Citations

Gastroesophageal reflux disease (GERD) is a prevalent condition impacting physical and mental health, characterized by symptoms like heartburn and acid regurgitation. GERD affects 18.1–27.8% of North Americans, rising to ~ 50% under less strict criteria. Effective management of GERD is critical to improving patients’ quality of life. Traditional treatments range from lifestyle modifications and pharmacological interventions to surgical approaches like laparoscopic anti-reflux surgery (LARS). Patients with erosive esophagitis receive a near 70–80% rate of “complete” symptom relief by 4 weeks using PPIs, in contrast to patients with non-erosive reflux disease (NERD), who demonstrate an intermediate response on the order of 50–60%. However, the invasiveness and associated side effects of surgical options have spurred the development of endoscopic techniques, including anti-reflux mucosectomy (ARMS) and transoral incisionless fundoplication (TIF). This review evaluates ARMS and TIF as therapeutic interventions for GERD, focusing on their risks, benefits, outcomes, and complications. ARMS is noted for shorter procedure times and fewer complications, particularly dysphagia and bleeding, making it an efficient choice for symptom control. TIF, while associated with a higher recurrence and reoperation rate, demonstrates superior long-term efficacy in medication reduction and sustained quality-of-life improvements, especially in patients without prior anti-reflux surgeries. Emerging advancements in endoscopic technologies, such as improved suturing techniques and refinements in mucosal resection, hold promise for reducing recurrence rates and enhancing procedural durability. The choice between ARMS and TIF should be tailored to individual patient needs, taking into account GERD severity, comorbidities, and surgical history. Both procedures exemplify significant advancements in minimally invasive GERD management, and ongoing innovations in endoscopic technologies are expected to further refine their safety and effectiveness. This comparative analysis provides insights into optimizing treatment selection and underscores the importance of personalized care in managing GERD.

e14626 Background: Despite advancements in neoadjuvant therapy and surgical techniques, patients with pancreatic ductal adenocarcinoma (PDAC) often experience high recurrence rates after total neoadjuvant therapy (TNT) and resection. Existing tumor response scoring systems, such as the College of American Pathologists (CAP) guidelines, fail to stratify recurrence risk effectively, emphasizing the need for novel, objective approaches. Methods: This study evaluated spatial characteristics of residual cancer and stroma in a multi-site cohort of 203 patients with resected PDAC following TNT, not having achieved a major pathologic response (CAP 2 or 3). Whole slide images (WSI) of hematoxylin and eosin-stained sections were digitized and analyzed using artificial intelligence to perform tissue segmentation. Metrics quantifying spatial morphology and configuration, inspired by principles of landscape ecology, were computed to explore spatial features of the tumor microenvironment (TME). Statistical models (recursive partitioning and regression tree [RPRT] model and Cox model with backwards eliminations) incorporating these features were developed to stratify recurrence risk. Results: Five metrics were used for risk classification model build. Three models successfully classified patients into high- and low-risk groups based on spatial metrics. Models demonstrated moderate discriminatory power (C-statistics: 0.560–0.566) and showed that increased tumor fragmentation, like stromal patch density and cancer patch shape index, were strongly associated with improved outcomes. Conclusions: Integrating spatial metrics of cancer-stroma configuration enhances risk stratification beyond conventional scoring systems. Given increased tumor fragmentation is associated with improved outcomes, these data indirectly suggest ecological mechanisms of treatment resistance. This approach offers a pathway toward personalized post-operative management strategies to improve outcomes in PDAC. Risk classification models. Model Description Event/n Median DFS (95% CI) HR(95% CI) p-value C-statistics 1(RPRT) High risk: log standard deviation of the stroma shape index > 0.651 87 / 101 8.22(5.72 – 10.1) 1.64(1.20 – 2.25) 0.002 0.562 Low risk: log standard deviation of the stroma shape index ≤ 0.651 71 / 102 11.90(9.24 – 25.1) Ref 2(RPRT) High risk: log standard deviation of the stroma shape index > 0.651 & mean cancer shape index ≤ 1.775 58 / 63 7.23(5.19 – 9.63) 1.82(1.31 – 2.52) 0.0003 0.560 Low risk: (log standard deviation of the stroma shape index > 0.651 & mean cancer shape index > 1.775) or log standard deviation of the stroma shape index ≤ 0.651 100 / 140 11.57(9.24 – 17.92) Ref 3(Backwards elimination) High risk: PI * > median 86 / 101 8.02(6.08 – 9.86) 1.73(1.26 – 2.37) 0.0007 0.566 Low risk:PI * ≤ median 72 / 102 15.72(9.97 – 25.05) Ref *PI: (0.2701 * log mean stroma area) + (0.3905 * log edge density).

