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1L olomorasib plus pembrolizumab +/- chemotherapy in <i>KRAS</i> G12C-mutant NSCLC patients +/- a prior cycle of SOC: Results from LOXO-RAS 20001 and SUNRAY-01.

8570 Background: Real-world data suggests allowing 1 cycle of standard of care (SOC) prior to enrollment into first-line (1L) NSCLC trials of targeted therapies could expand the potential enrollable population by accommodating molecular testing turnaround time and enabling a more representative patient (pt) population. Here, we report results from 1L pts who did or did not receive 1 prior cycle of SOC in LOXO-RAS-20001 and the dose optimization/safety lead-in of SUNRAY-01, which investigated olomorasib, a KRAS G12C inhibitor, with pembrolizumab +/- chemotherapy. Methods: Pts with advanced KRAS G12C-mutant NSCLC, PD-L1 0-100% and ECOG PS 0-1 were eligible to receive olomorasib (50 or 100 mg, orally BID) with either pembrolizumab (doublet) or pembrolizumab + chemotherapy (quad) at their physician’s discretion. One cycle of SOC prior to enrollment was permitted when timely initiation of treatment was clinically indicated, this included pembrolizumab (doublet) and pemetrexed + platinum +/- pembrolizumab, or pembrolizumab alone (quad). ORR was assessed in the efficacy evaluable population, defined as pts with ≥1 post-baseline response assessment or who discontinued treatment before the first response assessment. Safety was assessed across all treated pts. Results: As of 6 June 2025, 85 pts received the doublet and 77 pts received the quad; 13 pts (15%) and 23 pts (30%) received 1 prior cycle of SOC, respectively. Baseline characteristics of pts who did and did not receive 1 prior cycle of SOC were comparable. Accounting for small sample sizes, efficacy and safety were broadly similar across both the doublet and the quad among those who did and did not receive a prior cycle of SOC (Table). Conclusions: Treatment with 1 cycle of SOC prior to enrollment appeared to have no detrimental effect on safety and efficacy outcomes of olomorasib in combination with pembrolizumab +/- chemotherapy in pts with KRAS G12C NSCLC. This is the first analysis of the clinical impact of 1 prior cycle of SOC in a NSCLC clinical trial, allowing early access to treatment if clinically indicated. Implementation of this strategy in SUNRAY-01 and other 1L NSCLC trials may expand enrollment and allow for a more representative pt population. Clinical trial information: NCT04956640 , NCT06119581 . 1L treatment outcomes. Olomorasib + Pembrolizumab Olomorasib + Pembrolizumab + Chemotherapy 1 prior cycle of SOCn=13 No priorSOCn=72 1 prior cycle of SOCn=23 No priorSOCn=54 ORR, (%) (95 %, CI) 76.9(46.2, 95.0) 71.8(59.9, 81.9) 73.9(51.6, 89.8) 55.6(41.4, 69.1) DCR, %(95 %, CI) 100(75.3, 100.0) 88.7(79.0, 95.0) 95.7(78.1, 99.9) 87.0(75.1, 94.6) TRAE All Grade / Grade 3+ (%) 100 / 30.8 87.5 / 41.7 95.7 / 26.1 96.3 / 59.3 Grade ≥3 Hepatic Events* (%) 15.4 22.2 0 22.2 Grade ≥3 Diarrhea (%) 7.7 6.9 4.3 5.6 Grade ≥3 Neutropenia (%) 0 0 4.3 16.7 Discontinuation of regimen 15.4 11.1 0 11.1 Median Duration of Treatment, mo (IQR) 10.3 (5.6-13.3) 7.9 (3.8-9.9) *Consolidated term.

A phase 1 trial of the oncolytic virus SVV-001 with nivolumab and ipilimumab in patients with high-grade neuroendocrine neoplasms.

TPS2700 Background: Poorly differentiated neuroendocrine carcinomas (NECs), including small cell and large cell neuroendocrine tumors, and grade 3 neuroendocrine tumors (NETs) represent a highly aggressive disease collectively classified as high-grade neuroendocrine neoplasms (NENs). These tumors are marked by rapid tumor growth, early dissemination, genomic instability, and poor outcomes. Despite initial sensitivity to chemotherapy and radiotherapy, relapse rates remain high, and immune checkpoint inhibitors (ICIs) have demonstrated limited activity, highlighting a substantial unmet therapeutic need. Seneca Valley Virus (SVV-001) is a novel oncolytic picornavirus that has demonstrated synergistic antitumor activity with ICIs in preclinical models. Additionally, SVV-001 has shown a favorable safety profile and the ability to reverse ICI resistance in vivo, supporting its evaluation in combination with nivolumab + ipilimumab. Methods: This is an investigator-initiated, phase 1, dose-escalation and cohort-expansion study evaluating intratumoral SVV-001 in combination with nivolumab + ipilimumab in patients with histologically confirmed high-grade NENs who have progressed on at least one prior line of standard-of-care therapy. Eligible patients must have at least one lesion suitable to repeated intratumoral injections of SVV-001 (up to 6 injections every two weeks). The trial was activated in March 2025 at Sylvester Comprehensive Cancer Center, with enrollment currently ongoing and a planned accrual of up to 36 patients. Part 1 used a standard 3+3 dose-escalation design. Enrollment in the first three cohorts (Part 1A), evaluating single-dose SVV-001 in combination with nivolumab and ipilimumab, is complete with no dose-limiting toxicities observed. Enrollment into cohort 4 (Part 1B), which will evaluate multiple doses of SVV-001 (up to 6 injections) is planned to begin in February 2026 followed by Cohort 5. Part 2 consists of a cohort-expansion phase in which up to 6 additional patients will be treated at the optimal recommended phase 2 dose (RP2D) of SVV-001. The primary objective is to determine the maximum tolerated dose (MTD) and/or RP2D. Secondary objectives include radiographic progression-free survival (PFS), overall response rate (ORR), duration of response, clinical benefit rate (CBR), and safety. Correlative studies will assess viral kinetics, including viral release and viral load in plasma, as well as Tumor Endothelial Marker 8 (TEM8), a potential biomarker of SVV-001 sensitivity and its association with efficacy signals. Additional exploratory analyses will characterize the tumor immune microenvironment and gut microbiome markers in the dose-expansion cohort. ClinicalTrials.gov Identifier: NCT06889493. Clinical trial information: NCT06889493 .

