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The immunogenomic landscape of primary and metastatic gastroesophageal adenocarcinoma.

493 Background: Metastatic gastroesophageal adenocarcinoma (GEA) is a heterogeneous disease with an overall poor prognosis. The tumour microenvironment (TME) between the primary and metastatic compartment is not well characterized. This study aims to describe the immunogenomic features of matched primary and metastatic GEA and their correlation with clinical outcomes. Methods: We performed whole exome sequencing (WES, n=36) and total RNA sequencing (RNA-seq, n=36) on a prospectively collected cohort of metastatic GEA, of which 14 had matched primary and metastatic tissues. We used TME deconvolution (Bagaev et al., 2021) comparing between the primary and metastatic compartments. Using an orthogonal technology, we further integrated immune checkpoint-directed multiplex immunohistochemistry (mIHC) for 22 patients with matched primary and metastatic samples. Results: The median age of our cohort was 61 (range 27-89), primarily male (n=28, 77%), and non-Asian (n=32, 89%). All had metastatic GEA at time of diagnosis. Differential expression showed activation of immune pathways such as tumor necrosis factor signalling and interferon-gamma response in the metastatic compartment. Deconvolution of the TME demonstrated 29% of primary tissues having an immune-inflamed TME compared to 61% of metastatic tissues (p=0.032). Exploring immune cell types, metastatic compartment is characterized by higher abundance of naïve and mature B cell populations (p<0.001), while primary compartment is enriched with CD4+ T cells (p<0.01). In matched cases, only 2 of 14 (14%) had concordant TME subtypes between primary and metastatic samples suggesting high degree of immune divergence. Furthermore, expression of common immune checkpoints aligned more with TME subtypes than within patient compartments suggesting common pathways of immune evasion. M-IHC showed both T-cell and immune checkpoint markers are enriched at the tumor margins compared to the tumor center in both primary and metastatic compartments (CD4; p<0.0001, CD8; p<0.001, CD68; p<0.001). There was a significant increase in the number of CD68+/CD163+/PDL1+ M2-like macrophages in the tumor margins (p<0.0001). Consistent with our deconvolution analysis, there are higher CD4+ T cells in the matched primary compared to metastatic samples. Long-term survivors (>16 months) had decreased number of CD68+ macrophages in the tumor center (p=0.019). Conclusions: Primary and metastatic GEA have divergent TME. This may partially explain varying responses to chemo-immunotherapy approaches. Therapies aimed at modifying TME may provide personalized treatment options.

Integrating bulk and single-cell RNA sequencing data: unveiling RNA methylation and autophagy-related signatures in chronic obstructive pulmonary disease patients

Angiogenesis-promoting effect of SKP-SC-EVs-derived miRNA-30a-5p in peripheral nerve regeneration by targeting LIF and ANGPT2

Surgical treatment in patients with advanced gastrointestinal stromal tumours (GISTs) in second-line and later stages: A single-centre cohort study.

818 Background: Gastrointestinal stromal tumour (GIST) after imatinib treatment failure usually progresses rapidly with limited overall survival. Previous studies have suggested that surgery is beneficial for advanced GISTs in disease control to imatinib, but the role of surgery in > = 2 line patients remains unclear. Methods: Imatinib-resistant patients with advanced GIST between May 2009 and Nov. 2023 were included. Surgical treatments included tumour reduction, radiofrequency ablation and TACE. The primary endpoint was overall survival (OS) and secondary endpoints were time to second-line treatment failure (TTF) and postoperative morbidity. To balance clinicopathological characteristics, 1:1 propensity score matching (PSM) was used. Results: A total of 242 patients with advanced GIST treated with 2nd-line or later drugs were included, including 125 in the surgical group and 117 in the non-surgical group. The median follow-up was 30.3 months. OS was significantly better in the surgical group than in the non-surgical group (pre-PSM: 51.7m vs 35.9m , p = 0.001; post-PSM: 50.8m vs 38.8m, p = 0.043). Univariate analysis showed that surgical treatment (HR 0.487, 95% CI 0.320-0.740, p = 0.001), age ≤60 years (HR 0.640, 95% CI 0.411-0.997, p = 0.049) and low tumour burden (HR 0.491, 95% CI 0.293-0.822, p = 0.007) were associated with prolonged OS. Multivariate analysis indicated that surgical treatment (HR 0.541, 95% CI 0.348-0.843, p = 0.007) and low tumour burden (HR 0.510, 95% CI 0.300-0.865, p = 0.012) were significantly associated with OS benefit. Patients (n = 84) who had surgical treatment during second-line treatment had longer TTF compared to patients (n = 158) who had TKI only (14.2m vs 8.1m , p = 0.003). There were 29 (14.8%) postoperative complications with Clavien-Dindo classification ≥3, including 5 deaths. Conclusions: Surgical treatment can provide a survival benefit for patients with second-line and later advanced GIST, but further studies are needed for a more detailed indication of the surgical population.

