293 Background: Signet ring cell carcinomas (SRC) is a well know limitation for FDG PET/CT. SRC is rich in cancer associated fibroblast hence can be imaged by FAPI PET/CT scan. This study aims to evaluate the diagnostic utility of 68Ga-FAPI PET/CT in the initial staging of signet-ring cell carcinoma (SRC) with a correlation with diagnostic laparoscopy for peritoneal metastasis. Methods: We included 29 histologically proven stomach SRC patients referred for staging work up. Both 68Ga-FAPI and 18F-FDG PET/CT scan were done with-in a week time. Diagnostic laparoscopy for peritoneal disease or any other site biopsy for metastatic site was used as a gold standard. Additionally, the single voxel maximum standard uptake value (SUVmax) of the primary, lymph node, metastasis, and SUVmean of the right lobe of the liver were recorded. SUVmax and target-to-background ratio (TBR) were compared with Wilcoxon's signed-rank test. While diagnostic effectiveness was compared with McNemar’s test. The study is ethically approved by institutional review board (RGCIRC/IRB-BHR/27/2025). Results: Out of 29 patients, FDG showed metastasis in 7 patients with diagnostic sensitivity, specificity, PPV, NPV and accuracy of 50.0%, 100%, 100%, 65%, and 74% and all these patients were also positive on FAPI scan. In remaining 22 non-metastatic patients on FDG scan, FAPI detected additional 6 patients with peritoneal metastasis. Diagnostic sensitivity, specificity, PPV, NPV and accuracy of FAPI was 85.7%, 100%, 100%, 86.6%, and 92.5% for metastasis. 13 patients were true negative on both FDG and FAPI PET for peritoneal metastasis. While 2 patients were falsely negative on both FDG and FAPI scans for peritoneal metastasis. One case was false negative in both FAPI and FDG for primary stomach lesion. 8/29 (27.5%) patients were upstaged by 68Ga-FAPI PET/CT scan in comparison to 18F-FDG PET/CT scan. Overall, FAPI PET/CT has impacted management in 24.1% of the patients in this cohort. Conclusions: 68Ga-FAPI PET/CT has higher diagnostic accuracy for metastatic workup in SRC stomach staging specially for peritoneal metastasis. Its superiority has been tailoring the diagnostic laparoscopy and guiding biopsy sites for better yield. Diagnostic statistics for metastasis for 18F-FDG and 68Ga-FAPI PET/CT scans. FDG FAPI Statistic Value 95% CI Value 95% CI Sensitivity 50.0% 23.1% to 76.9% 85.7% 57.1% to 98.2% Specificity 100.0% 75.2% to 100.0% 100.0% 75.2% to 100.0% Positive Predictive Value 100.0% 59.0% to 100.0% 100.0% 73.5% to 100.0% Negative Predictive Value 65.0% 52.3% to 75.8% 86.6% 64.3% to 95.9% Accuracy 74.0% 53.7% to 88.8% 92.5% 75.7% to 99.0%

351 Background: In aging societies, the proportion of elderly patients with advanced gastric cancer (AGC) is increasing; however, clinical evidence regarding chemotherapy (CTx) in patients aged ≥80 years remains limited. Methods: We retrospectively analyzed patients with AGC who received first-line CTx at Nagoya Medical Center between 2009 and 2024. Patients were stratified into three age groups: <70, 70–79, and ≥80 years. The primary outcome was overall survival (OS). Secondary outcomes included time to treatment failure (TTF) of first-line CTx, objective response rate (ORR), and the proportion of patients receiving subsequent-line therapy. Survival was estimated by the Kaplan–Meier method and compared using the log-rank test. Prognostic factors were evaluated by multivariable Cox regression. Results: A total of 322 patients were included (<70 years: 144; 70–79 years: 124; ≥80 years: 54). With increasing age, baseline Eastern Cooperative Oncology Group Performance Status (ECOG PS, p=0.007), hemoglobin (p=0.002), albumin (p=0.028), creatinine clearance (p<0.001), and Prognostic Nutritional Index (p=0.025) were worse. S-1 monotherapy was more frequently selected in patients aged ≥80 years (p=0.037). Median survival time was 10.7, 12.8, and 7.1 months in the <70, 70–79, and ≥80 groups, respectively (p=0.074). Median TTF was 4.6, 5.9, and 2.8 months (p=0.711). The ORR of first-line therapy was 49.0%, 56.5%, and 51.5% in the three groups, respectively (p=0.417). Treatment discontinuation due to toxicity occurred in 7.2%, 14.9%, and 24.5% of patients (p=0.005). The proportion of patients who did not receive subsequent-line therapy was 35.9%, 44.7%, and 64.2% (p=0.002). In multivariable analysis, age ≥80 was not an independent prognostic factor, whereas ECOG PS, neutrophil-to-lymphocyte ratio, oral intake, and treatment era (pre- vs post-nivolumab approval) were independently associated with OS. Conclusions: Although outcomes in patients ≥80 years were unfavorable, chronological age alone was not a definitive prognostic determinant. Appropriate patient selection, treatment modification, and supportive care are essential to optimize outcomes in this population.

