Browse Articles

Molecular analysis of aggressive disease and treatment response in recurrent/metastatic head and neck squamous cell carcinoma.

e18033 Background: Immunotherapy (IO), alone or with chemotherapy, is standard first-line treatment for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Here, we evaluated molecular features associated with disease patterns and treatment response in HNSCC. Methods: Molecular profiling data were retrospectively reviewed for 80 patients with recurrent/metastatic HNSCC treated with systemic therapy. Clinically obtained next-generation sequencing reports (FoundationOne, Tempus, Caris, and institutional OncoPanel) were included. Genomic features were compared by metastatic pattern (bony vs non-bony) and clinical outcome (early failure ≤6 months vs sustained response ≥1 year). Non bony disease was defined as local-regional or visceral disease. Tumor mutational burden (TMB), somatic alterations, copy number changes, and mutational signatures were analyzed. Results: Among sequenced patients, 15 had bony metastases and 65 had non-bony metastatic disease. Patients with bony metastases were slightly older (mean 68.9 vs 64.6 years; p=0.11). Mean TMB was numerically higher in bony metastases (26.0 vs 5.8 mut/Mb), driven by high-TMB outliers, but was not statistically significant (p=0.28). Median overall survival was numerically longer in the TMB-high group (62.7 vs 48.3 months), (HR 1.47; 95% CI 0.72–3.01; p=0.29). Distinct genomic patterns were observed: non-bony metastases frequently demonstrated chromosome 11q13.3 amplifications ( CCND1, FGF3, FGF4, and FGF19 ) and tumor suppressor alterations ( TP53, CDKN2A, FAT1, and LRP1B ), while PTEN alterations were significantly enriched in bony metastatic disease by seven-fold (p<0.05). Clinical outcome analysis included 25 patients with early failure and 6 with sustained response. Mean TMB did not differ by outcome group (4.8 vs 5.1 mut/Mb; p=0.92). Early failure tumors demonstrated higher mutation frequencies in TP53 and CDKN2A , frequent co-occurring alterations, and greater mutational heterogeneity with increased transversions, including C>A substitutions. In contrast, sustained responders exhibited transition-dominant mutational patterns with low transversion rates and infrequent alterations, with occasional mutations in EP300, KMT2C, and FGFR3 observed in a small subset. Conclusions: Distinct molecular features characterize aggressive disease and treatment resistance in recurrent/metastatic HNSCC. Bony metastatic disease is enriched for PTEN alterations while early treatment failure is associated with TP53 and CDKN2A mutations, greater genomic complexity and heterogeneous mutational processes. These findings highlight biologic heterogeneity underlying metastatic behavior and treatment response and warrant validation in larger, uniformly characterized cohorts. Identifying mutational signatures in patients with metastatic HNSCC may guide treatment.

Novel transposon BAFF CAR-T cells (LMY-920) for non-Hodgkin lymphoma (NHL).

2563 Background: CAR-T cells targeting CD19 using scFv-based CARs have been effective and approved to treat lymphoma. Response rates are high, but a significant number of patients fail to respond or relapse. This has been linked to T cell exhaustion, immune dysregulation, and/or epitope loss. To overcome this, we developed a CAR-T cell product expressing a BAFF-ligand (LMY-920). The CAR consists of truncated human BAFF on a 3rd generation CAR backbone with CD28, OX40, and CD3z intracellular signaling domains. The BAFF-ligand domain confers ability to bind the 3 BAFF receptors (BAFFR/BR3, TACI and BCMA). These are attractive tumor-associated antigens being variably expressed in all B-lineage malignancies such as B cell NHL, chronic lymphocytic leukemia (CLL), hairy cell leukemia and multiple myeloma (MM), and are important for B-cell survival, reducing the chance of antigen escape. Additionally, they are expressed on B-lineage cells involved in antibody-mediated autoimmune diseases. BAFF ligand interactions are lower affinity than scFv interactions, potentially reducing T-cell exhaustion. The novel TcBuster transposon system is used to improve manufacturing time, efficiency, cost, and safety. Methods: Patients with refractory B cell NHL are treated in this study (NCT05312801). Autologous LMY-920 CAR-T cells are manufactured, then patients receive 3 days of fludarabine (30 mg/m 2 /d) and cyclophosphamide (500 mg/m 2 /d) lymphodepletion. LMY-920 is administered intravenously in a 3+3 dose escalation design from 1-8 x 10 6 BAFF-CAR-T cells/kg. Response is assessed using the Lugano criteria. CAR-T expansion and biologic characteristics are assessed. Results: Five patients have been treated with 1-2 x 10 6 BAFF-CAR-T cells/kg in this study, 2 patients each with mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), and one with marginal zone lymphoma (MZL). Patients had received 2 – 6 prior lines of therapy and all were refractory. One patient experienced grade 1 CRS (fever), but no ICANS was reported. All patients experienced grade 3 or higher hematologic toxicity that recovered prior to day 28, and grade 1-2 fatigue. There have been no dose limiting toxicities and dose escalation continues. Responses included 2 complete responses (CR) (DLBCL), a partial response (MZL), a mixed response (MCL) and one stable disease (MCL). Of note, one of the DLBCL patients in CR had received prior axicabtagene ciloleucel (anti-CD19) CAR-T cells as well as anti-CD20 bispecific antibodies, with lymphoma cells resulting in CD19 and CD20 antigen loss. Conclusions: The successful use of a novel transposon-engineered BAFF ligand-based CAR-T cell product demonstrates the potential of a new direction in CAR-T cell development. Safety and efficacy were seen, including patients with prior CAR-T failure and epitope loss, as hypothesized. This product is also being evaluated in patients with CLL, MM and systemic lupus erythematosus. Clinical trial information: NCT05312801 .

