Adamo, Daniel A.

Long-established prostate cancer cell lines provide limited insight into how contemporary early prostate cancer evolves into drug-resistant and neuroendocrine-like refractory disease. Patient-derived three-dimensional (3D) ex vivo models may better preserve this transition. Here, we found that 8 of 10 magnetic resonance imaging-guided biopsy specimens from patients with early-stage prostate cancer generated sustained 3D tumor spheroid cultures. After 12 weeks of enzalutamide selection, only one patient-derived culture acquired a resistant phenotype with treatment-emergent neuroendocrine prostate cancer (t-NEPC)-like features, including increased chromogranin A (CgA) and synaptophysin (SYP); reduced androgen receptor (AR), prostate-specific antigen (PSA), and prostate-specific membrane antigen (PSMA); and conversion from compact spheroids into irregular resistant aggregates. During this transition, WD repeat and SOCS box-containing protein 1 (WSB1) increased, whereas PSMA progressively decreased. WSB1 silencing restored PSMA, AR, and PSA expression and reduced neuroendocrine-associated features. A similar WSB1 dependency was observed in enzalutamide-resistant LNCaP cells, the castration-resistant prostate cancer model 22Rv1, and the neuroendocrine/small-cell prostate cancer model NCI-H660. Mechanistically, WSB1 functioned as a SOCS box-dependent E3 ubiquitin ligase adaptor that promoted PSMA ubiquitination and degradation. SOCS box deletion or T380A mutation impaired this process, while Aurora kinase A (AURKA) inhibition reduced WSB1-dependent PSMA ubiquitination. WSB1 depletion, AURKA inhibition with alisertib, and combined AURKA inhibition with EZH2 suppression reduced resistant aggregate growth and increased apoptosis-associated markers in patient-derived enzalutamide-resistant neuroendocrine-like spheroids and related models. These findings nominate the AURKA–WSB1–PSMA axis as a therapeutic vulnerability in refractory prostate cancer.

e18026 Background: Immune checkpoint inhibitor (ICI) therapy is part of standard of care first-line therapy for recurrent or metastatic (R/M) HNSCC. However, less than 20% of patients (CPS ≥1) have an objective response to ICI monotherapy, and most tumors progress within ~3 months. We sought to improve the proportion of patients who benefit from a chemotherapy-free regimen by combining intratumoral (IT) VV1 oncolytic virus (VSV-IFNβ-NIS) injections with the anti-PD-1 antibody, cemiplimab. We report a pre-planned analysis of Simon's stage 1 results. Methods: We activated a phase 2 study testing the efficacy of first line IT VV1 plus cemiplimab in 1 st line patients with R/M HNSCC. A Simon's two-stage design was employed whereby 10 patients would be accrued in stage 1, and if 3 or more responses were observed, 12 additional patients would be accrued for stage 2. The primary endpoint was objective response rate (ORR) per investigator (RECIST 1.1). Eligible patients had untreated R/M HNSCC from primary oropharynx, oral cavity, hypopharynx, or larynx sites with CPS ≥1. Patients had to have at least one measurable lesion amenable to IT injection. Treatment comprised of IT injections to 1-5 lesions of oncolytic VV-1 virus and IV cemiplimab 350 mg on day 1, repeated every 21 days. Each lesion could be injected 3 times; a 4th injection was allowed if a partial response (PR) was achieved after 3 injections. Cemiplimab could be continued for up to 2 years until progression or unacceptable toxicity. Results: Patient and tumor characteristics, as well as efficacy and toxicity are summarized in the table below. Ten patients were treated at the time of Stage 1 analysis, with 3 showing a confirmed PR for ORR of 30%. Responder CPS scores were 45, 12 and 20%. Two of the responders subsequently showed progression after 6.2 and 9.9 months, the third has maintained PR at 7.7 months to date. Eight of 10 patients showed decrease in the sum of target lesion size (mean decrease of 16%; range -57 to 77%). One grade 2 event of ICI nephritis resolved with corticosteroid treatment. Conclusions: Three patients showed confirmed PR by RECIST 1.1 in Simon's stage 1, meeting criteria to proceed to Simon's stage 2. A total of 22 patients in the HNSCC will be enrolled. VV1 plus cemiplimab shows promise in first line R/M HNSCC based on these initial results. Clinical trial information: NCT04291105 . Patient demographics. N (treated) 10 Sex 20% female Median age (y) 60 (54 – 76) Oropharynx 7 HPV+ 7 Oral cavity 3 PD-L1 CPS median (range) 7.5 (1-45%) Locoregional injection 3 Distant injection 6 Local and distant injection 1 Best response (RECIST 1.1) PR 3 SD 5 PD 2 Adverse Events #pts any VV1/cemiplimab-related G3 AE 4 Lymphopenia 3 Elevated ALK 1