First-line serplulimab for locally advanced or metastatic squamous non–small cell lung cancer: Updated survival from the ASTRUM-004R trial.

8581 Background: Although the ASTRUM-004 trial has confirmed that serplulimab plus platinum-based therapy improves survival in patients with locally advanced or metastatic squamous non-small cell lung cancer (sqNSCLC), evidence regarding its efficacy and safety in routine clinical practice remains limited. Previous results from the ASTRUM-004R trial have shown that a serplulimab plus platinum-based therapy exhibits promising antitumor activity in sqNSCLC. Here, we report the updated follow-up results from this study. Methods: The ASTRUM-004R trial is a retrospective, real-world study conducted across 14 centers in China. Patients with locally advanced or metastatic sqNSCLC received first-line serplulimab plus platinum-based therapy, followed by serplulimab maintenance treatment until disease progression, intolerable toxicity, or up to 2 years. This update presents the survival outcomes, including progression-free survival (PFS) and overall survival (OS). Additionally, PFS was assessed across various patient subgroups. Results: A total of 132 patients were enrolled in the analysis, with a median follow-up of 18 months as of October 31, 2025. The median patient age was 69 years. Overall, 92.4% (n = 122) were male, 71.2% (n = 94) were aged 65 or older, 19.7% (n = 26) had an ECOG performance status of 2, and 47.0% (n = 62) had stage IV disease. Maintenance therapy was administered to 50.8% (n = 67) of the patients. The median PFS for all patients was 14.8 months (95% CI: 11.9-19.6), with a 6-month PFS rate of 78.5% (95% CI: 71.5%-86.2%). The median PFS benefit was comparable between patients receiving nab-paclitaxel and those receiving paclitaxel (17.5 vs. 15.2 months, P = 0.677), suggesting no significant difference in efficacy between the two groups. Furthermore, a significantly longer median PFS was observed in patients with stage III disease compared to those with stage IV disease (20.4 vs. 11.9 months, P = 0.009). The median OS for all patients was 29.7 months (95% CI: 29.7-NR), with a 12-month OS rate of 90.1% (95% CI: 84.7%-95.9%). The updated findings confirm sustained antitumor activity, as evidenced by an objective response rate of 66.7% (95% CI: 57.9%-74.6%) and a disease control rate of 95.5% (95% CI: 90.4%-98.3%). Adverse events (AEs) of any grade occurred in 48 patients (36.4%), most of whom had hematological disorders. Immune-related AEs (irAEs) were reported in 35 patients (26.5%), including 9 (6.8%) who experienced grade ≥3 irAEs. Conclusions: Updated results from the ASTRUM-004R study show that first-line serplulimab platinum-based therapy provides a significant survival benefit with a manageable safety profile in locally advanced or metastatic sqNSCLC, consistent with findings from the ASTRUM-004 trial. The long-term survival benefit warrants further validation with extended follow-up.

A phase II trial of a FAK inhibitor combined with albumin-bound paclitaxel and an anti–PD-1/CTLA-4 bispecific antibody for metastatic, recurrent, or persistent gastric-type endocervical adenocarcinoma (GIFT Study).

TPS5630 Background: Gastric-type endocervical adenocarcinoma (GAC) is a rare, HPV-independent subtype of cervical cancer with an aggressive clinical course and an exceptionally poor prognosis. Current clinical guidelines offer largely non-specific treatment recommendations, and conventional chemotherapy-based regimens, even when combined with immunotherapy, frequently demonstrate limited efficacy and early resistance in patients with advanced, recurrent, or metastatic disease. Preclinical studies demonstrate that FAK inhibition can remodel the tumor microenvironment and enhance sensitivity to both cytotoxic chemotherapy and immunotherapy. This study aims to evaluate the efficacy and safety of the FAK inhibitor IN10018 in combination with immunotherapy and chemotherapy in patients with GAC. Methods: The GIFT study is a multicenter, open-label, single-arm, prospective phase II trial designed to evaluate the combination of the FAK inhibitor IN10018 with nab-paclitaxel and cadonilimab (a PD-1/CTLA-4 bispecific antibody) in patients with metastatic, recurrent, or persistent gastric-type endocervical adenocarcinoma. A total of 25 eligible patients will receive oral IN10018 (100 mg once daily) in combination with intravenous nab-paclitaxel (260 mg/m²) and cadonilimab (10 mg/kg) on day 1 of each 21-day cycle. Tumor response will be assessed every 6 weeks by imaging according to RECIST v1.1. Patients will receive up to six cycles of combination chemotherapy, followed by maintenance therapy with IN10018 and cadonilimab until disease progression or unacceptable toxicity. The primary endpoint is objective response rate. Secondary endpoints include progression-free survival, disease control rate, and safety. An additional exploratory objective is to longitudinally evaluate alterations in peripheral circulating cell-free DNA and the tumor microenvironment and to examine their association with therapeutic response. The study is currently active and enrolling patients. As of the data cutoff, 14 of the planned 25 patients have been enrolled. The trial is registered at ClinicalTrials.gov (NCT06654011). Clinical trial information: NCT06654011 .

