Citations

Abstract The prevalence of steatotic liver disease (SLD) is rising globally, presenting a significant public health challenge. While non-contrast computed tomography (CT) scans hold promise for the opportunistic detection of SLD, their full potential has not been systematically explored. Clinical indicators, such as serum data, are crucial for monitoring the progression of SLD. We introduce a novel Multimodal AI for Opportunistic Steatotic Liver Disease Screening (MAOSS), which integrates demographic data, serum tests, conventional CT biomarkers, and deep learning-derived CT image features to enhance model performance and explainability. MAOSS employs an innovative learning strategy, trained on a large-scale dataset (n = 1,783) encompassing both histopathologically-confirmed SLD and radiologically-reported steatosis cases. The model underwent extensive retrospective validation using steatosis grades derived from both histology and MRI-PDFF across internal and external datasets (n = 913), as well as real-world patient data (n = 18,504). It accurately detected mild to severe steatosis (≥ S1) with AUCs ranging from 0.903 to 0.929. Notably, MAOSS significantly improved the overall AUC for radiologists (n = 11) from 0.709 to 0.798 (p < 0.001). Furthermore, MAOSS was applied to optimize the standard clinical pathway for a simulated primary risk screening of SLD patients (n = 1,192), resulting in the identification of 31% more patients at risk of steatohepatitis and liver fibrosis progression, highlighting its potential to enhance SLD detection and management.

ABSTRACT Genes involved in the regulation of chromatin structure are frequently disrupted in cancer, contributing to an aberrant transcriptome and phenotypic plasticity. Yet, therapeutics targeting mutant forms of chromatin-modifying enzymes have yielded only modest clinical utility, underscoring the difficulty of targeting the epigenomic underpinnings of aberrant gene regulatory networks. Here, we sought to identify novel epigenetic vulnerabilities in diffuse large B-cell lymphoma (DLBCL). Through phenotypic screens and biochemical analysis, we demonstrated that inhibition of the H3K9 demethylases KDM4A and KDM4C elicits potent, subtype-agnostic cytotoxicity by antagonizing transcriptional networks associated with B-cell identity and epigenetically rewiring heterochromatin. KDM4 demethylases associated with the KRAB zinc finger ZNF587, and their enzymatic inhibition led to DNA replication stress and DNA damage-induced cGAS-STING activation. Broad surveys of transcriptional data from patients also revealed KDM4 family dysregulation in several other cancer types. To explore this potential therapeutic avenue, we performed high-throughput small molecule screens with H3K9me3 nucleosome substrates and identified novel KDM4 demethylase inhibitors. AI-guided protein-ligand binding predictions suggested diverse modes of action for various small molecule hits. Our findings underscore the relevance of targeting fundamental transcriptional and epigenetic mechanisms for anti-cancer therapy. HIGHLIGHTS Phenotypic screens identified JIB-04 as a potent anti-cancer agent for multiple subtypes of diffuse large B-cell lymphoma JIB-04 binds and inhibits KDM4 demethylases resulting in epigenomic rewiring of heterochromatin KDM4 demethylases cooperate with KRAB zinc fingers to limit DNA replication stress, and KDM4 inhibition instigates DNA-damage and cGAS-STING activation in several human cancers High-throughput small molecule screens with semi-synthetic nucleosome substrates and AI-guided molecular docking simulations identify novel KDM4 inhibitors

Abstract We present a comprehensive global analysis of genetic variants associated with autosomal-dominant Alzheimer’s disease (ADAD). A total of 550 variants in the APP, PSEN1 and PSEN2 genes were identified, of which 279 were classified as pathogenic or likely pathogenic based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria, utilizing data from the Dominantly Inherited Alzheimer Network (DIAN), literature and public databases. Symptomatic age at onset (AAO) data were estimated for 227 of these variants, allowing detailed characterization of their frequency, pathogenicity and AAO. Importantly, 226 variants met eligibility criteria for inclusion in disease-modifying clinical trials. Furthermore, we demonstrated the predictive value of mean variant AAO and parental AAO in predicting symptomatic AAO, validated against converters who became symptomatic during follow-up in the DIAN Observational Study. This dataset provides critical insights into the global landscape of ADAD and reveals the genetic and AAO heterogeneity of ADAD variants while refining variant trial eligibility criteria.

