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837 Background: A recent randomized trial suggested that CR may influence ICI activity in patients with lung cancer. However, the same has not been established in GI cancers, where reports have shown mixed results with variable definitions of 'early' vs 'late' IT. We evaluated multiple approaches to assess the impact of CR on first-line ICI in GI malignancies. Methods: This retrospective study included patients from three Mayo Clinic sites (N=455). Both previously reported IT cutoffs and a new cutoff derived from ROC analysis were evaluated. Patients were categorized by the median of all ITs, the median of the first four ITs, and whether ≥20% of ITs occurred before the identified cutoff. Univariate and multivariate Cox regression (adjusting for age, MSI status, type of cancer, metastasis status, number of cycles, and receipt of chemotherapy with ICI) assessed associations with OS. KM analyses were performed to illustrate survival differences. The primary endpoint was OS. Results: When patients were categorized based on whether ≥20% of infusions occurred before 14:00 (ROC-derived cutoff), a significant association with OS was observed. On univariate analysis, early infusion timing was associated with improved survival (HR 2.30, 95% CI 1.58–3.32, p <0.001). This remained significant after multivariable adjustment (HR 2.11, 95% CI 1.41–3.16, p < 0.001). Median OS was 14.2 months in the early group vs 3.8 months in the late group (log-rank p < 0.001). Using previously defined cutoffs, categorization by the median IT of all infusions or the median of the first four infusions did not demonstrate a significant association with OS in either univariate or multivariate Cox regression analyses. Conclusions: These findings highlight the potential role of infusion timing as a chronotherapy factor in GI cancers. Given the retrospective design and heterogeneous population, prospective studies are warranted to validate this signal and clarify its clinical relevance. Baseline demographics of patients by infusion timing (early vs late). Variables Early N=412 (%) LateN=43(%) Total N=455(%) p-value Age <70 249(60.4) 21(48.8) 270 (59.3) 0.1 >70 163(39.6) 22(51.2) 185 (40.7) Gender F 118(28.6) 16(37.2) 134 (29.5) 0.3 M 294(71.4) 27(62.8) 321 (70.5) Cancer Type Gastroesophageal 109 (26.5) 8 (18.6) 117 (25.7) 0.1 Hepatocellular 159 (38.6) 24 (55.8) 183 (40.2) Biliary 86 (20.9) 4 (9.3) 90 (19.8) MSI-H 58 (14.1) 7 (16.3) 65 (14.3) Metastasis No 150 (36.4) 22 (51.2) 172 (37.8) 0.1 Yes 262 (63.6) 21 (48.8) 283 (62.2) Immunotherapy Cycle Number <6 189 (45.9) 33 (76.7) 222 (48.8) <0.001 >6 223 (54.1) 10 (23.3) 233 (51.2)

830 Background: Immune checkpoint inhibitors (ICIs) are standard therapy for MSI-H GI cancers. Lynch syndrome, caused by germline mutations in mismatch repair (MMR) genes, leads to MSI-H tumors and robust ICI responses, but its effect on irAEs remains poorly defined. Clarifying this risk may inform treatment selection and toxicity monitoring. Methods: We retrospectively reviewed MSI-H or MMR-deficient (dMMR) GI cancer patients (pts) treated with ICIs across Mayo Clinic (AZ, MN, FL) from January 2017 to June 2025. Eligible pts were identified using Mayo Data Explorer. Demographics, treatment, and irAEs (graded per CTCAE v5.0) were collected. Lynch status was determined by germline testing when available. Logistic regression estimated odds ratios (ORs) for any grade and grade ≥3 irAEs, adjusting for age, cancer type, prior chemotherapy, and treatment regimen. Results: A total of 209 pts with dMMR/MSI-H GI cancer were included: 61 with Lynch syndrome and 148 without. Lynch pts were younger (median 58 vs 76 years, p < 0.001) and more likely to have received prior chemotherapy (62% vs 43%, p = 0.009). Colorectal cancer was the predominant cancer type (74%), but Lynch pts had proportionally more non-colorectal GI cancers (15% vs 2.7%, p = 0.007). Overall, 29% of pts experienced an irAE, with rates significantly higher in Lynch vs non-Lynch pts (43% vs 24%, p = 0.005). The most frequent irAEs were gastrointestinal, endocrine, and dermatologic, followed by hepatic and pulmonary events. Grade ≥3 irAEs occurred in 16% overall, with no significant difference between groups (p = 0.124). In adjusted models, Lynch syndrome was independently associated with a higher risk of any grade irAE (OR 2.14, 95% CI 1.09 - 4.19, p = 0.026), while risk of severe irAEs was not increased (OR 1.55, 95% CI 0.64 - 3.59, p = 0.316). Lynch syndrome pts were more likely to have combination therapy (17% vs 6.8%, p = 0.029). However, there were no differences observed in any grade irAE between monotherapy and combination immunotherapy (OR 1.36, 95% CI 0.49 - 3.54, p = 0.535). Conclusions: Lynch syndrome is associated with a higher prevalence of any-grade irAEs among dMMR/MSI-H GI cancer pts treated with ICIs, though severe events were not increased. Incorporating Lynch status into immunotherapy planning may improve risk stratification and guide regimen selection.