Global economic impact of modifiable risk factors in colorectal cancer: A comprehensive analysis using GBD 2023 across 189 countries.

e15740 Background: Colorectal cancer (CRC) generates major healthcare expenditures worldwide. Leveraging Global Burden of Disease 2023 (GBD 2023) data, we assessed the economic impact of modifiable risk factors for CRC across 189 countries. Methods: Using the GBD 2023 comparative risk assessment framework, we quantified CRC burden attributable to high body-mass index (BMI), tobacco use, alcohol consumption, physical inactivity, and low fruit/vegetable intake. Disability-adjusted life years (DALYs) were estimated based on standard life expectancy tables. Economic burden was calculated per WHO-recommended cost-of-illness methodology, integrating country-specific cost data from national health accounts and published analyses. Incidence and mortality were stratified by World Bank income classifications. Results: In 2023, there were 1,970,000 incident CRC cases and 915,000 CRC deaths globally, resulting in 21,400,000 DALYs. Modifiable risk factors contributed 32.8% (95% UI: 28.4%–37.2%) of total CRC burden, with high BMI accounting for 18.6% of DALYs, physical inactivity 8.4%, tobacco 3.8%, and low fruit/vegetable intake 2.1%. Direct medical costs attributable to these risk factors surpassed $142 billion USD annually, of which low- and middle-income countries incurred 58% despite representing only 42% of global cases. Indirect costs due to lost productivity totaled $89 billion USD. Countries in the highest quartile for risk factor exposure had 2.3 times higher per-capita CRC healthcare spending than those in the lowest quartile. Conclusions: Modifiable risk factors account for over $231 billion USD in annual economic losses from CRC, disproportionately affecting resource-limited settings. Interventions targeting high BMI and physical inactivity could reduce direct costs by 18–22% and prevent approximately 6.8 million DALYs each year.

Reporting of occupational mesothelioma in Brazil (2007-2024): A comparative analysis between clinical registries and official occupational notification.

e23205 Background: Mesothelioma is the primary sentinel cancer for asbestos exposure. Despite its well-known etiology, it remains a significant global public health challenge due to its long latency and frequently unrecognized work association. This study aimed to quantify the surveillance gap in Brazil by comparing official notifications of occupational disease with total mesothelioma diagnoses. Methods: A retrospective, nationwide observational study was conducted, comparing data of occupational mesothelioma notifications in Brazil from 2007 to 2024 (from the Notifiable Diseases Information System database, SINAN) with total mesothelioma diagnoses (from Population-Based Cancer Registries [RCBP, 2007-2020] and Unified Health System Informatics Department [DATASUS, 2021-2024]). The primary objective was to quantify the under-reporting rate of mesothelioma as an occupational disease in Brazil, defined as the ratio between work-related registrations and total clinical diagnoses. Results: From 2007 to 2024, a total of 613 overall mesothelioma diagnoses were identified in Brazil, with no significant variability in frequency over time, except for 2016-2020. During the same period, only 84 cases were officially registered as occupational diseases. Although notifications increased from 6 (2007-2010) to 27 (2021-2024), only 13.7% of all mesothelioma cases were appropriately registered as occupational diseases over 18 years (Table 1). In the latest reported period (2021-2024), only 15.9% of clinical diagnoses were recognized as work-related. The occupational cohort was mostly male (96.4%), black (45.2%), and aged 60-69 years (40.5%), with 42% having a smoking history. The majority had confirmed asbestos exposure (95.2%). Conclusions: A critical disparity was identified between the clinical diagnosis of mesothelioma and its official recognition as an occupational disease in Brazil. As this major underreporting hinders the evaluation of the real impact of asbestos-related cancers, improved awareness of disease association and case reporting are needed to guide public policy development and, thus, provide evidence-based health promotion approaches for at-risk workers. Overall mesothelioma diagnosis versus occupational notification in Brazil (2007-2024). 2007-2010 2011-2015 2016-2020 2021-2024 Total Occupational mesothelioma notification (n) 6 16 35 27 84 Overall mesothelioma diagnosis (n) 166 193 84 170 613 Occupational notification rate (%) 3.6 8.3 41.7 15.9 13.7

Impact of age on breast cancer outcomes in the neoadjuvant I-SPY2 trial.

592 Background: Historically, young women with early-stage breast cancer (EBC) have had worse outcomes than older women. This is based largely on population-based or adjuvant studies, with limited neoadjuvant data. Methods: Patients (pts) with Stage 2-3 EBC treated with neoadjuvant chemotherapy +/- immunotherapy (Cx-IT) on the I-SPY2 trial between 2010-2022 were included (data cutoff 07/2025). Pts were stratified by age at trial screening (&lt;40 vs ≥40 yrs), and clinical/molecular subtypes, including ImPrint, an immune signature predictive of Cx-IT response. Pathologic complete response (pCR), residual cancer burden (RCB), and event-free survival (EFS) were evaluated by age and disease subtypes using Kaplan-Meier methods and Cox proportional hazard ratios (HR). Results: Among 2117 evaluable pts, 510 (24%) were &lt;40 yrs and 1607 (76%) were ≥ 40 yrs. Overall, 43% of tumors were HR+/HER2-, 35% HR-/HER2- (TN), 22% HER2+. 34% / 66% were ImPrint +/- (27% / 73% for HR+; 44% / 56% for HR-), with similar rates of ImPrint+/- between age groups. Rates of pCR (31% vs 35 %) and RCB 0/1 (48% vs 51%) were similar between pts &lt;40 and ≥40. Overall, pts &lt; 40 had worse EFS (p &lt; 0.01) vs pts ≥ 40; however, in pts who achieved pCR, there was no difference in EFS in all biologic subgroups (HR 0.90, p=0.77). In contrast, in pts with residual disease, those &lt;40 had worse EFS than pts ≥40 (HR 0.72, p&lt;0.01). The worse EFS in pts&lt;40 with residual disease was limited to pts with ImPrint- disease, in both HR+/HER2- (HR 0.64, p=0.02) and TN (HR 0.62, p=0.04) subtypes, where response rates were lower. In ImPrint+ pts, no differences in EFS by age were observed (HR 1.01, p=0.98). Similar results were seen for pts with HR+/HER2- disease when stratifying by RCB (RCB 0/I vs 2/3). There was no difference in EFS by age for pts with RCB 0/1 disease in any subtype (HR 0.66, p=0.09). For ImPrint-, pts&lt;40 with RCB 2/3 disease had worse EFS than pts ≥40 (HR 0.61, p=0.01). For HR+/HER2-, 64% of tumors were MammaPrint (MP) High 1 vs 36% MP High 2, and 74% were Luminal. When stratifying by pCR or RCB 0/1, similar age-related EFS differences were observed in HR+/HER2- Luminal or MP High 1 tumors, as in ImPrint- tumors. Conclusions: Overall, young pts &lt;40 yrs with high-risk EBC in the I-SPY2 trial had worse 5-yr EFS than pts ≥40; however, when taking response into account, there were no age-related EFS differences for pts who had an excellent response to neoadjuvant Cx-IT (i.e. pCR or RCB 1). The EFS difference was driven by pts with residual disease, specifically in the subset with ImPrint- disease, which is associated with less response to Cx-IT. Whereas, for pts with ImPrint+ disease, there was no difference in EFS by age, regardless of pCR or RCB. This highlights the unmet need for more effective therapies for immune-negative tumors. Our results reinforce the importance and prognostic value of neoadjuvant therapy, particularly in our youngest pts, to better risk-stratify and optimize treatment based on tumor biology and response to therapy. Clinical trial information: NCT01042379 .