Objective: The purpose of this study was to evaluate the potential clinical value of spectral CT for image guidance during percutaneous thermal ablation, particularly investigating high monoenergetic (MonoE) for metal artifact reduction. Materials and Methods: A phantom experiment was performed in which an ablation probe was scanned in “continuous CT” (CCT) mode on a spectral CT scanner. ROI measurements quantified metal artifacts for conventional and MonoE CCT images. Subsequently, a retrospective reader study was conducted with 10 patient cases. Three radiologists reviewed cases to select the optimal MonoE setting and perform a Likert score rating (+2: MonoE preferred, −2: conventional preferred). Results: Phantom measurements indicated a reduction in metal artifact for high MonoE (150 keV: −46 HU) relative to conventional CCT (−122 HU). The MonoE setting preference was 151±21 keV. The mean Likert score was 1.2±0.7. Radiologists indicated a perceived benefit of high MonoE CCT when probe placement was near a critical structure. Conclusions: This study indicates a clinical preference for high MonoE CCT compared with conventional CCT. Insofar as spectral CCT can be offered at a clinically feasible time frame, our results support the assessment of 150 keV image to reduce metal artifact while maintaining satisfactory soft tissue contrast.

Introduction: Ureteral stents are widely used in the specialty of urology to preserve renal function and provide ureteral patency in cases of urolithiasis, strictures, malignancy, and trauma. This paper presents a novel application of prophylactic ureteral stents deployed under MRI-guidance for ureteral protection in the setting of in-bore salvage cryoablation therapy for recurrent and metastatic prostate cancer. This is the first known case series of ureteral stent placement using near real-time MRI. Materials and Methods: A retrospective chart review was performed for all patients who underwent MRI-guided ureteral stent placement prior to in-bore cryoablation therapy from 2021 to 2022. Each case was managed by an interdisciplinary team of urologists and interventional radiologists. Preoperative and postoperative data were collected for descriptive analysis. Physics safety testing was conducted on the cystoscope and viewing apparatus prior to its implementation for stent deployment. Results: A total of seven males, mean age 73.4 years (range 65–81), underwent successful prophylactic, cystoscopic MRI-guided ureteral stent placement prior to cryoablation therapy of their prostate cancer. No intraoperative complications occurred. A Grade 2 postoperative complication of pyelonephritis and gross hematuria following stent removal occurred in one case. The majority of patients were discharged the same day as their procedure. Conclusions: This case series demonstrates the feasibility of in-bore cystoscopic aided MRI guidance for ureteral stent placement. Ureteral stents can be used to increase the safety margin of complex cryoablation treatments close to the ureter. Furthermore, by following the meticulous MRI safety protocols established by MRI facility safety design guidelines, MRI conditional tools can aid therapy in the burgeoning interventional MRI space.