ObjectiveThe objective was to determine the mortality rate as well as the causes and predictors of death in antiphospholipid antibody (aPL)–positive patients with and without antiphospholipid syndrome (APS) classification.MethodsThe inclusion criterion for the multicenter international Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) registry is positive aPLs according to the Revised Sapporo Classification Criteria tested within one year before enrollment. Patients are observed every 12 ± 3 months with clinical data and blood collection. For this prospective analysis, we first analyzed the causes of death for patients reported as “deceased.” Secondly, we analyzed risk factors for death using the adjusted Cox proportional hazards model and calculated survival probability using the Kaplan‐Meier model based on different age groups.ResultsOf 967 patients, 43 (5%) were deceased after a median follow‐up of 5.3 years. Based on the univariate analysis, deceased patients, compared to living patients, were more likely to be older and have a history of arterial thrombosis, catastrophic APS, concomitant systemic autoimmune diseases (SAIDs), and baseline cardiovascular disease (CVD) risk factors. Based on the Cox proportional hazards model adjusted for age and for each of the strongest predictors of death, arterial thrombosis (hazard ratio [HR] 2.94, 95% confidence interval [CI] 1.50–5.76), concomitant SAIDs (HR 2.97, 95% 1.56–5.63), and baseline any CVD risk factor (HR 2.43, 95% CI 1.05–5.71) were significantly associated with mortality.ConclusionIn our cohort of persistently aPL‐positive patients, the mortality rate was 5% after a median follow‐up of five years and was highest for patients ≥60 years old at registry entry. History of arterial thrombosis, concomitant SAIDs, and baseline any CVD risk factor independently predicted future death.

Background and Aims: Severe alcohol-associated hepatitis (AH) is rising in incidence with a high mortality burden. While corticosteroids are recommended for eligible patients with severe AH, no guidance exists for the timing of steroid initiation, tapering regimens, and surveillance of adverse events. We aim to systematically review these variables and provide evidence-based recommendations for the inpatient and outpatient management of severe AH. Approach and Results: We performed a literature search from inception to May 30, 2024, to include clinical trials published in full form and assessed the quality of evidence using the Cochrane Risk of Bias tool. Data were collected on the timing of initiation, rate, and complications following steroid therapy, and taper regimens in the setting of severe AH. Of 28 studies that fulfilled our inclusion criteria, the median time from admission to steroid initiation was 6.5 days. The most common steroid dosing regimen was prednisolone 40 mg daily for 28 days. Twenty-five studies containing 3196 subjects reported adverse events, with exactly 50% in the steroid arm and the other half in the comparison arm. Infections, gastrointestinal bleeds, and renal impairment were the most frequently reported adverse events. Most infections occurred within the first month of the study. A 2-week steroid taper was the most frequently reported regimen. Conclusions: We recommend taking up to a week to systematically and thoroughly evaluate patients before initiating steroids, and vigilant monitoring in the first month of treatment. We also recommend the lowest possible steroid exposure with a 2-week steroid taper and close outpatient follow-up.