TPS274 Background: Surgical resection of locally advanced rectal cancer (LARC) can be morbid with debilitating effects on quality of life, particularly in patients who require a permanent colostomy. Total neoadjuvant therapy (TNT), where all systemic and radiation therapy (RT) is delivered prior to surgery, achieves higher response rates than traditional standard of care (SOC) neoadjuvant treatment. However, even with TNT, nearly 50% of patients will have residual disease or develop local regrowth requiring resection. There is evidence of significant hypoxia in LARC, which can contribute to radiation resistance and an unfavorable host-tumor immune microenvironment (TIME). Our preclinical data has established that targeting mitochondrial oxygen consumption (MOC) with an FDA-approved and repurposed mitochondrial complex I inhibitor papaverine (PPV) can reduce hypoxia and sensitize model tumors to RT potentially facilitating an improved anti-tumor immune response. In this study, we test an innovative strategy of inhibiting MOC to radiosensitize LARC with the hypothesis that reversing tumor hypoxia not only improves tumor radiation sensitivity but also leads to beneficial changes in the TIME. Methods: DINOMITE is a randomized two-center phase I study for patients with histologically confirmed microsatellite stable LARC who want to pursue non-operative management. Patients are randomized in a 1:2 manner: Cohort 1- SOC short course RT (SCRT) delivered as 5 Gy x 5 fractions; Cohort 2 – SCRT plus daily PPV. Following a 3-week break, patients start consolidation chemotherapy (CC) with mFOLFOX6 or CAPOX for 3-4 months. Eight weeks following completion of CC, patients will undergo SOC response assessment with MRI and endoscopy. Patients with clinical complete response (cCR) will enter surveillance with serial endoscopy/pelvic MRI. For those with persistent disease or recurrence in the rectum during surveillance, salvage surgery will be recommended. For Cohort 2, a single dose of PPV will be administered for correlative analysis prior to the combination with RT (week 0). The dose limiting toxicity period will include acute (week 0 to start of CC) and late (start of CC until 12 months from week 0) phases. Cohort 2 will be conducted using the time-to-event Bayesian optimal interval design to find the maximum tolerated dose (MTD)/recommended phase 2 dose of PPV in combination with RT. Once the MTD is determined, additional patients will be enrolled in cohort 2 as an expansion cohort (total of 24 patients maximum in cohort 2). The maximum sample size is 36 patients. Correlative studies including functional MRI, tumor tissue, stool, and blood will be obtained prior to treatment start, prior to CC, and if salvage surgery is performed. The trial began in January 2025, and patient recruitment is ongoing. Support: R01CA297752 Clinicaltrials.gov identifier: NCT06834126. Clinical trial information: NCT06834126 .