Quantum critical behavior of cuprate superconductors observed by inelastic X-ray scattering

Trends and disparities in cancer mortality among individuals with substance use disorder in the United States, 1999-2020.

e22602 Background: Cancer mortality in the United States has declined over the past two decades, reflecting advances in prevention, early detection, and treatment; however, these gains have not been equitably realized across all populations. Substance use disorder (SUD) often coexists with cancer and may be associated with worse outcomes through delayed engagement with cancer care, treatment interruptions, and coexisting substance-related conditions. National patterns of cancer mortality occurring in the context of SUD have not been studied. We examined national trends and disparities in cancer deaths with co-occurring substance use disorder. Methods: We conducted a retrospective, cross-sectional analysis of the CDC WONDER database from 1999-2020. Cancer was defined as the underlying cause of death, with substance use disorder listed as a contributing cause. Age-adjusted mortality rates (AAMRs) were calculated using the 2000 U.S. standard population and stratified by sex, race and ethnicity, urbanization level, and cancer site. Temporal trends were assessed using joinpoint regression, with results expressed as annual percent change (APC) and average annual percent change (AAPC) with 95% confidence intervals (CIs). Results: From 1999 to 2020, cancer mortality with co-occurring SUD increased significantly from 4.3 to 36.7 per 100,000 (AAPC 11.09%; 95% CI 9.71-12.62; p &lt; 0.000001). Mortality rates were higher among males than females (44.6 vs 23.1 per 100,000; p = 0.00006), with significant increases over time in both groups (male AAPC 11.0% [9.5-12.5]; female 11.0% [10.0-12.8]). Rates were higher in rural compared to urban populations (43.6 vs. 30.1 per 100,000; p = 0.01). By race and ethnicity, the highest AAMRs were observed among non-Hispanic White (35.9), American Indian/Alaska Native (35.5), and non-Hispanic Black individuals (31.0), while Asian (8.4) and Hispanic/Latino populations (11.7) had lower rates (p &lt; 0.0001). All racial and ethnic groups showed significant increases in AAPC over the study period. Conclusions: Despite overall declines in U.S. cancer mortality, deaths occurring in the context of substance use disorder have risen markedly over the past two decades, with pronounced disparities by sex, race and ethnicity, and rural residence. These findings suggest that individuals with co-occurring substance use disorder have not fully benefited from advances in cancer care, likely reflecting delayed engagement, treatment disruptions, and structural barriers. Targeted strategies integrating cancer care with substance use services are needed to reduce these widening mortality gaps.

Integration of individual sEV with single-cell analysis to reveal association of immune cell subsets with chemotherapy response in breast cancer.

e13114 Background: Small extracellular vesicles (sEVs) released by cancer cells directly interact with various immune cell types to mediate immune dysfunction in the tumor microenvironment (TIME). Membrane surface proteins on sEV specifically contact with the immune cells by receptor-receptor or ligand-receptor pairs. Chemotherapy is a crucial treatment of BC, while can be significantly regulated by immune cells. However, the precise impact of sEVs on immune cell activities in subjects who are resistant to chemotherapy remains unclear. Methods: We discovered that sEVs membrane surface proteins exhibit complex and diverse biological activities within breast cancer TIME, especially its interaction with macrophages. By integrating sEV surface protein data with breast cancer single-cell RNA-sequencing (scRNA-seq) and bulk RNA sequencing data, we have identified the crucial ligand-receptor interactions involving integrin ITGB2 and intercellular adhesion molecule ICAM1, which has the potential to significantly influence the activities of macrophages that mediate chemotherapy resistance. Results: Notably, the sEV surface proteins integrin ITGB2, and intercellular adhesion molecule ICAM1 are found to be elevated in sEVs derived from the tumor tissues of TNBC and Luminal A breast cancer patients. ITGB2 and ICAM1 mRNA levels are significantly increased in chemotherapy nonresponsive subjects who also have shorter survival time. More importantly, M0 macrophage is identified to be a risk factor of chemotherapy nonresponse. The expressions of ITGB2 and ICAM1 are correlated with M0 and M2 marker expressions, and the VCAM1-mediated signaling pathway. Based on the characteristics of ICAM1-ITGB2 interaction related genes between BC-derived sEVs and macrophages, we have established the chemotherapy prognosis signature. Moreover, the potential molecules for targeting ICAM1-ITGB2 in chemotherapy resistance have been identified by DGIDB database and molecular autodocking. Conclusions: Identification of crucial sEVs-cells interaction not only enables us to gain a more precise understanding of the pathological mechanism network, but also allows us to develop innovative therapeutic and diagnostic strategies to overcome the BC chemotherapy resistance.

