Cheville, John C.

Abstract Background Presacral tumours are rare, heterogeneous lesions. Historical classification systems for presacral tumours have provided a valuable framework, but were based on limited available data. This study aimed to develop a contemporary classification aligned with current tumour entities and clinical practice. Methods A prospectively registered systematic review of surgically managed presacral tumours published from 1975 to 2025 was combined with a retrospective multisite institutional surgical pathology review from 1986 to 2025. Pathological descriptors were extracted, cross-referenced, harmonized to current terminology, and organized through multidisciplinary expert review to obtain a new classification. Results The systematic review identified 5997 records, of which 203 studies met the inclusion criteria and contributed 181 pathological terms after generic and unclassifiable diagnoses were removed. Review of 3606 pathology reports identified 19 additional terms, bringing the total to 200 pathological terms. After harmonization to current terminology and exclusion of non-neoplastic processes, a contemporary classification was developed using biological descriptors: developmental versus acquired origin; tissue lineage (neurogenic, osseous/haematopoietic, soft tissue, or miscellaneous); and tumour behaviour (benign, locally recurrent without metastatic potential, locally recurrent with low metastatic potential, malignant non-sarcoma, or malignant sarcoma). Conclusion The Mayo Clinic classification of presacral tumours updates historical systems by reflecting the broader, more modern spectrum of neoplasms and distinguishing lesions by lineage and biological behaviour. It may improve diagnostic clarity, communication, and selection of appropriate observation, multidisciplinary assessment, and treatment pathways.

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.

TPS898 Background: Enfortumab vedotin with pembrolizumab (EV/Pembro) is now first-line therapy for locally advanced or metastatic urothelial carcinoma (la/mUC) following the EV-302/KEYNOTE-A39 trial, which demonstrated a 67.7% response rate and prolonged survival. However, ~35% of cancers exhibited primary resistance and most responders relapse within one year, with post-EV/Pembro therapies achieving < 15% response and median survival < 3 years. We previously showed that therapeutic plasma exchange (TPE) removed soluble PD-L1 and other immune checkpoint inhibitor (ICI) blocking soluble factors from the blood and that this overcame ICI resistance. Combining TPE with EV/Pembro rechallenge may overcome acquired resistance and restore antitumor immunity. Methods: RECIPE-B1 [NCT07087860] is an open-label, randomized phase II trial enrolling 50 patients (1:1) with EV/Pembro-refractory la/mUC and ECOG 0–2. Arm A receives TPE on days 1–3 followed by EV 1.25 mg/kg IV plus pembrolizumab 200 mg IV on day 3 of each 21-day cycle for the first three cycles, then continues EV/Pembro alone from cycle 4. Arm B receives investigator’s-choice next-line standard of care (SOC) per NCCN guidelines. Tumor assessments occur at the end of cycle 4 (±28 days) and every 12 weeks thereafter; safety is monitored each cycle (CTCAE v5.0). The primary endpoint is objective response rate (ORR) by RECIST 1.1, comparing TPE + EV/pembro versus SOC. Secondary endpoints include progression-free survival, overall survival, duration of response, quality of life (EORTC QLQ-CIPN20), and safety. Correlative studies evaluate circulating and urinary tumor DNA and exosomal biomarkers (including exosomal Nectin-4) as predictors of response and resistance. The trial is open at Mayo Clinic; as of September 2025, 2 of 50 patients have been enrolled, with planned accrual of ~2 patients/month and central coordination at Mayo Clinic and affiliates. Clinical trial information: NCT07087860 .

TPS892 Background: Enfortumab Vedotin (EV) plus pembrolizumab (Pembro) is now first-line therapy for advanced urothelial carcinoma (UC), yielding ~30% complete response (CR) rates; nevertheless, most patients (pts) progress within 1 year and median overall survival (OS) remains < 3 years. In muscle invasive bladder cancer, local consolidation after systemic therapy improves outcomes, suggesting that residual, treatment-refractory intravesical disease drives relapse. We hypothesize that cytoreductive cystectomy/nephroureterectomy (CC/U)—with metastasis-directed therapy (MDT) as needed—can consolidate responses to EV/Pembro and extend benefit in regionally advanced or metastatic UC. CAST-AI prospectively evaluates this multimodal strategy and integrates correlative studies of exosomal Nectin-4 and circulating tumor DNA (ctDNA) from blood and urine as predictive/MRD biomarkers. Methods: CAST-AI is a phase II, decentralized single-arm trial enrolling pts with histologically confirmed UC of the bladder or upper urinary tract with ≥N1 and/or M1 disease and ECOG PS 0–2 who are potential surgical candidates (planned n = 75). Treatment: EV 1.25 mg/kg IV D1 & D8 + Pembro 200 mg IV D1 q21d, ≥4 cycles; MDT permitted any time pre-surgery. Response assessments occur q9 weeks (±4) to 18 months, then q12 weeks (±4). Surgical eligibility requires: (A) fitness for surgery; (B) complete or partial response (CR/PR) or, for select low-burden/unmeasurable disease, urologist-adjudicated candidacy; (C) all distant sites addressed; and (D) procedure in pt’s best interest. Post-CC/U maintenance EV/Pembro is encouraged per clinical discretion and guided by definitive surgical pathology results, which provide true pathologic staging often unattainable through imaging after systemic therapy. Primary endpoint: 12-month progression-free survival (PFS). Secondary endpoints: Objective response rate (ORR), CR rate, down-staging at CC/U, PFS, OS, and safety (using CTCAE). Exploratory endpoints: longitudinal exosomal Nectin-4 and ctDNA dynamics as MRD and early relapse indicators; tissue–blood–urine Nectin-4 concordance; pt-reported tolerability (using CIPN20). Key exclusions: > 20% variant histology or disallowed subtypes (e.g., micropapillary, plasmacytoid, sarcomatoid, neuroendocrine); prior chemotherapy for UC; contraindications to surgery/EV/ICI; or active uncontrolled comorbidities/infections. Status: Enrollment is open and ongoing, with 25 of 75 pts enrolled as of September 2025. The trial uses a decentralized model, allowing pts to receive EV/Pembro at their local facility, with central coordination, biospecimen shipping, and surgical evaluation at Mayo Clinic or affiliated sites. ClinicalTrials.gov: NCT06764095. Clinical trial information: NCT06764095 .

