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Multi-organ immune-related adverse events following immune checkpoint inhibitor therapy in patients with metabolic dysfunction–associated steatotic liver disease.

e24203 Background: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs). Metabolic dysfunction–associated steatotic liver disease (MASLD) is a highly prevalent metabolic condition. As more patients with MASLD become candidates for ICI treatment, it is important to understand whether MASLD influences the development of irAEs. Methods: We conducted a retrospective cohort study using the TriNetX Research Network. Adults with cancer treated with ICI, including PD-1, PD-L1, or CTLA-4 inhibitors, between 2011 and 2026 were included. MASLD was defined by using diagnostic codes, with exclusion of other chronic liver diseases. Patients treated with ICIs were stratified into MASLD and non-MASLD cohorts and matched 1:1 using propensity score matching. Index date was the day of ICI initiation and patients were followed up in 1 year. Outcomes included organ-specific immune-related adverse events (irAEs). Multivariable analyses were performed to identify ICI regimens associated with a higher risk of irAEs among patients with MASLD. Analyses were conducted using Cox proportional hazards models, hazard ratios with 95% confidence intervals. Results: 11,097 patients with MASLD treated with ICIs were matched to patients without MASLD. MASLD was associated with higher risks of multiple irAEs, including endocrine (HR 1.17; 95% CI, 1.12–1.22; p < 0.001), musculoskeletal (HR, 1.16; 95% CI, 1.11–1.22; p < 0.001), hepatic (HR, 1.43; 95% CI, 1.34–1.52; p < 0.001), gastrointestinal (HR, 1.20; 95% CI, 1.15–1.26; p < 0.001), neurologic (HR, 1.10; 95% CI, 1.06–1.16; p < 0.001), and cutaneous irAEs (HR, 1.15; 95% CI, 1.10–1.20; p < 0.001). In contrast, MASLD was not associated with significantly different risks of renal (HR, 1.03; 95% CI, 0.97–1.09; p = 0.346), ocular (HR, 1.11; 95% CI, 0.99–1.25; p = 0.086), cardiac (HR, 1.02; 95% CI, 0.93–1.12; p = 0.716), respiratory (HR, 1.00; 95% CI, 0.94–1.06; p = 0.894), hematologic (HR, 1.03; 95% CI, 0.98–1.08; p = 0.224), or rheumatologic irAEs (HR, 1.10; 95% CI, 0.97–1.24; p = 0.150) compared with non-MASLD patients. In multivariable analyses, ipilimumab use was associated with a higher risk of hepatic irAEs (HR, 1.47; 95% CI, 1.03–2.11; p = 0.036). For endocrine irAEs, nivolumab (HR, 1.18; 95% CI, 1.02–1.36; p = 0.022) and pembrolizumab (HR, 1.11; 95% CI, 1.02–1.21; p = 0.014) were independently associated with increased risk. For cutaneous irAEs, ipilimumab (HR, 1.34; 95% CI, 1.03–1.75; p = 0.031) and cemiplimab (HR, 1.95; 95% CI, 1.21–3.14; p = 0.006) were independently associated with higher risk. Conclusions: MASLD is independently associated with an increased risk of multi-organ immune-related adverse events in patients receiving immune checkpoint inhibitors, supporting its role as a clinically important modifier of immunotherapy-related toxicity.

Targetable genomic alterations in early-onset colorectal cancer and their therapeutic implications: Real-world data.

e15542 Background: Colorectal cancer (CRC) diagnosed before the age of 50, referred to early-onset colorectal cancer (EOCRC), is increasing in incidence worldwide. The majority of cases are sporadic, with hereditary cancer syndromes accounting for only a small proportion. The clinical behavior and molecular characteristics of EOCRC remain incompletely characterized. This study aimed to compare the clinical and genomic features of EOCRC and late-onset colorectal cancer (LOCRC). Methods: Patients with CRC were identified from the GENIE Biopharma Collaborative (BPC) CRC v2.0 public dataset and the GENIE Cohort v18.0 public dataset, and were stratified into EOCRC and LOCRC groups based on age at the time of sequencing. Clinical and molecular characteristics were systematically analyzed. The prevalence of potentially targetable genomic alterations with FDA-approved or investigational therapies was evaluated using OncoKB, and levels of clinical actionability were assigned according to the OncoKB Therapeutic Level of Evidence (Version 2). Results: Among 21,853 patients with CRC, comprising 23,078 tumour samples, 5,879 (26.9%) were classified as EOCRC, and 14,490 (66.3%) as LOCRC. The median age at sequencing was 44 years (range, 17–50) in the EOCRC group and 64 years (range, 51–88) in the LOCRC group. Male predominance was more pronounced in the LOCRC cohort compared with the EOCRC cohort (53.8% vs. 50.5%, respectively; p < 0.001). Genomic profiling demonstrated that BRAF V600E, KRAS G12V, and CDK12 truncating alterations were significantly more prevalent in LOCRC tumors ( BRAF V600E: 8.66% vs. 3.42%, p < 0.0001; KRAS G12V: 8.60% vs. 7.39%, p = 0.0042; CDK12 truncations: 1.58% vs. 1.02%, p = 0.0079). In contrast, KRAS G12D, FBXW7 , NF1 , and POLE oncogenic mutations were enriched in EOCRC ( KRAS G12D: 13.48% vs. 11.26%, p < 0.0001; FBXW7 : 11.13% vs. 9.94%, p = 0.0121; NF1 : 2.64% vs. 2.12%, p = 0.0419; POLE : 1.16% vs. 0.39%, p = 0.0001). No significant differences were observed between groups for KRAS G12C, G12A, or G12S variants, nor for alterations in ARID1A , PIK3CA , PTEN , or POLD1 D402N. Conclusions: The distinct genomic profile of EOCRC, including increased prevalence of KRAS G12D and FBXW7 alterations, underscores potential biological differences from late-onset disease. Incorporating these insights into molecular testing strategies may enhance patient stratification and inform targeted therapeutic development. Alteration ≤50 >50 P-value Evidence level Therapy BRAF-V600E 201 (3.42%) 1254 (8.66%) <0.0001 1 Encorafenib + Cetuximab POLE 54 (1.16%) 43 (0.39%) 0.0001 2 Immunotherapy KRAS-G12D 792 (13.48%) 1631 (11.26%) <0.0001 3 ASP3082; MRTX-1133 KRAS-G12V 434 (7.39%) 1246 (8.60%) 0.0042 3 Daraxonrasib NF1 130 (2.64%) 238 (2.12%) 0.0419 3 Cobimetinib; Trametinib CDK12 47 (1.02%) 166 (1.58%) 0.0079 3 Immunotherapy FBXW7 648 (11.13%) 1420 (9.94%) 0.0121 4 Lunresertib + Camonsertib