LBA22 Background: Tumor-informed circulating tumor (ct) DNA testing is recognized as a powerful predictor of CRC recurrence. However, the benefit of systemic therapy to prevent or delay clinical recurrence in patients (pts) with molecular recurrence after curative surgery remains uncertain. Methods: Pts with CRC who had undergone curative resection of primary and/or metastatic sites + standard of care (SoC) adjuvant treatment if applicable, were enrolled in ALTAIR study if they (1) prospectively tested positive for ctDNA using a clinically validated, personalized assay (Signatera™, Natera, Inc.) within 3 months before enrollment and (2) had no recurrence on radiological (CT) imaging. Pts were randomized to receive FTD/TPI or placebo for 6 months. CT and ctDNA analyses were conducted every 2 months in the first year, every 3 months in the second year, and every 6 months in the third year. The primary endpoint was disease-free survival (DFS), with secondary endpoints including ctDNA clearance, overall survival (OS), and adverse events. The study assumed a median DFS of 8 months in the placebo group, an HR of 0.667 for the FTD/TPI group, 0.05 significance level, 0.80 power, 2-year enrollment, and 1-year follow-up, requiring 240 pts and 190 DFS events. Baseline ctDNA levels were evaluated by mean tumor molecules (MTM)/ml. Results: Between July 2020 and June 2023, 243 pts were enrolled and randomized to FTD/TPI (n=122) or placebo (n=121). Baseline characteristics were balanced, and 96.3% of pts received SoC treatment postoperatively. FTD/TPI group had a median DFS of 9.30 months vs. 5.55 months in the placebo group, but this difference did not reach statistical significance in the primary population (HR, 0.79; 95% CI, 0.60-1.05; P = 0.107). The FTD/TPI benefit was highly significant in resected oligometastatic stage IV pts as shown in Table. The baseline MTM/ml levels were significantly higher in resected oligometastatic Stage IV pts vs non-Stage IV (0.68 vs 0.32, P = 0.024). Overall, FTD/TPI benefit was significantly pronounced with higher MTM/mL, with linear benefit observed with increasing MTM/mL values at the enrollment time point. OS data remain immature, with 24 events reported across both arms. Grade ≥3 adverse events occurred in 73.0% of the FTD/TPI arm versus 3.3% in the placebo arm, with no new safety signals. Conclusions: Although statistical significance was not reached in the primary population, FTD/TPI showed clinically meaningful DFS benefit in pts with resected oligometastatic disease and a trend towards increasing DFS benefits with increasing MTM/mL values. Clinical trial information: NCT04457297 . Number Baseline MTM/ml Median DFS FTD/TPI(months) Placebo (months) Primary population 243 0.40 9.30 5.55 HR, 0.79 P = 0.107 Stage IV 66 0.68 9.76 3.96 HR, 0.53 P = 0.012 Non-Stage IV 177 0.32 9.26 6.05 HR, 0.86 P = 0.378

LBA14 Background: CALGB/SWOG 80702 previously showed that the addition of celecoxib to standard adjuvant chemotherapy with FOLFOX did not significantly improve disease-free survival (DFS) in patients with stage III colon cancer. Here, we evaluated the prognostic and predictive value of ctDNA in identifying a subpopulation of patients who may benefit from celecoxib. Methods: In the subset of patients with adequate biospecimens who participated in CALGB/SWOG 80702, a randomized phase III trial of 3 versus 6 months of adjuvant 5-FU, leucovorin, oxaliplatin (FOLFOX) +/- celecoxib, ctDNA assessment was performed using a clinically validated, tumor-informed 16-plex mPCR-NGS assay (Signatera(TM), Natera, Inc.) after surgery and before the start of adjuvant therapy (baseline). The Kaplan-Meier method was used to describe the distribution of survival time based on ctDNA positivity and log-rank testing was performed. Cox proportional hazards models were used to examine unadjusted associations between ctDNA positivity and disease-free (DFS) and overall survival (OS). Two-sided P values equal to or less than 0.05 were considered statistically significant, except for interaction P values (tested with a likelihood ratio). Results: In total, 1,011 of the 2,526 patients who participated in 80702 had ctDNA testing results from baseline; 189 were ctDNA positive (18.7%). ctDNA positivity associated with male sex, higher T stage, and N2 (versus N1) stage. ctDNA positivity was significantly associated with worse DFS (hazard ratio [HR] 6.52 [95% confident interval (CI) 5.09-8.34; p<0.0001] and OS (HR 6.28 [95% CI 4.63-8.51; p<0.0001]). Three-year DFS was 86.6% in ctDNA-negative cases and 36.8% in ctDNA-positive cases. Among patients who were ctDNA negative, celecoxib use was not significantly associated with worse DFS as compared to placebo (HR 0.75 [95% CI 0.54-1.05; p=0.095]) with a three-year DFS of 87.7% versus 85.5%, respectively. Among ctDNA-positive patients, celecoxib significantly improved DFS compared to placebo (HR 0.59 [95% CI 0.42-0.85; p=0.004]) with a three-year DFS of 44.1% versus 26.6% (P interaction = 0.25). Similar results were seen for overall survival with a hazard ratio of 0.86 (95% CI 0.56-1.33; p=0.49) for ctDNA negative cases and 0.63 (95% CI 0.41-0.96; p=0.028) for ctDNA-positive cases for celecoxib versus placebo (P interaction = 0.28). Conclusion: In a randomized phase III adjuvant therapy trial for stage III colon cancer, ctDNA was highly prognostic of DFS and OS. ctDNA positivity also appeared predictive of the benefit of adjuvant celecoxib for DFS and OS. These results suggest a potential role for ctDNA in determining which patients should consider celecoxib in addition to standard FOLFOX adjuvant therapy. Clinical trial information: NCT01150045 .

