Abstract Prostate cancer is a biologically and clinically heterogeneous disease, with incidence and mortality rates that vary substantially across racial and ethnic groups. Among Black American (BA) men, the incidence of prostate cancer is approximately 60% higher, and the mortality rate is two to three times greater than that observed in White American (WA) men. These disparities are multifactorial, involving both biological and social determinants such as genetic predisposition, comorbidities, socioeconomic status, environmental exposures, and cultural influences. While these factors obviously contribute to disease outcomes, growing evidence highlights the crucial role of the tumor immune microenvironment and its associated gene signatures in shaping prostate cancer biology and progression. To investigate ethnic variations in tumor immune gene signatures, we analyzed transcriptomic data from 35 radical prostatectomy specimens from treatment-naïve patients, including 20 BA and 15 WA men. Gene expression profiles from tumor and adjacent normal tissues were examined using EPIC, xCell, and Ingenuity Pathway Analysis. Differential gene expression was determined by rank testing, and prognostic associations were assessed via univariate Cox regression. WA tumors are enriched for pathways associated with neuroinflammation and oxidative phosphorylation including IL-8 signaling, neuroinflammation, dendritic cell maturation, oxidative phosphorylation, PKCθ signaling in T cells, and NFAT-mediated immune regulation, while PPAR and PD-1/PD-L1 pathways were less active. In contrast, BA tumors are characterized by increased activation of pro-inflammatory and immune-regulatory pathways; display elevated CREB signaling, Th1/Th2 activation, dendritic cell maturation, IL-17 and TREM1 signaling, and IL-17A/F-mediated cytokine production, with reduced activity in PD-1/PD-L1, ILK, IL-3, VEGF, and B-cell receptor pathways. Thirteen immune cell types showed race-specific gene expression patterns including ARG1, FA2H, FBXO39, IGLL3P, KLKB1, MERTK, SEMA3G, and TRPV5 markedly expressed in WA tumors, whereas ARSL, BAALC, CCL23, EPHA2, IGFL2, KRT5, NTM, and NDP upregulated in BA tumors. These results reveal distinct immune-oncological landscapes between BA and WA prostate tumors, highlighting pro-inflammatory pathway enrichment in BA men and underscoring opportunities for ethnicity-specific, genomically informed therapies. Citation Format: Shiv S. Verma, Pingfu Fu, Gregory T. MacLennan, Lee E. Ponsky, Sanjay Gupta. Ethnic differences in the immune landscape and gene signature in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5069.

Background MR fingerprinting (MRF) has shown utility in focal prostate lesion characterization as a complement to standard prostate MRI. Purpose To determine the utility of a rapid, B1-insensitive MRF technique, combined with standard diffusion MRI, in the characterization of focal prostate lesions in the peripheral zone (PZ), with MRI-guided transrectal US fusion biopsy-derived histopathologic analysis as the reference standard. Materials and Methods Between February 2021 and April 2024, consecutive adults with clinical suspicion of prostate cancer (PCa) who had not undergone biopsy underwent MRI, including rapid, B1-insensitive MRF (15 seconds per section) on a 3.0-T MRI unit. T1 and T2 from MRF and apparent diffusion coefficient (ADC) from diffusion MRI were assessed as independent variables to differentiate clinically significant PCa (csPCa) from clinically insignificant lesions (CILs) (benign lesions and Gleason score of ≤3 + 3 PCa). Both univariable and multivariable logistic regression analyses with receiver operating characteristic curve analyses were performed to calculate the area under the receiver operating curve (AUC), sensitivity, and specificity. Results Fifty-two males (mean age, 65 years ± 11 [SD]) with 51 PZ lesions (Prostate Imaging Reporting and Data System version 2.1, score ≥3) were included. The mean T2 and ADC were lower for csPCa (n = 22) than for CILs (n = 29) (T2, 56 msec ± 12 vs 80 msec ± 20, respectively [P < .001]; ADC, 668 × 10-6 mm2/sec ± 111 vs 876 × 10-6 mm2/sec ± 181, respectively [P < .001]). At univariable analyses, an optimal T2 cutoff of 58 msec yielded an AUC of 0.87 (95% CI: 0.76, 0.97) (sensitivity, 73% [16 of 22]; specificity, 93% [27 of 29]), whereas an ADC cutoff of 761 × 10-6 mm2/sec yielded an AUC of 0.83 (95% CI: 0.71, 0.95) (sensitivity, 82% [18 of 22]; specificity, 79% [23 of 29]). A multivariable model incorporating both T2 and ADC achieved a higher AUC (AUC, 0.90; 95% CI: 0.81, 1.00; P < .001). Further improvement in diagnostic performance was observed when serum prostate-specific antigen density (PSAD) was included (AUC, 0.94; 95% CI: 0.86, 1.0; P = .01). Conclusion Rapid, B1-insensitive prostate MRF-derived T1 and T2 combined with ADC and serum PSAD improved PCa characterization in the PZ. © RSNA, 2026 Supplemental material is available for this article. See also the editorial by Margolis and Gulani in this issue.