TPS283 Background: Emerging evidence suggests that metastasis-directed therapy (MDT) with stereotactic body radiotherapy (SBRT) can delay systemic therapy in oligometastatic castration-sensitive prostate cancer (omCSPC). However, the optimal timing of androgen deprivation therapy (ADT) and androgen receptor pathway inhibitor (ARPI) initiation in this setting remains undefined. While deferred ADT following MDT may preserve quality of life, early short-course ADT/ARPI may eradicate micrometastatic disease and extend progression-free survival. Extracellular vesicles (EVs) carrying PSMA-positive prostate cancer (PC) signals and circulating tumor DNA (ctDNA) may serve as real-time biomarkers of MRD and treatment response. Methods: DIVINE [NCT06378866] is an open-label, phase II, randomized trial enrolling men with omCSPC defined by 1–5 metastases (≥1 extrapelvic) on conventional imaging (CT/MRI and bone scan) and testosterone >100 ng/dL. PSMA PET may be obtained for correlative purposes but does not determine eligibility. Participants (N = 220) are randomized 1:1 to: Arm A (Early systemic): SBRT plus 6 months of ADT + ARPI. Arm B (Deferred systemic): SBRT alone with observation, reserving systemic therapy until radiographic progression not amenable to further SBRT (mrPD). SBRT is delivered per institutional standard; repeat SBRT is allowed until lesions become non-addressable. The primary endpoint, modified radiographic progression-free survival (mrPFS), is the time from randomization to death or radiographic progression not amenable to further MDT, defined by PCWG3 (bone) and modified RECIST 1.1 (soft tissue) criteria on conventional imaging. Soft-tissue progression requires ≥ 20% increase in measurable disease or a new lesion; bone progression requires ≥ 2 new confirmed lesions. Secondary endpoints include OS, biochemical PFS, time to local and distant progression, and grade 3–5 adverse events during systemic therapy. Exploratory endpoints evaluate EV and ctDNA kinetics as MRD markers, correlation of PSMA-positive EV burden with outcomes, and duration of response after short-course ADT/ARPI. Correlative analyses will longitudinally quantify PSMA-positive EVs and ctDNA at baseline, on treatment, and at progression to define MRD dynamics and resistance patterns. The trial uses Pocock–Simon dynamic allocation by EV strata and metastatic burden to ensure balance across arms. The trial is open and actively enrolling across all Mayo Clinic sites; as of October 2025, 35 of the planned 220 patients have been accrued. Clinical trial information: NCT06378866 .

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 High-grade gliomas (HGGs) are aggressive tumors with poor outcomes and limited treatment options. Here, we combined genomic and transcriptomic tumor profiling with drug testing in a patient-derived 3-dimensional culture model to identify individualized treatments and predictive biomarkers. Activity of single agents targeting frequently dysregulated glioma pathways was relatively poor ex vivo and generally reflected historical patient data. However, compounds targeting PI3K, epigenetic, and survival/senescence signaling were effective in some cases. Drug sensitivity correlated with transcriptional rather than genomic features and suggested heterogeneity as a resistance mechanism. Bromodomain and extraterminal domain inhibition was particularly effective in tumors enriched in the mesenchymal transcriptional subtype, promoted proneural transition, and was overcome by upregulated PI3K signaling. Notably, combinations were largely effective, with 6 strategies exhibiting stronger efficacy than corresponding single agents in most cases (58-77%). This study identifies HGG vulnerabilities and associated biomarkers, resistance mechanisms, and effective combination strategies that warrant further clinical validation. Graphical Abstract