Impact of geographic distance from transplant center on the risk of severe graft-versus-host disease after allogeneic hematopoietic cell transplantation.

e23055 Background: Geographic distance to care has been associated with outcomes in solid tumors, reflecting differences in access, follow-up, and supportive care. However, its relationship with biologic transplant toxicities such as graft-versus-host disease (GVHD) has not been well characterized. Understanding whether access-related factors are associated with immune-mediated complications is important for systems-level optimization of post-transplant care and survivorship. Methods: We conducted a retrospective cohort study of adult patients undergoing allogeneic hematopoietic cell transplantation using the CIBMTR hs1802 publicly available dataset. Distance from patient residence to the transplant center was categorized as less than 20 miles, 20 to 50 miles, 50 to 150 miles, and greater than 150 miles, with less than 20 miles as the reference group. Primary outcomes were acute GVHD and chronic GVHD within one year after transplantation. Secondary outcomes included overall survival. Multivariable Cox proportional hazards models were used to evaluate associations between distance and outcomes, adjusting for age, sex, race and ethnicity, HCT comorbidity index, conditioning intensity, donor type, GVHD prophylaxis, transplant era, disease type, and total body irradiation use. Results: A total of 5,473 patients were included, with a median follow-up of 60.2 months. Crude rates of acute GVHD increased with greater distance from the transplant center, occurring in 40.2 percent of patients living less than 20 miles away and 45.1 percent of those living more than 150 miles away. In adjusted analyses, residence more than 150 miles from the transplant center was associated with a higher risk of acute GVHD compared with less than 20 miles, with an adjusted hazard ratio of 1.15 and a 95 percent confidence interval of 1.00 to 1.31. No significant differences were observed for intermediate distance categories. For chronic GVHD within one year, patients living more than 150 miles away had a lower recorded risk compared with those living less than 20 miles away, with an adjusted hazard ratio of 0.79 and a 95 percent confidence interval of 0.71 to 0.88. Distance to transplant center was not significantly associated with overall survival. Conclusions: Greater geographic distance from transplant centers is associated with a higher risk of severe GVHD after allo-HCT. These findings suggest that access to specialized post-transplant care and close monitoring may influence immune-mediated outcomes. Strategies to improve follow-up care, including enhanced care coordination and telemedicine, may help mitigate GVHD-related disparities and inform health policy efforts aimed at improving access to specialized transplant services, reimbursement for remote monitoring, and regional models of post-transplant care delivery.

LLC cell lines’ response and resistance to KRAS G12C inhibitors.

e20710 Background: KRAS G12C mutations define a therapeutically targetable subset of non–small cell lung cancer (NSCLC); however, acquired resistance to covalent KRAS G12C inhibitors limits the durability of responses. The molecular determinants underlying differential sensitivity and resistance to these agents remain incompletely defined. Methods: KRAS G12C–mutant murine Lewis lung carcinoma (LLC) cell lines were evaluated in vitro, including parental cells and lines derived following prolonged exposure to KRAS G12C inhibition. Cells were treated with increasing concentrations of covalent KRAS G12C inhibitors, and proliferation was monitored over time. MAPK pathway activity was evaluated by immunoblotting for phosphorylated and total ERK1/2 and MEK1/2 following acute drug exposure, with signal intensities quantified and normalized to loading controls. Experiments were performed with biological replicates. Results: In parental KRAS G12C–mutant LLC cells, adagrasib treatment produced a clear, concentration-dependent reduction in proliferation across multiple concentrations, whereas sotorasib produced comparatively limited growth inhibition. LLC lines derived following continuous sotorasib exposure exhibited markedly reduced sensitivity to sotorasib but retained partial sensitivity to adagrasib. Analysis of downstream signaling revealed differential suppression of ERK and MEK phosphorylation between the two inhibitors, with resistant lines maintaining persistent MAPK pathway activity during sotorasib treatment. These signaling and proliferation patterns were consistent across multiple drug concentrations and time points. Conclusions: KRAS G12C–mutant lung cancer models with acquired resistance exhibit sustained MAPK pathway activity despite continued KRAS G12C inhibition, accompanied by distinct differences in growth suppression and downstream signaling between inhibitors. These findings suggest that resistance to KRAS G12C–targeted therapy is not uniform across the drug class and highlight the need to investigate drug-specific resistance mechanisms and strategies to modulate downstream pathway signaling.

Efficient machine learning for pulmonary nodule classification on computed tomography: A lightweight multilayer perceptron approach with global radiologist validation.