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

851 Background: Diffuse idiopathic skeletal hyperostosis (DISH) has been associated with increased risk of vertebral fractures in elderly men with prostate cancer. However, its potential role in the development of malignancies is poorly defined. In particular, the relationship between DISH and gastrointestinal (GI) cancers—including esophageal, gastric, colorectal, liver, biliary system, and pancreatic cancers—has not been examined. This study aimed to explore the risk of GI cancers among patients with DISH compared to those without DISH. We also assessed survival and incidence of vertebral fractures in these groups. Methods: Using the Mayo Clinic Platform (Full AMC1 dataset), we identified patients with and without a documented history of DISH. Outcomes included (1) prevalence and risk of GI cancers, (2) survival among GI cancer patients, and (3) vertebral fracture incidence. Relative risks (RRs) and hazard ratios (HRs) were calculated using SPSS20.0 and platform-based statistical tools, respectively. Kaplan–Meier survival analyses were performed to evaluate cancer survival outcomes. Results: A total of 6,189,860 patients were included, of whom 2,802 (0.05%) had DISH and 6,187,058 (99.95%) did not. Patients with DISH had a significantly higher prevalence of GI cancers compared with those without (RR = 1.63, 95% CI: 1.377–1.930). Survival analysis suggested worse outcomes among GI cancer patients without DISH (HR = 1.72, 95% CI: 1.25–2.35). Vertebral fracture incidence appeared lower among DISH patients, although low event numbers limit the reliability of this observation. Conclusions: DISH is associated with increased risk of GI cancers, while GI cancer patients without DISH may experience poorer survival. The observed trend toward lower vertebral fracture incidence among DISH patients should be interpreted cautiously due to limited event numbers. These findings highlight the importance of integrating musculoskeletal and oncologic perspectives in patient management and warrant further mechanistic and interventional studies. Survival analysis. Statistic Without DISH With DISH Patient Count 214,180 109 1 Month Survival 95.3% 98.2% 5 Month Survival 82.2% 87.9% 10 Month Survival 72.4% 85.1% 30 Month Survival 54.3% 74.1% 60 Month Survival 44.9% 60.6% Log-Rank 11.90 P-Value 0.00056 Hazard Ratio 1.72 (95% CI: 1.25 - 2.35)

365 Background: Robot-assisted gastrectomy using da Vinci Xi is increasingly adopted as a minimally invasive approach for gastric cancer. Recently, single port robot, da Vinci SP, was introduced in gastrectomy in some specialized hospitals. Our institution introduced da Vinci Xi system in August 2019 and subsequently implemented da Vinci SP system in May 2024. From the first SP case, we applied fusion surgery, which combines single-port robotic surgery with multiple assistant ports. The most critical concern in adopting a new robotic platform is the potential risk to patients during the initial implementation phase. This study aimed to evaluate whether SP can be safely generalized in Xi-experienced centers by analyzing short-term outcomes, the presence of a learning curve, and inter-surgeon reproducibility. Methods: We retrospectively analyzed 152 consecutive patients who underwent robot-assisted distal gastrectomy (RDG) at our institution between August 2019 and April 2025, including 122 cases with Xi-RDG and 30 cases with SP-RDG. Patient characteristics, perioperative outcomes, and short-term results were compared between groups. Sequential case analysis was performed to identify potential learning curves for both groups. Additionally, reproducibility between two surgeons was specifically evaluated in the SP group. Results: Baseline patient characteristics were comparable between the two groups. Compared with Xi-RDG, SP-RDG showed significantly less blood loss (13.5 vs 33 ml, p<0.001), shorter operative time (196 vs 307 min, p<0.001), and shorter console time (158 vs 261 min, p<0.001). The number of retrieved lymph nodes, postoperative hospital stay, and incidence of Clavien-Dindo grade ≥II complications were similar. Two cases of pneumonia occurred in the SP group, but no mortality or other life-threatening complications were observed. Sequential case analysis demonstrated no learning curve for SP-RDG, and reproducibility of surgical performance was confirmed between the two surgeons. Conclusions: SP-RDG can be introduced in Xi-experienced institutions without imposing additional risks or requiring a new learning curve. Furthermore, reproducibility was validated across different surgeons. SP contributed to significant reductions in operative and console times compared with Xi. Considering these, generalized applicability of da Vinci SP for gastrectomy would be high.

