Frank, Igor

ABSTRACT Background While guidelines state that patients with NCCN favorable intermediate risk (FIR) prostate cancer (PCa) may consider active surveillance (AS), there is a relative lack of longer term follow up data informing AS inclusion criteria of patients with Grade Group (GG) 2 prostate cancer in the MRI era. Here we evaluate patient outcomes from a MRI‐screened AS‐eligible cohort of FIR GG2 PCa receiving radical prostatectomy (RP). Methods Patients with prostate MRI, NCCN FIR GG2 PCa (PSA < 10 ng/mL, ≤ cT2a, < 50% core positivity), and no prior treatments who underwent RP from 2015 to 2023 were included from a prospectively maintained prostatectomy registry. Primary outcomes were adverse pathologic features (APF) at RP (GG3‐5, ≥ pT3a, or pN1) and biochemical recurrence (BCR). Logistic regression and Cox regression identified factors associated with APF at RP and time to BCR, respectively. Results Of 522 patients, 110 (21%) had APF at RP and 45 (9%) developed BCR with median follow up 2.4 years (IQR 1.3–2.8). On multivariable logistic regression, % Gleason pattern 4 (%GP4, %GP4 > 25% OR 2.14, 95% CI 1.28–3.58, p = 0.004) was independently associated with APF. On multivariable Cox regression for time to BCR, PSAD (HR 1.06, 95% CI 1.04–1.09, p < 0.001) and positive surgical margins (HR 1.06, 95% CI 1.09–3.78, p = 0.03) were independently associated with BCR. PIRADS, % core positivity, and specimen involvement were associated with neither APF nor BCR. Conclusions % Gleason pattern 4 > 25% and PSAD are the primary factors associated with adverse outcomes and should be considered for patients with FIR GG2 PCa considering active surveillance. PIRADS and measures of biopsy cancer volume were not associated with APF or BCR. These results may inform patient selection for active surveillance among patients with FIR GG2 PCa.

Abstract Objectives Sarcomatoid urothelial carcinoma (sUC) is associated with poor clinical outcomes. Herein, we evaluated clinicopathologic features (including PD-L1 expression) for institutional cases. Methods Sixty-five patients with sUC treated by radical cystectomy were matched for age, sex, and pathologic stage to 190 patients with pure urothelial carcinoma (UC). Outcomes were evaluated using the Kaplan-Meier method. Immunohistochemistry (IHC) results for tumor-specific PD-L1 expression in sUC were quantified using H-scores (range, 0-300). Cases with constitutive PD-L1 expression (cPD-L1; H-score ≥240) were evaluated for amplification events using fluorescence in situ hybridization (n = 28), mate-pair sequencing (Mpseq; n = 6), RNA sequencing (n = 5), and targeted next-generation sequencing (n = 8). PD-L1 regulatory pathways were evaluated using gene set enrichment analysis in the Cancer Hallmark dataset. Results Most patients with sUC had advanced disease (≥pT2, 62/65, 95%), without significant differences in overall and cancer-specific survival, when matched to pure UC. Median PD-L1 H-scores using different clones were 100 (SP142), 120 (SP263), and 195 (22C3). cPD-L1 was seen in 43% (28/65) of cases of sUC that were enriched for TP53, TERT, and CDKN2A/B alterations. PD-L1 amplification was identified in 7 (of 28, 25%) of these cases. Bionformatics analysis consistently identified IL6-JAK-STAT3 and interferon α/γ signaling in sUC with cPD-L1 expression. Conclusions Our results suggest that cPD-L1 expression in most sUC occurs secondary to IL6-JAK-STAT3 and interferon α/γ signaling. This provides a biologic rationale for evaluating response to immunotherapy in this patient population.