Background Accurate characterization of tumor grade and aggressiveness for renal neoplasms with noninvasive imaging methods is critical for patient management and outcome. Purpose To evaluate kidney MR fingerprinting (MRF) alone and in combination with diffusion-weighted imaging and arterial spin labeling (ASL) MRI for the diagnosis and characterization of renal neoplasms by assessing its performance in differentiating indolent from aggressive tumors. Materials and Methods Adults with suspected renal cell carcinoma (RCC) were recruited between November 2020 and October 2024 for this prospective proof-of-concept study. Histopathologic grading served as the reference standard, and renal masses were classified into indolent (low-grade or benign) and aggressive (high-grade or unclassified RCCs) types according to their natural biologic behavior. Noncontrast coronal T1 and T2 maps were acquired using breath-hold kidney MRF (two to five sections per participant) at 3.0 T. Respiratory-triggered diffusion-weighted imaging and ASL MRI were further applied to measure the apparent diffusion coefficient (ADC) and renal blood flow (RBF), respectively. Univariable and multivariable analyses were performed to identify parameters that differentiated renal neoplasms and correlated with histopathologic findings. Results Renal neoplasms from 24 participants (mean age, 61 years ± 11 [SD]; 16 female) were characterized as indolent (n = 14) and aggressive (n = 10) types. A between-group difference in T2 was observed (indolent, 86 msec ± 22; aggressive, 61 msec ± 14; P = .005), whereas no evidence of between-group differences in T1, ADC, or RBF were observed (P > .05). The area under the receiver operating characteristic curve (AUC) values of T1, T2, ADC, and RBF alone for between-group differentiation were 0.39, 0.83, 0.38, and 0.62, respectively. Multivariable analysis revealed that MRF-derived T1 and T2 provided complementary information in tumor type differentiation, achieving an AUC of 0.89 in this initial exploratory analysis. Conclusion Rapid multiparametric quantitative imaging with kidney MRF improved the ability to assess the grade and aggressiveness of renal neoplasms in 15 seconds per imaging section and without injectable MRI contrast material. © The Author(s) 2026. Published by the Radiological Society of North America under a CC BY 4.0 license. Supplemental material is available for this article.

Prostate cancer is a biologically and clinically diverse disease, with incidence and mortality rates varying significantly among different racial and ethnic groups. In African American (AA) men, the incidence of prostate cancer is approximately 60% higher, and the mortality rate is two to three times greater compared to Caucasian American (CA) men. These disparities are complex and encompass various biological and social determinants, including genetic predisposition, comorbid conditions, socioeconomic status, and environmental influences. The interplay of these elements has a clear association with disease outcomes. Recent research highlights the role of the tumor immune landscape and its associated genes in regulating prostate cancer biology at every stage of progression, ultimately impacting patient outcomes. We hypothesize that variations in immune cell gene signatures within tumors across different racial groups may influence prostate cancer outcomes. To investigate this, we analyzed transcriptomic data from 35 radical prostatectomy specimens obtained from treatment-naive patients, comprising 20 AA men and 15 CA men with prostate cancer. This analysis focused on the gene expression profiles of primary prostate tumors and adjacent normal tissues. We specifically selected immune-related genes to assess the immune-oncological differences between AA and CA prostate tumors, utilizing bioinformatics platforms such as EPIC, xCell, and IPA. To evaluate race-specific differential gene expression, we employed a rank test, and the effect of each gene’s expression on overall survival was further analyzed using a univariate Cox regression model. Prostate tumors in AA patients exhibit significant enrichment in the tumor microenvironment and a distinct gene immune profile compared to those in CA men. In AA patients we observed elevated z-scores in pathways such as CREB signaling, Th1 and Th2 pathways, dendritic cell maturation, IL-17 signaling, TREM1 signaling, and cytokine production in macrophage and T Helper cells mediated by IL-17A and IL-17F. We also noted increased cytokine levels in epithelial cells influenced by IL-17A and IL-17F. Conversely, pathways like PD-1, PD-L1, ILK, IL-3, chemokine signaling, adrenomedullin, erythropoietin signaling, IGF-1, VEGF, and B-cell receptor signaling exhibited low z-scores in AA prostate tumors. Additionally, our analysis identified 13 major immune cell types, and 27 genes significantly associated with immune cell infiltration in AA prostate cancer. The expression levels of ARSL, BAALC, CCL23, EPHA2, IGFL2, KRT5, NTM, and NDP (p < 0.05) were linked to overall survival in AA prostate cancer patients. Taken together, prostate cancer in AA patients demonstrates a unique immune repertoire and gene profile, characterized by significant enrichment in pro-inflammatory immune pathways that correlate with poorer outcomes. Shiv Shankar Verma, Pingfu Fu, Gregory T MacLennan, Lee E Ponsky, Chen-Han Wilfred Wu, Jonathan E Shoag, Sanjay Gupta. Distinct immune signature and regulated genes in prostate cancer disparity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3617.