Survival outcomes of PD1/PDL1 inhibitor-based regimens in unresectable stage IIIB, IIIC, and IV non-small cell lung cancer.

e20569 Background: The five-year survival for patients with unresectable Stage IIIB and IIIC non–small cell lung cancer (NSCLC) ranges from 12% to 26%, decreasing to 16% in Stage IV. The introduction of PD-1/PD-L1 inhibitors has changed the therapeutic approach for advanced NSCLC. We aimed to evaluate the survival outcomes of PD-1/PD-L1 inhibitor-based regimens in unresectable Stage IIIB, IIIC, and IV NSCLC. Methods: We conducted a retrospective analysis of adults with unresectable NSCLC treated with PD1/PDL1 inhibitors at a community-based Southern U.S. Health System from 2018 to 2024. Patients were categorized into PD1/PDL1 inhibitor Monotherapy (Group A), Dual-Modality with a PD1/PDL1 inhibitor plus chemotherapy (Group B), and Intensified Multi-agent Therapy (Group C), which included patients who received more than one agent: PD1/PDL1 inhibitors, anti-VEGF, or CTLA4 inhibitor with or without chemotherapy (Group C). A log-logistic survival model adjusted for sociodemographic and comorbidities was used to estimate the adjusted event time ratio (aETR). Results: A total of 133 patients met the inclusion criteria and were categorized into three treatment groups: A (21%), B (64.7%), and C (14.3%). The median age across the three groups was 72 years, 67 years, and 64 years, respectively. The most common PD1/PDL1 inhibitor was pembrolizumab in Groups A (67.9%) and B (67.4%). In Group C, 68.4% received more than one PD1/PDL1 inhibitor, and durvalumab was the most common agent (47.4%). PDL1 expression of more than 50% was seen in 69.2%, 29%, and 11.8% of Groups A, B, and C, respectively. The median survival was 16.2, 10.3, and 24.7 months. Mortality peaked earliest in Group B and latest in Group C during the duration of therapy. The survival model showed no significant difference in the expected survival between Groups A and B (aETR=1.66, 95% CI 0.92–2.99, P>0.05), Groups B and C (aETR=0.53, 95% CI 0.28–0.99, P=0.1), and Groups A and C (aETR=0.88, 95% CI 0.4–1.91, P>0.05). In patients with metastatic disease, the median survival was 16.2, 11.0, and 29.1 months. Mortality peaked earliest in Group B and latest in Group C. The survival model showed no significant difference in the expected survival between Groups A and B (aETR=1.54, 95% CI 0.89-2.66, P>0.05) and Groups A and C (aETR=0.71, 95% CI 0.34-1.51, P>0.05). Group B had a 53.6% lower expected survival (aETR=0.46, 95% CI 0.25-0.87, P=0.047) compared to Group C. Conclusions: Patients with unresectable Stage IIIB, IIIC, and IV non–small cell lung cancer treated with PD1/PDL1 inhibitor monotherapy and multi-agent therapy had longer survival compared to those receiving dual treatment. In patients with metastatic disease, multi-agent therapy had the longest survival of all three regimens. These findings support the benefit of PD1/PDL1 inhibitors. Prospective studies are needed to study its use as direct therapy and as neoadjuvant treatment.

cfDNA sequencing as a cutting-edge technology to identify pathogenic germline variants from 8353 patients with advanced tumors at the Gustave Roussy Institute.

3061 Background: Large cfDNA panels used for somatic profiling can incidentally reveal pathogenic variants of potential germline origin, with implications for patient management and hereditary cancer risk assessment. Methods: Between December 18 th , 2020 and July 22 nd , 2025, a weekly molecular tumor board reviewed cfDNA sequencing data from 8353 patients with advanced solid tumors treated at Gustave Roussy using the FoundationOne Liquid CDx panel, within the prospective STING trial (NCT04932525). We evaluated the yield, clinical relevance, and confirmatory outcomes of an MTB-governed workflow to flag putative germline pathogenic variants (PGPVs) from routine cfDNA profiling in advanced cancers. Across the 324 covered genes, we selected a list of 31 known hereditary cancer genes and 7 emerging candidates. Patients without prior germline confirmation were referred for genetic counseling and confirmatory testing on an independent sample. Turnaround times were compared with the conventional germline pathway. Results: Among 8,353 patients (mean age 62 years), 445 (5.3%) carried 471 PGPVs, including 23 patients with more than 2 variants. The most frequently implicated genes were BRCA2 (n=101), MUTYH (n=81) and BRCA1 (n=62). Overall, 54.6% of PGPVs were incidental findings (257/471); among incidental findings, 51.0% were clinically actionable (131/257), corresponding to 27.8% of all PGPVs (131/471). Germline status was confirmed in 172 patients (86 known prior to cfDNA profiling and 86 confirmed following cfDNA-guided referrals, including 60 incidental findings of which 52 were actionable; 14 variants (11 patients) were not confirmed and 6 were pending. For variants first flagged through cfDNA, the mean interval from liquid biopsy prescription to confirmatory germline report was 2 months, compared with 6 months through the conventional pathway. In evaluable paired cases, cfDNA showed high diagnostic performance for identifying germline findings (sensitivity 98.3%, specificity 97.4%). Conclusions: In an advanced pan-cancer real-world cohort, an MTB-governed cfDNA workflow identified PGPVs in 5% of patients, with over half representing incidental findings and 28% of all PGPVs being actionable. cfDNA profiling can accelerate referral and confirmation of hereditary cancer risk when coupled with expert interpretation and confirmatory germline testing, while acknowledging limitations for certain alterations.