e20021 Background: Lung cancer remains the leading cause of cancer mortality worldwide. Pulmonary nodules detected on Computed tomography(CT) are critical for early detection, but interobserver and nodule variability limit interpretation. Deep learning models are computationally intensive, restricting routine use. Lightweight multilayer perceptron (MLP) offer scalable and clinically deployable alternative for pulmonary nodule assessment. Aims:To develop and externally validate a lightweight MLP model for pulmonary nodule classification on CT imaging; to assess whether structured preprocessing preserves diagnostic performance while reducing computational complexity; to evaluate clinical feasibility through independent radiologist assessment across diverse healthcare environments. Methods: We analyzed 8,147 anonymized CT studies comprising normal or benign findings (n = 3,892), indeterminate nodules (n = 2,255), and malignant nodules (n = 2,000) from publicly available datasets (LIDC-IDRI, LUNA16, Lung Nodule Analysis 2016) with consensus radiologist annotation and pathologic correlation when available. Images were standardized and transformed using Gaussian random projection followed by principal component analysis to reduce dimensionality while preserving morphologic features. A two-layer feedforward MLP with batch normalization and dropout was trained using AdamW optimization on 80% of the data, with independent validation and testing cohorts. Performance metrics included accuracy, sensitivity, specificity, F1-score, and AUROC. External validation was conducted on independent datasets. The model was deployed on cross-platform infrastructure and evaluated by radiologists across six continents. Results: The MLP achieved 88.6% accuracy on the independent test set with balanced class-wise performance. Sensitivity for malignant nodules was 89.7% with specificity of 93.6%, yielding an F1-score of 0.915. Macro-averaged F1-score exceeded 0.90, and AUROC values were greater than 0.91 across all classes. External validation accuracy ranged from 86% to 90% across heterogeneous CT protocols. Compared with radiologist interpretation, the model reduced false-negative rates by 38% in the indeterminate nodule category. The model contained 2.7 million parameters and achieved inference times of 0.32 seconds per nodule on standard CPU hardware. Overall, 94.1% of radiologist evaluators rated the system clinically useful for screening triage. Conclusions: A computationally efficient multilayer perceptron accurately classifies pulmonary nodules on CT while reducing model complexity and hardware requirements. Reduction of false negatives, together with external validation by global radiologists, confirms scalability, enabling AI-assisted screening across resource-diverse settings.

<i>ATM</i> mutations in pancreatic cancer: A real-world analysis of molecular landscapes, clinical heterogeneity, and prognostic impact.

e16376 Background: ATM is a core DNA damage repair gene. Its mutations occur in 2%-8% of pancreatic cancers, but the heterogeneity of the mutational spectrum, clinicopathological correlations, and prognostic significance remain poorly defined, especially for germline versus somatic alterations. Methods: We retrospectively analyzed 665 pathologically confirmed pancreatic cancer patients with NGS data. Patients were categorized: ATM-mutant (n=44, including somatic-only [n=35], germline-only [n=4], and co-mutant [n=5]) and ATM-wild-type (n=621). Analyses included: mutational spectrum, clinicopathological correlations, pathway enrichment (KEGG/GO/Reactome), and overall survival (OS). Statistical tests: Fisher's exact, Log-rank, and Cox models. Results: Molecular Features: ATM-mutant tumors showed a distinct co-mutation pattern, with significantly lower TP53 mutation frequency (adjusted p&lt;0.05). Germline-related ATM mutations (n=9) were enriched for CDKN2A/B inactivation (p&lt;0.05), linked to cell cycle pathways. Pathway analysis indicated reduced MAPK/RTK-RAS signaling and enriched mutations in chromatin remodeling (SWI/SNF) genes. Clinical Phenotypes: ATM-mutant patients had: (1) Higher prevalence of personal cancer history (ovarian/breast/colorectal: 16.0% vs. 5.6%, p=0.03); (2) Less local invasiveness (higher T1-2 stage: 56.8% vs. 42.4%, p=0.02). Context-Dependent Prognosis: (1) ATM status was not prognostic in the overall cohort. (2) Among initially unresectable patients, the somatic/germline co-mutant subgroup had the most favorable OS vs. wild-type and somatic-only groups (p=0.044). (3) Stratified analysis identified novel markers: In resectable ATM-mutant patients, CA199&gt;265 U/ml or RUNX1 mutation predicted poor OS (p=0.0053; p=0.0023). In stage III/IV patients, concurrent ARID1A or CDKN2A mutations were associated with shorter OS (p=0.025; p=0.0011). Genomic Stability: No significant difference in TMB among subgroups (p=0.83). Most patients were microsatellite stable. Conclusions: ATM-mutated pancreatic cancer represents a distinct subgroup with unique molecular and clinical features. Its prognostic value is highly context-dependent: somatic/germline co-mutation may be a favorable marker in unresectable disease, while RUNX1, ARID1A, CDKN2A mutations and CA199 levels enable refined risk stratification in other settings. These findings provide a new basis for personalized management of ATM-mutant pancreatic cancer.

CLERAD-PROBE: Dosimetric analysis of I-124 PET–guided remnant radioiodine ablation in differentiated thyroid carcinoma.

3068 Background: The role of adjuvant radioiodine therapy (RIT) in differentiated thyroid carcinoma (DTC) remains controversial due to a lack of long-term data from randomized controlled trials. Consequently, international guidelines diverge; while some advocate broad application, others prioritize a restrictive, risk-adapted approach. The CLERAD-PROBE trial aims to bridge this gap by comparing both strategies regarding blood dose — as an established surrogate for secondary malignancy risk — and oncological outcomes. Methods: CLERAD-PROBE is a prospective, randomized, bicentric study (NCT01704586) in adult DTC patients, excluding those with unifocal papillary microcarcinomas ≤ 10 mm limited to the thyroid. Following thyroidectomy, patients in Arm 1 underwent I-124 PET for staging and dosimetry. Adjuvant RIT was administered if one or multiple of the following risk factors were present: incomplete surgical resection, tumor size &gt;4cm or extrathyroidal extent, lymph node metastases and age ≥ 45 years, distant metastases, and/or iodine-avid lesions on I-124 PET. In Arm 2, adjuvant RIT was generally performed. Follow-up was performed every 4–6 months using thyroglobulin measurements and cervical ultrasound. The primary endpoint was the mean blood dose after complete remission or 18 months. Secondary endpoints included progression- and recurrence-free survival at 3 and 10 years. Results: The primary endpoint was evaluable in 315 patients, enrolled from May 2015 to May 2021 (148 in Arm 1, 167 in Arm 2). Study arms were matched with regards to histology, age, and tumor/nodal stage, though Arm 1 had significantly fewer men (22% vs. 34%, p = 0.02). I-124 PET identified lymph node metastases in 49 patients and distant metastases in 13 patients. RIT was performed in 68 of 148 (46%) patients in Arm 1. Of these, 13 patients with low-risk carcinoma underwent RIT because of new metastases found on I-124 PET. The mean absorbed blood doses (252 mGy vs 447 mGy, range: 4 - 3217 mGy vs. 48 - 2520 mGy; p &lt; 0.001) and administered I-131-activities (2.3 GBq vs. 4.9 GBq; range: 0 – 18.6 GBq vs. 1.0 – 26.2 GBq; p &lt; 0.001) were lower in Arm 1. Conclusions: I-124 PET identifies persistent, iodine-avid disease in patients who would not routinely receive adjuvant RIT pursuant to ATA Guidelines, while enabling individualized selection in the others to minimize secondary malignancy risk. The impact on long term oncological outcomes has yet to be determined. Three years follow-up analyses evaluating recurrence rates and overall oncological safety are currently in progress and will be presented at the congress. Clinical trial information: NCT01704586 .