Purpose:This study aims to identify specific genotypes within the UK Biobank (UKB) cohort contributing to a genetic predisposition for bladder cancer (UBC). It highlighted the impact of environmental exposures and the broader role of certain genes in UBC development, offering a comprehensive understanding of the genetic basis for UBC susceptibility. Experimental Design:Leveraging the rich data from the UKB- a longitudinal study involving participants across the UK-the primary outcome was the presence of UBC, determined using ICD-10 and ICD-9 codes. The study employed rigorous Genome-Wide Association Study (GWAS) protocols, Phenome-Wide Association (PheWAS) frameworks, and gene-level pleiotropy analyses. Quality control measures were applied, such as single-nucleotide polymorphisms (SNP) missingness and minor allele frequency thresholds. Polygenic Risk Score (PRS) evaluations were also conducted based on the Mavaddat score using UKB's high-density genome-wide SNP dataset. Results:Our GWAS identified significant associations between UBC risk and genetic variants, notably in the PSCA and TERT genes. The UGT1A polymorphism was found to be protective against UBC, particularly in heavy smokers. The PheWAS framework linked UBC-predisposition polymorphisms to other conditions, such as prostate cancer. Conclusions:Our GWAS identified significant associations between UBC risk and genetic variants across loci, including PSCA, TERT, TACC3 and TMEM129. The protective effect of the UGT1A variant against UBC, especially concerning tobacco exposure, suggests the potential for genetic-based preventive strategies in UBC management.Patient summary In our study of a large group from the United Kingdom (UK), we explored genetic factors that might increase the likelihood of developing UBC. We discovered that certain genetic changes offer protection against UBC, particularly in individuals exposed to tobacco smoke. Understanding these genetic factors could improve strategies for preventing and treating UBC.

Purpose While SABR is associated with excellent local control of primary renal cell carcinoma (RCC), outcomes based on clear cell RCC (ccRCC) and non-clear cell RCC (nccRCC) histologies are not well defined. This retropsective study's objective is to report the outcomes following SABR for uncommon subtypes of primary RCC. Methods and Materials Individual data of adult patients with biopsy-confirmed primary RCC receiving SABR between 2007 and 2021 from 16 institutions in Australia, Canada, Germany, Japan, and the USA were pooled. Patients with metastatic disease or upper tract urothelial carcinoma were excluded. The primary outcome was local failure (LF), based on the Response Evaluation Criteria in Solid Tumors version 1.1. Distant failure (DF), cancer-specific survival (CSS), treatment-related toxicity, and renal function changes following SABR were defined as secondary outcomes. Kaplan-Meier estimates were generated for LF, DF, and CSS stratified by ccRCC versus nccRCC histology, and compared using the log-rank test (for CSS) or Gray’s test (for LF and DF). Results Two hundred eleven patients with a biopsy-confirmed ccRCC (n = 167) or nccRCC (n = 44) were included. In the nccRCC group, 59% (n = 26/44) and 11% (n = 5/44) were papillary and chromophobe histologies, respectively. Patients with nccRCC were more likely to be older (median age at SABR, 77.2 years vs 71.5; p = .009) and to be treated with multifraction SABR (82% [n = 36/44] vs 38% [n = 63/167]; p < .001) than the ccRCC group. The median follow-up was 4.02 years (IQR, 3.43-4.94) and 4.25 years (IQR, 3.02-5.00) for the ccRCC and nccRCC groups, respectively. The 5-year cumulative incidence of LF was 1.5% (95% CI, 0.3%-4.8%) in the ccRCC group versus 2.4% (95% CI, 0.2%-11.0%) in the nccRCC group (hazard ratio [HR], 0.90; 95% CI, 0.10-8.31; p = .922). The corresponding cumulative incidence of DF at 5 years was 6.0% in the ccRCC group versus 2.9% in the nccRCC group (HR, 0.34; 95% CI, 0.04-2.68; p = .304). The 5-year estimated CSS was 96.4% in the ccRCC group versus 96.4% in the nccRCC group (HR, 2.04; p = .561). From baseline, the mean ± SD estimated glomerular filtration rate reduced by 11.4 ± 13.4 mL/min at 3 years and by 12.2 ± 14.0 mL/min at 5 years. Sixteen patients (7.6%) experienced grade 2 or higher toxicities, with grade 2 fatigue (5.7%) being the most common. Conclusions SABR provides excellent oncologic outcomes, irrespective of ccRCC or nccRCC histology.

