Browse Articles

Molecular progression defined by longitudinal ctDNA dynamics for prediction of outcomes in immune checkpoint inhibitor–treated solid tumors.

2572 Background: Reliable early biomarkers of immune checkpoint inhibitor (ICI) resistance remain an unmet need due to delayed imaging and non-classical response kinetics. While ctDNA has shown promise, current methods often require tumor tissue or rely on static comparisons. We investigated whether longitudinal ctDNA dynamics measured using a tumor-naive, methylation-based assay could define molecular progression and predict outcomes in patients receiving ICIs. Methods: Patients with advanced solid tumors treated with ICI regimens were analyzed in a primary cohort (n=65) with serial plasma sampling. Tumor Methylation Scores (TMS) were generated using Northstar Response. Molecular progression based on ctDNA trajectory was assessed for associations with PFS and OS and compared with conventional landmark ctDNA approaches and RECIST v1.1. Independent validation was performed in a second cohort (n=72). Results: Molecular progression strongly stratified survival in the primary cohort (OS HR=4.9, p<0.001; PFS HR=5.3, p=0.0002) and demonstrated superior prognostic performance relative to RECIST. These results were independently validated (PFS HR=4.6, p=0.00004; OS HR=4.3, p=0.005). Notably, among RECIST-defined non-progressors at 6 months, molecular progression identified patients with markedly worse outcomes (PFS HR=6.7, p=0.002; OS HR=4.5, p=0.011). Molecular progression preceded radiographic and clinical progression by median lead times of 63.5 and 77 days, respectively. Conclusions: Longitudinal ctDNA dynamics measured using a tumor-naive methylation assay define molecular progression that robustly predicts survival and identifies early ICI resistance, including in RECIST-stable patients. This approach offers clinically meaningful lead time and supports integration of ctDNA dynamics into response assessment frameworks for immunotherapy.

The neo-epitope-based vaccine OSE2101 with or without pembrolizumab versus best supportive care as maintenance in platinum-sensitive recurrent ovarian cancer patients with controlled disease after platinum-based chemotherapy: The academic randomized TEDOVA/GINECO-OV244b/ENGOT-ov58 trial.

5510 Background: OSE2101 is a neo-epitope vaccine targeting 5 tumor-associated antigens (TP53, MAGE2, MAGE3, CEA and HER2) modified to increase both HLA-A2 and TCR affinity, designed to turn immunogenic ‘cold’ ovarian cancer (OC) to ‘hot’ tumors. Patients with platinum sensitive OC (PSOC) relapsing post-PARP inhibitor (PARPi) and bevacizumab (BEV) represent an area of unmet medical need. Methods: This international multicenter GINECO-sponsored phase II study randomized PSOC patients in CR, PR, or SD after platinum therapy to best supportive care (BSC, arm A), or maintenance treatment with OSE2101 ((SC, q3w until week 18, then q6w to week 48, then q12w, arm B) or OSE2101+pembrolizumab (IV q6w, Arm C) (1:1:2) for up to 2 years. Eligible pts were HLA-A2 positive and previously treated with, or ineligible for, BEV and a PARPi. Primary endpoint was PFS and randomization was stratified for best response to platinum (CR/PR vs SD). Sample size was calculated to provide 90% power to detect an improved PFS in arm C vs A with HR=0.57. Subsequent hierarchical testing then compared arms C vs B, and arms B vs A. Results: 185 pts were randomized to BSC (N=48), OSE2101 (N=46) or OSE+PEMBRO (N=91). Histology was mainly high grade (93%) and serous (93%), 20% harbored a BRCA1/2 mutation, 51% of pts were in CR/PR and 49% in SD at randomization, 85% and 83% of pts were PARPi and BEV-exposed, respectively. Baseline characteristics were balanced between arms. With a median follow up of 22 months, PFS was significantly improved with OSE2101+Pembro vs BSC (4.1 vs 2.8mo in arms C vs A; HR=0.53, 95%CI, 0.36-0.78; p<0.001), especially among pts in CR/PR to platinum (HR=0.31, 95% CI, 0.17-0.53; p<0.01; test for interaction p=0.02). For OSE2101+Pembro vs OSE2101, HR was 0.72 (p=0.074) and for OSE2101 vs BSC, HR was 0.70 (p=0.099). Treatment emergent AEs were increased in arm C vs B with most common being injection site reaction (57% vs 35%), cytokine release syndrome (CRS, mainly G1/2: 28% vs 9%), arthralgia (21% vs 17%) and >G2 immune related events (18% vs 4%). Conclusions: This is the 1 st trial demonstrating a significant improvement in PFS with a combination of a neo-epitope vaccine and an anti-PD1 as maintenance after platinum for patients with platinum sensitive relapsed OC progressing post-PARPi and bevacizumab. Clinical trial information: 2024-516096-32-00.