Enfortumab vedotin plus pembrolizumab (EV+P) vs chemotherapy for previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC): 3.5-year follow-up and response analyses from the phase 3 EV-302 study.

4507 Background: EV+P is the preferred standard of care for previously untreated la/mUC based on the EV-302/KEYNOTE-A39 trial (NCT04223856). We present updated data with 3.5 years of median follow-up, including exploratory subgroup analyses focusing on patients who achieved a complete response (CR) after an initial partial response (PR). Methods: Patients were randomized 1:1 to EV 1.25 mg/kg IV (days 1 and 8 of each 3-wk cycle) and P 200 mg IV (day 1) or gemcitabine + cisplatin/carboplatin, with treatment until disease progression, toxicity, or maximum number of cycles. Dual primary endpoints were progression-free survival by blinded independent central review and overall survival (OS); safety was a secondary endpoint. Results: With 42.8 months of median follow-up (data cutoff: October 6, 2025), OS benefit favoring EV+P (n=442) vs chemotherapy (chemo; n=444) was maintained (median OS, 33.6 vs 15.9 months; 42-month OS rate, 44.0% vs 24.6%; HR, 0.53 [95% CI, 0.45-0.63]), with no new safety signals. Of responding patients, 45.1% achieved a CR in the EV+P arm (n=295) and 32.8% in the chemo arm (n=195. Data cutoff was Aug 8, 2024. Among patients with confirmed CR in the EV+P arm, 66.2% achieved a PR initially, then converted from a PR to a CR with a median of 5 additional EV cycles (IQR, 3.0-8.0). In this subgroup, mOS was not estimable (NE), and >80% of patients were alive after 3.5 years. Longer treatment duration did not lead to new safety concerns. Overall, the most common first subsequent treatment was platinum-based chemo in the EV+P arm (n=135 [30.5%]) and a PD-L1 inhibitor in the chemo arm (n=265 [59.7%]). In the EV+P arm, investigator-assessed responses to subsequent platinum chemo occurred in 28 of 135 evaluable patients (20.7%). Conclusions: EV-302 represents the longest follow-up available for EV+P in a phase 3 trial. After 3.5 years of median follow-up, EV+P continues to demonstrate superior efficacy vs chemo, with no new safety signals. Two-thirds of patients achieving CR converted from an initial PR, suggesting that treatment duration is relevant in maximizing outcomes. Clinical trial information: EV-302 NCT04223856 . EV+PAll CR (n=133) EV+PCR after PR (n=88) Median OS (95% CI), months NE (NE-NE) NE (NE-NE) 42-month OS rate (95% CI), % 83.6 (75.6-89.1) 82.4 (71.8-89.43) Median time to CR (IQR), monthsTime to PRTime from PR to CR 4.3 (2.2-8.4)–– 6.6 (4.3-12.1)2.1 (1.9-2.2)4.5 (2.2-10.1) Median EV cycles prior to CR (IQR), nEV cycles prior to PREV cycles from PR to CR 6.0 (3.0-9.0)–– 8.0 (6.0-11.5)3.0 (3.0-3.0)5.0 (3.0-8.0) Median P cycles prior to CR (IQR), nP cycles prior to PRP cycles from PR to CR 6.0 (3.0-10.0)–– 9.0 (6.0-12.0)3.0 (3.0-3.0)6.0 (3.0-9.0) Median total EV cycles (IQR), n 13.0 (8.0-28.0) 15.0 (9.0-30.0) Median total P cycles (IQR), n 28.0 (10.0-35.0) 31.0 (12.5-35.0)

Facile synthesis and characterization of α-Fe2O3 and α-Fe3O4 nanoparticles with potential biomedical applications

Twenty years of induced pluripotent stem cells

Advances in the management of metastatic gastric cancer: current strategies and emerging therapeutics

Sustainable development and ANN-based prediction of bio-waste-filled flax–pineapple–epoxy hybrid composites for enhanced mechanical performance

Abstract With the increasing demand for sustainable and cost-effective materials, natural fiber-reinforced composites are gaining traction among manufacturers and consumers. This study addresses the growing need for eco-friendly and structurally reliable composite materials. It focuses on the incorporation of bio-waste fillers into epoxy composites reinforced with flax and pineapple fibers, assessing their suitability for lightweight structural applications in automotive and construction sectors. Four fillers—coconut shell powder (CSP), teak wood dust (TWD), eggshell powder (ESP), and rice husk powder (RHP)—were added at a fixed 10 wt% to fabricate hybrid composites using a combination of hand layup and hot-pressing techniques. Mechanical properties such as tensile strength, impact resistance, interlaminar shear strength (ILSS), fracture toughness, and flexural strength were evaluated. Among all, CSP-reinforced composites showed superior mechanical performance, with enhancements ranging from 1.95% to 42.8% over other variants. Scanning Electron Microscopy (SEM) analysis revealed improved fiber–matrix bonding and minimal voids in CSP composites. In addition, an Artificial Neural Network (ANN) model was employed to predict mechanical properties with high accuracy: 95.85% (tensile), 83.9% (flexural), and 89.83% (impact). These results underscore the potential of using agricultural and industrial waste fillers in natural fiber composites for sustainable, high-performance applications in structural engineering.