ABSTRACT Purpose The natural history of biochemical recurrence (BCR) after radical prostatectomy (RP) remains understudied, with limited long‐term data from large cohorts inclusive of both salvage radiotherapy (SRT)‐treated and untreated patients. Herein, we sought to evaluate the outcomes of patients with BCR and the impact of SRT on disease progression. Materials and Methods Patients undergoing RP who developed BCR (PSA ≥ 0.20 ng/mL) were included. Patients with BCR treated with SRT were compared to untreated patients using risk‐set matching with time‐dependent propensity scores. The primary outcome was metastases, analyzed using Kaplan–Meier and Cox models. The number needed to treat (NNT) with SRT to prevent progression was derived at 5 and 15 years. Results Among 6881 patients with BCR, 2109 received SRT. At a median follow‐up of 10.2 years, 1147 patients developed metastases. The median PSA at the time of SRT was 0.50 ng/mL. After 1:1 propensity score matching (2109 patients per cohort), SRT significantly reduced the risk of metastases at 5 (12.7% vs. 19.3%, p < 0.0001) and 15 years (28.6% vs. 31.5%, p < 0.001). On multivariable analysis, SRT independently reduced metastasis risk (HR 0.75, 95% CI 0.63–0.90, p = 0.002), translating to NNT of 23 and 15 at 5 and 15 years, respectively. Interaction analyses between SRT and nodal status ( p = 0.04) showed greater metastasis risk reduction in pN+ (HR 0.41, 95% CI 0.22–0.77, p = 0.005) compared to pN− disease (HR 0.81, 95% CI 0.67–0.97, p = 0.02). Conclusions Most patients with BCR post‐RP do not progress to metastasis. For those who do progress, SRT inarguably improves the oncologic outcomes in the BCR setting. However, careful patient selection and shared decision making should be encouraged in order to limit overtreatment and side effects.

Abstract Addressing the limited responsiveness to immune checkpoint blockade (ICB) in human cancers remains a critical challenge. Efforts over the past two decades have primarily focused on enhancing CD8 T cell function and preventing their exhaustion. However, less attention has been given to understanding the molecular mechanisms that contribute to the immunosuppressive tumor microenvironment (TME), which impedes CD8 T cell infiltration and fosters ICB resistance. The TME in ICB-resistant tumors is characterized by Transforming Growth Factor beta (TGF-β) cytokine signaling, leading to a fibrotic extracellular matrix (ECM) and the accumulation of immunosuppressive fibroblasts and myeloid cells. These features hinder CD8 T cell penetration, thereby promoting immune escape. The immune checkpoint molecule B7-H3, overexpressed in ICB-resistant cancers, has been linked to impaired CD8 T cell infiltration and poor prognosis. However, the molecular mechanisms governing B7-H3 function remain poorly understood. We investigated the relationship between B7-H3 gene expression and ICB response using transcriptomic data from two randomized phase 3 trials (IMvigor010 and IMvigor210). Bulk RNAseq data, tissue staining, and spectral flow cytometry were used to characterize the TME composition of B7-H3 high and low tumors. Multi-omic profiling of tumor cell lines with manipulated B7-H3 expression was performed to identify downstream targets of B7-H3. Syngeneic mouse tumor models were used to assess the impact of B7-H3 on tumor growth and antitumor immunity. High B7-H3 expression was associated with shorter overall survival in both IMvigor010 (HR=0.48, 95% CI: 0.33-0.70, p&lt;0.0001) and IMvigor210 trials (HR=0.68, 95% CI: 0.51-0.92, p=0.01). In ICB-refractory cancers, B7-H3 expression correlated with high levels of fibroblasts, collagen deposits, and M2 macrophages. Gene set enrichment analysis revealed a positive association between B7-H3 and TGF-β signaling. Genetic deletion of B7-H3 in tumor cells reduced the surface expression of MMP14, a metalloprotease that activates TGF-β. Pan-cancer analysis identified MMP14 as the gene most correlated with B7-H3 (Pearson r=0.69, p&lt;0.0001). TGF-β activation was reduced by 70% in B7-H3 knockout cells compared to wild-type. Loss of B7-H3 led to MMP14 accumulation in lysosomes, resulting in its degradation. We generated a B7-H3 inhibitor, 5D10, which promotes MMP14 degradation and inhibits TGF-β activation. In humanized B7-H3 mouse models, 5D10 significantly reduced TGF-β activation, enhancing CD8 T cell infiltration and impairing tumor growth. Our research identifies B7-H3 as a driver of immune exclusion and ICB resistance. We describe a novel, receptor-independent mechanism where B7-H3 promotes TGF-β activation via stabilization of MMP14. Targeting B7-H3 represents a strategy to modulate the TME, transforming immune-excluded tumors into immune-inflamed states that may respond better to ICB. Citation Format: Fabrice Lucien, Roxane Lavoie, Jack Korleski, Yohan Kim, Bharath Wootla, Liguo Wang, Ava Farrell, Kelly Harper, Martine Charbonneau, Claire Dubois, Igor Frank, Sounak Gupta, John Cheville, Jacob Orme, Stephen Boorjian, Parash Shah, Eugene Kwon, Sean Park, Haidong Dong. The immune checkpoint molecule B7-H3 is a driver of tumor immune exclusion by mediating TGF-β activation [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B034.