Validation of Immunoscore for prognostic stratification in HPV-associated oropharyngeal cancer: An international multicenter study.

6077 Background: Treatment optimization in HPV-associated oropharyngeal cancer (OPSCC) remains challenging due to the limited results of de-escalation trials. Existing patient selection criteria, mainly based on smoking history and TNM classification are insufficient and highlight the urgent need for standardized prognostic biomarkers. Herein, we present the first validation of the Immunoscore (IS) as a prognostic stratification tool in HPV-associated OPSCC. Methods: A cohort of 191 HPV-associated (p16⁺ and HPV DNA/RNA⁺) OPSCC patients treated between 2015–2024 was analyzed, including a French training cohort ( N = 48) and three independent validation cohorts: a French retrospective monocentric ( N = 48), a French prospective multicenter ( N = 50) and a US retrospective multicenter cohort ( N = 45). IS, an IHC-based standardized clinical digital pathology assay, quantifies CD3⁺ and CD8⁺ cell densities in tumor cores and invasive margins of FFPE sections. IS cut-offs were defined using the 25 th percentile of immune cell density in the training cohort and subsequently validated across all cohorts. Associations with disease-free survival (DFS), time to recurrence (TTR), and overall survival (OS) were assessed, along with immune profiling by 3′RNA-seq and sequential immunofluorescence. Results: Median age 65; 80% male; 74% smokers; 66% T1-2; 82% N0-1 (AJCC 8 th ). Treatments included surgery only (9%), radiotherapy ± chemotherapy (27%) and surgery + radiotherapy ± chemotherapy (64%). 52.4% were IS-High ( N = 100) and 47.6% IS-Low ( N = 91). IS-High patients showed significantly improved DFS, consistently across the training and validation cohorts 1-3 (log-rank P = 0.0004, 0.003, 0.006, and 0.001, respectively). Multivariable analysis identified IS-Low as the strongest independent risk factor for DFS (HR 9.27; 95% CI: 4.14-20.76; P < 0.001), outperforming smoking status, T/N stage, and treatment modality. The model combining IS with clinical factors showed higher predictive accuracy for DFS (C-index 0.82) than clinical variables alone (0.70; P < 0.0001). Similar strong prognostic value of IS was observed for TTR (HR 7.64; 95% CI: 3.37-17.33; P < 0.001) and OS (HR 7.26; 95% CI: 2.77-18.99; P < 0.001). IS-High tumors showed enrichment of lymphoid and myeloid immune cell populations, contrasting with immune-poor signatures in IS-Low tumors (all P < 0.05). Conclusions: IS is a robust biomarker that outperforms standard clinical variables in both prognostic and predictive accuracy. The enriched cytotoxic immune infiltrate in IS-High tumors explains favorable outcomes and supports their potential suitability for treatment de-escalation. Prospective validation in future trials is warranted.

Epimedin A to prevent glioblastoma growth and invasion.

e14078 Background: Glioblastomas (U87) are an aggressive brain tumor that arises from glial cells and invades surrounding parts of the brain. The prognosis for glioblastoma is poor, with a median survival rate of 15 months with treatment. Treatments are aggressive with severe side effects. Molecular therapeutics are required to control U87 cell growth with a better safety profile. Several plant-derived compounds were tested for chemo preventive effects against glioblastoma. However, the role of Epimedin A, isolated from the genus of low-growing plants known as Epimedium (Horny Goat Weed), in preventing cancer growth is not clear. We examined the chemo preventive effects of Epimedin A in U87 cells. We specifically investigated the effects it has on cell proliferation, apoptosis, oxidative signaling, and migration. Methods: U87 cells obtained from ATCC were treated with an increasing concentration of Epimedin A (0-100 uM) ± EGF. Cell viability was examined using the MTT assay, while invasion and migration were assessed by scratch and transwell migration assays, respectively. Expression of various apoptotic proteins was measured by an antibody array. Reactive oxygen species levels were measured using fluorescence-based assay. Statistical comparisons were performed using one sided t test for a prespecified directional hypothesis and reported using mean ± standard deviation. Results: Our results suggest that Epimedin A prevents the growth of U87 cells in a dose-dependent manner, with 60µM producing the greatest reduction in cell proliferation under EGF stimulation. Furthermore, Epimedin-A also prevented the invasion and migration of U87 cancer cells. Additionally, Epimedin A increased caspase-3 expression, as measured by PARP cleavage under EGF stimulation, and reduced the formation of reactive oxygen species. Epimedin A also regulates the expression of various pro- and anti-apoptotic proteins such as Bcl-x, HIF-1alpha, Bad, Bax, cleaved Caspase-3, Cytochrome C, SMAC/Diablo. Conclusions: Epimedin A has displayed inhibitory effects on U87 cells' viability. Specifically, studies showed inhibitory effects on proliferation, migration, and ROS. Further, Epimedin A regulates the expression of various pro- and anti-apoptotic factors and inflammatory markers in cancer cells. We next planned to examine its in vivo efficacy using nude mice xenografts. Thus, our results indicate that Epimedin A inhibits the growth of U87 cells and may act as a chemo preventive agent.