National trends and in-hospital outcomes of intracoronary imaging during percutaneous coronary intervention in patients with active malignancy: A National Inpatient Sample analysis.

e13700 Background: Intracoronary imaging–guided percutaneous coronary intervention (PCI) improves procedural outcomes in the general population. However, utilization patterns and in-hospital safety of intracoronary imaging in patients with active malignancy (a high-risk population with competing mortality and unique physiologic considerations) are not well defined. Methods: We analyzed the National Inpatient Sample (2016–2021) to identify hospitalizations of adults with active malignancy (ICD-10-CM) undergoing PCI. Temporal trends in intracoronary imaging use (intravascular ultrasound and/or optical coherence tomography) were assessed. The primary outcome was in-hospital mortality. Secondary outcomes included acute kidney injury, major bleeding, blood transfusion, stroke, vascular complications, mechanical ventilation, length of stay, and total hospital charges. Survey-weighted multivariable regression was used to estimate adjusted odds ratios (aORs), adjusting for demographics, clinical presentation, comorbidities, and hospital characteristics. Results: Among 54,300 weighted hospitalizations, intracoronary imaging utilization increased from 6.1% in 2016 to 18.1% in 2021 (r = 0.974; P = .001). Imaging use was not associated with in-hospital mortality (5.4% vs 5.5%; aOR, 0.92; 95% CI, 0.80–1.05; P = .214). There were no significant differences in acute kidney injury (aOR, 1.06; P = .101), major bleeding (aOR, 1.04; P = .412), or stroke (aOR, 1.04; P = .670). However, imaging was associated with higher odds of vascular complications (aOR, 1.82; 95% CI, 1.24–2.65; P = .002), mechanical ventilation (aOR, 1.15; 95% CI, 1.03–1.30; P = .016), and blood transfusion (aOR, 1.44; 95% CI, 1.30–1.58; P &lt; .001). Imaging was also associated with longer length of stay (+0.46 days; P = .019) and higher hospital charges (+$23,324; P &lt; .001). Conclusions: Use of intracoronary imaging during PCI among patients with active malignancy has increased nearly threefold over six years. Imaging was not associated with higher in-hospital mortality or major complications, including acute kidney injury, bleeding, or stroke. Associations with vascular complications and increased resource utilization likely reflect greater case complexity rather than imaging-related harm. These findings support the procedural safety of intracoronary imaging in this high-risk population.

An integrated multidisciplinary analysis of pre-treatment cachexia in locally advanced non–small cell lung cancer.

8040 Background: Cancer-associated cachexia is underdiagnosed and not routinely captured in cancer registries, despite its negative impact on quality of life and survival. We aim to determine the prevalence of cachexia in patients with locally advanced NSCLC and to perform a multidisciplinary characterization of cachexia to inform the development of future therapeutic interventions. Methods: In this prospective study, 51 patients diagnosed with locally advanced unresectable NSCLC candidates to concurrent chemoradiotherapy followed by immunotherapy at the HUB-ICO Comprehensive Cancer Centre (2022-2024) were included. The primary objectives were to (1) determine the frequency of cachexia according to Fearon’s criteria and (2) characterize patients before and after completing chemoradiotherapy in terms of nutritional status, metabolic parameters, body composition and circulating cytokine levels. Baseline assessment results are reported here. Results: Most patients were male (80%) and ever smokers (98%), with a median age of 68 years. All patients completed the planned concurrent chemoradiotherapy regimen, whereas only 43% initiated durvalumab consolidation therapy. At baseline, 27 patients met the diagnostic criteria for cachexia (53%, 95% CI 39-66) and women were more likely to have cachexia than men (80% vs 46%, respectively), although this difference was not statistically significant. Cachexia was significantly associated with more advanced tumor stage (p &lt; 0.001), worse performance status (p = 0.027), lower skeletal muscle index (p = 9e-4) and reduced total adipose tissue index (p = 0.004), elevated C-Reactive Protein blood levels (p = 0.004), moderate to severe malnutrition (p &lt; 0.001), reduced caloric intake (p = 0.007) and decreased physical strength (p = 0.001). Cachectic patients had lower fat intake compared with non-cachectic individuals (p = 0.006), while protein intake was similar in both subgroups. Proteomic profiling using the O-link platform identified significant differences in circulating cytokine levels between cachectic and non-cachectic patients. Cachexia was associated with significantly increased levels of CCL23, IL-6, C1QA, CSF1, motilin and agouti-related protein (AGRP), among others, which showed varying degrees of correlation with caloric intake. By contrast, GDF-15 was significantly associated with weight loss (p = 0.00014) but showed no association with caloric intake or body composition parameters. Conclusions: This prospective study reveals that cancer-associated cachexia is highly prevalent in patients with unresectable locally advanced NSCLC before treatment initiation. Beyond previously described inflammatory mediators, we identified several understudied cytokines, which may contribute to the progression of the cachexia phenotype and represent potential targets for future therapeutic interventions.

