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PURPOSE Bone metastases (BM) occur in approximately 30% of patients with metastatic renal cell carcinoma (mRCC) and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, and cabozantinib, a tyrosine kinase inhibitor, have demonstrated activity in BM. RADICAL (Alliance A031801; ClinicalTrials.gov identifier: NCT04071223 ) evaluated cabozantinib ± radium-223 in mRCC with BM. METHODS This phase II trial enrolled patients with mRCC of any histology with ≥1 BM. Patients were randomly assigned 1:1 to cabozantinib ± radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, opioid use, and International mRCC Database Consortium (IMDC) risk. The primary end point was SSE-free survival (SSE-FS). Secondary end points included safety, objective response rate (ORR), progression-free survival, and overall survival (OS). A target of 124 evaluable patients was planned, with a prespecified interim futility analysis at 50% of expected SSE-FS events; the trial would stop if the stratified hazard ratio (sHR) > 1.0. RESULTS The prespecified interim futility analysis was conducted after 90 patients were enrolled and crossed the futility boundary, leading to closure at 98 patients. The final analysis included all 98 patients. Median age was 63 years, 82.7% had clear cell histology, and 79.6% were using an OTT. IMDC risk was favorable (18.4%), intermediate (67.3%), and poor (14.3%). Median follow-up was 13.1 months. Median SSE-FS for cabozantinib with radium-223 versus cabozantinib was 16.7 versus 17.6 months (sHR, 1.46 [90% CI, 0.86 to 2.51]). Median OS was 28.3 versus 19.7 months (sHR, 1.40 [95% CI, 0.70 to 2.79]). ORR was 19.4% versus 25.0% ( P = .78). Grade ≥3 adverse events were similar across arms (69.6% v 75.5%). CONCLUSION Radium-223 did not improve SSE-FS when added to cabozantinib. The combination demonstrated a manageable safety profile.

Abstract Cancer outcomes vary widely between individual patients, each accumulating an irregular record of treatments, diagnoses, measurements, and complications. Current prognostic models reduce this complexity into a single snapshot, focus on narrow clinical settings, and rarely generalize across hospitals. Here we introduce Chronicle , an explainable transformer that learns from entire patient trajectories to predict diverse clinical outcomes throughout the disease course while capturing both short- and long-term temporal dependencies. Trained on 53.7 million longitudinal data points from 51,711 patients spanning 67 cancer types, Chronicle operates natively on irregular data without imputation and jointly predicts eight endpoints within a flexible framework adaptable to additional outcomes. Chronicle outperformed cross-sectional models for overall survival prediction (C-index 0.84 vs 0.76-0.79), stratified patients more accurately than established prognostic systems, including TNM stage, and predicted seven adverse event and transfusion endpoints (AUC 0.80-0.92). Applied without retraining to 69,341 patients in Germany, Switzerland, and the United States, Chronicle generalized across healthcare systems and improved further with local fine-tuning. Integrated explainability traced each risk update to patient-specific clinical factors, revealing distinct temporal persistence of prognostic information, with relevance half-lives ranging from weeks for therapies to nearly one year for baseline characteristics. These findings demonstrate that learning from hospital-wide patient trajectories enables interpretable and continuously updated predictions, providing a scalable framework to support individualized treatment decisions.

Subretinal and intravitreal injection of retinal gene therapy is associated with serious adverse events and poor efficacy. We sought to improve retinal gene therapy delivery by developing fibrin hydrogel encapsulated adeno-associated virus (FE-AAV). Here we investigate conditions for storage and stability for FE-AAV. FE-AAV containing 1.9 × 109 genome copies of AAV2/2-CMV-GFP was manufactured using fibrinogen reconstituted in 0.01 M sodium citrate, pH 7 (NaC) or phosphate-buffered saline containing 0.001% (v/v) Pluronic F68 (F68). Samples were stored at either −80 °C or 4 °C for up to 16 weeks. Changes in transduction efficiency, and mechanical and physical properties were evaluated. In vitro transduction was significantly (p < 0.05) reduced for FE-AAV manufactured with NaC. In contrast, we observed no change in transduction through 16 weeks for FE-AAV made with F68. Physical changes occurred in FE-AAV stored at −80 °C. In contrast to FE-AAV formulated with NaC, FE-AAV formulated with F68 and stored at 4 °C for 16 weeks was essentially equivalent to freshly made FE-AAV and retained the ability to transduce retinal pigment epithelial (RPE) cells in the pig eye. We conclude that FE-AAV formulated with F68 and stored at 4 °C is stable and shows potential for retinal gene therapy for at least 4 months following manufacture.