62 Background: Both Regorafenib (R) and Trifluridine/Tipiracil (T) ± BEV are widely used treatments for mCRC in later lines. This RW study evaluated optimal sequencing and associated outcomes among patients who initiated R and T in sequential lines of therapy (LOT) between LOT1-LOT6 within community oncology settings in the US. Methods: A retrospective study utilizing electronic medical record data from The US Oncology Network examined adult patients with mCRC who initiated R and T ± BEV sequentially between 09/01/2015 and 11/30/2022 (index date), with follow-up until 05/31/2023. Treatment patterns, overall survival (OS) and time to next treatment (TTNT) after sequence were assessed overall, R first (R-T) and T first (T-R). Multivariable Cox regression adjusting for age, sex, ECOG, tumor stage, and prior medication, assessed the association of factors with OS and TTNT. Results: In total, 308 mCRC patients initiating R and T (R-T, 156 pts [140 R-T and 16 R-T+BEV]; T-R, 152 pts [136 T-R and 16 T+BEV-R]) met study criteria. Baseline demographic (mean age 63 yrs, males 55%) and clinical characteristics (70% colon cancer, 58% ECOG 0-1) were similar between the cohorts. Most patients initiated index therapies at the third line of therapy (LOT3) (49% R-T, 45% T-R). The median (IQR) sequence duration was 7.4 (5.6), 6.7 (4.4), and 7.0 (4.7) months, respectively in patients with R-T, T-R, and overall. The median (95% CI) OS was 12.8 (11.2, 14.1) months among R-T and 10.2 (8.8, 11.9) months among T-R patients. Compared to R-T, the adjusted HR for the T-R sequence was 1.2 (95% CI 0.9–1.6; p=0.2). The median (95% CI) TTNT was 9.3 (8.4, 10.3) and 8.6 (7.8, 9.4) months, for R-T and T-R, respectively; the adjusted HR was 1.1 (95% CI 0.8–1.4; p=0.62). Conclusions: Patients initiating R first appeared to have a longer duration of treatment and survival, although not statistically significant. The one-year median duration of survival in this real-world setting confirms the importance of access to these treatments in patients with mCRC and can inform physicians regarding the choice of medications while sequencing therapies in mCRC. Clinical outcomes among R-T and T-R mCRC patients. Variable Level R-T (± BEV)[N 1 = 156] T (± BEV) -R[N 1 = 152] Adjusted 3,4 HR 5 (95% CI)[R-T Reference] Effect OverallSurvival Months – median (95% CI) 12.8(11.2, 14.1) 10.2(8.8, 11.9) 1.20 (0.91, 1.58) 0.20 TTNT 2 Months – median (95% CI) 9.3(8.4, 10.3) 8.6(7.8, 9.4) 1.07 (0.83, 1.37) 0.62 1 Entire R-T and T-R cohorts are presented since 16 patients in each cohort initiated T+BEV. 2 Time To Next Treatment. 3 Overall Survival adjusting for age, gender, stage at diagnosis, ECOG, prior anti-VEGF treatment. 4 Time To Next Treatment adjusting for age, gender, stage at diagnosis, and line of therapy. 5 Hazard Ratio.

TPS309 Background: Patients with oligometastatic colorectal cancer (CRC) often experience long-term progression-free survival and overall survival (OS) following aggressive local treatment of isolated metastases, especially in the liver. However, the effectiveness of local ablative therapies, such as microwave ablation (MWA) and stereotactic body radiation therapy (SBRT), in patients with inoperable limited metastatic CRC or those with additional metastases outside the liver or lungs, remains uncertain. Despite the historical use of local therapy for oligometastatic CRC, often influenced by provider bias rather than strong evidence, questions persist about the potential benefits of applying this approach to patients with more extensive disease. This trial aims to address this clinical challenge by evaluating the safety and efficacy of adding total ablative therapy (TAT) of all disease sites to standard systemic treatment in patients with limited metastatic CRC. Methods: A022101/NRG-GI009 is a randomized phase III study within the National Clinical Trials Network, set to enroll 364 patients with newly diagnosed metastatic CRC (BRAF wild-type, microsatellite stable). Patients with liver-only metastatic disease are excluded. Pre-registration during first-line systemic therapy induction is encouraged. Eligible lesions must be treatable with surgical resection, MWA, and/or SBRT. Patients without significant radiographic progression after 12-39 weeks of first-line systemic therapy, with 4 or fewer disease sites post-induction chemotherapy, will be randomized 1:1. Randomization will be stratified by the number of metastatic organ sites (1-2 vs. 3-4), timing of metastatic disease diagnosis (de novo vs. secondary), and the presence of metastatic disease outside the liver/lungs in at least one site. Patients in Arm 1 will receive TAT, targeting all metastatic sites with a combination of surgical resection, MWA, and/or SBRT, followed by standard systemic therapy. Patients in Arm 2 will continue with standard systemic therapy alone. The choice of systemic therapy is at the discretion of the medical oncologist and may include continued therapy, maintenance chemotherapy, or observation. The primary endpoint is OS, with secondary endpoints including event-free survival, treatment-related toxicities, and local recurrence. Exploratory biomarker analyses will also be conducted. The study requires 346 evaluable patients across the two arms to demonstrate an OS improvement with a hazard ratio of 0.7, providing 80% power with a one-sided alpha of 5%. The trial employs a group sequential design with two interim analyses (at 25% and 50% of events) to assess futility. The trial began in January 2023, and patient recruitment is ongoing. Clinical trial information: NCT05673148 .