Association of immune checkpoint inhibitor administration timing with toxicity and survival in uterine cancer: A real-world analysis.

e17640 Background: Evolving data suggest the time of day (ToD) of immune checkpoint inhibitor (ICI) administration may influence toxicity and efficacy, with potentially greater effects in older adults and women. However, data in specific cancer populations, including uterine cancer (UC), remain limited. We evaluated associations between ToD of ICI administration and toxicity and survival outcomes in patients with UC. Methods: We conducted a retrospective cohort study of patients with UC treated with intravenous ICIs, with first dose administered between January 1, 2020, and November 10, 2025, within a statewide health system. Patients who received at least two ICI infusions were categorized as early (&gt;50% of the first four infusions before 1 PM) or late (≤50% before 1 PM). The primary outcome was steroid-requiring immune-related adverse events (SRirAEs). Secondary outcomes included real-world progression-free survival (rwPFS), real-world overall survival (rwOS), and subgroup analyses based on population demographics. Survival was estimated using Kaplan-Meier methods and compared using log-rank tests. Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (CIs). This study was approved by the IRB of the University of North Carolina. Results: A total of 290 patients were included (186 early, 104 late). Baseline demographics were notable for: 42% endometrioid carcinoma, 90% stage III/IV disease, 97% pembrolizumab use, 52% receipt of ICI with chemotherapy, and 28% dMMR tumors. SRirAEs occurred less frequently in the early compared with the late group (16% vs 33%, p=0.001). No significant differences were observed in rwPFS (14.4 vs 15.6 mos; HR 1.02, 95% CI 0.74-1.41) or rwOS (42 vs 35 mos; HR 1.04, 95% CI 0.70-1.54). No differences in SRirAE rates or efficacy outcomes were observed based on MMR status or concurrent therapy (ICI monotherapy, chemotherapy, or lenvatinib). To further evaluate the increased SRirAE rate noted with later ICI administration, we completed a subgroup analysis of patients who received their first four infusions all before or all after 1 PM (n=132; 108 early, 24 late). Using this criterion, similar SRirAE rates were observed between groups (18% early vs 21% late, p=0.71), with no significant differences in rwPFS (26.7 vs 15.7 mos; HR 0.70, 95% CI 0.38-1.28) or rwOS (not reached vs 35.0 mos; HR 0.62, 95% CI 0.29-1.30). Conclusions: In patients with UC treated with ICIs, receipt of &gt;50% of the first four infusions before 1 PM was associated with lower rates of SRirAEs, but this association varied depending on the time cutoff and number of infusions given around that cutoff. A specific time cutoff that may be predictive of ICI efficacy and toxicity remains unclear. These findings emphasize the need to evaluate toxicity in addition to efficacy in future prospective studies to optimize timing of ICI therapy.

Physical activity and glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) plasma levels in different age cohorts

Physical activity (PA) has numerous positive health effects, including improvements in cognitive function. PA stimulates the release of glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) from the liver, resulting in hippocampal neurogenesis in mice and improved cognition. Interestingly, PA also increases plasma GPLD1 in healthy humans, suggesting a role in cognition, but regulatory factors modulating its concentrations remain unclear. We investigated whether different PA modes, diseases (obesity, hypertension, and diabetes), and age affect plasma GPLD1 levels using three different study cohorts. Plasma GPLD1 levels were analyzed in three studies cohorts comprised of 1) young adults (25 yrs) performing moderate exercise, 2) elderly (68.9 yrs) and 3) of prediabetic subjects (59.4 yrs) performing different habitual PA. We found that prediabetic subjects had higher plasma GPLD1 levels than elderly and young adults. Elderly with diabetes showed significantly higher GPLD1 levels than non-diabetic subjects. In elderly, plasma GPLD1 correlated negatively with average steps, but there was no association after taking their diabetes status into account. GPLD1 exhibited a positive correlation with age in elderly with normal glucose tolerance, and with BMI in subjects with impaired glucose tolerance. Average step numbers negatively correlated with BMI and diastolic BP in the elderly, and BMI in prediabetic subjects. BMI was positively correlated with both diastolic and systolic BP in elderly subjects, and with diastolic BP in young adults. In conclusion age and diabetes affect plasma GPLD1 levels in humans. Age is one of the determining factors, as moderate exercise in young adults did not change plasma GPLD1 levels. Habitual physical activity did not alter plasma GPLD1 levels in individuals with prediabetes or diabetes. The release of GPLD1 into the blood and its mechanistic influences on cognitive functions would need further investigation in humans.

Graphene nanomechanical sensing of trap-assisted charge dynamics in leaky silicon oxide

Nanomechanical resonators can detect electronic degrees of freedom through their sensitivity to small electrical forces. Here, we use few-layer graphene membranes as nanomechanical probes to investigate the slow dynamics of injected charge carriers in a trap-rich, leaky dielectric substrate. The dielectric consists of thermally grown SiO2 containing charge trapping centers introduced by the milling of cavities with a Ga+ focused ion beam. When suspended over these cavities, the resonators exhibit anomalous electromechanical behavior: their vibrational resonant frequencies are hysteretic when sweeping a dc gate voltage, and voltage steps result in an initial sharp increase in both frequency and static displacement, followed by a gradual relaxation toward steady values. We attribute this behavior to trap-assisted transport, in which injected charges undergo trapping and detrapping and gradually leak through the oxide, leading to a time-dependent evolution of the effective electrostatic force. Finally, we show that long-lived trapped charges give rise to a built-in potential that enables detection of the driven mechanical response even in the absence of an applied gate voltage, indicating opportunities for nanomechanical sensing of environmental charge dynamics.