e16072 Background: Gastric cancer is a leading cause of mortality worldwide, with pronounced variations in outcomes across populations. This study investigates U.S. trends in age-adjusted mortality rates (AAMRs) for gastric cancer from 1999 to 2023, examining differences by gender, race, region, and urbanization to uncover critical patterns and inequities. Methods: Data were extracted from the CDC WONDER database using ICD-10 code C16 to identify gastric cancer-related deaths in adults aged 25 and older. AAMRs per 1,000,000 population were calculated and stratified by year, gender, race/ethnicity, geographic region, and urban-rural classification. Trends were analyzed using Joinpoint regression to determine annual percentage changes (APC) and 95% confidence intervals (CI). Statistical significance was set at p < 0.05. Results: From 1999 to 2023, there were 312,300 gastric cancer deaths (185,391 men, 126,909 women). Overall, AAMRs declined consistently, with APCs of -3.4 for the period 1999 to 2007, -2.2 for 2007 to 2018, and -1.2 for 2018 to 2023. Men showed a more pronounced decline, with APCs of -3.6 for 1999 to 2009 and -2.2 for 2009 to 2023, compared to women, who had APCs of -3.1 for 1999 to 2008, -1.9 for 2008 to 2018, and -0.8 for 2018 to 2023. Non-Hispanic Black populations experienced a decline in AAMR with an APC of -3.3 for 1999 to 2020, while Hispanic/Latino and Asian/Pacific Islander populations showed declines with APCs of -2.8 for 1999 to 2011 and -3.8 for 1999 to 2020, respectively. Metropolitan areas saw AAMR reductions with APCs of -3.3 for 1999 to 2008 and -2.2 for 2008 to 2020, while non-metropolitan areas had larger initial declines with an APC of -3.6 for 1999 to 2006 but slower decreases with an APC of -2.0 for 2006 to 2020. Geographically, the Northeast had the highest AAMR (62.9), followed by the West (61.7), South (57.4), and Midwest (50.9). Hawaii recorded the highest state-level AAMR (96.5), while Wyoming had the lowest (36.6). States in the top 90th percentile included Alaska, California, and New York, whereas Utah, Idaho, and Iowa were among the lowest. Conclusions: Gastric cancer mortality in the U.S. has declined over the past two decades, but the pace of reduction has slowed in recent years. Significant disparities persist across gender, racial, and geographic groups, underscoring the need for targeted interventions to address these inequities and improve outcomes in vulnerable populations.