5555 Background: Platinum-resistant/refractory ovarian cancer presents a significant therapeutic challenge and despite several attempts, immunotherapies have not delivered satisfactory results to be approved. Identifying biomarkers of response to novel therapies is crucial for personalizing treatments and improving patient outcomes, especially since certain patients do experience long term benefit after the treatment with pembrolizumab and igrelimogene litadenorepvec (TILT-123; an oncolytic adenovirus coding for TNF and IL-2). Methods: Tumor biopsies (n=62), ascites (n=8) and blood (n=234) were collected from 15 patients treated in the PROTA trial (Phase I, NCT05271318). These patients received pembrolizumab intravenously plus igrelimogene litadenorepvec intravenously, followed by local administration intratumorally or intraperitoneally. Sampling took place prior to therapy, during therapy and after it. Tumor proteome (IHC, mIF) and transcriptome was analyzed to assess immune changes and virus presence. Ascites and blood samples were assayed to measure cell counts, phenotypes, cytokine and protein counts, as well as for the presence of antiviral neutralizing antibodies (NAbs). Biological parameters were correlated with overall survival (OS), RECIST 1.1 evaluations and tumor size changes. For analysis of OS, logrank test was used. For group comparisons two-tailed Mann-Whitney U-test was used. Pearson or Spearman tests were used for correlations. Results: Patients experiencing a drop in circulating lymphocytes 8-24 hours after treatment were more likely to experience longer OS (p=0.044). Additionally, patients with a higher lymphocyte count at baseline experienced similar OS benefit (p=0.018) plus a positive correlation with disease control (p=0.023). Most patients (11/15) showed antiviral immunity at baseline but eventually all patients developed neutralizing activity, and the same was observed in ascites. The presence of NAbs at baseline as well as development of highest titers were positively correlated with longer OS (p=0.004) and disease control (p=0.003). Conclusions: Igrelimogene litadenorepvec and pembrolizumab are therapies designed to attract, activate and/or protect lymphocyte-mediated antitumor activity. These findings suggest that having a fit immune system able to mobilize effector immune cells as well as responding to immunostimulant agents increases therapeutic success. As a disease with few therapeutic options, ovarian cancer patients often receive multiple lines of chemotherapy that might decrease the efficacy of immediate immunotherapies. The potential use of these biomarkers will be studied in larger studies to validate their utility in guiding the use of immunotherapy in this challenging patient population. Clinical trial information: NCT05271318 .

Abstract Background Percutaneous ablation of parathyroid adenomas provides a minimally invasive treatment option for primary hyperparathyroidism. However, the overall performance of this technique remains underexplored. This meta-analysis evaluates the effectiveness and safety of various ablation techniques for parathyroid adenomas. Methods Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, multiple databases, including Ovid MEDLINE and Cochrane, were systematically searched. Studies that provided separate data for radiofrequency (RF), microwave ablation (MWA), and ethanol ablation technique were included. Outcomes of interest were changes in serum calcium, PTH, and phosphorus levels, along with normocalcemia rates at 6 to 12 months after ablation. Safety outcomes included transient hoarseness, permanent hoarseness, severe hemorrhage, major complications, and severe hypocalcemia. Data were pooled using a random-effects model, with pooled prevalence and 95% CIs calculated. Also, the publication bias was assessed with Egger's test for each outcome measure. Results Twenty studies (815 patients) were included. The posttreatment normocalcemia rate at 6 to 12 months was 85.6% (95% CI, 80.48-90.72). Serum PTH and calcium levels significantly decreased, with mean differences of 101.49 pg/mL (95% CI, 73.50-129.48) and 0.39 mmol/L (95% CI, 0.34-.45), respectively. Permanent hoarseness and major complications were rare, with incidences of 0.28% (95% CI, 0.00-1.05) and 0.31% (95% CI, 0.00-1.09). The safety and efficacy outcomes of RF, MWA, and ethanol ablation were comparable. Conclusion Our findings indicate that percutaneous ablation of parathyroid adenomas is safe and effective within the first year of the treatment. Additionally, they suggest that RF, MWA, and ethanol ablation techniques can each be employed depending on patients' needs without particular limitations.