The E3 ligase β-TRCP1 earmarks OTUD3 for destruction to fine-tune cGAS activation

Benchmarking free energy computational methods for revealing the key interactions driving PARP1 selective inhibition.

e13004 Background: Accurately predicting inhibitor selectivity among closely related protein paralogues remains a central challenge in computational drug discovery. Methods: In this work¹, we systematically compared three computational methods—MM/PBSA, free energy perturbation (FEP), and potential of mean force (PMF) calculations—to assess their ability to predict PARP1 vs PARP2 selectivity across eight clinically relevant PARP inhibitors used in ovarian, breast, prostate, and related cancers 2 . Results: MM/PBSA offered rapid, low-cost qualitative insight but proved highly sensitive to the choice of static binding pose, limiting its reliability when energetic differences between paralogues are small. In contrast, atomistic FEP and PMF simulations performed with explicit solvent show substantially improved agreement with experimental binding affinities. Our atomistic simulations near-quantitatively captured the experimental relative binding preferences, demonstrating that both PMF and FEP calculations using the a99SB- disp 3 and OpenFF 4 force fields reliably reflect selectivity patterns. Based on these findings, we analysed protein–ligand contact frequencies to identify the stabilising interaction network and contact connectivity inducing protein selectivity. The most frequent protein–inhibitor contacts are primarily mediated by tyrosine triads and electrostatic interactions, showing a cooperative complex network of intermolecular contacts which strongly relies on protein multivalency. To dissect the decisive role of individual residues across the binding site, we also performed targeted mutagenesis of the catalytic pocket in complex with saruparib, replacing several active-site amino acids by glycines. Progressively increasing the number of mutations markedly reduces binding stability, with distinct residue combinations exerting two primary effects: destabilization of the final bound state and the emergence of energetic barriers along the ligand association pathway 5 . Conclusions: Together, our results provided a coherent mechanistic framework for understanding PARP1 selectivity and informs the rational design of next-generation inhibitors with improved efficacy and safety. References: 1) Feito et al., bioRxiv , 10.64898/2025.12.29.696816, (2025). 2) Jackson et al., NAR Cancer , 4 (4), zcac042, (2022). 3) Robustelli et al., PNAS 115 (21), E4758-E4766, (2018). 4) Boothroyd et al., JCTC , 19 (11), 3251-3275, (2023). 5) Feito et al., bioRxiv , 10.1101/2025.10.13.681983, (2025).

General population interest in multi-cancer early detection (MCED) testing: Insights from a seven-country survey on drivers of engagement and cross-national differences.

e22507 Background: Most cancers lack organized screening programs, and limited access to primary care further hampers early diagnosis. MCED testing may complement available screening programs and expand the reach of screening to more cancer types. This study assessed public perceptions, motivators, and behavioral intent regarding MCED testing across multiple countries. Methods: An online survey was fielded in the US, Canada, UK, France, Germany, Spain, and Italy (N=1100; ages 21–85) between July 21 and August 1, 2025. After being shown a definition, respondents rated their likelihood to request a MCED test and reported demographic, socioeconomic, and health-related factors. Analyses explored cross-country variation and characteristics associated with three MCED engagement segments: Reluctant (1–4/7), Interested (5–6/7), and Eager (7/7). Results: Overall, 55% (95% CI 52-58%) of respondents reported high likelihood (6–7/7) of requesting an MCED test, increasing to 71% (95% CI 68-74%) when framed as physician recommend. Country-level differences at 95% CI were observed in self-reported quality of life (US, CA: 5.4/7, SP:5.2/7 > DE, IT:4.8/7), health-literacy (Need help reading medical information: FR: 2.2/5, IT:2.5/5 < all others 1.5-1.8/5), ease of accessing care (US: 5.6/7, SP:5.4/7 > all others 3.8-4.6/7) and cancer-related worry (SP: 5.7/7, IT:5.5/7 > all others 3.9-4.3/7). Despite these variations, mean likelihood to request testing was consistent across countries (5.2–5.6/7). Analysis revealed clear distinctions among Reluctant (1–4/7), Interested (5–6/7), and Eager (7/7) groups in demographic, experiential, and healthcare-access factors influencing intent. Conclusions: Public interest in MCED testing is substantial in all countries, with physician recommendation a key additional adoption driver. Engagement varies by demographic and experiential factors, highlighting the need for targeted communication strategies to ensure equitable awareness and uptake, particularly among populations less likely to participate in cancer screening. Factors related to likelihood to request MCED test via a doctor. A - Reluctant (n=295) B -Interested (n=418) C -Eager(n=387) Male vs. Female 49% vs. 50% 55% vs. 45% 52% vs. 48% Relationship: married 48% bc 58% a 59% a Employment: full-time / retired 32% BC / 40% B 48% A / 28% A 43% A / 33% Annual household income 5 th bracket 9% bc 15% a 16% a Help reading medical information: Occasionally / Never 15% c / 65% c 15% C / 58% 22% aB / 56% a Accessing healthcare when I need to is easy 4.9/7 C 4.9/7 C 5.3/7 AB Worried about being diagnosed with cancer 3.5/7 BC 4.5/7 A c 4.8/7 Ab Knows someone close to them diagnosed with cancer in the last 5 years 33% bC 41% a 43% A Has not been screened for any type of cancer in the past 34% BC 22% A 17% A Column comparison symbols: a, b, c (p <= 0.05), A, B, C (p <= 0.01).

Preoperative assessment of peritoneal carcinomatosis with [ ⁶⁸ Ga]Ga-FAPI-46 PET/CT.