Anthracyclines in Early Breast Cancer: The Long Goodbye

A novel 2-2 5-5 model for stratifying liver metastasis burden in patients with pancreatic cancer.

711 Background: In metastatic pancreatic cancer (MPC), hepatic metastasis is uniformly counted as just ‘one organ metastasis’ regardless of its metastatic tumor burden. This study aims to develop a novel stratification system for liver metastasis based on tumor burden, and to evaluate its prognostic significance in MPC patients. Methods: Patients with MPC treated at Seoul National University Bundang Hospital from 2011 to 2021 were included as the training cohort. Patients with liver-only metastasis were selected for analysis. Liver metastasis burden was categorized by the number and maximum diameter of metastases as measured from diagnostic CT images. Optimal cutoffs for metastasis number and size were determined using Cox proportional hazards regression, adjusted for chemotherapy regimen. An independent cohort from Seoul St. Mary’s Hospital and Hallym University Sacred Heart Hospital served as the validation group. The ‘H category classification’ suggested by the Japanese Society for Cancer of the Colon and Rectum (JSCCR) was also referenced. Results: A total of 1,257 patients were included, with 1,084 in the training cohort and 173 in the validation cohort. In the training cohort, data from 311 patients with liver-only metastasis were analyzed to derive the Two-two five-five (‘2-2 5-5’) criteria, classifying metastasis into Oligo-metastasis (≤2 metastases and ≤2 cm), Meso-metastasis (non-oligo and non-mega), and Mega-metastasis (≥5 metastases or ≥5 cm). Median overall survival (OS) significantly differed between the groups: Oligo (11.4 months), Meso (9.2 months, HR 1.66, 95% CI 1.14–2.43), Mega (5.6 months, HR 2.63, 95% CI 1.94–3.58) in the training cohort; Oligo (5.8 months) vs Mega (1.81 months, HR 1.94, 95% CI 1.16–3.22) in the validation cohort. Conclusions: This 2-2 5-5 model effectively stratifies MPC patients with hepatic metastasis into three prognostic groups, demonstrating significant survival differences in both training and validation cohorts. This could rationalize the independent therapeutic strategies by extent of hepatic metastasis. Demographic characteristics of patients classified according to “two-two five-five” criteria. Oligo-metastasis(n = 88) Meso-metastasis(n = 59) Mega-metastasis(n = 164) Total(n = 311) P-value* Age, median (range) 66.0 (33.2-91.0) 67.1(37.2-86.9) 68.7 (40.1-94.6) 67.9 (33.2-94.6) 0.587 Male, n (%) 43 (48) 36 (61) 91 (55) 170 (54) 0.330 Tumor location(Head), n(%) 47 (53) 27 (45) 60 (36) 134 (43) <0.05 Number of liver metastasis, median (range) 1 (1-2) 3 (1-4) 12 (2-14) 5 (1-14) <0.05 Maximal size of liver metastasis, cm (IQR)Average size of liver metastasis, cm (IQR) 10.6 (8.1-13.1)10.3 (8.0-12.1) 15.9 (10.1-24.2)13.5 (7.8-19.1) 21.6 (16.8-33.7)13.2 (10.5-19.2) 17.2 (10.9-25.2)11.9 (9.2-17.1) <0.05<0.05 CA19-9 (U/mL) 462 (103-1,334) 560 (89-1,480) 1,170 (100-9,500) 745 (100-3,700) <0.05

Nest site selection during the second breeding attempt in Japanese tits (Parus minor): effects of nest site characteristics

Liver fatty acid binding protein FABP1 transfers substrates to cytochrome P450 4A11 for catalysis

Nivolumab (NIVO) + chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 5-year (y) follow-up results from CheckMate 649.