399 Background: The standard of care for resectable GEA adenocarcinomas is perioperative chemotherapy with the FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel) regimen. Recent studies investigating the addition of checkpoint inhibitors (CPIs) to perioperative chemotherapy have shown mixed results. An NMA can leverage both direct and indirect comparisons to evaluate the relative efficacies of available regimens in this setting. Methods: MEDLINE, EMBASE, Scopus, Web of Science and CENTRAL were searched until August 27th, 2025. Eligible studies included phase 3 randomized trials evaluating perioperative or neoadjuvant chemotherapy +/- CPIs ± radiation in resectable GEA. The primary outcomes were disease-free survival (DFS) and overall survival (OS). Hazard ratios and 95% confidence intervals (CIs) were estimated using a frequentist NMA framework. Results: Fifteen trials including 8072 patients were analyzed. For DFS, perioperative durvalumab + FLOT (dFLOT) ranked highest (P-score = 0.99), followed by FLOT (P-score = 0.84) (HR for dFLOT vs. FLOT was 0.71, 95% CI 0.58-0.86). dFLOT also ranked higher than perioperative pembrolizumab + cisplatin and fluorouracil/capecitabine (KN-585), though this comparison was not statistically significant (HR 0.65, 95% CI 0.40-1.04). Compared with CROSS, dFLOT showed superior DFS (HR of 0.48, 95% CI 0.36-0.63). For OS, dFLOT ranked the highest (P-score=0.95) and was superior to CROSS (HR 0.57, 95% CI 0.42-0.77). While dFLOT appeared favorable versus FLOT (HR 0.78, 95% CI 0.62-0.98), this finding was primarily driven by MATTERHORN, which did not meet its prespecified OS significance boundary (P = 0.03 vs threshold P < 0.0001), and the proportional hazards assumption was violated. Similarly, no significant OS difference was observed between dFLOT and the KN-585 arms (HR 0.75, 95% CI 0.45-1.23). Conclusions: In this NMA, perioperative FLOT remained the benchmark regimen for resectable GEA. dFLOT has shown promising early results, ranking the highest for DFS and showing favorable, but not statistically definitive OS trends in comparison to FLOT. Importantly, the network enabled indirect comparisons not tested in head-to-head trials, demonstrating that dFLOT ranked above pembrolizumab+CF/CX (KN-585) without reaching statistical significance, and also outperformed CROSS. However, these findings should be interpreted with caution, as they are primarily driven MATTERHORN data in which OS did not cross the prespecified threshold and proportional hazards assumptions were violated. Perioperative immunotherapy combinations appear promising, but final MATTERHORN results and further confirmatory studies are needed before dFLOT can be considered as a new standard of care.