Summary Long-read nanopore sequencing enables simultaneous detection of germline variation and native DNA base modifications on individual DNA molecules, providing a unique opportunity to investigate allele-specific epigenetic regulation. Here, we performed whole-genome nanopore sequencing on normal and tumor prostate tissues to characterize differential methylation, methylation entropy, and allele-specific methylation (ASM) associated with noncoding genetic variants. Genome-wide analysis identified extensive cancer-associated differentially methylated regions (DMRs), with hypermethylated DMRs significantly enriched near transcription start sites and transcriptional regulatory regions. Integration with transcriptomic datasets revealed strong inverse relationships between promoter methylation and gene expression, while 5-hydroxymethylcytosine (5hmC) levels positively correlated with transcriptional activity across gene bodies. Using fragment-level methylation patterns enabled by long-read sequencing, we further quantified methylation entropy incorporating both 5mCG and 5hmCG states. Cancer-hypermethylated DMRs exhibited markedly reduced entropy, consistent with clonal fixation of methylation states during tumor progression. Entropy profiling across chromatin annotations demonstrated maximal epigenetic heterogeneity at partially modified enhancer-associated regions. To investigate cis-regulatory genetic effects, we developed a simple ASM framework (nanoASM) that can partition sequencing reads by allelic state and identifies allele-specific DMRs directly from long-read data. Compared with conventional population-level mQTL analysis, ASM demonstrated substantially improved statistical efficiency by leveraging within-individual contrasts and reducing sample-level heterogeneity. Although germline single nucleotide polymorphisms (SNPs) were largely shared between normal and tumor tissues, ASM patterns differed substantially, with tumor-associated ASM regions displaying significantly larger genomic span and stronger allelic methylation differences. Comparative analysis with TCGA prostate mQTL and GTEx prostate eQTL datasets demonstrated substantial concordance between ASM directionality and downstream transcriptional effects, particularly for variants located within DMRs and near transcription start sites. At the IRX4 prostate cancer risk locus, ASM identified an androgen-responsive regulatory domain overlapping AR ChIP-seq and H3K27ac peaks, nominating rs6885084 as a candidate functional variant. At the PSCA locus, ASM anchored by rs4736369 was associated with allele-specific methylation, chromatin activation, transcript abundance, and isoform usage. Together, these findings establish nanopore-based ASM analysis as a powerful approach for resolving functional noncoding variants and their regulatory domains they control in prostate cancer.