398 Background: At 4-y follow-up, 1L NIVO + chemo continued to demonstrate clinically meaningful overall survival (OS) and progression-free survival (PFS) benefit vs chemo with acceptable safety in patients (pts) with advanced non-HER2+ GC/GEJC/EAC from CheckMate 649. We report efficacy and safety results of NIVO + chemo vs chemo at 5-y follow-up. Methods: Adults with previously untreated, unresectable, advanced or metastatic, non-HER2+ GC/GEJC/EAC were enrolled, regardless of programmed death ligand 1 (PD-L1) expression. Pts were randomized to NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: Pts were randomized to NIVO + chemo (n = 789) or chemo (n = 792). NIVO + chemo continued to show OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5, pts with PD-L1 CPS ≥ 1, and all randomized pts at 60-month (mo) minimum follow-up (Table). OS rates at 60-mo were higher with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5, pts with PD-L1 CPS ≥ 1, and all randomized pts (Table), and OS benefit with NIVO + chemo continued to be observed in most prespecified subgroups. Objective response rates (ORRs) were higher and responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5, pts with PD-L1 CPS ≥ 1, and all randomized pts (Table). No new safety signals were identified. Conclusions: These results represent the first report of 5-y follow-up for anti–PD-1 + chemo combination therapy in GC/GEJC/EAC to our knowledge. NIVO + chemo continued to provide sustained long-term survival vs chemo with an acceptable safety profile after 5 y of follow-up. These data continue to support the use of NIVO + chemo as a standard 1L treatment for advanced GC/GEJC/EAC. Clinical trial information: NCT02872116 . Efficacy PD-L1 CPS ≥ 5 PD-L1 CPS ≥ 1 All randomized NIVO + chemo(n = 473) Chemo (n = 482) NIVO + chemo (n = 641) Chemo (n = 656) NIVO + chemo (n = 789) Chemo (n = 792) mOS (95% CI), mo 14.4 (13.1–16.2) 11.1 (10.1–12.1) 13.8 (12.4–14.8) 11.4 (10.7–12.3) 13.7 (12.4–14.5) 11.6 (10.9–12.5) HR (95% CI) 0.71 (0.61–0.81) 0.76 (0.67–0.85) 0.79 (0.71–0.88) 60-mo OS rate (95% CI), % 16 (12–19) 6 (4–9) 13 (11–16) 5 (4–7) 12 (10–14) 6 (4–8) mPFS a (95% CI), mo 8.3 (7.0–9.4) 6.1 (5.6–6.9) 7.5 (7.0–8.5) 6.9 (6.2–7.1) 7.8 (7.1–8.6) 6.9 (6.7–7.2) HR (95% CI) 0.71 (0.61–0.82) 0.77 (0.68–0.87) 0.79 (0.71–0.89) ORR a,b (95% CI), % 60 (55–65) 45 (40–50) 60 (55–64) 46 (42–51) 58 (54–62) 46 (42–50) mDOR a,c (95% CI), mo 9.6 (8.3–12.4) 7.0 (5.7–8.0) 8.6 (7.9–10.5) 6.9 (5.8–7.6) 8.5 (7.7–9.9) 6.9 (5.9–7.6) a Per BICR. b In pts with measurable target lesions at baseline. c In all measurable responders. DOR, duration of response; m, median.

GOBLET platform study: Preliminary safety and tumor response results for the relapsed anal carcinoma cohort in patients treated with pelareorep and atezolizumab.