5553 Background: Accurate preoperative mapping of peritoneal carcinomatosis (PC) is essential for selecting patients for cytoreductive surgery (CRS) and guiding treatment planning. Conventional imaging including [ 18 F]FDG PET/CT may underestimate PC tumour burden. This study evaluated [ 68 Ga]Ga-FAPI-46 PET/CT for preoperative PC assessment using a surgico-pathological reference standard and compared its performance with MRI and [ 18 F]FDG PET/CT. Methods: In this prospective phase II study (FAPeCa, NCT06061874), patients with colorectal or ovarian cancer with known or suspected PC underwent [ 68 Ga]Ga-FAPI-46 PET/CT, [ 18 F]FDG PET/CT (FDG PET), and MRI within 4 weeks before diagnostic laparoscopy and/or CRS. PC extent was quantified using a 10-segment adaptation of the Peritoneal Cancer Index (PCI). Reference standard was intraoperative PCI with histopathological confirmation, with pathology adjudicating discordant findings. Agreement between imaging-derived total PCI and the reference-standard PCI was assessed using intraclass correlation coefficient (ICC, two-way mixed, absolute agreement). Segment-level diagnostic performance was evaluated after dichotomisation (PCI 0 vs ≥1). Subgroup analyses were performed according to recent chemotherapy (<3 months). Results: Sixty-one patients were enrolled. Median (IQR) total PCI values were 11 (18.5) for the reference standard, 12 (15.5) for FAPI PET, 6 (15.5) for MRI, and 4 (6.5) for FDG PET; FAPI-PCI was higher than MRI-PCI and FDG-PCI (Wilcoxon signed-rank, p<0.001). Agreement with the reference standard was highest for FAPI PET (ICC 0.81; BCa 95% CI 0.67–0.89), followed by MRI (ICC 0.76; BCa 95% CI 0.63–0.85) and FDG PET (ICC 0.54; BCa 95% CI 0.29–0.74). In the recent chemotherapy subgroup, FAPI PET maintained good agreement with the reference standard (ICC 0.75, BCa 95% CI 0.56–0.86), whereas agreement declined to moderate for MRI (ICC 0.65, BCa 95% CI 0.41–0.82) and was lower for FDG PET (ICC 0.46, BCa 95% CI 0.17–0.75). Segment-level sensitivity, specificity, and accuracy were 77.6%, 71.2%, and 74.8% for FAPI PET; 67.0%, 84.4%, and 74.7% for MRI; and 47.5%, 91.8%, and 67.2% for FDG PET . Overall segment-level sensitivities and specificities differed across the three modalities (Cochran’s Q, p<0.001). Conclusions: [ 68 Ga]Ga-FAPI-46 PET/CT demonstrated the strongest agreement with surgico-pathological PCI and maintained good agreement after recent chemotherapy. It showed higher detectability than MRI and [ 18 F]FDG PET/CT, albeit at the expense of lower specificity. These findings support[ 68 Ga]Ga-FAPI-46 PET/CT as a promising modality for preoperative PC mapping. Clinical trial information: NCT06061874 .

Application of long-read sequencing to resolve cryptic genomic instability across cancer types.

3067 Background: Computational mutational signatures can identify tumors with homologous recombination deficiency (HRD), mismatch repair deficiency (MMRD), and focal tandem duplication (FTD) phenotypes, nominating patients for PARP inhibitors or immune checkpoint blockade. However, many signature-positive cases lack identifiable causative alterations by conventional sequencing, forcing patients toward empiric therapy or clinical trial enrollment without molecular confirmation. We evaluated whether long-read nanopore sequencing could provide definitive molecular diagnoses to guide evidence-based treatment selection. Methods: We analyzed 768 patients with advanced prostate (n=505), breast (n=246), and ovarian (n=17) cancers enrolled in the MiOncoSeq precision oncology program. Computational signature analysis identified cases with HRD, MMRD, or FTD phenotypes. Cases unresolved by standard short-read sequencing underwent long-read nanopore sequencing with integrated structural variant detection, methylation profiling, and haplotype phasing. Results: Signature analysis identified 164 cases (21.3%) with genomic instability phenotypes. Short-read sequencing resolved 118/164 cases (71.9%), leaving 46 patients without molecular confirmation. Long-read sequencing achieved mechanistic resolution in 32/46 cases (69.6%), with complete resolution of MMRD (5/5, 100%) and FTD (7/7, 100%). Secondary signature analysis reclassified 11/14 unresolved HRD cases as non-classical, likely reflecting alternative DNA repair defects or replication stress, refining diagnostic yield to 86.9% (20/23) for credible HRD. Cryptic mechanisms included promoter hypermethylation ( BRCA1 , MLH1 , RAD51C ), balanced structural rearrangements ( CDK12 , PMS2 ), and deep intronic splice variants ( PALB2, BARD1 ). Long-read sequencing also uncovered 3 previously undetected pathogenic germline variants ( BARD1 , BRIP1 , PALB2 ) with direct implications for hereditary cancer risk assessment and family screening. Combined analysis identified actionable findings enabling targeted therapy selection in 19.5% of patients. Conclusions: Long-read sequencing provides definitive molecular diagnoses for patients with signature-positive tumors, enables evidence-based therapy selection over empiric treatment, and uncovers cryptic germline variants informing hereditary cancer risk.

Association of routine electronic symptom monitoring with reduced opioid use in patients with head and neck cancers.