Abstract Background: The trajectory of metastatic castration-sensitive prostate cancer varies based on disease presentation and biology. While proteomic profiling studies of primary prostate tissue have linked protein expression with metastatic progression and prognosis, few studies have explored biological changes after treatment and their associations with response. Therefore, we conducted proteomic profiling of patients with oligometastatic castration-sensitive prostate cancer (omCSPC) treated with stereotactic ablative radiotherapy (SABR) or observation in the ORIOLE phase 2 randomized clinical trial (RCT). Methods Plasma from omCSPC patients in the ORIOLE trial was collected at baseline (day 1), day 90, and day 180. Protein abundance was quantified using the Olink Explore Assay. Differential expression from baseline to day 90 or 180 in each treatment arm was analyzed using a 2-sided t-test with Benjamini-Hochberg correction. Changes in protein expression at day 90 and 180 were compared with a Pearson correlation. Pathway enrichment was performed via gene set enrichment analysis (GSEA) using Reactome, KEGG, and Hallmark gene sets. Associations with progression-free survival (PFS) were analyzed using Kaplan-Meier and log-rank tests. Results In total, 1,472 proteins were assayed across 130 samples from 46 patients over 3 time points. Significant changes in expression post-SABR were noted at day 90 and 180 compared to baseline (using adjusted p-value cutoff of 0.05). At day 90, four proteins (FCRL1, CD22, TCL1A, FCER2) were downregulated; at day 180, only FCRL1, a Fc receptor-like gene family preferentially expressed in B cells, remained downregulated. No significant expression changes were found in the observation arm. Differential expression of proteins during follow-up were associated with PFS. In particular, LTO1, a maturation factor of ABCE1 important for ribosomal biogenesis and translation, was overexpressed at both day 90 and 180 post-SABR, and overexpression was associated with improved PFS at day 90 (median 24.5 mo vs 6 mo; p=0.017) and day 180 (median 33 mo vs 6 mo; p=0.043). These associations were absent in the observation arm. For proteins differentially expressed in the SABR arm at day 90, several signaling pathways were significantly enriched for patients with prolonged PFS, including positive enrichment of unfolded protein response (UPR) (p=0.008) and IL-4/IL-13 (p=0.009). At 180 days, several pathways were enriched for patients with prolonged PFS including negative enrichment of CTLA4 inhibitory signaling (p=0.005) and CD28 co-stimulation (p=0.008). Conclusion Proteomic analysis in omCSPC patients from the ORIOLE trial reveals significant expression changes at days 90 and 180 after SABR. B-cell signaling proteins were selectively downregulated in the SABR arm, and pathways associated with protein translation and immune response were enriched post-SABR for patients with prolonged PFS. Further research will explore connections to genomic and transcriptomic changes, with additional validation needed. Citation Format: Jarey H. Wang, Amol Shetty, Yang Song, Noura Radwan, Soha Bazyar, Xiaolei Shi, Theodore L. DeWeese, Daniel Y. Song, Ryan M. Phillips, Matthew P. Deek, Philip Sutera, Ana P. Kiess, Phuoc T. Tran. Proteomic profiling of oligometastatic castration-sensitive prostate cancer treated with stereotactic ablative radiotherapy. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B031.