6 Background: Patients with relapsed unresectable squamous cell carcinoma of the anal canal (SCCA) have limited treatment options after failure of standard first-line therapy. While checkpoint inhibitor monotherapy is possible, response rates are low (10-24%). Therapies that induce an inflammatory tumor microenvironment may improve the susceptibility of SCCA to immunotherapy. Pelareorep (pela) is a non-genetically modified, intravenously administered reovirus that stimulates the expansion of tumor-infiltrating lymphocyte (TIL) clones and simultaneously makes tumors visible to the immune system by upregulating interferon-induced gene expression. Pela-based combination therapies have demonstrated activity in metastatic breast and pancreatic cancer. In the GOBLET platform study, the efficacy of pela plus atezolizumab (atezo) in SCCA is being evaluated. Methods: GOBLET is a phase 1/2, open-label, non-randomized, Simon two-stage platform study in patients with advanced or metastatic GI cancers. SCCA patients in the trial are treated with pela plus atezo. Ten evaluable patients will be enrolled in Stage 1 and an additional 18 evaluable patients will be enrolled in Stage 2 if the prespecified Stage 1 success criterion is met (≥2 responses). The coprimary endpoints are tolerability of the treatment regimen and objective response rate (based on RECIST v1.1). Safety data are reviewed in an ongoing manner by an independent Data Safety Monitoring Board (DSMB). In addition, tumor and blood samples are being collected to assess TIL clonal expansion and other biomarkers. Results: Twelve patients are currently evaluable for tumor response in the SCCA cohort. Four out of 12 patients have achieved an objective response to therapy including 1 prolonged complete response (>15 months) and 3 partial responses- resulting in an ORR of 33.3%. Final ORR, progression-free survival, and overall survival results are pending. The DSMB has identified no safety signals and has recommended that enrollment continues without modification. TIL clonal expansion in the blood has been observed at treatment cycle 4 in all 3 responding patients for whom data are available. Conclusions: Twelve patients are currently evaluable for tumor response in the SCCA cohort. Four out of 12 patients have achieved an objective response to therapy including 1 prolonged complete response (>15 months) and 3 partial responses resulting in an ORR of 33.3%. Final ORR, progression-free survival, and overall survival results are pending. The DSMB has identified no safety signals and has recommended that enrollment continues without modification. TIL clonal expansion in the blood has been observed at treatment cycle 4 in all 3 responding patients for whom data are available. Clinical trial information: 2020-003996-16.

Immune checkpoint inhibitors in digestive tumors with mismatch repair deficiency or microsatellite instability (dMMR/MSI-H): Effectiveness, safety, and prognostic factors in real-world practice.

202 Background: ICIs have shown durable responses in dMMR/MSI-H digestive tumors in phase II-III clinical trials. The aim of this study is to evaluate the efficacy, safety and prognostic factors in the context of real-world practice. Methods: We conducted a retrospective multicenter observational study of patients with dMMR/MSI-H digestive tumors treated with ICIs in routine clinical practice across seven university hospitals in northwest Spain. We analyzed clinicopathological characteristics, treatment response data, efficacy, and adverse events. Results: A total of 122 patients treated with ICIs between November 2015 and February 2024 were included. The median age was 70.4 years (range 29-89), and 52.4% were male. The most frequent origin was colorectal (54.9%; 67.2% located in the right colon and 37.3% BRAF V600mt), followed by gastroesophageal adenocarcinoma (34.4%). 16.4% had >3 metastatic sites (including 30.3% liver metastases and 44.3% peritoneal metastases). Baseline performance status (ECOG PS) was 0/1/2 in 21.7%/58.7%/19.8%, respectively. 39.3% had received one prior line of treatment. 92.6% received pembrolizumab monotherapy. The objective response rate (ORR) was 77.7% (including 31.3% complete response, 46.4% partial response, 13.4% stable disease, and 8.9% progressive disease), and the disease control rate (DCR) was 90.1%. Median overall survival (OS) was 53.2 months (95% CI: 42.6 – 63.7 months), and progression-free survival (PFS) was 46 months (95% CI: 30.6 – 61.4 months). The most common grade 3-4 treatment-related adverse events included nephritis (4.0%), hepatitis (3.3%), asthenia (2.5%), and pneumonitis (1.6%). 81.1% of patients discontinued treatment (including 24.6% due to progression, 21.3% after completing 2 years of treatment, and 14.8% due to toxicity). Potential prognostic factors identified in univariate analysis included ECOG PS, primary tumor resection, number of metastatic sites, and best treatment response. In multivariate analysis, a significant association was confirmed between ECOG PS, the presence of liver metastases, and best response to treatment with ICIs and overall survival. Conclusions: Our series confirms the efficacy and safety of ICIs in dMMR/MSI-H digestive tumors in routine clinical practice. The identified prognostic factors may be useful for identifying patients who could benefit the most from ICI treatment.

Validation of histopathology foundation models through whole slide image retrieval

The effect of cachexia and anti-cancer therapies on GDF-15 levels in patients with pancreatic adenocarcinoma.

