1 in 2015 (P= 0.58). Connecticut had the lowest unadjusted infectious complication rate per 100 biopsies at 0.64, whereas West Virginia had the highest at 2.34. Multivariable analysis revealed higher Elixhauser status and patient age were associated with higher odds of infectious complications (P0.05).While rates of infectious complications attributable to prostate biopsies remain relatively stable, significant variation exists at the state level regarding this adverse outcome.

533 Background: Activation of HER2 and cMET signaling has been implicated in the pathogenesis of urothelial carcinoma subsets, and the use of anti-PD-(L)1 agents is well established in this disease. Novel therapeutic combinations targeting both immune checkpoints and the cMET or HER2 pathways are currently under investigation in metastatic urothelial carcinoma (mUC). Co-expression of these molecular targets has not been characterized in mUC. We hypothesized that the rate of PD-L1 co-expression with cMET and HER2 may be low. Therefore, we sought to define tumor protein co-expression of PD-L1, HER2 and cMET in a cohort of mUC patients. Methods: Patients with mUC were identified from an institutional database. FFPE tumor specimens from metastatic sites and available paired primary tumors underwent immunohistochemical staining for PD-L1 (SP-142), cMET, and HER2 expression. High expression was defined using the following thresholds: PD-L1: >=5% of infiltrated immune cells; cMET: >=50% of tumor cells; HER2: score=3+ (complete membrane staining that is intense and >10% of tumor cells). Simple and Weighted Cohen’s kappa Statistics (κ) were utilized to assess the agreement in expression and co-expression between paired primary and metastatic samples. Cohen’s interpretation of the κ results is provided. Results: Specimens from 143 mUC patients were analyzed, including 79 with available paired primary tumors. In primary tumors (N=79), high expression of PD-L1, cMET, and HER2 was observed in 15.2%, 34.2%, and 12.7%, respectively. In metastatic samples (N=143), high expression of PD-L1, cMET and HER2 was detected in 9.8%, 41.3%, and 9.8%, respectively. Expression agreement rates between primary and metastatic specimens (n=79) were PD-L1: 79.7% (κ=0.09, slight agreement), cMET: 69.6% (κ=0.35, fair agreement), HER2: 84.8% (κ=0.17, slight agreement) and were driven by high prevalence of low expression. High PD-L1/cMET co-expression was observed in only 5.1% (n = 4) of primary and 4.9% (n =7) of metastatic specimens. High co-expression of PD-L1/HER2 occurred in only 3.8% (n=3) of primary samples and in no metastatic samples. The overall co-expression agreement rate between paired primary and metastatic samples was 55.7% (κ = 0.22, fair agreement) for PD-L1/cMET and 67.1% (κ = 0.06, slight agreement) for PD-L1/HER2. Importantly, however, agreements rates for high co-expression between primary and metastatic samples were very low (2.5% for PD-L1/cMET and 0% for PD-L1/HER2). Conclusions: Tumor co-expression of high cMET or HER2 and PD-L1 is low in this cohort of metastatic urothelial carcinoma patients. Furthermore, agreement of high co-expression between primary and metastatic sites is rare. These results suggest that investigational strategies combining immune checkpoint inhibition with either cMET or HER2 targeted agents in mUC may have limited synergistic activity.

Small cell bladder carcinoma (SCBC) represents a rare histologic variant with a poor prognosis and for which no routine biomarkers exist. Limited reports of genomic sequencing in SCBC have demonstrated a high prevalence of TP53 and RB1 gene mutations, though the prognostic value of these and other gene variants in SCBC remains undefined. In this study, we performed targeted genomic sequencing on a cohort of SCBC patients and correlated genomic findings with clinical outcomes to identify potential novel biomarkers.Thirty-one patients with SCBC and available treatment-naïve tumor specimens were identified from an institutional database (23 limited stage [LS], 8 extensive stage [ES]). Small cell carcinoma specimens were microdissected and subjected to tumor next-generation whole-exon sequencing with a 592 gene panel. Kaplan-Meier techniques and Cox proportional hazards models were used to evaluate genomic aberration association with relapse-free survival (RFS) and overall survival (OS) in the limited stage cohort.The most common pathogenic gene variants included ARID1A (48%), TP53 (48%) and RB1 (48%). Mutations in genes with potential therapeutic targets not routinely evaluated in SCBC included BRCA1/2 (16%), POLE (13%), JAK2 (13%), PDGFB (13%) and FGFR3 (3%). Multiple novel biomarker candidates showed trends for improvements in OS in the LS subset including ERCC2 (HR 0.322, P = 0.122) and RB1 (HR 0.481, P = 0.182), while LS patients with TP53 mutations (HR 2.730, P = 0.056), and MCL1 gene amplification (HR 4.183, P = 0.018) suggested inferior OS. Additionally, gene or copy number variants with potential prognostic benefit included UBR5 and DAXX (P = 0.02, [hazard ratios nonestimable due to zero events in biomarker positive groups]).These results support the role for tumor genomic profiling in SCBC and identify multiple potential novel biomarkers and therapeutic targets in this rare disease. Efforts to validate these findings should lead to improved decision-making and treatment outcomes in SCBC.