Chemo-immunotherapy as a reshaper of immunosuppressive activity and gene expression of circulating monocytes in advanced non–small cell lung cancer.

e14538 Background: Circulating monocytes (CM) may acquire immunosuppressive activity (IA) and contribute to resistance to immune checkpoint inhibitors (ICIs), while the ICIs impact on CM function is not fully clarified. We previously reported that ICIs can downregulate cellular FLICE-inhibitory protein (c-FLIP), a mediator of CM IA, in non-progressing non–small cell lung cancer (NSCLC) patients (pts). Methods: Pts with advanced NSCLC treated with first-line ICIs, alone (I) or with chemotherapy (CI), were prospectively enrolled at the University of Verona. Blood samples were collected at baseline (T0) and after 3 months (T1). Pts were classified as responders (R; PFS ≥6 months) or non-responders (NR; PFS < 6 months). CM were isolated and co-cultured with anti-CD3/CD28–activated healthy donor PBMCs to assess IA by flow cytometry. Group comparisons used unpaired t tests (p < 0.05). c-FLIP interactome was analysed by liquid chromatography–mass spectrometry in nuclear and cytoplasmic fractions of FLIP-overexpressing monocytes. RNA-seq libraries were performed with TruSeq RNA Prep Kit v2 and sequenced with NovaSeq 6000. Results: From 2021 to 2025, 80 pts were enrolled: 57 evaluable for CD3⁺ T-cell proliferation at T0, 40 receiving CI (70.2 %) and 17 receiving I (29.8%). Between CI-treated pts, 21 (52.5%) were classified as R and 19 (47.5%) as NR. CM from R pts showed higher IA than NR (p = 0.03). At T1, considering specifically pts receiving CI, CM from R pts showed reduced IA after treatment (p = 0.04), whereas IA increased in NR (p = 0.03). Based on RNA-seq analysis, transcriptional profile of CM from R is affected by CI (T1 vs T0, fdr (padj) < 0.1; up-regulated genes: 587, down-regulated genes: 476). Gene-set enrichment analysis revealed a strong modulation of lipid metabolism (MLXIPL, SPHK1, NR1D1) and biological processes related to cell-differentiation (FOSL2, NR4A1, MAFB). Analysis of nuclear and cytoplasmic c-FLIP interactome identified lactate dehydrogenase A (LDH-A) as a c-FLIP–interacting protein in both compartments. According to TCGA analysis, high LDH-A expression in the tumor microenvironment was associated with worse survival in lung adenocarcinoma (p < 0.0001). Accordingly, in our cohort of CI-treated patients, R had significantly lower baseline LDH levels than NR (p = 0.0071). Conclusions: CI reshapes circulating monocytes in NSCLC, reducing IA and modifying transcriptional profiles associated with CM differentiation in responders. Moreover, LDH levels could serve as an immunologically plausible and easy-to-use tool to select pts. Clinical trial information: 1839CESC.

First-in-human phase 1 dose escalation and expansion study of PIN-5018, a CK1α-selective molecular glue degrader, in patients with advanced solid tumors.

TPS3168 Background: Casein kinase 1 alpha (CK1α) is a serine/threonine kinase involved in multiple oncogenic signaling pathways regulating cell proliferation, differentiation, and survival. Dysregulation of CK1α has been implicated across several solid tumor types, supporting its evaluation as a therapeutic target. PIN-5018 is an orally administered, CK1α-selective molecular glue degrader designed to induce targeted proteasomal degradation of CK1α via cereblon-mediated ubiquitination. Previously presented preclinical studies have demonstrated selective CK1α degradation and antitumor activity in multiple solid tumor models, providing the scientific rationale for first-in-human clinical evaluation. In addition to safety and dose optimization, the study incorporates tumor- and blood-based correlative analyses to characterize CK1α degradation and downstream pathway modulation. Methods: PIN-5018-001 is an ongoing, first-in-human, open-label, multicenter phase 1 study evaluating PIN-5018 in patients with progressive, locally advanced (unresectable), or metastatic solid tumors who have exhausted standard treatment options. The study consists of a dose escalation phase followed by dose expansion at selected dose levels based on safety, pharmacokinetics, and preliminary antitumor activity. PIN-5018 is administered orally once daily in 21-day cycles (14 days on treatment followed by 7 days off). Dose escalation evaluates six planned dose levels (10–100 mg) using a Bayesian Optimal Interval (BOIN) design with a target dose-limiting toxicity rate of 25%. Dose-limiting toxicities are assessed during Cycle 1. Up to 36 patients may be enrolled in dose escalation, with plan to add dose optimization and dose expansion cohorts. Eligible patients are adults (≥18 years) with ECOG performance status 0–1 and at least one measurable lesion per RECIST v1.1. Mandatory pre-treatment and on-treatment tumor biopsies are required when medically feasible to support correlative biomarker analyses. Enrollment has begun. Cohort 1 has been completed without DLT, and enrollment to subsequent cohorts is ongoing. Clinical trial information: KCT0011322.

