803 Background: It has been suggested with limited data that a "false positive" result on a stool multi-target DNA (mtDNA) test is not clinically significant and warrants no further diagnostic evaluation. We aimed to compare the incidence of non-colorectal aerodigestive malignancies in patients who had a false positive versus negative result by stool mtDNA. Methods: All patients who underwent colorectal cancer screening by mtDNA at our institution from 2014 to 2024 were identified. Patients with a positive result who did not have a colonoscopy and those who had a true positive finding (colorectal cancer or advanced precancerous polyp) were excluded. We compared baseline demographics, incidence of aerodigestive cancers, and cancer free survival (CFS) in those who had a negative result versus those who had a false positive result. Results: We identified 48,919 patients who had stool mtDNA testing, 3,352 (6.9%) of whom had a false positive result and 45,567 (93.1%) of whom had a negative result. The median follow-up was slightly longer for the false positive group at 36.0 months (interquartile range 18.0-58.0 months) versus 33.0 months (interquartile range 16.0-51.0 months) for the negative group. Patients with a false positive result had a statistically-significantly higher incidence of aerodigestive cancer than those with a negative result (4.3% vs 1.5%, p<0.001), including head and neck (0.6% vs 0.4%, p=0.018), lung (1.5% vs 0.5%, p<0.001), and non-colorectal gastrointestinal malignancies (2.2% vs 0.6%, p<0.001) (Table). Patients with a false positive result also had a shorter cancer free survival than those with a negative result (mean 75.6 months, 95% CI 74.9-76.3 v 85.0 months, 95% CI 84.5-85.3; p<0.001; median not reached for either group). When controlling for demographic variables that were different between the two groups, false positive stool mtDNA was an independent predictor of cancer free survival (HR 1.49, 95% CI 1.23-1.72). Conclusions: These data suggest that a false positive finding on a stool mtDNA test is clinically relevant and does warrant further diagnostic work-up, potentially with upper endoscopy and/or cross-sectional imaging. Incidence of non-colorectal aerodigestive cancers in patients with false positive vs negative mt-sDNA. Aerodigestive Cancer Type False Positive (N=3,352) Negative (N=45,567) P Head and Neck 21 (0.63%) 166 (0.36%) 0.021 Lung 50 (1.49%) 227 (0.50%) <0.001 Non-colorectal GI 74 (2.21%) 276 (0.61%) <0.001 Total 145 (4.32%) 669 (1.47%) <0.001

Background The USA is a low-incidence country for gastric cancer and screening is not performed. The use of diagnostic endoscopy (EGD) is not well standardized. As a result, patients most commonly have advanced-stage disease at diagnosis. Patients and Methods All patients with gastric cancer treated at a single center over the past 10 years were identified, and demographics, presenting symptoms, diagnostic evaluations, stage at diagnosis, and outcomes were analyzed. Results A total of 249 patients with gastroesophageal junction (GEJ) or gastric or GEJ adenocarcinoma were identified. The presence of gastrointestinal (GI)-related symptoms at diagnosis was associated with more advanced disease (p < 0.001), but 73% of stage I patients were symptomatic. The median self-reported duration of symptoms prior to first EGD was 2 months (range 0-35 months), but nearly 50% of patients with stage IV were diagnosed by cross-sectional imaging before performance of EGD. In addition, 182 patients (73%) were participating in colon cancer screening. The median overall survival (OS) of the entire cohort was 23.0 months (95% CI 14.4-31.6) and was not reached for stage I patients, 47 months (95% CI 24.3-69.7) for stage II, 23.0 months (95% CI 19.9-26.3) for stage III, and 11.0 months (95% CI 6.6-15.4) for stage IV (p < 0.001). Non-EGD method of original diagnosis was an independent predictor of poorer survival, regardless of stage (HR 1.46, 95% CI 1.03-2.09; p = 0.036). Conclusions Diagnostic EGD is underutilized in symptomatic patients, particularly those with dyspepsia, while most patients were participating in colon cancer screening. Novel protocols to standardize the use of diagnostic EGD should be investigated in the USA.