334 Background: Sarcopenia, or decreased skeletal muscle mass, has been associated with worse surgical and oncologic outcomes across multiple malignancies. This study investigates the impact of sarcopenia on outcomes after multimodal therapy for esophageal cancer. Methods: Retrospective observational cohort study including adult patients who underwent neoadjuvant therapy followed by esophagectomy for primary esophageal cancer from January 2000 - December 2021. A fully automated abdominal segmentation using deep convolutional neural network was utilized to calculate skeletal muscle index (SMI) from preoperative CT scans performed at our institution. Males with SMI <52.4 cm 2 /m 2 and females with SMI <38.5 cm 2 /m 2 at any point before surgery were classified as sarcopenic. The relationship between sarcopenia and patient demographics, operative details, and complications were explored using chi-square tests. The relationship between sarcopenia and disease-free survival and overall survival were investigated using parsimonious multivariable analysis retaining variables with p-value <0.05 using backward selection method. Results: We identified 200 patients meeting the study criteria with 142 (71%) having sarcopenia at any time prior to surgery. Patients with sarcopenia were significantly older [65.2 (59.6, 71.2) vs 63 (53.6, 67.5), p = .023] and more likely to have had open surgery [129 (90.8%) vs 46 (79.3%), p = .034]. There were no significant differences in sex, history of diabetes, coronary artery disease, renal disease, smoking, cancer type, cancer stage, tumor size, tumor location, or margin status between sarcopenic groups ( p > .05). Sarcopenic patients were significantly more likely to require blood transfusion ≥3 units after esophagectomy [79 (55.6%) vs 8 (13.8%), p < .001] or to experience complications requiring surgical intervention [36 (24.6%) vs 7 (12.1%), p = .048]. Multivariate analysis revealed that sarcopenia was associated with disease-free and overall survival (Table). Conclusions: Sarcopenia is a prognostic factor in patients undergoing multimodal therapy for esophageal cancer. Interventions that aim to prevent decreases in SMI after initiating neoadjuvant therapy should be investigated. Multivariate analysis with sarcopenia predicting outcomes. Disease free survivalHR (95% CI) p-value Overall survivalHR (95% CI) p-value Age 1.04 (1.02, 1.06) < .001 1.04 (1.02, 1.07) < .001 Epicenter Middle Upper 1.88 (1.21, 2.86)3.16 (1.67, 5.98) .001.005< .001 1.96 (1.26, 3.04)4.00 (1.90, 8.44) < .001.003< .001 Stage Stage II Stage III Stage IV 1.88 (0.95, 3.71)2.90 (1.46, 5.75)16.02 (6.12, 41.93) < .001.069.002< .001 1.65 (0.83, 3.25)2.76 (1.37, 5.55)10.14 (4.03, 25.53) < .001.151.005< .001 Cancer type - - 1.76 (1.03, 3.02) .039 Transfusion > 3 pRBC - - 1.54 (0.99, 2.40) .057 BMI prior to cancer diagnosis - - 0.98 (0.94, 1.01 .208 Sarcopenic 1.76 (1.16, 2.67) .007 1.64 (1.04, 2.60) .033

103 Background: Clinicians spend significant time extracting and synthesizing information to risk-stratify and make adjuvant chemotherapy (AC) recommendations for CRC. By automating parts of this process, LLMs could help reduce documentation burden and variability in decision-making. Methods: We selected 144 stage III, pMMR CRC patients treated at Mayo Clinic (2017–2021). HIPAA-compliant Gemini-2.0-Flash-001 and GPT-4o extracted clinical variables (age, neuropathy grade, pathological stage) from EHRs and generated AC recommendations. Two approaches were compared: (1) a rule-based algorithm with nested if/else statements translating variables into NCCN-based recommendations, and (2) a dynamic LLM agent generating recommendations using a structured prompt informed by NCCN guidelines. Concordance with treating physicians was assessed, with disagreements reviewed by a blinded GI oncologist. Results: The dataset included 144 patients with median age 67 (IQR 66–68), 48.6% female. The LLM pipeline extracted neuropathy grade with 100% accuracy and pathological T/N stages with 99.3% accuracy. Concordance with physician recommendations was 93.1% for the rule-based algorithm and 62.5% for the LLM agent. In discordant cases, blinded adjudication by a GI oncologist favored the algorithm and LLM agent over physicians in most cases (Table 1). Conclusions: This exploratory work shows LLM agents can reliably extract variables and generate evidence-based treatment recommendations for stage III CRC. The high rate of expert preference for LLM recommendations in discordant cases is intriguing but limited by small sample size and possible adjudicator bias. Discordant physician recommendations reflect the complexity of decision-making, including patient preferences, performance status, comorbidities, and subtle findings not fully captured in EHRs. Rather than replacing judgment, we envision LLMs as decision support tools—analogous to an advanced trainee reviewing charts and presenting evidence-based recommendations to the attending physician with ultimate authority. Larger multi-institutional studies with multiple adjudicators are needed to validate these findings and clarify AI’s role in oncology. Patient characteristics, LLM extraction accuracy, and concordance with physician recommendations. Metric Result Total patients 144 Median age (IQR) 67 (66-68) Female (%) 48.6% LLM extraction accuracy – Neuropathy grade 100% LLM extraction accuracy – Pathological T and N stages 99.3% Primary Concordance – Rule-based algorithm vs. physician 93.1% Adjudicator preference of rule-based algorithm over treating physician for discordant cases 100% Concordance – LLM agent vs. physician 62.5% Adjudicator preference of LLM agent over treating physician for discordant cases 82.0%