4500 Background: BM occur in ~30% of RCC pts and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, prolongs survival in advanced prostate cancer. A pilot study of radium-223 with VEGF tyrosine kinase inhibitors (TKI) in RCC with BM showed safety and early efficacy (McKay, CCR, 2018). Cabozantinib is a TKI that showed efficacy in BM. RADICAL (NCT04071223) was designed to investigate cabozantinib ± radium-223 in RCC with BM. Methods: This open label multicenter study enrolled RCC pts with ≥1 symptomatic BM not previously irradiated and Karnofsky performance status ≥60%. Prior therapies were allowed; non-clear cell population was limited to 20%. Randomization was 1:1 to cabozantinib with (Arm A) or without (Arm B) radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, baseline opioid use, and IMDC risk. In Arm A, cabozantinib was 40 mg daily cycle 1, 60 mg thereafter if tolerated; radium-223 was 1.49 microcurie/kg IV every 28 days for 6 doses. In Arm B, cabozantinib was 60 mg daily. The primary endpoint was SSE-free survival (SSE-FS). Secondary endpoints were safety, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). The study was designed with 85% power to detect improvement in 6-month SSE-FS from 65% to 78% (one-sided α=0.05), with planned interim futility analysis at 50% of expected events. Results: From 12/2019 to 9/2025, 90 pts were enrolled and evaluable for the interim analysis. Median age was 63 years; 74.4% male, 90.0% White, 83.3% clear cell histology. 11.1% were treatment naïve, 80.0% received OTT, 51.1% had baseline opioid use. IMDC risk was 16.7% favorable, 68.9% intermediate, 14.4% poor. Median cabozantinib dose was 31.4 mg (Arm A) and 40.0 mg (Arm B); median radium-223 cycles was 6. Median follow-up was 13.1 (range 0.1-49.4) months with 50 events, 17 SSEs (Arm A: 10; Arm B: 7) and 33 deaths (Arm A: 13; Arm B: 20). Outcomes are in Table. 71 pts were evaluable for response. ORR was 22.2% (Arm A), 22.9% (Arm B). Any grade treatment-related adverse events were 97.7% (Arm A), 93.2% (Arm B); grade ≥3 were 65.9% (Arm A), 56.8% (Arm B). The trial closed after interim analysis as SSE-FS did not meet the prespecified futility boundary (HR≤1). Conclusions: Radium-223 did not improve the primary endpoint of SSE-FS when added to cabozantinib but a numerical prolongation in OS was observed. Combination treatment was safe. Alternative radiotherapeutics warrant investigation in RCC. Clinical trial information: NCT04071223 . Interim efficacy analysis. Arm Median(95% CI) HR (95% CI) Stratified SSE-FS A 17.9 (15.0-NE) 1.24 (0.62-2.48) B 17.6 (10.9-NE) Unstratified SSE-FS A 17.9 (15.0-NE) 0.90 (0.51-1.59) B 17.6 (10.9-NE) OS A 32.2 (17.9-NE) 0.77 (0.42-1.41) B 21.3 (12.3-NE) Stratified PFS A 11.0 (5.8-17.4) 1.39 (0.72-2.66) B 11.2 (9.0-18.5)

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel’s discussions on select 2026 updates to the guidelines regarding nonmetastatic disease: the elimination of the very-low-risk group, updates to the Principles of Active Surveillance, and caution in the use of focal therapy in newly diagnosed patients.

OBJECTIVE Protocols for intraoperative mapping during awake craniotomy vary widely. The aim of this study was to evaluate how the number and type of intraoperative neuropsychological paradigms administered via NeuroMapper, a tablet-based platform, during awake glioma surgery affect positive mapping rates, return to work (RTW), and oncological outcomes. Factors associated with the operative duration and early postoperative neurological deficits were of additional interest. METHODS This single-center retrospective study included patients with diffuse low- and high-grade gliomas who underwent awake craniotomy with NeuroMapper-guided mapping between 2018 and 2024. Primary outcomes were RTW, progression-free survival (PFS), and overall survival (OS); operative duration and early postoperative deficits were secondary outcomes. Covariate balancing propensity score (CBPS) analysis was used to address confounding by tumor grade, with all postweighting standardized mean differences < 0.10. A weighted logistic regression model assessed RTW, and CBPS-weighted Cox models assessed PFS and OS. Linear regression was used to analyze intraoperative variables, operative duration, and early postoperative deficits. RESULTS Of 189 patients included in the analysis, 65 had LGG (median age 39 years) and 124 had HGG (median age 56 years). Mapping complexity varied, with 1–6 tasks used (median 4). Weighted multivariate logistic regression analysis identified the following independent predictors of RTW: preoperative Karnofsky Performance Status score ≥ 80 (OR 1.37, p = 0.039), absence of recurrent disease (OR 0.30, p < 0.001), use of 5–6 paradigms (OR 1.54, p = 0.047), positive mapping (OR 2.41, p = 0.017), and subtotal resection (OR 4.43, p = 0.002). Intraoperative seizure, early postoperative deficit, and the resection technique were not significant. IDH mutation status was associated with improved PFS (HR 0.15, p < 0.001), while subtotal resection was associated with worsened PFS (HR 3.00, p < 0.001). Positive mapping was associated with better OS (HR 0.57, p = 0.04). The operative duration was unaffected by mapping variables but was longer in patients with obesity (β = 0.28, p = 0.038). CONCLUSIONS Positive NeuroMapper-guided mapping of more diverse linguistic functions was associated with RTW and longer OS. Additionally, mapping complexity did not prolong surgery times, supporting potential standardization.