403 Background: The success of immunotherapy to treat metastatic microsatellite instability high (MSI-h)/deficient mismatch repair (dMMR) cancers has generated interest for potential use in the neoadjuvant setting. The National Comprehensive Cancer Network (NCCN) Guidelines for MSI-h gastric, gastroesophageal, and rectal cancer recommend considering neoadjuvant immunotherapy in the localized setting, but the recommendation is based on small phase II trials with only a few dozen patients. Despite promising initial results, evidence to support this practice remains limited. Methods: To strengthen the case for using neoadjuvant immunotherapy to treat localized gastric, gastroesophageal, and rectal cancers, we conducted a systematic review to identify patients who received neoadjuvant immunotherapy for localized MSI-H/dMMR gastric, gastroesophageal, colon, and rectal cancers to determine the overall pathologic complete response (pCR) and major pathologic response (MPR, defined as at least 90% tumor shrinkage) rate following neoadjuvant immunotherapy. PubMed search parameters included microsatellite instability high (MSI-high) OR Mismatch repair deficient (dMMR) AND neoadjuvant immunotherapy. Case reports were excluded. Results: Review of the MSI-h/dMMR gastric and gastroesophageal populations included 264 patients from 18 studies, with a pCR (45.42%) and 28 with 90-99% tumor shrinkage for a MPR 55.28%. In the colon and rectal cancer populations, 701 patients across 18 studies showed pCR 70.19% and MPR 79.74% (68.91% and 83.58% for colon, respectively, and 89.36% and 94.68% for rectal). Conclusions: Our findings strengthen the NCCN guidelines recommending the use of neoadjuvant immunotherapy for MSI-h/dMMR localized gastrointestinal cancers. Further research should seek to determine the optimal immunotherapy regimen, including duration, and evaluate the potential for nonoperative management in patients who have a complete clinical response to treatment. Rate of pCR/MPR in MSI-high/dMMR gastric, gastroesophageal, colorectal cancers. Number of patients Number of studies pCR (%) MPR (%) Gastric and gastroesophageal cancers 264 18 45.42 55.28 Colorectal cancers 701 18 70.19 79.74

133 Background: Clonal hematopoiesis (CH) has emerged as a possible biomarker of immune modulation in cancer. Preliminary data have suggested an important role of inflammatory processes in CH with possible benefit of immunotherapy in mismatch repair proficient (MMRp) colorectal cancer. The combination of regorafenib (REGO) and nivolumab (REGONIVO) has shown limited activity in MMRp metastatic colorectal cancer (mCRC), but predictive biomarkers of benefit remain undefined. Methods: We conducted a retrospective cohort study of 55 patients with refractory MMRp mCRC treated with regorafenib alone or in combination with nivolumab at Moffitt Cancer Center. Patients were stratified by the presence or absence of CH based on tissue/blood based next-generation sequencing (NGS). Clinical and molecular characteristics including KRAS/BRAF status, tumor sidedness, prior line of treatment, liver metastasis were collected. Progression-free survival (PFS) was assessed using Kaplan-Meier analysis. Results: CH mutations were detected in 31 patients (56%) and 24 patients (44%) were classified as non-CH mutations. The median lines of treatment before REGO or REGONIVO was similar between both groups. Among CH-negative patients, median PFS was 2.9 months with REGO and 2.4 months with REGONIVO. Among CH-positive patients, median PFS was 3.1 months with REGONIVIO and 1.8 months with REGO with no statistically significant improvement on univariate analysis (p = 0.05) but statistically significant on multivariate analysis (HR = 0.18, 95% CI = 0.1 – 0.87). Presence of liver metastasis was found to be significant adverse risk factor in patients with CH mutations. Conclusions: Although CH status did not show a clear benefit on univariate analysis, multivariate analysis suggested that patients with CH status may derive greater benefit from REGONIVO therapy. These findings indicate that CH may influence response to combined regorafenib and nivolumab treatment and warrants further validation in larger prospective studies. Multivariate analysis. Age HR P value 18 – 40 1 41 – 60 0.1 (0.01 – 2.3) 0.1 61 – 75 0.05 (0. 00 – 1.6) 0.09 Sex Male 1 Female 1.04 (0.22 -4.9) 0.05 KRAS Wild 1 Mutated 0.4 (0. 9 – 1.7) 1.44 Prior lines of treatment < 2 1 3 - 5 1.4 (0.3 – 7.4) 0.7 More than 5 0.7 (0.8 – 5.3) Liver metastasis No 1 Yes 25 (1.2 – 545) 0.03 Treatment Regorafenib 1 Regorafenib + nivolumab 0.18 (0.04 – 0.88) 0.03