Purpose: To quantify population-specific differences in prostate cancer (PCa) presentation between African American (AA) and White (W) men on MRI using radiomics. Materials and Methods: We identified N = 149 men with PCa who underwent 3T MRI, a confirmatory biopsy and for whom self-reported race was available. Patient studies were partitioned into training (D Tr ) and hold-out test set (D Te ). Three hundred radiomic features quantifying textural patterns were extracted from radiologist delineated PCa regions of interest (ROI) on biparametric MRI. Features with significant differences ( P < .05) between clinically significant (csPCa) and insignificant (ciPCa) PCa were identified. Machine learning models were trained separately for AA and W men (C AA , C W ) on D Tr to distinguish csPCa and ciPCa. Validation on D Te was assessed for AUC and compared against a population agnostic model (C PA ) in combination with clinical parameters (age, PSA, Prostate Imaging Reporting and Diagnostic System and tumor volume). Results: Radiomic features from PCa ROIs on biparametric MRI associated with csPCa were observed to be different in AA compared with W men, especially in the peritumoral region. Population-specific radiomic models outperformed similarly trained C PA models (AUC = 0.84, 0.57 with C AA , C PA ; P < .05) in AA men on D Te . Similar findings were observed for W men (AUC = 0.71, 0.60 with C W , C PA ; P < .05). Integrating clinical and radiomics further improved the risk stratification for AA men (AUC = 0.90) and W men (AUC = 0.75). Conclusions: Accounting for population-specific differences in radiomics may enable improved PCa risk stratification at MRI among AA men compared with a population agnostic approach.

INTRODUCTION:Women diagnosed with bladder cancer (BCa) are more likely to die of their disease as compared with men. Historical data suggest that this difference is in part due to delayed diagnosis, as the initial symptoms of BCa are often attributed to other causes, including UTI. Whether efforts to address this disparity have resulted in improvements in time to diagnosis in women is unknown. METHODS:We used the Merative MarketScan database to identify men and women diagnosed with BCa from January 2012 to December 2021 who had documented hematuria or UTI within the preceding year. The primary end point was time to BCa diagnosis following initial diagnosis of hematuria or UTI. RESULTS:A total of 12,667 patients with hematuria and 2350 patients with UTIs were included in our study. The median time to diagnosis was similar for women compared with men when the presenting diagnosis was hematuria (35.0 days, IQR: 14.0-79.8 vs 33.0 days, IQR: 14.0-69.0, P = .005) and longer when the presenting diagnosis was a UTI (82.0 days, IQR: 29.0-180.0 vs 63.0 days, IQR: 18.8-156.0, P < .001). Women presenting with hematuria were more likely to receive a subsequent diagnosis of UTI (28% vs 18%, P < .001) before BCa diagnosis. Men were less likely to experience delays in diagnosis of > 3 months (odds ratio 0.83, 95% CI: 0.79-0.91). CONCLUSIONS:Women continue to experience delays in BCa diagnosis, especially following diagnosis with a UTI. Our findings suggest that this disparity is driven largely by clinical suspicion of UTI.

BACKGROUND AND OBJECTIVE:Optimal management for high-risk prostate cancer is unclear. Using individual patient data from two contemporaneous North American cooperative group phase 3 randomized controlled trials (RCTs), we compared the outcomes of high-risk prostate cancer patients treated with radiotherapy-based and radical prostatectomy (RP)-based treatment strategies. METHODS:Data were collected from newly diagnosed high-risk prostate cancer patients enrolled in NRG/RTOG 0521 who received radiotherapy-based treatment (2005-2009), and those enrolled in CALGB 90203 who received surgery-based treatment (2006-2015). Patients received radiotherapy plus 24 mo of androgen deprivation therapy (ADT) ± six cycles of adjuvant docetaxel versus RP with personalized postoperative therapy ± neoadjuvant six cycles of docetaxel and 18-24 wk of ADT. The primary objective was to compare the cumulative incidence of distant metastasis considering death as a competing event using the inverse probability of treatment weighting (IPTW). KEY FINDINGS AND LIMITATIONS:Overall, 1290 patients (radiotherapy n = 557, RP n = 733) were included with similar follow-up (median 6.4 [interquartile range {IQR}: 5.6-6.9] yr and 6.4 [IQR: 4.7-8.5] yr, respectively). Patients who received surgery had generally more favorable prognostic features and were younger relative to those who received radiotherapy. After IPTW, the cumulative incidence of distant metastasis was significantly lower in patients who underwent radiotherapy-based compared with RP-based treatment (8-yr distant metastasis: 15% [95% confidence interval {CI} 9.3-21] vs 22% [95% CI 18-26]; adjusted subdistribution hazard ratio [sHR] 0.58 [95% CI 0.42-0.81]; p = 0.001). We did not find any significant difference in the incidence of deaths after distant metastasis (adjusted sHR 0.98 [95% CI 0.61-1.58]) between the two groups. CONCLUSIONS AND CLINICAL IMPLICATIONS:High-risk prostate cancer patients enrolled in RCTs had a significantly lower incidence of distant metastasis with a radiotherapy-based treatment strategy than with an RP-based treatment strategy, while the risk of deaths after distant metastasis was similar in the two groups.