Abstract Background: Ad5/3-E2F-D24-hTNFa-IRES-hIL-2 (TILT-123) is an oncolytic adenovirus armed with TNFa and IL-2. The cytokine pairing demonstrated superior tumor immunomodulation in preclinical studies. Subsequent studies supported evaluation of TILT-123 in PROTA, a phase 1 study of TILT-123 in combination with pembrolizumab in platinum resistant or refractory ovarian cancer patients. Biomarker analysis is ongoing. Experimental procedures: In this phase 1a dose escalation trial (NCT05271318), 15 patients received an initial single intravenous dose of TILT-123 ranging from 3x1011 to 4x1012 VPs, followed by intratumoural and/or intraperitoneal injections ranging from 1x1011 to 5x1011 VPs. Patients also received i.v. pembrolizumab (200mg) every three weeks starting on day 36. The primary endpoint was safety by day 92, while efficacy by RECIST1.1 and overall survival (OS) were secondary endpoints. Collection of tumour biopsies and blood, including PBMCs and serum, enabled evaluation of MoA and identification of preliminary biomarkers. Summary of data: ORR was 7.1% in evaluable patients (1/14). Disease control rate was 64% in evaluable patients (n = 14) and median OS was 190 days (n =15). Patients with disease control and no disease control by 92 achieved a median OS of 571 days and 138 days respectively. Correlations of complete blood count with differential to OS (n =15) and imaging response (n = 14) revealed a greater drop in lymphocyte count after treatment, as well as baseline lymphocyte count positively correlated with OS and disease control (PR/SD vs PD). Correlation of prothrombin INR to OS revealed patients with a slower blood-clotting rate at baseline and post-treatment positively correlated with OS. Analysis of anti-adenovirus neutralizing antibody (nAb) titer revealed 77% of all patients were positive for nAbs prior to treatment. All patients developed nAbs in blood and ascites (ascites n = 3). Patients presenting with nAbs at baseline achieved longer OS than those not positive. Additionally, a higher titer post-treatment positively correlated with OS and disease control. Percentage and fold change increase in IgM expression on plasma cells on day 36 positively correlated with OS. In addition, a higher expression of IgM on the surface of plasma cells at baseline was observed in patients achieving disease control. Conclusion: These preliminary results identify a key role of circulating lymphocyte re-distribution and humoral immune response as markers of treatment benefit. Initial phenotyping implicates IgM producing plasma cells as a potentially relevant immune cell population. Additionally we observed a correlation between the coagulation cascade and OS. Citation Format: James H. Clubb, Matthew Block, Johanna Mäenpää, Victor Arias, Mirte van der Heijden, Santeri Pakola, Dafne C. Quixabeira, Tatiana Kudling, Elise Jirovec, Lyna Haybout, Tuomo Alanko, Daniel Adamo, Susan Ramadan, Jorma Sormunen, Juha Kononen, Michael J. Chisamore, Julia W. Cohen, Nadena Singh, John Goldfinch, Suvi Sorsa, Riikka Havunen, Claudia Kistler, João M. Santos, Víctor Cervera-Carrascon, Akseli Hemminki. Clinical-immunological correlates in platinum resistant or refractory ovarian cancer patients treated with chimeric oncolytic adenovirus encoding TNFa and IL-2 (TILT-123) in combination with pembrolizumab [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 2035.

Abstract Objectives: Radiologist participation in multidisciplinary tumor board can be time-consuming and demanding, requiring substantial preparation. Anecdotally radiologist participation is felt to help identify discrepancies in previous interpretations; however, there are limited data assessing the actual impact of their tumor board review on patient management. This prospective study aims to evaluate how the reinterpretation of outside imaging and review at hepatobiliary tumor board (HBTB) affects the diagnosis and management of patients with hepatobiliary neoplasms. Methods: This prospective analysis included all patients presented at the weekly HBTB between 6/13/2023 - 6/25/2024. One radiologist reviewed the available reports of outside imaging, the local reinterpretation of outside imaging, the updated local imaging, and documented conclusions from discussion of the case at HBTB. HBTB included 4 radiologists who had reviewed each case. Discrepancies (presence/absence, number, and reasons for) were recorded. When discrepancies occurred, the impact on patient management (5-point Likert scale) was determined by two of the radiologists present at the HBTB in consensus, with input from clinicians if needed. A six-month follow-up was performed to confirm suspected diagnoses. Results: 208 cases (128 males, 104 chronic liver disease patients) were presented at HBTB. Disagreements in the detection or characterization of lesions were found in 59/208 (28.4%) of cases. A change in management occurred in 38/59 (64.6%) of these discrepant cases. In cases with recorded discrepancies in which follow-up confirmation was available, the final interpretation was confirmed in 34/41 (82.9%) of cases. Conclusion: Our study found a discrepant interpretation in nearly one-third of cases presented at a weekly HBTB and a resultant change in management in 65% of those cases. These findings highlight the importance of reinterpretation of prior imaging studies and the presence of radiologists at HBTB to guide optimal patient management.

Radiologists play a key role in the management of renal masses, and it is important to understand the nonsurgical treatment options for solid renal masses, typical imaging findings after treatment, common complications, and methods to avoid pitfalls.