778 Background: Growth differentiation factor 15 (GDF15) is a novel biomarker in the setting of pancreatic adenocarcinoma (PDAC). Preliminary studies have found that downstream effects of GDF-15 promote the progression of pancreatic cancer. PDAC has a high prevalence of cachexia which is commonly treated with enzyme supplementation and nutritional support. Platinum-based therapies often used to treat PDAC increase the likelihood of patients experiencing cachexia. The purpose of this study was to observe the GDF-15 levels in respect to weight change of PDAC patients being treated with cachexia and anti-cancer therapies. Methods: Serum and Plasma samples were collected from locally advanced and advanced PDAC patients on 5 IRB approved studies from 2014-2024. Samples were analyzed using the R-PLEX Human GDF-15 Antibody Set. The study objective was compared using two-sample paired t-tests and Pearson correlation matrices. Elevated GDF-15 was determined as >1500 pg/mL. Results: Samples from 73 patients were utilized for this study (63% female; median age: 69; BMI: 23.31±4.96 kg/m 2 ). At baseline 71.8% (46/64) had elevated GDF-15, at Cycle 3 76% (25/33), and at Cycle 5 86% (25/29). In the total sample set, there was a slight negative correlation in the change of weight (-1.75 kg, p = 0.013) and GDF-15 (577.5 pg/mL, p = 0.278) from C1 to C3 (r = -0.185, p = 0.366). There was a slight negative correlation (r = -0.44, p = 0.076) in the difference of weight and GDF-15 from C1 to C3 in patients receiving chemotherapy. A strong negative correlation was observed in the change of GDF15 and weight from C1D1 to C1D8 in patients treated with platinum-based therapy (r = -0.530, p = 0.212) and a weak negative correlation (r = -0.421, p = 0.065) for patients with non-platinum-based therapy. There was a strong positive association (r = 0.993, p < 0.01) between the change in weight and GDF-15 from C1 to C5 in patients not receiving chemotherapy. There was no significant decrease in GDF-15 levels across the patients at all time points. Conclusions: Despite cachexia and anti-cancer treatment, the GDF-15 levels of PDAC patients continue to remain elevated in consecutive blood draws. Further research in GDF-15 kinetics is warranted. Clinical trial information: NCT02400398 , NCT03207724 , NCT04098237 , NCT05336266 , NCT04634539 . Weight and GDF-15 levels across different chemotherapy regimens. Baseline Cycle 1 Cycle 3 Cycle 5 BMI (kg/m2) Weight (kg) GDF15 (pg/mL) Weight (kg) GDF15 (pg/mL) Weight (kg) GDF15 (pg/mL) Chemotherapy 23.21 63.83 3243.25 63.44 3498.76 60.14 3201.33 No Chemotherapy 23.77 65.85 3113.73 62.32 2949.56 71.05 2944.54 Platinum Based 20.88 59.89 6527.78 51.7 3600.87 58.1 5152.50 Non-platinum-based chemotherapy 23.86 64.89 2442.14 64.67 3487.41 60.39 2957.43

Circulating tumor DNA for detection of molecular residual disease (MRD) in patients (pts) with stage II/III colorectal cancer (CRC): Final analysis of the BESPOKE CRC sub-cohort.

15 Background: BESPOKE CRC, a multicenter, prospective, observational study investigated the clinical utility of ctDNA for detecting MRD-based early recurrence in pts with surgically resected CRC. The primary endpoint was to assess the impact of ctDNA testing on treatment decisions and asymptomatic recurrence rates. The secondary endpoint was to assess the MRD clearance rate, survival of MRD-negative pts, overall survival, and patient-reported outcomes. Methods: Complete clinical and laboratory data were available for 1001 pts with stages II–III CRC. Longitudinal ctDNA testing was performed prospectively using a clinically validated, personalized, tumor-informed 16-plex mPCR-NGS assay (Signatera, Natera, Inc.). Plasma time points (n=8,536) were collected during the MRD (2-12 weeks postoperatively) and surveillance (post-adjuvant chemotherapy [ACT] completion/12 weeks postoperatively for pts observed) windows. We evaluated the correlation between ctDNA status and disease-free survival (DFS) as part of exploratory analysis. Results: Following curative resection, 62.4% (625/1001) pts received ACT: 25.9% (115/443) stage II, and 91.3% (510/558) stage III.Among pts with ctDNA results available during the MRD window with a median follow-up of 23.15 (range: 2.89-33.45) months, ctDNA-positivity was observed in 8.1% (34/420) of stage II and 24.9% (126/505) of stage III pts. A significant association between ctDNA positivity and inferior DFS was observed in stage II (HR=10.4; p<0.0001), and stage III (HR=10.1, p<0.0001) pts. 18/24 month DFS estimates for stages II-III combined were: (MRD-negative: 93.0%/91.7%; MRD-positive: 44.4%/41.4%). Analysis of surveillance was performed separately for pts observed (N=368) vs. ACT-treated (N=597). During surveillance, in the observation cohort, 6.8% (22/323) of stage II, and 33.3% of stage III (15/45) pts tested ctDNA-positive correlating with significantly worse DFS (stage II: HR=34.9; p<0.0001, stage III: HR=34.1; p=0.0008). Likewise, in the ACT cohort, 10.9% (12/110) of stage II and 21.1% of stage III (103/487) pts turned ctDNA-positive and had significantly worse DFS (stage II: HR=131.4; p<0.0001, stage III: HR=54.6; p<0.0001). Analysis of primary and secondary endpoints will be presented. Conclusions: ctDNA positivity was highly prognostic of DFS within MRD and surveillance windows in a subset of stages II-III pts enrolled in the BESPOKE CRC study. Our results highlight the potential value of ctDNA-based MRD detection for treatment-decision making, and findings relevant to clinical utility will be reported in the conference presentation. Clinical trial information: NCT04264702 .