Background and objective: Renal function preservation is particularly important following nonoperative treatment of localized renal cell carcinoma (RCC) since patients are often older with medical comorbidities. Our objective was to report long-term renal function outcomes after stereotactic ablative radiotherapy (SABR) including patients with a solitary kidney. Methods: Patients with primary RCC treated with SABR with >= 2 yr of follow-up at 12 International Radiosurgery Consortium for Kidney institutions were included. Renal function was measured by estimated glomerular filtration rate (eGFR). Key findings and limitations: In total, 190 patients (56 with a solitary kidney) underwent SABR and were followed for a median of 5.0 yr (interquartile range [IQR]: 3.4- 6.8). In patients with a solitary kidney versus bilateral kidneys, pre-SABR eGFR (mean [standard deviation]) was 61.1 (23.2) versus 58.0 (22.3) ml/min (p = 0.32) and the median tumor size was 3.65 cm (IQR: 2.59-4.50 cm) versus 4.00 cm (IQR: 3.00-5.00 cm; p = 0.026). At 5 yr after SABR, eGFR decreased by -14.5 (7.6) and -13.3 (15.9) ml/min (p = 0.67), respectively, and there were similar rates of post-SABR dialysis (3.6% [n = 2/56] vs 3.7% [n = 5/134]). A multivariable analysis demonstrated that increasing tumor size (odds ratio [OR] per 1 cm: 1.57; 95% confidence interval [CI]: 1.14-2.16, p = 0.0055) and baseline eGFR (OR per 10 ml/min: 1.30; 95% CI: 1.02-1.66, p = 0.034) were associated with an eGFR decline of >= 15 ml/min at 1 yr. Conclusions and clinical implications: With long-term follow-up after SABR, kidney function decline remains moderate, with no observed difference between patients with a solitary kidney and bilateral kidneys. Tumor size and baseline eGFR are dominant factors predictive of long-term renal function decline. Patient summary: With long-term follow-up, stereotactic ablative radiotherapy (SABR) yields moderate long-term renal function decline and low dialysis rates even in patients with a solitary kidney. SABR thus represents a promising noninvasive, nephron-sparing option for patients with localized renal cell carcinoma. (c) 2024 Published by Elsevier B.V. on behalf of European Association of Urology.

Abstract Introduction: Striking racial disparities in prostate cancer (PCa) outcomes among American Black men warrant significant efforts to identify early predictors of lethal PCa, to avoid over- treatment of clinically favorable disease with minimal risk of progression. Building on prior work, this study examined independent and joint roles of proteomic markers and social determinants of health (SDOHs) in predicting prostate disease aggressiveness in a racially diverse cohort of men undergoing prostate biopsy. Methodology: A retrospective cohort of 300 men biopsied for prostate cancer was assembled at University Hospitals (UH) Seidman Cancer Center in Cleveland, Ohio between January 1, 2005-May 2022. An extensive medical chart review was performed to identify Black and White men undergoing transrectal ultrasound- guided biopsy that resulted in: (i) a negative biopsy in patients with a history of 1+ prior negative biopsy and no PCa history (“NEG”); (ii) a biopsy-detected PCa of Gleason sum 6 (“GL6”); and (iii) biopsy-detected PCa with nodal and/or distant metastases at initial cancer detection (“METS”). Prostate biopsy tissues were obtained on each patient, balancing 100 men per biopsy group, and balanced on race (1:1) within each biopsy group. Informed by findings from an untargeted analysis of the entire proteome of 60 patients (“Discovery cohort”), we conducted a targeted proteomics analysis of 16 protein markers generated from prostate biopsy tissue, using mass spectrometry, on n=240 patients (“Verification cohort”). Chi-square testing and Analysis of Variance (ANOVA) were used to assess associations between protein expression, neighborhood-level SDOHs, and biopsy group. Race-stratified analyses were performed to examine statistical interactions between study associations. Principal components (PC) analysis was used to identify protein markers that predicted the greatest variance in biopsy group. Multivariable logistic regression (MLR) was used to predict METS (vs. NEG and GL6, combined), as a function of PC-selected protein markers and census block-group level area deprivation index (ADI). Bonferroni correction was used to establish the threshold for the decision rule of statistical significance (alpha error 0.05/16 markers: p< 0.0031). Results: Median patient age was 68 years. Protein expression distributions were transformed into quintiles due to non-normality. Of 16 protein markers, 14 were significantly correlated with biopsy group, including PARP 1 and TGFB1, for which METS patients had the highest expression. ADI was strongly correlated with race but not protein expression. ADI was significantly higher in METS patients, followed by GL6 and lowest in NEG group; however no associations were seen for ADI with protein expression. Eight proteins were found to predict METS in PC and MLR analysis. Conclusions: These data support use of proteomics markers to predict a metastatic versus non-metastatic biopsy result. Next steps include deep exploration of proteome findings generated in the Discovery cohort, such as biological pathways. Citation Format: Jennifer Cullen, Tao Liu, Holly Hartman, Fangzhou Liu, Anood Alfahmy, Rini Ghosh, Ayesha Shafi, Julia Payne, Randy Vince, Lee Ponsky, Gregory MacLennan. Joint roles of proteomics and neighborhood-level social determinants of metastatic prostate cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A039.