5060 Background: Rucaparib significantly improved radiographic progression-free survival (rPFS) in men with BRCA-mutated chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) vs a control arm of physician’s choice of therapy (docetaxel or androgen-receptor pathway inhibitor [ARPI] therapy: abiraterone acetate or enzalutamide) in the randomized, multicenter, open-label, phase 3 TRITON3 (NCT02975934) study. Herein, we conducted an analysis to determine the impact of germline vs somatic mutation status on the efficacy of rucaparib. Methods: Patients were randomized 2:1 to receive rucaparib 600 mg BID or physician’s choice of docetaxel or ARPI following progression while on 1 prior second-generation ARPI in any setting. The primary endpoint was rPFS. Color Health did genetic testing. Treatment-emergent adverse events (TEAEs) were reported for the BRCA subgroup. Results: In the rucaparib arm, 201/270 patients had BRCA mutations, and in the physician’s choice arm, 101/135 patients had BRCA mutations. Of patients with BRCA mutations: in the rucaparib arm, 80/201 (40%) were germline and 116/201 (58%) were somatic with 5/201 (2%) BRCA mutation status unknown, while in the physician’s choice arm, 39/101 (39%) were germline and 48/101 (48%) were somatic with 14/101 (14%) BRCA mutation status unknown. rPFS was significantly improved with rucaparib treatment vs physician’s choice in both the germline and somatic mutation groups (germline: HR, 0.52 [95% CI, 0.32–0.84]; somatic: HR, 0.38 [95% CI, 0.25–0.59]). Incidence rates of TEAEs were similar overall between patients with germline and somatic BRCA mutations in both arms. Conclusions: Rucaparib improves progression-free survival for patients with mCRPC with either germline or somatic BRCA mutations with a manageable safety profile. These data support the use of rucaparib as a beneficial treatment option for patients with BRCA-mutated mCRPC with germline or somatic mutations. Clinical trial information: NCT02975934 .

e16001 Background: Esophageal carcinoma ranks among the top 10 malignancies in the world, contributing to high morbidity and mortality. With radiotherapy being one of the most administered treatment options, different variations of administration have evolved. Two such variations include intensity-modulated radiotherapy and 3D conformational radiotherapy. These modalities have been investigated for their efficacy and rate of adverse events. However, conclusions from the trials conducted have been variable. In this systematic review and meta-analysis, we aim to collate these findings to assess the exposure of cancerous cells and rates of adverse events following IMRT or 3D-CRT. Methods: A comprehensive literature search was conducted across three databases for all articles published from inception till September 2024. All primary studies evaluating the comparative efficacy of IMRT vs 3D-CRT were included. Outcomes assessed include dose volume histograms (DVHs) at heart and lung, Dmax at the spinal cord, and irradiation toxicity. Data analysis was conducted in RevMan 5.4 using a random-effects model. Results: A total of twenty records were included in the study, with a sample size of 3090 patients. Radiation dosage, estimated as DVHs, was equal across both regimens at heart (MD: 2.67; 95%CI: –0.15 to 5.48; P = 0.06), except at 40 Gy of radiation, where a lower DVH was noted among patients being administered IMRT (MD: 6.64; 95%CI: 0.25 to 13.03; P = 0.04). At the lung, a higher DVH was noted, especially for doses of 20 Gy or above, on using IMRT. Similarly, a lower dosage in the spinal cord was noted in the IMRT group (MD: 2.87; 95%CI: 1.04 to 4.70; P = .002). Consequently, a lower risk of esophagitis was noted among the IMRT group (OR: 1.54; 95%CI: 1.14 to 2.07; p = 0.009]). While considering patient outcomes, the odds of survival were higher in the IMRT group at 3 years post-treatment (OR: 0.53; 95%CI: 0.31 to 0.92; P = 0.02). Conclusions: IMRT was superior to 3D-CRT in terms of volume of tissue irradiated and lower spinal toxicity. A higher chance of survival was noted in the IMRT group. Further trials are needed to strengthen these findings. Outcome Mean Difference (MD) 95% confidence interval (CI) P value Mean dosage at lung 1.14 0.6, 1.68 <0.0001 Mean dosage at heart 2.67 -0.15, 5.48 0.06 Radiation esophagitis Odds ratio, OR: 1.38 1.09, 1.76 0.009 Radiation pneumonitis OR:1.37 0.62, 3.01 0.43 3-year OS OR: 0.69 0.56, 0.84 0.0003 5-year OS OR: 0.53 0.31, 0.92 0.02 Maximum dosage at spinal cord 2.87 1.04, 4.7 0.0002