Colorectal cancer care disparities in an urban diverse population: A tale of two hospitals in the nation’s capital.

38 Background: Colorectal cancer (CRC) disparities by race and ethnicity are well-documented nationally. In the District of Columbia (DC), Black Americans have an 18% higher incidence and 46% higher mortality rate compared to overall rates among all races/ethnicities. These disparities often stem from long-standing inequities in the social determinants of health, which affect access to cancer prevention, early detection, and treatment. MedStar Georgetown serves a large, urban, diverse population at 2 hospitals: the MedStar Georgetown University Hospital (MGUH) and the MedStar Washington Hospital Center (MWHC). MWHC serves a higher proportion of minoritized patients (pts) with multiple social determinant barriers to care, including those without private health insurance. We hypothesized that disparities would be found in CRC pt care and outcomes when comparing MWHC with MGUH. Methods: We conducted a retrospective study of all CRC pts treated during the 2021-2023 period at MGUH and MWHC using the COTA real-world database. Pt demographics, insurance status, and selected clinical data, including but not limited to treatment site, disease stage, tumor molecular testing, and pt survival, were abstracted for analysis. Descriptive, bivariate, and multivariate analyses focused on gender, race/ethnicity, insurance status, receipt of tumor testing, and the interval between diagnosis and therapy initiation and explored survival by these factors in addition to the site of care (MGUH versus MWHC). Results: Of the 379 CRC pts receiving care at the Lombardi Comprehensive Cancer Center during the study period, 53% were treated at MGUH and 47% at MWHC. CRC pts at MWHC were more likely than CRC pts at MGUH to be Black Americans (65% vs. 28%, p<0.001) and have 3 or more comorbidities (16% vs. 8%, p=0.22) but were less likely to have early onset CRC (p<0.01) and be on private insurance (36% vs. 23%, p=0.01). Pts treated at advanced stages (stages 3-4) were similar between the two hospitals (64%). In spite of these differences, we did not find any differences between MWHC and MGUH in molecular tumor testing (83% vs. 86%, p=0.41), median time (days) to treatment initiation (28 vs. 26 days, p=0.18), or short-term survival (90% vs. 91%, p=0.95). In analyses comparing care/treatment-related factors with race/ethnicity and insurance status across the 2 hospitals, we did not find any statistically significant differences. Conclusions: Contrary to our expectations of finding significant cancer care disparities, we did not observe any differences in molecular tumor testing rates, time to initiation of therapy, or short-term survival by treatment site or race/ethnicity status. Our results suggest that integrated, specialized, guideline-concordant care in comprehensive cancer centers has the potential to eliminate CRC outcome disparities among pts diagnosed at these centers.

PDE4B promotes ferroptosis in nucleus pulposus cells and is involved in intervertebral disc degeneration

A randomized phase II clinical trial evaluating the safety and efficacy of initial dose adjustment of zolbetuximab plus chemotherapy in patients with HER2-negative and CLDN18.2-positive unresectable advanced or recurrent gastric, gastroesophageal junction cancer or esophageal adenocarcinoma (GENTLE-Z).