1579 Background: Patient reported outcomes (PROs) have become increasingly important in modern healthcare. Head/neck cancer (HNC) is associated with numerous side effects that significantly impact patients quality of life short and long term. We developed FACT-HN-RAD, a brief cancer and treatment specific PRO aiming to efficiently capture side effect burden for patients with HNC undergoing radiotherapy (RT). Here we report the clinical implementation of this measure through the electronic medical record (EMR) at two institutions. Methods: The PRO was prospectively integrated into routine clinical care for patients with HNC through deployment in the EMR weekly during RT (up to 7 weeks) and at 1-, 3-, 6-, 9-, and 12-month post RT. We compared a historic cohort of patients (treated July 2021-July 2023) to those treated after PRO deployment (Aug 2023-Aug 2025), assessing PRO adherence, opioid use, emergency room (ER) encounters and inpatient admissions. Baseline demographic characteristics were summarized using descriptive statistics. Clinical outcomes were compared using parametric and nonparametric statistical tests. Results: OF the 2,288 patients, 1,304 were in the PRO cohort and 984 were in the historic cohort. Patients had a median age of 65 (IQR 56-73) and were mostly White (81.9%), non-Hispanic (91.3%), and current/former smokers (57.5%) with a median of 20 smoking pack years (IQR 3.8-46.5). In the PRO cohort, 51.9% (n=677) submitted at least one response to the assigned PRO. Within each individual patient for the total assigned series, within patient adherence was 50.9% (ie each patient filled out approximately half of the assigned PROs over a one year timeframe). Patients in the PRO cohort required less opioids with 49.1% (n= 640) receiving any opioid prescription in the PRO cohort as compared to 60.9% (n=577) historically (p<0.001). The average daily strength of opioids decreased 28% in the PRO cohort (mean MME 150.1mg, SD 458.7) versus historically (mean MME 207.9mg, SD 574.8) (p<0.001), and the total opioids prescribed to patients decreased 44% in the PRO cohort (mean MME 3,565mg, SD 12,105) versus historically (mean MME 6,363mg, SD 18,387) (p<0.001). Patients in the PRO cohort overall had fewer ER visits during and within the first year after finishing RT, with 13.3% (n=173) visiting the ER as compared to 29.4% (n=289) historically (p<0.001). Patients in the PRO cohort had fewer inpatient admissions within the first year after finishing RT, 28.8% (n=375) as compared to 48.8% (n=480) historically (p<0.001). Conclusions: We demonstrate that the integration of routine electronic PROs into the care of patients undergoing HNC RT is associated with clinical benefits when compared to a historic cohort including reduced opioid use, reduced ER visits, and reduced inpatient admissions. This promising approach in the definitive RT setting warrants further study in a randomized clinical trial.

Baseline peripheral blood absolute lymphocyte count and survival outcomes in patients with PD-L1-positive advanced gastric cancer treated with immune checkpoint inhibitor plus chemotherapy.

e16075 Background: Tumor PD-L1 expression guides the use of immune checkpoint inhibitor (ICI) plus chemotherapy in advanced gastric cancer (AGC), yet clinical benefit varies even among PD-L1–high tumors. Baseline peripheral blood absolute lymphocyte count (ALC), a marker of host immune competence, may influence the clinical impact of PD-L1 expression, but this has not been evaluated. We investigated whether baseline ALC influences the association between tumor PD-L1 expression and outcomes with first-line ICI plus chemotherapy. Methods: Using multicenter retrospective data (Asan Medical Center and Seoul St. Mary’s Hospital), patients treated with first-line ICI plus chemotherapy or chemotherapy alone were analyzed. PD-L1 was assessed by combined positive score (CPS; cutoffs 5 and 10). Baseline ALC was dichotomized at 1,880 cells/µL (maximally selected rank statistics). Progression-free survival (PFS) and overall survival (OS) were evaluated in PD-L1–ALC strata. Treatment benefit was assessed within strata, and multivariable Cox models included an interaction term. Results: Among 645 patients treated with ICI plus chemotherapy (n = 417 derivation; n = 228 validation), survival outcomes varied by PD-L1 and baseline ALC. Across CPS ≥5 and ≥10 in both cohorts, ICI plus chemotherapy showed the most favorable survival when both tumor PD-L1 expression and ALC were high. In contrast, when ALC was low, outcomes were poor even in the presence of high tumor PD-L1 expression and were comparable to those observed in PD-L1–low tumors. At CPS ≥10, median PFS was longest in the PD-L1–high/ALC–high subgroup (median PFS, not reached), followed by PD-L1–low tumors (9.1 mos), whereas PD-L1–high/ALC–low had similarly short PFS (8.0 mos). Similar patterns were seen for OS. The benefit was greatest in patients with CPS ≥10 and high ALC (PFS HR 0.31; OS HR 0.48), whereas attenuated benefit was observed in PD-L1–high patients with low ALC and in PD-L1–low subgroups. In multivariable models, ALC significantly modified the effect of ICI plus chemotherapy on PFS, with a stronger interaction in higher tumor PD-L1 expression (CPS ≥5: interaction HR 0.59, 95% CI 0.37–0.94, p = 0.025; CPS ≥10: interaction HR 0.40, 95% CI 0.21–0.75, p = 0.004). Conclusions: Baseline ALC dictated the clinical impact of tumor PD-L1 expression in AGC treated with first-line ICI plus chemotherapy. Favorable outcomes and the greatest relative benefit from adding ICI to chemotherapy were concentrated in patients with concomitantly high PD-L1 expression and high baseline ALC, whereas PD-L1–high patients with low baseline ALC experienced outcomes comparable to PD-L1–low disease. These findings suggest that baseline ALC may complement PD-L1–based clinical decision-making when guiding first-line ICI-based chemotherapy.