Trends and disparities in hypertension mortality among patients with lung cancer: A retrospective CDC-WONDER analysis (1999-2020).

e20159 Background: Lung cancer (LC) is the leading cause of cancer deaths in the U.S., with older adults disproportionately affected. Hypertension (HTN) is highly prevalent in this population and may worsen outcomes. National trends in LC mortality among adults with HTN remain poorly described. This study used CDC WONDER data to evaluate temporal trends, demographic disparities, and geographic variation in LC-related mortality among adults ≥55 years with HTN from 1999–2020. Methods: Death certificate data from CDC WONDER database were analyzed for adults ≥55 years with LC as the underlying cause and HTN as a contributing cause (ICD-10: C34.0–C34.9; I10–I15). Age-adjusted mortality rates (AAMRs) per 100,000 were calculated using the 2000 U.S. standard population. Joinpoint regression estimated annual percent change (APC) with 95% confidence intervals. Analyses were stratified by age, sex, race/ethnicity, Hispanic origin, urbanization, and state. Results: Between 1999 and 2020, 217,037 deaths occurred among U.S. adults aged ≥55 years with LC and HTN listed as underlying or contributing causes. Overall age-adjusted mortality rates (AAMRs) increased from 7.6 (95% CI: 7.4–7.8) per 100,000 in 1999 to 16.5 (95% CI: 16.3–16.8) in 2020. Mortality rose significantly from 1999–2001 (APC 18.03%, 95% CI: 8.64–27.34; p < 0.001), declined modestly between 2007–2018 (APC −0.63%, 95% CI: −2.92 to −0.14; p = 0.02), and increased again from 2018–2020 (APC 8.65%, 95% CI: 2.62–11.76; p < 0.001). Across age strata, all groups demonstrated early increases followed by mid-period declines and significant pandemic-associated peaks (p < 0.01), with the highest AAMRs observed in adults aged ≥85 years. Men consistently had higher AAMRs than women (17.0 vs 11.0 per 100,000; p < 0.001), though both sexes showed significant increases after 2018 (p < 0.001). Racial disparities were evident, with the highest AAMRs among Non-Hispanic (NH) Black/African American adults (20.27 per 100,000), followed by Hispanic Latino (14.03) and NH White populations (13.07). Non-metropolitan areas exhibited higher AAMRs than metropolitan areas (16.17 vs 13.16 per 100,000). States with age-adjusted mortality rates at or above the 90th percentile (≥19.2 per 100,000) included Oklahoma (27.0), Mississippi (26.2), West Virginia (21.6), Ohio (21.2), Nebraska (19.3) and Kentucky (19.2). Conclusions: LC mortality among adults with HTN rose substantially from 1999–2020, disproportionately affecting older adults, males, NH Black/African Americans, and rural populations. These findings highlight the need for targeted interventions, including risk factor management, early screening, and improved access to care in high-risk groups.

Spatial distribution and functional heterogeneity of CD56bright and CD56dim natural killer cells and the effects on the immune microenvironment in ovarian cancer.

5593 Background: Natural killer (NK) cells are key components of antitumor immunity, yet their functional heterogeneity and spatial distribution within the tumor microenvironment (TME) remain incompletely understood in ovarian cancer. CD56bright and CD56dim NK cell subsets exhibit distinct immunologic functions, but their relative infiltration patterns and associations with other immune cell populations have not been systematically characterized. Methods: A total of 157 ovarian cancer specimens were analyzed using multiplex immunofluorescence staining. NK cells were classified as CD56bright and CD56dim subsets, and their densities were quantified separately in tumor parenchyma and stroma. The associations between NK cell infiltration patterns and the densities of multiple immune cell populations. Results: Overall, ovarian cancer exhibited a CD56dim NK cell–dominant infiltration pattern. In tumor parenchyma, the mean density of CD56bright NK cells was 149 cells/mm², whereas CD56dim NK cells reached 406 cells/mm². In tumor stroma, CD56bright and CD56dim NK cell densities were 108 cells/mm² and 277 cells/mm², respectively. Patients with higher overall NK cell infiltration showed significantly increased densities of multiple immune cell populations in both tumor parenchyma and stroma, including CD8⁺ T cells (P=0.0091, 0.0167), M1 macrophages (P=0.0002, 0.0001), M2 macrophages (P=0.0011, 0.0008), PD-L1⁺ macrophages (P=0.0164, 0.0006), CD20⁺ B cells (P=0.0001, 0.0193), CD4⁺ T cells (P=0.0001, 0.0001), and CD4⁺FOXP3⁺ regulatory T cells (P=0.0001, 0.0001). When comparing NK cell subset dominance, patients with lower CD56dim than CD56bright NK cell infiltration in tumor parenchyma exhibited significantly higher M1 macrophage density (342 vs 180 cells/mm², P=0.0344) and lower stromal M2 macrophage infiltration (P=0.0356). In tumor stroma, lower CD56dim-dominant cases showed significantly increased infiltration of M1 macrophages (435 vs 242 cells/mm², P=0.0336), M2 macrophages (171 vs 48 cells/mm², P=0.0053), CD8⁺PD-1⁺ T cells (34 vs 10 cells/mm², P=0.0299), CD4⁺ T cells (140 vs 25 cells/mm², P=0.0119), and CD4⁺FOXP3⁺ T cells (73 vs 4 cells/mm², P=0.0016). Conclusions: Ovarian cancer is characterized by predominant infiltration of CD56dim NK cells; however, the balance between CD56bright and CD56dim NK cell subsets is closely associated with distinct immune microenvironment patterns. These findings highlight the functional heterogeneity of NK cell subsets and provide a potential mechanistic explanation for the variable prognostic and therapeutic relevance of NK cells across tumor types and immunotherapy contexts. Spatially resolved profiling of NK cell subsets may offer valuable insights for immunotherapy stratification in ovarian cancer.