382 Background: The natural history of biochemical recurrence (BCR) after radical prostatectomy (RP) is heterogeneous, with most patients not progressing to metastasis. Determining the impact and optimal timing of salvage radiation therapy (SRT) remains challenging, particularly in the absence of prospective randomized trials with a surveillance control arm. Our objective isto quantify the oncologic benefit of SRT among men with BCR after RP. Methods: Patients who underwent RP at Mayo Clinic between 1990 and 2017 and developed BCR (PSA≥0.20ng/mL) were included. Patients treated with SRT were compared to those managed with surveillance using risk-set matching with time-dependent propensity scores, accounting for covariates at BCR and post-BCR. The primary outcome was metastases, analyzed via Kaplan-Meier and Cox proportional hazard models. The number needed to treat (NNT) with SRT to prevent progression was calculated using regression outputs at 5 and 15 years post-BCR. Interaction analyses identified factors modifying SRT’s effect on metastasis. Results: Of 6,881 patients with BCR, 2,109 received SRT. At a median follow-up of 10.2 years, 1,147 patients with BCR developed metastases. After 1:1 matching, SRT was associated with lower metastasis risk than surveillance at 5 years (12.7% vs 19.3%, p<0.0001) and 15 years (28.6% vs. 31.5%, p<0.001). SRT was independently associated with decreased metastasis risk (HR 0.75, 95%CI 0.63–0.90, p=0.002) on multivariable analysis, translating to NNT of 23 and 15 at 5 and 15 years, respectively (Table). Additionally, we noted a significant interaction between PSA at SRT and the association of SRT with metastasis (p-interaction=0.02), such that the reduction in metastatic progression with SRT vs. surveillance was restricted to the cohort of patients who received SRT for PSA>0.40ng/mL (HR 0.66, 95%CI 0.54–0.80, p<0.001). Conclusions: Most patients with BCR post-RP do not develop metastases. Indeed, the NNT with SRT to reduce metastasis versus surveillance indicates a generally indolent disease course. Further, the lack of a significant association of SRT with reduction of metastases in patients with a PSA≤0.40ng/mL underscores the importance of careful patient selection when considering early SRT. Our data establish the rationale for a randomized trial comparing early SRT versus surveillance for appropriately selected patients with BCR after RP. Hazard ratios of SRT after matching by propensity scores, and number needed to treat for systemic progression, prostate cancer specific mortality and overall mortality. DiseaseOutcome Hazard Ratio(95% CI) P value Number Needed to Treat* (95% CI) 5 years 15 years Systemic progression 0.75(0.63 – 0.90) 0.002 23(17 – 41) 15(11 – 27) Prostate cancer mortality 0.81 (0.64 – 1.03) 0.086 103(62 – 494) 26(15 – 124) Overall mortality 0.79 (0.70 – 0.89) 0.0001 38(29 – 62) 12(9 – 20) *Number needed to treat (NNT) calculated using regression based absolute differences in event free survival between salvage radiation therapy (SRT) and observation.

BACKGROUND: The creation of operative reports is a tedious documentation task that increases administrative burden, which is a potential driver of burnout. Additionally, operative reports are inherently subjective and may contain inaccuracies and incomplete information. Recent advances in artificial intelligence (AI) technology have enabled computer vision systems to accurately detect operative steps on surgical video. We aim to develop a platform for the automated creation of video-based AI surgical operative reports in robotic-assisted radical prostatectomy. STUDY DESIGN: An AI computer vision algorithm was used to automatically detect surgical steps. Each step detected on video was mapped to prespecified text, which was then compiled into a narrative AI operative report. The accuracy of the AI operative reports was compared with operative reports written by surgeons, using expert review of raw surgical video footage as the ground truth. RESULTS: A total of 158 cases from a tertiary referral center were included. In surgeon operative reports, 84 cases (53.2%) had at least 1 discrepancy between the operative report and surgical video. Of these, 43 cases (27.2%) had a clinically significant discrepancy based on expert video review. In AI operative reports, 46 cases (29.1%) had at least 1 discrepancy between the operative report and surgical video. Of these, 20 cases (12.7%) had a clinically significant discrepancy. Overall accuracy was higher for AI operative reports compared with surgeon operative reports (87.3% vs 72.8%, p = 0.001). CONCLUSIONS: Operative reports created by AI achieved higher accuracy than those written by surgeons. To our knowledge, this is the first report of automated video-based AI surgical documentation. Future studies are warranted to explore the potential for this novel tool to reduce documentation burden, improve operative report accuracy, promote surgical transparency, and decrease subjectivity in surgical documentation.