e16423 Background: Pancreatic cancer (PC) is one of the most aggressive malignancies, disproportionately affecting older adults. Leveraging data from the Global Burden of Disease (GBD), this study investigates gender-specific trends in disability-adjusted life years (DALYs) and mortality rates for PC among adults aged 70 and older from 1990 to 2021. Methods: DALYs and mortality rates associated with PC were extracted for both genders from the GBD-2021 study from 1990 to 2021. The Annual Percentage Change (APC) and the Average Annual Percentage Change (AAPC) were calculated, along with 95% confidence intervals (CI), to assess the statistical significance of the trends using the p-value. Results: In 1990, DALY rates were 837.25 for men and 711.95 for women, increasing to 950.68 and 768.31, respectively, by 2021. Mortality rates followed a similar pattern: men’s rates rose from 52.05 in 1990 to 61.37 in 2021, while women’s increased from 47.31 to 53.40. Men consistently experienced higher burdens than women. The AAPC analysis revealed that men exhibited a steeper rise in both DALYs and mortality rates associated with PC compared to women over the past three decades. Notably, the gender disparity was more evident in DALYs (+0.1929%) than in mortality rates (+0.1358%), with all AAPC values demonstrating statistical significance (p < 0.000001). Following the APC analysis, additional significant trends were identified. Among males, DALY rates demonstrated the most pronounced increase between 1997 and 2021 (APC: 0.5397, 95% CI: 0.5118, 0.5645), whereas in females, the most significant rise occurred from 1990 to 1993 (APC: 0.6593, 95% CI: 0.3608, 1.1016). Conversely, the slowest increase in DALY rates among females was observed between 1993 and 2003 (APC: 0.0925, 95% CI: -0.2053, 0.1641). For mortality rates, the most notable rise in males was observed between 2007 and 2010 (APC: 1.2314, 95% CI: 1.0292, 1.3195), while females experienced their sharpest escalation from 1990 to 1994 (APC: 0.6891, 95% CI: 0.4322, 1.0720). In contrast, the slowest rate of progression in mortality among females occurred between 1993 and 2002 (APC: 0.1736, 95% CI: 0.0180, 0.2368). Conclusions: Over the past three decades, men have experienced a significantly more pronounced rise in DALYs and mortality rates related to PC compared to women.These findings highlight the urgent need for gender-specific interventions to address the growing burden of PC in aging populations. Trends in DALY and mortality rates per 100,000 by gender (1990-2021). Metrics Gender 1990 2021 APC (1990-2021) Daly Rates per 100,000 Male 837.25 950.68 0.4422 Female 711.9 768.31 0.2493 Mortality Rates per 100,000 Male 52.05 61.37 0.5366 Female 47.31 53.40 0.4008

e22570 Background: Aging into the seventh decade of life marks a pivotal shift in cancer susceptibility, with pancreatic cancer (PC) emerging as one of the most relentless threats to global health. This study utilizes three decades of Global Burden of Disease (GBD) data to unravel unprecedented insights into the prevalence and incidence of PC among adults aged 70 and older. Methods: We analyzed data from the GBD study to assess the temporal trends in the incidence and prevalence of PC from 1990 to 2021. The Annual Percentage Change (APC) and Average Annual Percentage Change (AAPC), along with 95% confidence intervals (CI), were utilized to assess the overall trends, with statistical significance evaluated using p-values. Results: Over the past three decades, the global burden of PC has surged significantly. In 1990, the global incidence of PC stood at 45.12 per 100,000, escalating to 54.47 per 100,000 by 2021. Likewise, global prevalence increased from 30.33 per 100,000 in 1990 to 40.60 per 100,000 in 2021, with incidence rates consistently exceeding prevalence, suggesting an accelerating number of new cases of PC worldwide. The AAPC analysis revealed a significant upward trajectory in both global incidence (AAPC: 0.6085, 95% CI: 