TPS504 Background: Zolbetuximab, a monoclonal antibody targeting CLDN18.2, was recently approved in Japan for patients with HER2-negative/CLDN18.2-positive metastatic gastric or gastroesophageal junction cancer (mGC/GEJC). On-target GI toxicities such as nausea and vomiting are commonly observed during first infusion, occasionally leading to early treatment discontinuation. Effective management of these toxicities is essential for the successful use of zolbetuximab in clinical practice. This study aims to assess whether omitting the loading dose in the first cycle can reduce zolbetuximab-related GI toxicities without compromise efficacy . Methods: GENTLE-Z is a prospective, open-label, multi-intuitional, randomized phase II trial designed to compare the safety and efficacy of fixed-dose of zolbetuximab without loading dose vs. the standard zolbetuximab dose in combination with first-line mFOLFOX6 or CAPOX for patients with HER2-negative/CLDN18.2-positive mGC/GEJC. Patients are randomly assigned (1:1) to receive either a fixed dose of zolbetuximab (400 mg/m 2 q2w or 600 mg/m 2 q3w) or standard zolbetuximab regimen (800 mg/m 2 loading dose followed by 400 mg/m 2 q2w or 600 mg/m 2 q3w) with chemotherapy. The primary endpoint is the vomit-free rate during cycle 1, and secondary endpoints include efficacy outcomes such as objective response rate, progression-free survival and overall survival. The sample size is set based on the hypothesis that omitting loading dose will improve the vomit-free rate from 50% to 75%. The planned sample size is 86 patients, with a one-sided alpha error of 5% and power of 75%, over an estimated enrollment period of 1.5 years. Enrollment has been ongoing since September 2024 across 55 sites in Japan. This trial is registered in Japan Registry of Clinical Trials (jRCTs031240347). Clinical trial information: jRCTs031240347.

Enhancing a low-cost, minimally invasive screening test for dihydropyrimidine dehydrogenase mutations linked to 5-fluorouracil sensitivity by integrating computational mutation predictions.

226 Background: 5-Fluorouracil (5-FU), a common chemotherapy for solid tumors, is metabolized primarily by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. With > 200 known variants, individuals with nonfunctional DPYD alleles exhibit impaired 5-FU metabolism and are at risk of severe toxicity. Approximately 35% of the population has partial DPD deficiency, and 0.2% completely lack enzymatic activity. Despite this, DPYD genotyping is not standard practice. This study evaluates the use of non-invasive saliva samples for DPYD genotyping and combines AI-based molecular prediction modeling to search for novel variants within DPYD coding region. Saliva samples were collected from fifty-six healthy individuals and from gastrointestinal (GI) cancer patients including a family cohort of nineteen individuals and three unrelated patients undergoing chemotherapy. Methods: gDNA was sequenced for nine DPYD variants reported to reduced or abrogate DPD activity: c.1905+1G > A, c.1679T > G, c.2846A > T, c.1129-5923C > G, c.1236G > A, c.299_302delTCAT, c.703C > T, c.2983G > T, and c.557A > G. cBioPortal was utilized to search the TCGA database for studies involving colon cancer patients with novel DPYD mutations exhibiting a total FIS score of at least 2 or identified through 3D modeling of DPD using PyMol based on their proximity to or the presence of polar contacts within the active site. Putative pathogenic mutations were analyzed using AlphaMissense and ChimeraX to assign a RSMD score, assessing their potential negative impact on DPD function. Results: Computational studies identified three mutations in DPYD from TCGA colon cancer patients with an unknown impact on DPD and a FIS greater than 4 (c.198G > C/T, c.2161G > A, c.2185G > A), suggesting potential disruption of its function. Four mutations (c.424T > G, c.427T > G, c.2460G > C, c.2909C > A) were identified through protein modeling using PyMol, but only two had a FIS greater than 2. Of these seven identified mutations, four (c.198G > C/T, c.2161G > A, c.2185G > A, c.2909C > A) also scored highly using AlphaMissense and ChimeraX. In silico prediction models from VarSome listed c.2185G > A as Pathogenic Moderate and c.2909C > A as Pathogenic Very Strong. Sequencing of saliva samples indicated mutations c.1129-5923C > G and c.1236G > A were present in four and three volunteers, respectively, and c.1905+1G > A in one case. Mutations identified in GI cancer patients were c.1129-5923C > G and c.1236G > A. Conclusions: By combining computational modeling with the analysis of naturally occurring mutations in colon cancer patients, we have successfully identified potentially pathogenic mutations in the DPYD gene. This information can enhance existing clinical diagnostic tests, providing a more comprehensive assessment of DPYD mutations, including novel variants.