You have accessJournal of UrologyProstate Cancer: Detection & Screening V (PD50)1 May 2024PD50-11 POPULATION SPECIFIC RADIOMICS MODEL IMPROVES PROSTATE CANCER DIAGNOSTIC RISK STRATIFICATION AT MRI IN AFRICAN AMERICAN MEN Abhishek Midya, Siddharth Balakrishnan, Sree Harsha Tirumani, Leonardo K. Bittencourt, Amogh Hiremath, Lee Ponsky, Anant Madabhushi, and Rakesh Shiradkar Abhishek MidyaAbhishek Midya , Siddharth BalakrishnanSiddharth Balakrishnan , Sree Harsha TirumaniSree Harsha Tirumani , Leonardo K. BittencourtLeonardo K. Bittencourt , Amogh HiremathAmogh Hiremath , Lee PonskyLee Ponsky , Anant MadabhushiAnant Madabhushi , and Rakesh ShiradkarRakesh Shiradkar View All Author Informationhttps://doi.org/10.1097/01.JU.0001008620.35181.96.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Radiomics and machine learning models have demonstrated improved detection of clinically significant PCa (csPCa) on Magnetic Resonance Imaging (MRI)2-5. However, they have not explicitly accounted for disparities between African American (AA) and Caucasian American (CA) men.1 We hypothesize that radiomics can be used to quantify population specific PCa heterogeneity on MRI and build risk stratification models tailored for AA men potentially allowing for improved diagnosis and treatment outcomes. METHODS: This IRB approved, HIPAA complaint retrospective study comprised of N=111 PCa patients (55 AA, 56 CA) who underwent 3Tesla MRI prior to systematic/MRI guided biopsy. Gleason grade group (GGG) from biopsy was used to define csPCa (GGG>1) and clinically insignificant PCa (ciPCa; GGG=1). 2 board certified radiologists annotated PCa regions on MRI. Radiomic features quantify texture and shape-based heterogeneity were derived from T2-weighted (T2W) MRI within PCa region9. Dataset was split into training (DT; N=85 (42 AA, 43 CA)) and validation (DV; N=26 (13 AA, 13 CA)). Random forest machine learning models were trained in conjunction with mRMR feature selection method on DT to distinguish csPCa and ciPCa for AA specific (CAA), CA specific (CCA) and race agnostic (CRA), and validated on DV. Wicoxon rank-sum test was used to assess significant differences (p<0.05) in radiomics and classification models were assessed using area under receiver operating characteristics curve (AUC). RESULTS: Radiomic 1st order statistics from T2W quantifying voxel intensities were associated with csPCa in AA men. Intensity cooccurrence radiomic features quantifying neighborhood intensity relationships on T2W were associated with csPCa among CA men. Radiomics associated with csPCa among AA men did not show significant differences in CA men and vice-versa. Population specific models CAA and CCA resulted in AUC=0.75 and 0.73 on AA and CA men respectively, while CRA resulted in AUC=0.54 and 0.55 for AA and CA patients in DV. CONCLUSIONS: Population specific radiomics model resulted in improved diagnostic risk stratification among AA men compared to a population agnostic approach. Future work involves validation on larger, multi-institutional datasets and correlation against genomic biomarkers. Download PPT Source of Funding: Research reported in this publication was supported by the National Cancer Institute under award numbers R01CA268287A1, U01CA269181, R01CA26820701A1, R01CA249992-01A1, R01CA202752-01A1, R01CA208236-01A1, R01CA216579-01A1, R01CA220581-01A1, R01CA257612-01A1, 1U01CA239055-01, 1U01CA248226-01, 1U54CA254566-01, National Heart, Lung and Blood Institute 1R01HL15127701A1, R01HL15807101A1, National Institute of Biomedical Imaging and Bioengineering 1R43EB028736-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the Office of the Assistant Secretary of Defense for Health Affairs, through the Breast Cancer Research Program (W81XWH-19-1-0668), the Prostate Cancer Research Program (W81XWH-20-1-0851), the Lung Cancer Research Program (W81XWH-18-1-0440 and W81XWH-20-1-0595), the Peer Reviewed Cancer Research Program (W81XWH-18-1-0404, W81XWH-21-1-0345, and W81XWH-21-1-0160), (W81XWH-22-1-0236) the Kidney Precision Medicine Project (KPMP) Glue Grant, sponsored research agreements from Bristol Myers-Squibb, Boehringer-Ingelheim, Eli-Lilly, and AstraZeneca, American Cancer Society Institutional Research Grant from Winship Cancer Institute, and Winship Invest$ Pilot Grant from the Winship Cancer Institute © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e1061 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Abhishek Midya More articles by this author Siddharth Balakrishnan More articles by this author Sree Harsha Tirumani More articles by this author Leonardo K. Bittencourt More articles by this author Amogh Hiremath More articles by this author Lee Ponsky More articles by this author Anant Madabhushi More articles by this author Rakesh Shiradkar More articles by this author Expand All Advertisement PDF downloadLoading ...