Proteogenomic profiling of gallbladder cancer for identification of distinct biology and subtype-specific therapeutic vulnerabilities.

e16263 Background: Gallbladder cancer (GBC) is an aggressive malignancy accounting for 80-95% of biliary tract cancers, with a 5-year survival rate of less than 10%. Limited molecular characterization and therapeutic options highlight the need for comprehensive multi-omics analysis to uncover subtype-specific vulnerabilities. Methods: Integrated proteogenomic profiling (whole-exome sequencing, genomics, RNA sequencing, label-free proteomics, phosphoproteomics, and lactylomics) was performed on 53 pairs of treatment-naïve primary GBC tumors and matched adjacent normal tissues. Somatic mutations, copy number alterations (CNAs), and post-translational modifications were analyzed. Molecular subtyping was conducted via unsupervised non-negative matrix factorization (NMF) of multi-omics data. Functional validation included in vitro experiments (CCK8, Western blot, comet assay, immunofluorescence) to assess the role of PARP1 lactylation in proliferation and chemoresistance. Results: A total of 10,201 nonsynonymous mutations were identified, with TP53 (62%) and TTN (29%) as the most frequently mutated genes. CNA analysis revealed high-prevalence 17q12 amplifications (19.2% of cases) and 18q21.2 deletions (40% of cases). Three distinct multi-omics subtypes (NMF1, NMF2, NMF3) were defined: NMF1 (metabolic signature, enriched 17q12 amplification/ERBB2/ERBB3 overexpression), NMF2 (EMT/stromal expansion, immune-suppressive microenvironment with TGF-β pathway activation), and NMF3 (high proliferation, DNA repair/G2M checkpoint activation, elevated Ki67 IHC score and multi-gene proliferation scores). Global hyperlactylation was a hallmark of GBC tumors, with PARP1 K654 lactylation (K654la) significantly upregulated in NMF3 (log2 fold-change = 1.8, p = 2.3e-06). Functional experiments confirmed that PARP1 K654la enhanced ADP-ribosylation activity (1.5-fold higher than wild-type, p < 0.01), promoted cell proliferation (K654T mutant vs. WT: relative proliferation = 1.32 at 72h, p < 0.05), and conferred resistance to cisplatin (IC50 = 3.2 μM vs. 1.8 μM in K654R mutant, p < 0.01) and olaparib. Additionally, 18q21.2 deletion was associated with immune exclusion (reduced CD4+/CD8+ T cells and NK cells) via HNF4G upregulation. Conclusions: This comprehensive proteogenomic study delineates novel molecular subtypes of GBC and identifies PARP1 K654 lactylation as a key mediator of proliferation and chemoresistance in the high-proliferation subtype. The findings provide a foundational resource for developing personalized treatment strategies, including targeting ERBB2 for NMF1, TGF-β/immune checkpoint combinations for NMF2, and PARP1 K654 lactylation or CDK inhibitors for NMF3.

Colorectal cancer with hypertension among middle aged and older adults in United States, 1999-2023.

e15683 Background: Colorectal cancer (CRC) is a major cause of cancer-related morbidity and mortality globally. Hypertension is a common chronic condition that may contribute to cancer development through mechanisms such as chronic inflammation, metabolic changes, and vascular dysfunction. Investigating this association is important for identifying high-risk groups and improving prevention and management strategies. Methods: We analyzed CDC WONDER data (1999–2023) for adults aged ≥45 years with colorectal cancer (ICD-10: C18–C20) and hypertension (ICD-10: I10–I15). Age-adjusted mortality rates per 100,000 population were calculated and stratified by sex, race/ethnicity, and geographic region. Temporal trends were assessed using Joinpoint regression to estimate the average annual percent change. Results: From 1999 to 2023, a total of 141,347 deaths were reported among hypertensive patients with colorectal cancer, with most occurring at the decedent's home. The overall AAMR increased from 2.8 in 1999 to 5.65 in 2023 (AAPC: 2.78; 95% CI: 1.45–4.14), with the most significant rise observed between 1999 and 2001 (APC: 22.96; 95% CI: 7.29–40.92), followed by a notable decline through 2017 (APC: -2.04; 95% CI: -3.03 to -1.05), before rising again significantly by 2023 (APC: 6.15; 95% CI: 4.43–7.91). Adults aged 65–85 years and older experienced the greatest annual increase (2.04%). Men consistently showed higher annual increases in mortality compared with women (3.15 vs. 2.00). The highest AAMRs were observed among non-Hispanic Blacks, while the lowest were noted among non-Hispanic Asians. Geographically, the Midwest experienced the greatest increase, while the Northeast showed the smallest rise. Metropolitan areas showed a steeper increase than non-metropolitan areas (AAPC: 2.26 vs. 1.74). Mississippi and Oklahoma ranked highest, falling within the top 90th percentile. Conclusions: Colorectal cancer in patients with hypertension is highest among men, older adults, NH Black individuals, and people living in the Midwest, showing differences in risk and health outcomes. These results emphasize the need for targeted prevention, early detection, and better management to improve care and reduce disparities in these high-risk groups. Deaths and Age-adjusted Mortality Rates (AAMRs) per 100,000 for trends related toColorectal cancer in Hypertensive patients from 1999 to 2023. Variable Deaths AAMR (95%CI) 1999 AAMR (95% CI)2023 Overall 141,347 2.8(2.69 to 2.9) 5.65(5.53 to 5.77) Male 68,760 2.94(2.76 to 3.12) 7.04 (6.83 to 7.25) Female 72,587 2.7(2.56 to 2.83) 4.52(4.38 to 4.67) NH Blacks 21,185 5.94 (5.39 to 6.48) 8.6(8.11 to 9.08) NH Asians 3,832 2.01 (1.39 to 2.83) 3.41(3 to 3.82) Midwest 33,515 3.3 (3.06 to 3.53) 5.02 (4.77 to 5.28) Northeast 25,498 2.97 (2.73 to 3.21) 4.25 (4 to 4.49) Metro 91,987 2.79 (2.67 to 2.91) (2020) 4.76 (4.63 to 4.81) Non- metro 24,860 2.86 ( 2.62 to 3.11) 6.64 (6.31 to 6.96)

Plasma-TMB (pTMB) and circulating tumor fraction (ctF) dynamics as biomarkers of benefit from the addition of atezolizumab to first-line FOLFOXIRI/bevacizumab in metastatic colorectal cancer (mCRC): A translational analysis of the AtezoTRIBE study.