Association of vitamin D deficiency with risk in multiple myeloma: A real-world cohort analysis.

e19543 Background: Multiple myeloma (MM) is a plasma cell malignancy characterized by immune dysfunction and end-organ damage. Emerging preclinical evidence suggests vitamin D is implicated in MM biology through effects on plasma cell differentiation and immune regulation. Vitamin D deficiency is common among patients with MM, yet its prognostic significance remains unclear. Clarifying its role may inform risk stratification and supportive management in MM. Methods: We conducted a retrospective cohort study using the multicenter TriNetX research network. Adults aged ≥20 years diagnosed with MM between 2011 and 2024 were included. Vitamin D status was defined using serum 25-hydroxyvitamin D levels, with deficiency defined as ≤30 ng/mL and normal levels defined as 31–80 ng/mL. Patients were stratified into two groups based on vitamin D status at the time of MM diagnosis. Propensity score matching (1:1) was performed to balance age, sex, race, baseline laboratory values, and clinically relevant comorbidities between groups. Kaplan–Meier survival analyses and Cox proportional hazards models were performed for outcome analyses. Results: A total of 36,273 patients with MM were included, of whom 42% (n = 15,262) had vitamin D deficiency. After propensity score matching, 14,023 vitamin D–deficient patients were well balanced with 14,006 non-deficient patients across baseline characteristics. In the matched cohort, the mean age was 64 years, 49% were female, and 64% were White. At five years, vitamin D deficiency was associated with a significantly higher risk of mortality (hazard ratio [HR] 1.63, 95% CI 1.54–1.72), with lower five-year overall survival (OS) compared with non-deficient patients (71.1% vs 80.8%, p<0.05). Vitamin D deficiency was also associated with increased risks of pneumonia (risk ratio [RR] 1.11), bacteremia (RR 1.22), and critical care admission (RR 1.30) (all p<0.05). Additionally, deficient patients had higher risks of acute kidney injury (AKI) (RR 1.19) and venous thromboembolism (RR 1.18) (both p<0.05). Notably, the risk of MM relapse was modestly increased among vitamin D-deficient patients (RR 1.07, 95% CI 1.01–1.13). No significant associations were observed between vitamin D deficiency and amyloidosis or pathologic fractures. In multivariable Cox regression, vitamin D deficiency remained independently associated with worse five-year OS (adjusted HR 1.60, 95% CI 1.52–1.67). Conclusions: This study highlights the negative impact of vitamin D deficiency in patients with MM. It identifies a high-risk subgroup of patients characterized by worse five-year OS, higher rates of serious infections, AKI, critical care utilization, and an increased risk of MM relapse. These findings suggest vitamin D deficiency as a clinically relevant prognostic marker in MM. Prospective studies are warranted to determine whether vitamin D level optimization can improve MM outcomes.

Score evaluation and prevalence of Her2 status in pleural mesothelioma (PM): MESOHER study.

e20066 Background: Tumors that overexpress HER2 have been historically associated with poorer survival compared with HER2-negative tumors. HER2 status classification has been evolving and while there are clear guidelines for breast and gastric cancers, in other tumor types have no clear guidelines. HER2 rappresents a validated target in many tumors. In this report were analyzed the HER 2 status in PM. Methods: From January 2019 to June 2024 in IRCCS-AUSL Reggio Emilia, Italy, 53 consecutive patients (pts) diagnosed with PM were analyzed examining HER2 expression by immunohistochemical (IHC) analysis and subsequent confirmation by fluorescence in situ hybridization (FISH) on diagnostic biopsies or surgical specimens. The antibody used was anti-HER-2/neu clone 4B5 (Rabbit Monoclonal Primary Antibody, Ventana). HER2 IHC was evaluated according to the 3 different HER2 Testing Guidelines for breast cancer, gastric and colorectal adenocarcinoma. Results: HER2 membrane staining was observed in 9 of 53 cases (16.9%), while 44 cases (83.1%) were completely negative. 6/9 cases was epithelioid histotype and 3/9 biphasic histotype. According to the Breast Cancer Guidelines, most cases with HER2 staining (6/9, 66.7%) were scored as 0 (Ultra-Low) with weak/barely perceptible segmental positivity in 1 to 10% of neoplastic cells (mean 3.8%); 2 cases (22.2%) were scored 1+ with weak/barely perceptible segmental positivity in 15% and 25% of neoplastic cells, respectively. In line with Gastric Adenocarcinoma Guidelines, most cases with HER2 staining (5/9, 55.6%) were scored as 1+ with weak/barely perceptible segmental positivity in 5% to 25% of neoplastic cells (average 12%); 3 cases (33.3%) were scored 0 with weak/barely perceptible segmental positivity in 1% of neoplastic cells. According to the Guidelines for adenocarcinoma of the large bowel, all cases with HER2 staining, with the exception of case 2+ (8/9, 88.9%), were found to be score 1+ with weak/barely perceptible segmental positivity in 5% to 25% of neoplastic cells (average 12%). HER2 results in the 9 PM cases showing any expression of HER2, reported according to the different guidelines currently available in clinical practice (Table1.Concordance between scores Fleiss’ Kappa 0.363). Conclusions: In this study, 16.9% of cases of PM showed any HER2 IHC membrane staining. The expression is infrequent and consistently low, affecting a small fraction of tumour cell and lacking gene amplification. HER2 results in the 9 PM cases showing any expression of HER2, reported according to the different guidelines currently available in clinical practice. Cases with any expression of HER2 HER2 Testing Guidelines Breast Cancer Gastric cancer Colorectal cancer 1 1+ 1+ 1+ 2 1+ 1+ 1+ 3 2+ 2+ 2+ 4 0 1+ 1+ 5 0 0 1+ 6 0 1+ 1+ 7 0 0 1+ 8 0 1+ 1+ 9 0 0 1+