Gastric cancer is a significant global health concern, with CDH1-associated gastric cancer representing a small but important subset of cases. Historically, individuals with CDH1 pathogenic germline variants were advised to undergo prophylactic total gastrectomy due to the high reported risk of gastric cancer and the limited sensitivity of upper endoscopy in detecting signet ring cell carcinoma (SRCC). However, emerging data suggest that the cumulative lifetime risk of advanced gastric cancer among CDH1 germline pathogenic variant carriers is lower than previously thought, and early-stage SRCC detected on endoscopy does not necessarily indicate imminent-or even eventual-progression to advanced cancer. The near-universal presence of T1a SRCC in gastrectomy specimens from asymptomatic CDH1 pathogenic variant carriers calls into question the reflexive recommendation for gastrectomy, including upon detection of SRCC during surveillance. Furthermore, the morbidity and quality-of-life impact associated with total gastrectomy require careful consideration. Active endoscopic surveillance has shown promise as an alternative management strategy for gastrectomy in patients lacking indicators of >T1a SRCC, though current data are limited by short follow-up periods and selection bias. This review synthesizes recent findings on the natural history of CDH1-associated gastric cancer and evaluates the risks and benefits of gastrectomy versus active endoscopic surveillance, with the goal of helping clinicians provide personalized and evidence-based recommendations for patients with CDH1 pathogenic variants.

Background: Patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) often have extensive cancer burden, long operative times, and reduced mobility postoperatively - known risk factors for venous thromboembolism (VTE). It is unknown whether risk factors differ for early versus late VTEs post-CRS-HIPEC. Methods: We retrospectively studied patients undergoing CRS-HIPEC from 2007 to 2021 and analyzed VTEs occurring within 60 days of surgery. VTEs <= postoperative day (POD) 7 were "early"; those after POD 7 were "late". Associated risk factors were analyzed using student's t-test, Chi-squared test, and logistic regression. Results: By POD 60, 35 of 682 CRS-HIPEC patients (5.1 %) had VTEs - eight (22.9 %) early and 27 (77.1 %) late. All early VTEs were pulmonary emboli vs. 63 % of late VTEs (p = 0.041); five (62.5 %) early VTEs were serious (Clavien-Dindo grade >= 3) vs. two (7.4 %) late VTEs (p = 0.005). Early VTEs were associated with primary ovarian cancer (37.5 % vs. 4.2 %, p < 0.001), extensive pelvic dissection (87.5 % vs. 50.1 %, p = 0.035), PCI 31-39 (p = 0.002), OR time (558 vs. 420 min, p = 0.015), EBL (650 vs. 150 mL, p = 0.005), and intraoperative transfusion (62.5 % vs. 13.1 %, p = 0.002). Late VTEs were associated with higher Caprini score (9 vs. 8, p = 0.038), lower serum albumin (4.1 vs. 4.3, p = 0.002), PCI 31-39 (p = 0.012) and serious inpatient postoperative complications (22.2 % vs. 7.3 %, p = 0.008). Conclusions: Severity and risk factors are markedly different for early vs. late VTEs following CRS-HIPEC. Early VTEs are more serious and associated with primary ovarian cancer and extensive cytoreduction including pelvic dissection highlighting the need for alternative prophylaxis strategies and clinical scrutiny in these populations.

While minimally invasive gastrectomy (MIS) is well-utilized in Asia, its adoption in the West to treat gastric adenocarcinoma has been slower. We compare survival outcomes between open gastrectomy and MIS in a high-volume Western US center. In this retrospective review, demographic and clinical characteristics of gastric adenocarcinoma patients who underwent curative-intent MIS (robotic or laparoscopic approaches) or open surgery were compared via descriptive statistics. Multivariable Cox hazard regression models were constructed to assess the effects of gastrectomy type on overall survival (OS) and recurrence-free survival (RFS) in the overall cohort and a locally advanced subgroup (pathologic stage 2–3 patients). A total of 135 gastric adenocarcinoma patients were studied; 67

PURPOSE Mucinous neoplasms of the gastrointestinal tract are characterized by a propensity for metastasis to the peritoneum, resulting in peritoneal mucinous carcinomatosis (PMC). A subset of these tumors, most often originating in the appendix, harbor mutations in the GNAS oncogene. While the natural history of GNAS -mutant PMC varies, patient outcomes are generally poor, as is response to cytotoxic chemotherapy. The purpose of this study was to evaluate the clinical efficacy of single-agent palbociclib, a cyclin-dependent kinase (CDK)4/6 inhibitor, in patients with GNAS -mutant PMC. PATIENTS AND METHODS We enrolled 16 patients with PMC in a single-arm personalized cancer therapy trial. For all patients, tumor tissue and/or circulating tumor DNA genomic profiling using next-generation sequencing and, when possible, PD-L1 expression, tumor mutational burden, and microsatellite instability status was assessed. Twelve of 16 patients had previous disease progression on at least one previous line of chemotherapy. The primary tumor was appendix in 13 patients, unknown in two patients, and pancreas in one patient. Eleven cases were classified as low grade, and five as high grade. RESULTS In 13 of 16 patients, we observed a decrease in carcinoembryonic antigen (CEA), and in six patients, the CEA declined by >50%. As measured by clinical and modified peritoneal RECIST criteria, 50% of evaluable patients had stable disease after 12 months of palbociclib. At a median follow-up of 17.6 months, median survival has not been reached. Clinical response to CDK4/6 inhibition was mirrored in tumors with GNAS mutation and mucinous histology using an ex vivo preclinical platform. CONCLUSION CDK4/6 inhibition with palbociclib had clinical activity in PMC characterized by mutations in GNAS that was superior to that previously reported with cytotoxic chemotherapy. CDK4/6 inhibition is a novel therapeutic strategy worthy of further evaluation in this subgroup of gastrointestinal neoplasms.