Enhanced Recovery After Surgery (ERAS) protocols have been increasingly applied to urologic surgeries such as cystectomy and prostatectomy, though research defining protocols and outcomes for renal ERAS programs (RERAS) for nephrectomy remains limited. We aim to assess perioperative outcomes following implementation of our RERAS protocol modified from ERAS society cystectomy guidelines, as well as describe compliance with protocol guidelines.We performed a retrospective cohort analysis of 400 patients who underwent partial or radical nephrectomy between October 2017 and August 2020. RERAS protocol was initiated September 30, 2018, and patients were categorized into pre- and post-RERAS implementation cohorts based on surgery date. Perioperative outcomes including complications, 30-day readmissions, length of stay, and opioid consumption were compared across pre- and post-RERAS cohorts. Protocol compliance was reported based on adherence to program recommendations.Among 400 patients included in analysis, the pre-RERAS cohort included 133 patients and the post-RERAS cohort included 267 patients. There were no differences in overall complications (P = 0.354) and 30-day readmissions (P = 0.078). Length of stay (P0.001) and postoperative opioid consumption (P0.001) were significantly reduced post-RERAS. We observed an increase in compliance with RERAS recommendations over time (P0.001).RERAS implementation was associated with decreased length of stay and opioid usage, underscoring the benefits of program adoption in an era of opioid dependence and strained hospital capacity. Successful initiation of a RERAS protocol requires intentional organization and buy in from all providers involved.

294 Background: Black men have the highest incidence of clear cell renal cell carcinoma (ccRCC) and have a worse prognosis than women or White patients in the curative setting. We previously reported that women with metastatic ccRCC have an inferior prognosis to men which is dynamic with age. The prognosis of Black patients with metastatic ccRCC is not well described. Methods: Clinicopathologic features and survival of patients diagnosed with clinical stage IV ccRCC between 2004-2016 were obtained from the National Cancer Database (NCDB). Patients were stratified according to their age at diagnosis, race, and sex. Uni- and multi-variable chi-square, logistic regression, and overall survival (OS) analyses were used for comparisons. Results: In this cohort, there were 900 Black men, 461 Black women, 13,422 White men, and 6363 White women. Black patients were less likely to have private insurance, lung metastases, or to live in high income zip codes and were more likely to have liver metastases. Compared to White race, Black race was associated with worse OS in the overall cohort (HR 1.17 [95% CI 1.10-1.24], p65yr 9.7 vs 14.5mo, p=0.002). When stratified by age and race, males had similar or superior survival compared to females in most subgroups, however Black males under 50yrs had markedly inferior OS compared with Black females (median OS 10.4mo vs 17.1mo for Black females, p=0.0083) and compared with White patients (Table). Conclusions: Young Black males with metastatic ccRCC demonstrate remarkably poor OS in this cohort; whereas males otherwise have a more favorable prognosis. Potential hypotheses to explain this disparity include differences in obesity and smoking incidence in this population as well as unmeasured factors impacting access to care.[Table: see text]

151 Background: The use of PARP inhibitors (PARPi) may trigger synthetic lethality of tumor cells in the context of deficient homologous recombination repair (HRR). Approximately 10-20% of patients with prostate cancer harbor mutations in the HRR pathway, but HRR-associated mutations do not consistently predict the response to PARPi. Considering alternative methods to define Homologous Recombination Deficiency (HRD)—the inability to repair double strand breaks—may aid in identifying additional tumors that are sensitive to PARPi. Here, we evaluate the relationship between HRD status and HRR mutations amongst a large cohort of patients with prostate cancer. Methods: Retrospective analysis of 1,022 de-identified patients with prostate cancer that underwent next generation sequencing (NGS) with the Tempus|xT assay (DNA-seq of 648 genes at 500x coverage, whole-exome capture RNA-seq) was performed. Comparison groups were defined based on HRR alterations—either mono- or bi-allelic alterations of BRCA1 or BRCA2 ( BRCA1/2), ATM, or other HRR pathway genes. HRD status was determined via the Tempus RNA-based HRD algorithm. Results: Among this cohort, mono (-/+) or biallelic (-/-) alterations of HRR genes were found in 432 patients: BRCA1/2 -/- (n = 31), BRCA1/2 -/+ (n = 87), ATM-/- (n = 24), ATM-/+ (n = 67), other HRR-/- (n = 54), other HRR-/+ (n = 169) or no HRR alterations (n = 590). The BRCA1/2-/- group had a higher frequency of Asians (17% vs. < 7% in all other groups) and were diagnosed at younger ages (median 62 years vs. > 65 for all other groups). We identified 130/1022 (13%) patients with prostate cancer to be HRD-positive (HRD+) and observed significant differences in HRD positivity according to the type of HRR alteration observed (Table). Notably, 54% (70/130) of HRD+ patients had no mutations in any genes associated with the HRR pathway. Conversely, 89% (278/314) of patients with non- BRCA1/2 HRR mutations were HRD negative. Amongst all individuals with biallelic loss of any HRR gene, HRD positivity was most enriched for BRCA2-/- (16/29, p < 0.001) and PALB2-/- (3/4, p = 0.082). Conclusions: By using an RNA-based HRD algorithm, we found 13% of patients with prostate cancer are HRD+. This RNA-based HRD signature not only captures patients with HRR mutations but also identifies a substantial population of HRD+ patients who are currently undetectable by methods based solely on sequencing HRR genes. Further research is needed to assess the clinical response to PARPi in this HRD+ population, as well as the response to PARPi in the HRD negative population who harbor HRR gene alterations.[Table: see text]