SUMMARY Artificial intelligence (AI)-based methods are increasingly critical in peptide drug discovery, but their applications are limited in a narrow scope such as antimicrobial peptides. For indications where peptide therapy inherently excels, such as metabolism, endocrinology, and tissue regeneration, AI-based pipeline for therapeutic peptide discovery is long awaited but still unmet. Here, we propose a deep learning-based pipeline, Deepeptide, capable of identifying therapeutic oligopeptides for various metabolism-related indications. Leveraging the intrinsical relationship of ‘disease indication — biological processes — molecular functions’, Deepeptide discovers oligopeptides with indication-ameliorating-related molecular functions as lead candidates for indication of interest. Deepeptide was applied in five representative indications of metabolism, endocrinology, and tissue regeneration: angiogenesis, lipid metabolism, osteogenesis, glucose metabolism, and anti-angiogenesis. Overall, 62% of the identified oligopeptide candidates demonstrated significant bioactivity in vitro, with most of them showing comparable potency to the first-line drugs. Notably, the heptapeptide AP7 exhibited angiogenic potency comparable to VEGF in excisional wound splinting mouse model by promoting cell migration rather than proliferation, and hexapeptide TP6 showed significant dual-efficacy against hyperlipidemia and obesity in high-fat diet mice by inhibiting lipid synthesis and regulating gut microbiota. These findings highlight the potential and generalizability of Deepeptide in therapeutic oligopeptide discovery for metabolic diseases.

Abstract Impaired kidney function is a risk factor for cognitive decline and dementia, but most studies use serum creatinine-based equations to estimate kidney function as estimated glomerular filtration rate (eGFR); these equations include age, also a strong driver of cognitive impairment, and produce eGFR estimates with substantial error compared to gold-standard objective measures of GFR (mGFR). The purpose of this study was to determine eGFR and mGFR associations with cognitive function in African American adults, a population disproportionately impacted by both chronic kidney disease and dementia. We conducted a cross-temporal analysis of 368 participants (Age: 66.4 ± 7.4y, 75% Female) in the Genetic Epidemiology Network of Arteriopathy study with eGFR (CKD-EPI 2021 Creatinine Race-Free Equation) and mGFR assessed. eGFR was assessed using the CKD-EPI 2021 Creatinine Race-Free Equation and mGFR (urinary clearance of non-radiolabeled iothalamate). Memory (Rey Auditory Verbal Learning Test; RAVLT) and executive function (Digit Symbol Substitution Test; DSST) were assessed. Linear regression models were used to relate eGFR, mGFR, and serum creatinine to cognitive function with and without adjustment for age and sex. In unadjusted models, eGFR was positively associated with DSST scores (β = 0.19, 95%CI:0.11, 0.27) and RAVLT scores (β = 0.10, 95%CI:0.04, 0.16). mGFR was marginally associated with DSST scores (β = 0.07, 95%CI:-0.00, 0.14), but not RAVLT scores (β = 0.03, 95%CI:-0.01, 0.07). Associations of serum creatinine with cognitive function were mostly null to marginal. Age and sex adjustment greatly attenuated all associations. The observed differential renal function associations with cognition suggest age may largely explain prior reported associations.

Abstract Multiple myeloma (MM) with t(11;14)(CCND1;IGH) remains the only subset sensitive to the BCL2 inhibitor venetoclax. However, not all patients with t(11;14)(CCND1;IGH) respond to treatment, and some progress early after initial response. To investigate this, we examined 44 whole-genome and whole-exome sequencing data samples from 34 patients with t(11;14) MM treated with venetoclax. The presence of mutations in the RAS pathway was strongly associated with shortened progression-free survival (PFS) and was validated in an independent cohort of 21 patients with MM. The presence of 1q gain was also associated with shorter PFS in patients without RAS mutations. In 10 patients with paired prevenetoclax and postvenetoclax treatment samples, postvenetoclax progression was recurrently driven by the selection of genomic events in the BCL2/MCL1 and RAS pathways and of high-risk features (eg, loss of TP53 and CDKN2C). Overall, our study shows that comprehensive genomic profiling can identify most mechanisms underlying resistance to BCL2 inhibition in t(11;14)(CCND1;IGH) MM.