Comparison between neoadjuvant chemotherapy followed by surgery and definitive chemoradiotherapy for survival in patients with resectable esophageal squamous cell carcinoma (JCOG2305A).

417 Background: Neoadjuvant triplet chemotherapy followed by surgery (Neo-S) has become the standard treatment for resectable esophageal squamous cell carcinoma (ESCC) based on the results of JCOG1109. However, definitive chemoradiotherapy (CRT) remains an option for organ preservation with curative intent. This analysis aimed to explore subgroups of patients undergoing CRT, including salvage treatment, to identify those with survival outcomes potentially equivalent to Neo-S. Methods: Pooled data from two clinical trials of patients with resectable (T1N1-3M0 and T2-3NanyM0) ESCC. JCOG0909 was a single-arm trial that evaluated upfront CRT consisting of 5-FU (1000 mg/m 2 on day1-4, 29-32) and cisplatin (80 mg/m 2 on day1, 29) combined with radiotherapy at a dose of 50.4 Gy, including salvage treatment. If there was no progression at the time of salvage treatment, it was not regarded as an event for progression-free survival (PFS) in JCOG0909. JCOG1109 compared neoadjuvant treatment with doublet chemotherapy, triplet chemotherapy, and doublet chemotherapy with radiotherapy followed by surgery. The patients were enrolled in JCOG0909 between 2010 and 2014 and in JCOG1109 between 2012 and 2018. Subgroup analyses of clinical data, including tumor location, cT, cN, and clinical stage, were conducted on overall survival (OS) and PFS using Cox proportional hazards regression models for patients with JCOG0909 and JCOG1109. When a subgroup with a multivariable hazard ratio (HR) of more than 0.91 was detected, CRT including salvage treatment was considered not to be inferior to Neo-S in that subgroup. Results: Ninety-three patients in the CRT group from JCOG0909 and 196 patients in the Neo-S group from the triplet chemotherapy arm of JCOG1109 were included in this analysis. Although there were no significant differences, PFS and OS tend to be better in the Neo-S group than in the CRT group (PFS, HR 0.72, 95% confidence interval [CI] 0.50-1.03; OS, HR 0.89, 95% CI 0.59-1.36). For patients with Ut/Mt or cT1-2 disease, OS in the Neo-S group had a HR of 0.91 or more compared with those in the CRT group (Table). Conclusions: Subgroups in which OS after CRT including salvage treatment was not inferior to that of Neo-S were identified. Hazard ratios of Neo-S to CRT by subgroups in multivariable Cox regression. Progression-free survival Overall survival Subgroups Hazard ratio 95% confidence interval Hazard ratio 95% confidence interval Ut/Mt 0.85 0.56-1.28 1.13 0.70-1.83 Lt 0.45 0.21-0.97 0.44 0.19-1.00 cT1-2 0.88 0.46-1.68 1.45 0.65-3.24 cT3 0.66 0.42-1.02 0.72 0.44-1.16 cStage IB+II 0.79 0.45-1.36 1.06 0.56-2.00 cStage III 0.75 0.45-1.23 0.92 0.52-1.62 Overall 0.72 0.50-1.03 0.89 0.59-1.36 Ut upper thoracic esophagus, Mt middle thoracic esophagus, Lt lower thoracic esophagus.

Fully automated CFD simulation system research based on design scheme tree

Abstract Compared with the remarkable achievements of computer-aided drug discovery systems for drug discovery, the role of computational fluid dynamics (CFD) in flow channel design requires further development. While CFD has undergone rapid evolution, the absence of integrated geometry and mesh processing hinders the potential development of advanced applications of this technology. To overcome this limitation, in this paper, the JIACFD toolset is presented, and a fully automated CFD simulation system is established. The simulation system is also constructed on a design scheme tree, which is more in accordance with engineering logic. The control parameter trend analysis method is introduced to select appropriate candidates from the design scheme tree. Additionally, the control parameter trend assumption, which is proven via the Spearman method, is proposed to improve the efficiency of the system. During the verification process for the study case, two independent control parameters exhibit correlating trends, and one control parameter converges when the number of meshes increases, indicating a lack of trend sensitivity. The design scheme tree and trend curve are subsequently utilized to effectively analyze the flow field characteristics of different schemes. Finally, the control parameter trend analysis method is employed to rank the design scheme tree and verify that the ranking of candidates is not dependent on the number of meshes. This paper investigates and verifies the presented system, method, and assumption and explores the possibility of an established system playing a more critical role in performance design work.