2575 Background: TMB-high pMMR mCRC patients (pts) do not seem to derive benefit from immune checkpoint inhibitors (ICIs). In the CO.26 trial, pMMR/MSS mCRC pts with high baseline pTMB had better outcome with ICIs than those with low pTMB. Moreover, in the AtezoTRIBE study, tissue TMB was identified as a promising biomarker able to identify a subgroup with potential benefit from the addition of atezolizumab to first-line FOLFOXIRI/bev. In that trial, the addition of atezolizumab did not improve ORR, and PFS curves separated only after approximately 6 months. Given this delayed treatment effect observed, we hypothesized that dynamic liquid biopsy biomarkers could identify early molecular changes associated with subsequent immune-sensitivity. Here we evaluated the prognostic and predictive role of both pTMB and on-treatment ctF dynamics in the AtezoTRIBE trial. Methods: Pts with untreated mCRC enrolled in the AtezoTRIBE trial (NCT03721653) and with available plasma at baseline (T0) and at the end of induction (T1) were included. Samples were analyzed using the Tempus xF assay, a 105-gene cell-free liquid biopsy panel, to determine ctF by Tempus xFv2 cTF algorithm, and pTMB. pTMB was assessed as a dichotomous variable (high: ≥26 mut/Mb). ctF dynamics between T0 and T1 identified molecular responders (MRs), i.e. pts with the top 30% relative ctF reduction including clearance below quantification/detection limits at T1, and non responders (nMRs). Cox models stratified by liver metastases, and including treatment-by-biomarker interaction when appropriate, were used for PFS analyses (likelihood ratio test, p<0.15). Results: pTMB was evaluable in 123/155 (79%) T0 samples, and 20 (16%) were classified as pTMB-high. Baseline characteristics were balanced between pTMB-high and pTMB-low groups. High pTMB was associated with longer PFS (HR: 0.69 [90%CI 0.43-1.10], p=0.095), while no interaction between pTMB and treatment arm was observed (p int =0.871). Among 89 pts with evaluable ctF at T0 and T1, 63 (71%) were MRs. Baseline clinical and molecular characteristics did not differ in the MR and nMR groups. A significant interaction (p=0.132) between ctF dynamics and MR was reported, with nMRs achieving higher benefit from the addition of atezolizumab to FOLFOXIRI/bev (HR: 0.33 [90%CI: 0.16-0.69]) than MRs (HR: 0.76 [90%CI: 0.03- 3.95). A sensitivity analysis including 6 additional pts with undetectable ctF both at T0 and T1 provided consistent findings (p int =0.108). Conclusions: The addition of ICI to first-line chemotherapy may be more efficacious among mCRC pts with lower molecular response to the upfront induction regimen, as measured by ctF dynamics. If independently validated, ctF molecular response biomarker might be useful for future trials’ design.

Detection of adaptive immune receptor CDR3s in tumor proteomes and correlations with survival probabilities.

e12597 Background: T cell receptors (TCRs) and immunoglobulins (IGs) play an important role in cancer. Specifically, the complementarity determining region-3 (CDR3), encoded at the adaptive immune receptor gene recombination site, is a crucial factor in binding of cancer antigens. There have been very few, if any, successful attempts to identify TCR or IG CDR3s in the tumor proteome. Proteomics-based detection of CDR3s in tumor samples may provide insight into potential biomarkers and better understanding of cancer antigen binding. Methods: Exome and RNA sequencing data from primary breast cancer samples were obtained from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) dataset. TCR and IG recombination reads were identified in the exome and RNA-seq files via a high-stringency search algorithm. These reads were translated into amino acid sequences, yielding productive CDR3 protein sequences. Then, mass spectrometry-based proteomics data from the TCGA-BRCA tumor samples were analyzed using the FragPipe proteomics pipeline. The abundance of proteins corresponding to the previously identified TCR and IG CDR3 sequences was quantified by the FragPipe algorithm. For each TCGA-BRCA case, mean CDR3 quantity (TCR and IG combined) was calculated. Cases were stratified into high- and low-abundance groups based on the cohort median. Overall survival (OS) probability differences were evaluated using Kaplan-Meier analysis and the log-rank test. Results: Proteins corresponding to CDR3 sequences identified in exome files were detected in mass spectrometry-based proteomics data, and their abundance was quantified. For exome-derived CDR3s, TCGA-BRCA cases represented by a mean CDR3 quantity above the 50th percentile had a higher OS probability than cases below the 50th percentile (n = 105, p = 0.049). Similarly, proteins corresponding to CDR3 sequences identified in RNA-seq files were detected and quantified in mass spectrometry data, and TCGA-BRCA cases with mean CDR3 quantity above the 50th percentile again exhibited higher OS probability than cases below (n = 105, p = 0.034). Conclusions: Adaptive immune receptor CRD3s were detected in the tumor proteome and, when present in higher quantity, were correlated with better OS probabilities. Future, more extensive proteomics analyses may offer better understanding of the potential of CDR3s as biomarkers and better understanding of CDR3 specificity for certain cancer epitopes.