54 Background: There are limited data on the impact of TNT on complete response (CR) rates for LARC treated in community settings. Methods: A retrospective cohort study was conducted at two health centers, from January 2019 to August 2023. All consecutive patients with LARC staged cT3-cT4 and/or lymph node- positive (AJCC 8th Edition) who received at least one application of neoadjuvant therapy (NAT)—radiotherapy and/or chemotherapy—were included. The primary outcome was the overall CR rate, stratified by NAT: TNT versus Non-TNT. CR was defined as cases achieving pathological complete response (ypCR) or sustained complete clinical response (cCR) after 12 months for patients undergoing a watchful waiting protocol. Secondary endpoints were ypCR rates and clinical/ hematological toxicities (CTCAE version 5.0) stratified by NAT. Results: Overall, 137 patients were included, with 60 (43.8%) receiving TNT and 77 (56.2%) receiving Non- TNT. The median age was 58.9 years [standard deviation (SD): ±11.2] for the TNT group and 59.0 years (SD: ±11.0) for the Non-TNT group. Initial staging for the TNT and Non-TNT groups was as follows: cT3 (61.6% and 67.5%), cT4 (18.3% and 16.8%), and positive lymph nodes (68.3% and 66.2%), respectively. The median distance from the anal verge was 5.5 cm [Interquartile range (IQR): 5–9.5] for TNT and 6.0 cm (IQR: 5–10) for Non-TNT. The overall CR rates for the TNT and Non-TNT groups were 28.3% (17/60) and 11.6% (9/77), respectively [Odds ratio (OR) = 2.98; 95% CI: 1.24–7.17]. The ypCR rates were 20.0% (12/60) for TNT and 7.8% (6/77) for Non- TNT (OR = 2.96; 95% CI: 1.07–8.14). Grade ≥3 clinical toxicities during NAT occurred in 5.0% (3/60) of the TNT group and 6.4% (5/77) of the Non-TNT group (OR = 0.76; 95% CI: 0.19–3.01). Grade ≥3 hematological toxicities during NAT occurred in 3.3% (2/60) of the TNT group and 5.2% (4/77) of the Non-TNT group (OR = 0.62; 95% CI: 0.11–3.49). Conclusions: The data suggest a higher CR rate in the TNT group compared to the Non-TNT group among patients with LARC treated in community settings.

645 Background: NENs are a heterogeneous group of malignancies with complex care needs. Patients and caregivers increasingly use social media to share experiences, exchange information, and seek support, yet large-scale systematic analyses of public NEN discourse remain lacking. Methods: We conducted a computational analysis of publicly available social media posts by patients and caregivers (April 2022–March 2025) using Talkwalker, an NLP-enabled listening platform. English-language posts from Bluesky, Instagram, YouTube, and X were analyzed via a two-stage pipeline: rule-based filters (Boolean operators, custom lexicons) identified candidate posts, followed by human-in-the-loop verification of self-identification. Texts were preprocessed (tokenization, normalization, noise reduction) and thematically classified. Effect sizes were quantified with standardized mean differences (SMDs), and between-group significance was tested. A p-value <0.05 was considered statistically significant. Results: Of 8,961 available posts from 1,088 authors, 87% (n=7,793) were from patients and 13% (n=1,168) from caregivers. Major themes were treatment (23.6%), survivorship (15.2%), and diagnosis (14.4%) for patients, and treatment (24.3%), diagnosis (28.6%), and clinical trials (16%) for caregivers. Compared to caregivers, patients’ conversations focused significantly less on research/clinical trials (SMD -0.21, p<0.001) and diagnosis (-0.24, p<0.001) and more on symptoms (SMD=0.13, p<0.001), finances (0.12, p=0.004), insurance (0.25, p<0.001) and fear/anxiety (0.15, p<0.001). Among patients, females were less likely to focus on treatment -0.10, p<0.001) and insurance-related discussions (-0.06, p=0.03) and more likely to discuss financial issues (0.06, p=0.02) compared to males. Younger patients (18-44 years of age) were less likely to discuss research/clinical trials (-0.21, p<0.001) compared to older patients. U.S.-based patients were significantly less likely to discuss research/clinical trials (-0.22, p<0.001), travel (-0.07, p=0.02), policy (-0.14, p<0.001), end-of-life care (-0.286, p<0.001) and diagnosis (-0.07, p=0.03) , and more likely to discuss treatment (0.15, p<0.001) and insurance-related issues (0.16, p<0.001) compared to their counterparts overseas. Conclusions: We identified thematic priorities in public online discourse by patients with NENs and their caregivers, with unmet needs in financial, insurance, and psychosocial support. Geographic differences existed in focus on treatment, research, policy, among others. This work provides the first direct insight at scale from patients and care partners to inform patient-centered care and interventions in NENs.