Introduction The current standard of care for high-risk non-muscle invasive bladder cancer (HR-NMIBC) is Bacillus Calmette Guerin (BCG), however, it carries a non-responder rate of 30-50% with high risk of progression and side effect profile. Sequential intravesical gemcitabine and docetaxel (Gem/Doce) is an increasingly utilized treatment for HR-NMIBC, although prospective validation is pending. Our previous analyses have demonstrated an increased abundance of Lactobacillus rhamnoses GG (LGG) within the tumor stroma of responders, thus, we aimed to assess the role of intravesical LGG instillation as potential therapy in tumor-bearing mice. Methods We used the BBN model to recapitulate the histological and genetic characteristics of human bladder cancer in C57BL/6 mice. Upon ultrasound confirmation of tumor, mice were treated with live LGG (106 CFU) given via intravesical instillation for six weeks. Tumor burden was measured weekly with US. Additional comparative therapy included saline, BCG (106 CFU), and Gem/Doce. (Figure 1A) Cytokine urine analysis utilizing CodePlex Secretome Adaptive Panel* was collected at week 4. Immunohistochemistry was performed with bladder tissue and T-lymphocyte and total CD8 T-lymphocytes per high-power field were calculated. Following monocyte purification and stimulation, we assessed differentiation into macrophage and dendritic cells in both BCG and LGG group using FACS Aria, and processed results through Cell Quest. Additional supernatant cytokine production of monocytes, T-cells, and monocytes and T-cells to LGG and BCG was evaluated using Human CodePlex Adaptive Panel**. Results Complete response was seen in LGG (4/10), NS (0/10), BCG (2/10), and Gem/Doce (4/10) with tumor volume in LGG and Gem/Doce (5.1 cm3, 5.6 cm3). (Figure 1B). Week 4 urine cytokine demonstrated increased expression of KC (CXCL-1, 538.95 pg/ml), IP-10(CXCL10, 355.17 pg/ml), IL-6(477.05 pg/ml), IL-4(89.35 pg/ml), IL-1B (240.21 pg/ml) and MIP-1a (210.67 pg/ml) in LGG group (p<0.001).(Figure 1E) IHC of LGG demonstrated an increased Tumor/Stroma T-cell Infiltration;(0.93;±0.70).(Figure 1C, D) In vitro stimulation of human monocytes (CD14+/CD16+) and T-cells (CD3+/CD8+/CD4+) with LGG resulted in increased of IL-6 (1.82±;0.82pg/ml), IL-7 (0.68±0.14 pg/ml), and Granzyme B (0.64;±;1.91 pg/ml),;(Figure 1F) with increasing differentiation to immature dendritic cells (CD1+/CD11C-) (88.41 vs 54.33%) Conclusions Analysis of a murine intravesical therapy model revealed superior tumor response in both LGG and Gemcitabine/Docetaxel groups compared to control NS and standard of care BCG in the treatment of BBN induced tumor. Analysis of urinary LGG cytokine profile demonstrates enhanced immune activation through dendritic cell differentiation and Th2 pathway with direct antitumor effects through enhanced apoptosis.**(GM-CSF, Granzyme B, IFN-γ, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-13, IL-15, IL-17A, IP-10, MCP-1, MIP-1α, MIP-1β, Perforin, sCD137, TNF-α, TNF-β).*(GM-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-17A, IP-10, KC, MCP-1, MIP-1α, RANTES, TNF-α)

Supplementary Figure 6: Gut Microbiome Dynamics During Neoadjuvant Chemotherapy A: Relative abundance of major bacterial genera before, during, and after chemotherapy. Each color represents a different genus, with patient-specific changes highlighted to illustrate shifts in microbial composition over the course of treatment. B: Violin plots representing alpha diversity indices (ACE, Chao1, Observed, Pielou, Shannon, and Simpson) at three stages of chemotherapy: before, during, and after treatment. C: Cladogram derived from LEfSe analysis illustrating the most significantly altered taxa at each treatment stage. Colored nodes indicate taxa with statistically significant differences in abundance, with arrows highlighting key changes before, during, and after chemotherapy. D: Each segment shows the percentage composition of each genus by treatment stage. E: Venn diagram summarizing the overlap and unique bacterial taxa found at each stage of chemotherapy, quantifying shared and exclusive genera before, during, and after treatment. F: Principal Coordinates Analysis (PCoA) plot based on weighted UniFrac distances, showing the clustering of microbial communities at different treatment stages. G: Bar graph illustrating the proportional changes in specific bacterial genera over the course of chemotherapy, quantified and compared across three phases.