Expanding access to tyrosine kinase inhibitors for treatment of Philadelphia chromosome–positive acute lymphoblastic leukemia in low- and middle-income countries.

1600 Background: Acute lymphoblastic leukemia (ALL) is a hematological malignancy affecting 300,000 people worldwide, with an estimated incidence of 100,000 new cases annually. An important cytogenetic abnormality, the Philadelphia chromosome, causes an aggressive form of disease that affects 3-4% of pediatric and 20-30% of adult patients. Since the early 2000s, tyrosine kinase inhibitors (TKIs) have dramatically transformed the treatment of Philadelphia chromosome positive ALL (Ph+ALL). In high-income countries, different TKI regimens in combination with chemotherapy achieve remission rates >90%, but survival rates in low- and middle-income countries (LMICs) are persistently worse, largely due to access barriers, including high costs of innovative therapies. Methods: The Max Foundation provides TKIs at no cost to eligible patients with Ph+ALL and other diseases in resource-limited settings worldwide. We conducted a retrospective review of all patients with a diagnosis of PH+ALL initiating treatment with TKIs between January 1, 2007 and July 31, 2025 through the Glivec International Patient Assistance Program (2007-2017) or Max Access Solutions (since 2017). Data on age at diagnosis, treatments, sex, country of origin, program status, and reason for closure were analyzed using descriptive statistics, with correlations between available variables and length of treatment explored. Results: Of 1,671 patients enrolled, 342 (20.5%) remained active at the time of analysis. Males accounted for 967 patients (57.9%). Patients enrolled from 47 LMICs in the Americas (542, 32.4%), Asia excluding India (414, 24.8%), Eastern Europe (365, 21.8%), Africa (219, 13.1%), and India (131, 7.8%). Median age at diagnosis was 29, with 485 (29.0%) 18 years old or younger. Most patients (1594, 95.4%) initiated treatment with imatinib as first-line treatment; of these, 110 (6.9%) moved to a second-line treatment and 18 (1.1%) to a third-line. Among 1,329 closed cases, reasons for closure included death (526, 39.8%), lost to follow-up (291, 21.9%), and clinical reasons (260, 19.6%). Median treatment length was 17 months (range 0-197 months). Patients who died were older at diagnosis (median 34 vs 28 years old) and had a shorter median treatment duration (13 vs 19 months) compared with other patients. Treatment duration tended to decrease with age; with a significant negative correlation between age at diagnosis and total months of treatment ( r =-0.171, p<0.001). Since 2024, 25 patients received additional supportive services through The Max Foundation, including transportation assistance. Conclusions: This program demonstrates the feasibility of providing TKIs for the treatment of PH+ALL in diverse resource-limited geographies. Increasing access to TKIs is a critical step in eliminating global disparities in the burden of Ph+ALL.

Next-generation multi-cancer early detection (MCED) assay: Independent blinded validation of a locked serum multi-omics NMR test with stage I sensitivity.

10536 Background: Blood-based MCED assays could complement existing screening, but many approaches show reduced sensitivity in early-stage disease. Wholomics developed a serum multi-omics MCED assay integrating metabolomic, lipidomic, and proteomic features quantified by proprietary NMR-based technology, designed to capture systemic biology associated with early tumor development. We report independent, blinded validation of a locked MCED assay developed on multi-center data; across training and validation, the program included >1,400 individuals and >13 cancer types. The full assay pipeline was locked before application to the independent validation cohort. Methods: Model development leveraged prior multi-center data (N = 1,211) from five European centers (669 cancers, 65% were stage 0-II; 442 controls plus precancerous/benign cohorts). We evaluated an independent validation cohort (N = 216) with 116 cancers (50% were stage 0-II [stage I n = 40; stage II n = 16]; cancers included colon, rectal, pancreatic, cervical, uterine, bladder, breast, gastric, renal, ovarian) and 100 controls with screening-relevant conditions (e.g., dyslipidemia, prediabetes, benign prostatic hyperplasia, osteoarthritis, etc.). Samples were analyzed with fully prespecified locked assay pipeline (proprietary NMR profiling according to SOP with predefined QC, data preprocessing, biomarker feature set, machine-learning model, and decision threshold) and applied to blinded outcome labels. Primary endpoints were specificity and sensitivity (overall, stage I, stage III-IV). 95% CIs for sensitivity and specificity were calculated using the Wilson score method; AUC 95% CIs were calculated using DeLong’s method. Results: The locked MCED assay achieved specificity of 99.0% (99/100; 95% CI 94.6–99.8; false-positive rate 1.0%) and overall sensitivity of 93.1% (108/116; 95% CI 87.0–96.5). Stage I sensitivity was 95.0% (38/40; 95% CI 83.5–98.6), Stage III-IV sensitivity remained high in advanced stages at 93.1% (54/58; 95% CI 83.6–97.3). AUC was 0.991 (95% CI 0.979-1). High overall sensitivity was observed across multiple tumor types, including pancreas, stomach, kidney, colon (each 100% overall) and rectum (92.3% overall). Conclusions: In an independent blinded validation, a locked serum multi-omics NMR-based MCED approach demonstrated high specificity and high sensitivity, including strong stage I performance, across multiple solid tumors in a screening-relevant case-control setting. These findings support clinical utility for shifting detection toward earlier, more treatable stages and warrant prospective studies to confirm real-world performance and downstream impact.