ABSTRACT Background Retrospective evaluations of multidisciplinary team (MDT) review of pancreatic cystic lesions (PCL) demonstrate improved PCL management. Endoscopic ultrasound (EUS) evaluates PCL for worrisome features; however, its influence on MDT is unclear and may be attenuated by anchoring/confirmation bias. We aimed to evaluate the impact of EUS and the overall performance of MDT evaluation of PCL. Methods Four mock MDT sessions at two institutions were presented imaging from 40 consecutive PCL cases (20 “high‐risk” with advanced neoplasia, 20 “low‐risk” with pathologic low‐grade dysplasia or ≥ 3 years of non‐progression on surveillance), with and without upfront EUS/FNA (cytology, CEA, Amylase), in a randomized, crossover design. Group 1 adjudicated without EUS, Group 2 adjudicated with EUS, and Group 3 adjudicated with EUS after initially adjudicating without it. Results The cohort included branch‐duct ( n = 20), mixed type ( n = 6), and main duct ( n = 4) IPMN, MCN ( n = 5), and non‐mucinous PCL ( n = 5). Group 2 (EUS) correctly identified mucinous PCL with 97% sensitivity and 70% specificity, significantly higher than Group 1 (No EUS) (Sensitivity 91%, Specificity 20%; p = 0.04). Group 3 (Unblinded to EUS) performed significantly worse in mucinous PCL identification compared with Group 2, indicating cognitive bias (Sensitivity 97%, Specificity 10% ( p = 0.0003)). Group 2 correctly identified high‐risk PCL that required surgical intervention with 85% sensitivity and 85% specificity, significantly higher than Group 1 (Sensitivity 60%, Specificity 75%; p = 0.0016) and Group 3 (Sensitivity 73%, Specificity 80%, p = 0.0485). Conclusion While susceptible to cognitive bias, EUS significantly improves MDT assessment of PCL. MDT establishes a high bar for iterative additions of biomarkers to PCL analysis.

162 Background: Clinical trial conduct in advanced prostate cancer has changed dramatically with the continued development of new imaging approaches, molecular phenotypes and genetic subtypes, prognosis assessments, and effective therapies across a range of disease states. This created a need to redefine terminology and best practices for clinical trials. Methods: We convened PCWG4, an international expert committee of multidisciplinary working groups, between 2016 and 2025 to update and expand PCWG2-3 recommendations based on emerging evidence and clinical trial data in an innovative biomarker and imaging context to provide guidance for clinical trial design, eligibility, and endpoint assessments. Results: PCWG4 redefines terminology around disease states and prior therapies in a patient-centric context, considering imaging modalities, with a particular focus on PET-defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, imaging and non-imaging-based responses. We define delay/prevent endpoints including responses by pathology, ctDNA, circulating tumor cells, and PSA declines, and specify intervals for re-assessments including imaging, biomarker assessments, and patient reported outcomes. We propose new imaging-specific rPFS criteria including guidance with serial PSMA PET/CT imaging (Table). We provide recommendations in a biomarker-based context for the indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. Conclusions: PCWG4 expands guidance on patient and tumor profiling, as well as therapy development, to include both androgen deprivation therapy sensitive and resistant settings, reflecting today’s more heterogeneous and diverse patient population to optimize outcomes. PCWG4-defined radiographic progression by imaging modality for patients with metastatic disease. Pretreatment Scan On-treatment Scan #1(≥week 8) On-treatment Scan #2 All Subsequent Scans Bone scintigraphy Comparator Comparator for subsequent scansPOD never called here POD:PCWG3 criteria (2+2 additional new lesions) POD:≤5 new lesions: PCWG3 criteria 2 new lesions confirmed≥6 new lesions CT/MRI Any measurable disease Comparator PCWG3/RECIST PCWG3/RECIST PCWG3/RECIST PSMA PET Bones, and lymph nodes and lung metastases (non-RECIST qualifying by + on PET only) Comparator POD:≤5 new lesions: 2 new lesions confirmed on a subsequent scan≥6 new lesions Same as prior Same as prior Liver and non-pulmonary viscera Comparator POD:Any single new lesion that represents disease Same as prior Same as prior