Real-world outcomes of tarlatamab across small cell carcinoma subtypes, including transformed and non-lung primary.

e23350 Background: Tarlatamab, a bispecific antibody targeting delta-like ligand-3 and CD3, has been approved for small cell lung cancer (SCLC) following progression on chemo-immunotherapy. However, the benefit of Tarlatamab in patients with transformed small cell cancer or primary small cell carcinoma of a non-lung site remains unclear. We report real-world outcomes of Tarlatamab in patients with small cell carcinoma, including transformed disease and non-lung primary. Methods: We performed a retrospective review of patients who received at least one dose of Tarlatamab at our institution between June 2024 and January 2026. Patients were identified as SCLC or transformed and non-lung primary (T/NL). Progression-free survival (PFS) was defined as time from first dose until progression or death. Overall survival (OS) was defined as time from first dose until death. Since some patients with disease progression in the central nervous system (CNS) alone were treated with radiation and continued Tarlatamab, we calculated a PFS excluding CNS progression. Patients were censored at the date of last known with no progression or alive. Duration of Response (DoR) was defined as time from first response until time of progression in patients with confirmed response. Results: Among 37 patients that received Tarlatamab, median age was 69, and 19 were female (51.4%). Median prior therapies was 2. Thirty patients had SCLC, and 7 had T/NL. Thirty-three patients were evaluated for response as 4 enrolled on hospice before assessment. Seventeen patients (51.5%) had a response, including 4 of the 7 (57.1%) T/NL. For all patients, median OS (mOS) was 7.3 months, median PFS (mPFS) was 2.3 months, and mPFS excluding CNS progression was 2.3 months. Median DoR (mDoR) was 2.7 months, and mDoR excluding CNS progression was 4.7 months. Estimated 12-month survival was 28% (11 – 49%). In T/NL patients, mOS was not reached at a median follow up of 3.9 months. Median PFS was 2.9 months, and mPFS excluding CNS was 12.3 months. Median DoR was 4.2 months while mDoR excluding CNS was 8.4 months. Estimated 12-month survival of the T/NL cohort was 63% (14 – 89%). Cytokine release syndrome (CRS) was seen in 54.1% (20/37) and 18.2% (6/33) of patients on day 1 and day 8, respectively. Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) was seen in 5.4% (2/37) and 3.0% (1/33) of patients on day 1 and day 8, respectively. All CRS and ICANS events were grade 1 or 2. Conclusions: This real-world analysis of Tarlatamab demonstrated slightly worse clinical outcomes with respect to PFS and OS although similar tolerability compared to the clinical trial. Notably, transformed and non-lung primary small cell carcinoma patients showed promising outcomes with Tarlatamab. This study was limited by the small sample size but highlights the importance of further studies of Tarlatamab in this unique patient population.

Rare forms of endometrial cancer: Growth factor levels in tumor tissue and patient serum.

e17623 Background: The pathogenesis of uterine serous carcinoma (USC) and clear cell carcinoma (CCC) is not well understood. Investigating growth factors is crucial for understanding the mechanisms behind their aggressive behavior. The aim of this study was to evaluate the levels of TGFβ1, EGF, and EGFR in tumor tissue and serum of patients with different histological types of endometrial cancer. Methods: The study included 21 patients with USC and 20 with CCC. The comparison group consisted of 20 patients with grade 3 endometrioid endometrial carcinoma (EEC). The diagnosis was morphologically verified and confirmed by postoperative histological examination. The mean patient age was 59 ± 6.8 years. Levels of EGF, EGFR, and TGFβ1 were determined by enzyme-linked immunosorbent assay (ELISA) in tumor tissue homogenates and serum samples. Control samples included intact endometrium (from 20 patients with uterine fibroids) and serum from healthy women (n=20). All patients provided written informed consent. Statistical analysis was performed using parametric and nonparametric tests with correction for multiple comparisons. Results: EEC was characterized by a 1.3- to 2.1-fold increase in EGF, EGFR, and TGFβ1 levels in tumor tissue and serum compared with controls. In USC and CCC tumor samples, TGFβ1 and EGF levels were significantly lower (1.8- to 4.2-fold) than in EEC tumors, while EGFR concentration showed no significant differences. Furthermore, EGF and TGFβ1 levels in CCC and USC tumors were 1.6- to 2.2-fold lower compared with intact endometrium. In contrast, serum levels of the studied growth factors in patients with rare endometrial carcinomas exceeded control values by 2.1- to 3.1-fold but did not differ significantly from levels in EEC patients, with the exception of EGF, the concentration of which was on average 1.5-fold higher. Conclusions: USC and CCC are distinguished from EEC by low levels of EGF and TGFβ1 in tumor tissue but elevated concentrations of EGF in the blood, which may be associated with the activation of alternative signaling pathways. USC and CCC likely actively produce and release EGF into the bloodstream, a process linked to the inflammatory response that stimulates angiogenesis and metastasis. The identified growth factor profiles may contribute to the aggressiveness of rare endometrial carcinomas and explain their resistance to therapy.

Efficacy of multimodal thermal therapy combined with immune checkpoint inhibitors and chemotherapy in unresectable pancreatic cancer with liver metastases.