Prevalence of Congenital Heart Disease and Associated Factors among Infants with Myelomeningocele: A cross-sectional study

Background Meningomyelocele (MMC) is believed to commonly coexist with congenital heart disease (CHD), due to embryological pathways involving neural crest cells and risk factors such as folate and homocysteine metabolism abnormalities. However, evidence from developing countries is limited. Therefore, this study assessed the prevalence of CHD among infants with MMC and identified factors associated with the occurrence of CHD in infants with MMC. Methodology This hospital-based cross-sectional study was conducted at Hawassa University Comprehensive Hospital between May 1 and August 1, 2025. Infants with MMC born from January 1, 2018, to January 1, 2024, who underwent echocardiographic evaluation were included. Data were collected through chart review. Prevalence of CHD in infants with MMC was described using frequencies and percentages, and binary logistic regression identified factors associated with CHD. Results A total of 265 infants with MMC were included in this study. The prevalence of CHD among infants with MMC was 7.2%. The presence of maternal history of spontaneous abortion [AOR = 2.51, (95% CI: 1.12, 9.83); P = 0.03], maternal overweight or obesity [AOR = 2.93, (95% CI: 1.15, 7.98); P = 0.01], maternal diabetes mellitus [AOR = 2.22, (95% CI: 1.13, 8.45); P = 0.01], extracardiac anomalies in the infant [AOR = 2.94, (95% CI: 1.11, 8.78); P = 0.04] were associated with CHD in infants with MMC. Conclusion CHD was relatively common among infants with MMC, affecting 7.2% of cases. Factors associated with CHD included maternal history of spontaneous abortion, maternal overweight or obesity, maternal diabetes mellitus, and the presence of extracardiac anomalies in the infant. These findings highlight the significance of routine cardiac evaluation and targeted maternal risk assessment in infants with MMC to improve early detection and management.

Reductive Photocatalysis Unlocks the Hydrodeoxygenation of Polycarbonate Plastic Into Fuel‐Range Hydrocarbons

ABSTRACT Polycarbonate (PC) is among the most challenging plastics to recycle because its robust aromatic C─O linkages resist conventional depolymerization strategies. Here, we report the first visible‐light‐driven photocatalytic system for the reductive depolymerization and hydrodeoxygenation of PC under ambient conditions, selectively producing propane‐2,2‐diyldicyclohexane (DCHP), a saturated hydrocarbon relevant to jet fuel applications. A multifunctional Ru@P‐CHS(g‐C 3 N 4 ) catalyst integrates light harvesting, electron mediation, acidity, and hydrogen activation, enabling near‐quantitative conversion of bisphenol A with ∼94% molar selectivity toward DCHP. The catalyst also efficiently depolymerizes a range of real‐world PC waste. Mechanistic investigations, including in situ UPS, kinetic isotope effect measurements, H 2 ─D 2 scrambling experiments, and DRIFT‐IR spectroscopy, reveal light‐driven electron accumulation at Ru sites and the formation of Ru─H intermediates, confirming illumination‐induced H 2 activation at Ru that drives C─O bond cleavage. This work establishes a sustainable strategy for converting end‐of‐life plastics into fuel‐range hydrocarbons and introduces reductive photocatalysis as a new paradigm for plastic upcycling.

Urban air quality monitoring with silane-grafted rGO filters for high-performance PM₂.₅ particulate retention and enhanced sensing

Mechanisms and disease relevance of mitochondrial translation in humans

Chiral Manganese Halide Co‐Crystals: A New Avenue for Efficient Circularly Polarized Luminescence

ABSTRACT Chiral metal halides have emerged as promising candidates for circularly polarized luminescence (CPL) due to their structural versatility and exceptional optoelectronic properties. However, achieving both a high luminescence dissymmetry factor ( g lum ) and photoluminescence quantum yield (PLQY) remains a critical challenge due to the inherent trade‐off between inducing chirality and minimizing non‐radiative losses driven by polyhedral distortion. Here, we present a ligand‐engineering approach to design a pair of chiral metal halide co‐crystals, achieving near‐unity PLQY (98%) and a | g lum | of 7.4 × 10 −3 . By leveraging Coulomb interactions instead of conventional hydrogen bonding between ligands and inorganic halide units, we effectively circumvent polyhedral distortions and substantially reduce electron–phonon coupling. This structural innovation reduces the non‐radiative decay rate by nearly three orders of magnitude, from 2.20 × 10 4 to 51.9 s −1 , thereby substantially enhancing luminescence efficiency. Consequently, the resulting figure‐of‐merit (FOM = PLQY × | g lum |) reaches an impressive 7.25 × 10 −3 , surpassing conventional hydrogen‐bonded counterparts by more than an order of magnitude (6.7 × 10 −4 ). This co‐crystal strategy paves the way for developing advanced CPL emitters with superior performance.

Next‐Generation Short‐Wave Infrared LED Phosphors Based on Chromium Doped Rare Earth Sulfides

ABSTRACT External quantum efficiency (EQE) and thermal stability of phosphors are two critical parameters for next‐generation short‐wave infrared (SWIR) phosphor‐converted light‐emitting devices (pc‐LEDs). However, it remains a significant challenge to develop SWIR‐emitting phosphors that simultaneously exhibit high EQE and excellent thermal stability. Here, by leveraging the strong covalency, low phonon energy and structural symmetry of sulfides, we successfully realize high‐performance tunable SWIR emission in sulfide phosphors NaLnS 2 : Cr 3+ (Ln = Lu, Y, Gd), peaking at 980, 1020, and 1080 nm, respectively. Notably, NaLuS 2 : Cr 3+ simultaneously achieves a record ‐ high EQE of 61.55% along with superior thermal stability, while an EQE of 48.55% is also demonstrated at 1080 nm in NaGdS 2 : Cr 3+ . The corresponding SWIR pc‐LED delivers a high SWIR output power of 169.2 mW@350 mA, significantly outperforming the commercial devices. Finally, advanced palm vein recognition and portable non‐destructive detection are successfully demonstrated. This study provides new insights and an effective materials platform for developing high‐performance SWIR‐emitting materials toward advanced photonic applications.