0.5801, 0.6273 p < 0.000001) and prevalence (AAPC: 0.9467, 95% CI: 0.9188, 0.9659 p < 0.000001) of PC. Following the APC analysis, several notable trends emerged. The global incidence of PC experienced its most substantial increase between 2003 and 2010 (APC: 1.0806, 95% CI: 0.9817, 1.3206 p < 0.000001), while the slowest growth in incidence occurred from 1990 to 2003 (APC: 95% CI: 0.9817, 1.3206 p = 0.000400). Conversely, the global prevalence of pancreatic cancer saw its most pronounced rise between 1998 and 2001 (APC: 2.0389, 95% CI: 1.2005, 2.1962 p < 0.000001), with the slowest increase occurring from 1994 to 1998 (APC: 0.4632, 95% CI: 0.2544, 1.9767 p = 0.001200). Conclusions: The persistent rise in both incidence and prevalence of PC over the past three decades underscores a critical global health challenge, with a marked acceleration in recent years. These findings highlight the urgent need for targeted interventions and a deeper understanding of the factors driving this expanding burden, particularly as the incidence consistently outpaces prevalence. Metric Overall 1990 2021 AAPC with 95% CI (1990-2021) INCIDENCE RATES PER 100,000 Global Incidence 45.12 54.47 0.61 (0.58, 0.63) PREVALENCE RATES PER 100,000 Global Prevalence 30.33 40.60 0.95 (0.92, 0.97)

Abstract Despite advances in surgery and chemotherapy, patients with resectable pancreatic ductal adenocarcinoma (PDAC) face high recurrence rates (40-60%). Total neoadjuvant therapy (TNT) seeks to enhance margin-negative resections (R0) and address micrometastatic disease, with potential survival benefits. Yet, TNT still results in high recurrence rates, with 1-, 2-, and 3-year disease-free survival (DFS) at 65%, 48%, and 32%, respectively. Residual cancer extent is a key prognostic factor in PDAC after TNT. Tumor response scores show favorable outcomes only for patients achieving near-complete or complete pathologic response. In a cohort of 511 PDAC patients treated with TNT and surgery (2015-2022), improved DFS was only found in those with a complete pathologic response (pCR, 7.8%). This highlights the limited use of current response scoring in stratifying post-TNT patient risk, underscoring the need to better understand disease persistence and relapse. Here we developed a quantitative method to assess residual cancer. Using a digital pathology H&E library from 2180 PDAC cases (2000-2022), an AI platform segmented tissue into cancer epithelium, stroma, and normal regions. For 202 TNT-treated cases without pCR, we calculated a ratio of cancer area to stromal area from representative slides. Modeled after the histologic tumor regression grade (HTRG) system, cases were classified into &lt;5%, 5-50%, or &gt;50% cancer-to-stroma ratios. However, this measure alone showed no difference in DFS, suggesting tumor burden cannot fully explain differences in clinical outcomes. We hypothesized that the spatial organization of the tumor microenvironment (TME) is a determinant of patient outcomes. Drawing from landscape ecology, which studies spatial properties of ecosystems, we applied similar principles to analyze tissue architecture. Using an AI-based two-class segmentation of whole-slide images, we assessed spatial features like patch area, perimeter, density, and Shannon diversity. Python’s ‘pylandstats’ package calculated 21 spatial metrics, reduced via stepwise Cox regression using the Akaike information criterion (AIC). The final model included mean Shannon diversity, mean and standard deviation of stromal patch areas, and stromal patch density. Kaplan-Meier analysis of 202 samples stratified model predictions into quartiles, correlating with high (mean DFS 10.85 months), medium (19.32 months), and low risk (25.92 months) groups. These findings aligned with model expectations, underscoring the potential of spatial TME analysis to predict outcomes. Citation Format: Andrea V. Maraone, Zafar Siddiqui, Luis H. Cisneros, Merih D. Toruner, Mark Truty, Cornelius Thiels, Robert R. McWilliams, Steven R. Alberts, Rondell P. Graham, Carlo Maley, Qian Shi, Martin E. Fernandez-Zapico, Ryan M. Carr. Tumor spatial configuration predicts pancreatic cancer recurrence risk after total neoadjuvant therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5070.