4209 Background: Treatment of pancreatic cancer with liver metastasis (PCLM) remains extremely challenging. Multimodal thermal therapy (MTT) is a novel treatment method consisting of alternated liquid nitrogen cooling and radiofrequency heating, which was proven to effectively remodel the immune environment and trigger systemic antitumor immunity. This study aims to explore the primary application of MTT combined with subsequent ICls-based systemic therapy in PCLM. Methods: Patients aged 18-70 years with primary diagnosed unresectable PCLM were enrolled in this single-center, prospective clinical trial. Participants received MTT at least one of the liver metastases combined with subsequent ICls and chemotherapy (camrelizumab 200 mg IV on Day 1, gemcitabine 1000 mg/m2 IV, and nab-paclitaxel 125 mg/m2 IV on Days 1 and 8, every 3 weeks for 6 cycles), which was started on day 7 post MTT. The primary endpoints were safety and efficacy. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Exploratory endpoints included immune marker changes induced by MTT. Results: Five patients were enrolled in the trial group and four patients in the control group. All patients in the trial group were well tolerated with MTT, and the MTT-treated liver tumors were completely ablated. One patient withdrew due to autoimmune hepatitis after the first ICIs treatment. One patient achieved success conversion and underwent curative resection 6 months after MTT. Median OS per RECIST was 16.0 months (95% CI 15.3–16.7) in the trial group surpassing 6.2 months (95% CI 1.8–9.2) in the control group (HR 0.26 [95% CI 0.04–1.99]). Histological analysis indicated that combination therapy reversed the immunosuppressive tumor microenvironment, accompanied by enhanced immune-cell infiltration and tertiary lymphoid structures formation within both primary and metastatic lesions. Single-cell RNA-seq of peripheral blood immune cells on day 7 after MTT but prior to ICIs and chemotherapy revealed that MTT promoted the maturation of APCs, increased expression of homing-associated chemokine receptors on circulating B cells and monocytes, and induced the expansion of tumor-trafficking monocytes and CD8 + T cells subsets, which were correlated with favorable prognosis. The effector functions of T cells were also enhanced post MTT, accompanied by increased PD-1 level, which provided the basis for subsequent anti-PD-1 therapy. Conclusions: MTT reshaped both primary and metastatic tumor immune environments, sensitized tumors to subsequent immunotherapy and chemotherapy, well correlating to prolonged OS of PCLM patients. Clinical trial information: NCT06307080 .

Neoadjuvant immunotherapy in combination with chemotherapy in resectable locally advanced head and neck squamous cell carcinoma: Updated efficacy and safety data from a randomized phase II trial.

6091 Background: Neoadjuvant immunotherapy combined with chemotherapy is a promising strategy for resectable LAHNSCC. While most regimens employ single-target PD-1 inhibitors, dual-target agents (PD-1/CTLA-4 or PD-1/VEGF) have shown superior efficacy in recurrent/metastatic HNSCC. Building on our preliminary data (ASCO 2025) which suggested high pathological response rates, this ongoing randomized phase II trial aims to compare single- versus dual-target NAI regimens in an expanded cohort to identify the optimal treatment strategy. Methods: This is an ongoing randomized, open-label, phase II trial. Eligible pts were randomized (1:1:1) to receive 3 cycles of neoadjuvant therapy as follows: Cohort 1 will receive ivonescimab (PD-1/VEGF bispecific antibody, 10 mg/kg every 3 weeks), Cohort 2 will receive cadonilimab (PD-1/CTLA-4 bispecific antibody, 6 mg/kg every 3 weeks), and Cohort 3 will receive penpulimab (PD-1 antibody, 200 mg every 3 weeks), all in combination with cisplatin and nab-paclitaxel. After neoadjuvant treatment, Surgery was performed with the surgical margins based on pre-treatment (baseline) evaluation. Pts with pCR received adjuvant immunotherapy for up to 16 cycles. Pts without pCR received adjuvant radiotherapy or chemoradiotherapy, followed by 16 cycles of adjuvant immunotherapy. Results: Up to Dec. 2025, all 59 pts completed 3 cycles of neoadjuvant therapy and were evaluable, with a median follow-up of 12 months. The pCR rates were 60% (12/20) in Cohort 1, 42.1% (8/19) in Cohort 2, and 40% (8/20) in Cohort 3. The major pathologic response (MPR) rates were 75% (15/20), 57.9% (11/19), and 55% (11/20) in Cohort 1, 2, and 3, respectively. The ORR was 95% in Cohort 1 (CR: 8/20, PR: 11/20) and 84.2% in Cohort 2 (CR: 5/19, PR: 11/19), while Cohort 3 had an ORR of 80% (CR: 4/20, PR: 12/20). To date, pts have received a median of 6 cycles of adjuvant immunotherapy. The most common treatment-related adverse events (TRAEs) (>20%) were: leukopenia, anemia, neutropenia, thrombocytopenia, lymphocytopenia, hypothyroidism, hypertriglyceridemia, radiation dermatitis, stomatitis, vomiting, decreased appetite, and fatigue. Conclusions: Neoadjuvant dual-target (PD-1/VEGF) immunotherapy combined with chemotherapy demonstrated a higher pCR rate compared to dual-target (PD-1/CTLA-4) and single-target PD-1 regimens in resectable LAHNSCC. The treatment was well-tolerated, with all pts completing the intended neoadjuvant therapy and the observed most common TRAEs consistent with expected chemotherapy and radiotherapy profiles. Further analyses are ongoing with continued enrollment. Clinical trial information: NCT06444009 . RECIST and pathologic response. RECIST Pathologic Response CR PR SD PD pCR MPR pPR pNR (RVT=0) (0<RVT<10%) （RVT:10-49%） (RVT:≥50%) Cohort 1 (n=20) 8 11 1 12 3 2 3 Cohort 2 (n=19) 5 11 3 8 3 2 6 Cohort 3 (n=20) 4 12 4 8 3 0 9