Abstract Concomitant mutations in KRAS and GNAS have been linked to mucinous histology in gastrointestinal neoplasms of the appendix, colon, and pancreas (IPMN). Upon progression, these tumors are characterized by metastasis which favors the peritoneal surface, resulting in mucinous carcinomatosis peritonei (MCP). Recently we have described a novel technique which allows for long term culture and drug intervention of human MCP tumors ex-vivo. With evidence of durable clinical benefit of CDK4-6 inhibition in a single patient with chemo refractory MCP of appendiceal origin, we sought to further investigate anti-tumor responses using CDK4-6 inhibition in ex-vivo tumor slices, in order to identify candidates for a personalized clinical therapy trial. Here, in a comparison of ex-vivo patient tumor slices from 18 individual donors, treatment using CDK4-6 inhibitors revealed a significant reduction in cancer cell specific proliferation in mucinous GNAS-mut tumors compared to non-mucinous cancers. Anti-tumor responses of CDK4-6 were determined to be tumor-cell intrinsic, as CDK4-6 inhibition blocked proliferation of stromal cells in the TME independently of patient tumor mutational and mucin status. Based on these finding a personalized clinical trial was conducted where we report that 13 of 16 patients (81%) enrolled with MCP treated with palbociclib had at least a 10% decrease in CEA, as compared to historical chemotherapy responses rates reported from 14-30%. These results indicate that CDK4/6 inhibition is a novel and efficacious treatment for patients with MCP. Citation Format: Jonathan Weitz, Daisuke Nishizaki, Jay Patel, Isabella Ng, Siming Sun, Dana Ramms, Jingjing Zou, Joel Baumgartner, Kaitlyn Kelly, Hitendra Patel, Rebekah White, Jula Veerapong, Peter Vu, Silvio Gutkind, Herve Tiriac, Shumei Kato, Andrew Lowy. An ex-vivo organotypic culture platform of mucinous carcinomatosis peritonei identifies CDK4-6 inhibition as a novel treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6777.

Gastric cancer poses a major diagnostic and therapeutic challenge as surgical resection provides the only opportunity for a cure. Specific labeling of gastric cancer could distinguish resectable and nonresectable disease and facilitate an R0 resection, which could improve survival. Two patient-derived gastric cancer lines, KG8 and KG10, were established from surgical specimens of two patients who underwent gastrectomy for gastric adenocarcinoma. Harvested tumor fragments were implanted into the greater curvature of the stomach to establish patient-derived orthotopic xenograft (PDOX) models. M5A (humanized anti-CEA antibody) or IgG control antibodies were conjugated with the near-infrared dye IRDye800CW. Mice received 50 µg of M5A-IR800 or 50 µg of IgG-IR800 intravenously and were imaged after 72 hr. Fluorescence imaging was performed by using the LI-COR Pearl Imaging System. A tumor-to-background ratio (TBR) was calculated by dividing the mean fluorescence intensity of the tumor versus adjacent stomach tissue. M5A-IR800 administration resulted in bright labeling of both KG8 and K10 tumors. In the KG8 PDOX models, the TBR for M5A-IR800 was 5.85 (SE ± 1.64) compared with IgG-IR800 at 0.70 (SE ± 0.17). The K10 PDOX models had a TBR of 3.71 (SE ± 0.73) for M5A-IR800 compared with 0.66 (SE ± 0.12) for IgG-IR800. Humanized anti-CEA (M5A) antibodies conjugated to fluorescent dyes provide bright and specific labeling of gastric cancer PDOX models. This tumor-specific fluorescent antibody is a promising potential clinical tool to detect the extent of disease for the determination of resectability as well as to visualize tumor margins during gastric cancer resection.