Introduction Bladder cancer, the most prevalent urological malignancy worldwide, accounts for a staggering 600,000 new cases annually. Its etiology is complex and multifactorial, influenced by various risk factors. Recent advances in genomic research, particularly genome-wide association studies (GWAS), have led to the discovery of new single nucleotide polymorphisms (SNPs) and associations in diverse cohorts. GWASs have proven to be a powerful tool for identifying links between genetic variants and SNPs. Additionally, phenome-wide association studies (PheWAS) have explored associations between specific genetic variants and a wide range of phenotypes, enabling the identification of genetic variants associated not only with bladder cancer but also with other diseases and traits that may share genetic risk factors. Our study, conducted using data from the UK Biobank's prospective cohort, aims to combine the findings from GWAS and PheWAS to identify both epidemiological and genetic risk factors associated with bladder cancer. Methods 375,981 healthy individuals and 5,090 bladder cancer patients analyzed. Genotype calling, quality control, and imputation processes;previously described. Generic risk variants, like;single nucleotide polymorphisms (SNPs), selected based on conventional genome-wide significance thresholds (p<5×10-6) and specific criteria (MAF >0.01 and r 2 <0.001 for LD). Functional GWAS analysis using FUMA;performed to annotate GWAS results, prioritize genes,assess chromatic interaction mapping and tissue enrichment.To explore association between bladder cancer and other phenotypes, PheWas (phenome-wide association studies) associations conducted using GLM function in R. Covariates like sex, smoking, age, alcohol consumption, air pollution exposure, daily traffic intensity, dietary habits, and workplace exposure were included in all associations. Logistic regression models with log-transformed odds ratios;used for binary dependent variables. Statistical inferences relied on two-sided tests at significance level of 0.05, unless specified differently. The analysis done;using SAS software v.9.4 (SAS Institute, Cary, NC) and R v.3.6.0 software. Results Our study identified;SNPs;associated with increased bladdercancer risk, including variants in;PSCA;TMEM129;TERT;LYNX1-SLURP2;LSP1, and;HIPK1;(Fig1A). Protective associations for bladder cancer with SNPs within;UGTA1, THEM6, RAPGEF5, LY6K, LY6D, LNCOC1, JRK, and CLPTML;(Figure1A,B). Gene prioritization using FUMA and tissue mapping with chromatin interaction analysis revealed 9 lead SNPs across 8 genomic risk loci, with exonic SNPs exhibiting highest Combined Annotation Dependent Depletion;(CADD) scores indicating deleteriousness (Figure1C,D). Additionally, gene set enrichment analysis of common SNPs uncovered significant associations with biological processes like;Flavonoid & Xenobiotic Glucuronidation and Glucuronosyltransferase, closely linked to bladdercancer (Fig1E). PheWAS analysis revealed four phenotypes linked to bladder cancer risk, including prostate cancer (rs2242652), seborrheic keratosis and skin conditions (rs2242652), and BPH (rs31489) (Figure1F). Regression analysis for modifiable risk factors;demonstrated significant associations with bladder cancer susceptibility for BMI, heavy smoking, and male sex. Conversely, alcohol intake 3-4 drinks/week is protective. Conclusions The study sheds light on various relevant SNPs and novel associations among germline mutations in bladder cancer, which have not been previously reported. Through further functional analysis, we discovered germline variants associated with glucuronosyltransferase activity, providing supporting evidence of toxin metabolism and its impact on bladder cancer risk. Additionally, our PheWAS analysis revealed co-associations with prostate cancer, prostatic hyperplasia, and dermatologic conditions linked to specific SNPs.Furthermore, our study reaffirmed well-known risk factors associated with bladder cancer, including sex and smoking, while also highlighting the protective effect of moderate alcohol consumption in the context of carcinogenesis.These findings have the potential to offer valuable insights into common pathways underlying bladder cancer, inform screening recommendations, and identify potential therapeutic targets for the disease.