Heart failure–related mortality among U.S. liver and intrahepatic bile duct cancer patients: A 25-year CDC WONDER analysis.

e16220 Background: Liver and intrahepatic bile duct cancer (L/IBDC) is a leading cause of cancer mortality worldwide. Comorbid heart failure (HF) may exacerbate outcomes, yet national trends in HF-related mortality among L/IBDC patients remain poorly characterized. This study evaluates U.S. mortality trends from 1999–2023. Methods: This study, adhering to STROBE guidelines, analyzed heart failure–related mortality trends among U.S. adults (≥25 years) with liver and intrahepatic bile duct cancer from 1999–2023 using CDC WONDER Multiple Cause of Death (MCOD) data. Deaths were identified via ICD-10 codes for L/IBDC (C22.0–C22.4, C22.7, C22.9) and HF (I50.0–I50.1, I50.9), with demographic categorization by age, sex, race/ethnicity, census region, state, place of death, and urbanization. Crude and age-adjusted mortality rates (CRs and AAMRs) were calculated per 100,000 population. Joinpoint regression assessed trend changes, reporting Annual Percent Changes (APCs) and Average Annual Percent Change (AAPCs) with 95% CIs. Results: From 1999–2023, 15,669 deaths occurred among adults with L/IBDC and HF (AAMR: 0.21–0.50). Overall, AAMRs increased, with APCs of 0.57 (1999–2012) and 7.53 (2012–2023). Males had higher AAMRs than females throughout the study period, with the largest rise from 2014–2023 (0.35–0.71; APC 7.58). Older adults (65–85+) had the highest mortality, with AAMRs increasing from 0.92–2.18 (APC 8.90, 2014–2023). Regionally, the Southern U.S. experienced the highest mortality (0.51; 95% CI: 0.47–0.56; APC 8.71), while the lowest increases were observed in the West (0.24–0.78). Metropolitan areas had consistently higher AAMRs than non-metropolitan areas (0.18–0.36; APC 6.32, 2012–2020). Non-Hispanic Whites had higher mortality than non-Hispanic Blacks (0.18–0.51; APC 8.56, 2012–2023). Most deaths occurred at home (1999–2020: n = 4,512; 2021–2023: n = 1,580). State-level AAMRs were highest in Mississippi (0.39; 95% CI: 0.33–0.45, 1999–2020) and Minnesota (0.78; 95% CI: 0.63–0.93, 2021–2023), and lowest in Arizona (0.13; 95% CI: 0.11–0.15) and New York (0.24; 95% CI: 0.20–0.28). Conclusions: HF-related mortality among L/IBDC patients has risen steadily over the past two decades, particularly among males, older adults, non-Hispanic Whites, and residents of Southern metropolitan regions. Recognition of these trends can guide targeted interventions, improve management of HF in L/IBDC patients, and inform public health strategies.

Prognosis of mediastinal lymph node metastases in pediatric patients with osteosarcoma and lung metastases.

e22006 Background: Metastasectomy is recommended for select pediatric patients with osteosarcoma with resectable pulmonary parenchymal metastases. It is unclear whether pulmonary metastasectomy confers the same benefit to patients with hilar or mediastinal lymph node metastases (LNM). This study aims to characterize pediatric patients with osteosarcoma with thoracic LNM and their outcomes compared to those with only pulmonary parenchymal metastasis. Methods: This is a retrospective cohort study of patients aged 0-21 with osteosarcoma metastatic to the lung who underwent pulmonary metastasectomy between 2000-2024. Patients were categorized into groups based on the presence or absence of LNM on imaging reviewed by pediatric surgeons and radiologists. Descriptive statistics and Wilcoxon rank sum, chi-square or Fisher’s exact tests evaluated differences between patients with and without LNM. Kaplan-Meier survival curves with log-rank tests evaluated the relationship between the presence of LNM and outcomes. The primary outcome was overall survival (OS) with secondary outcomes of recurrence-free survival (RFS) and disease-free survival (DFS). Results: 39 patients met inclusion criteria for this study, of which 13 (33%) had LNM (Table). Of the 13 patients with LNM, 8 (62%) had a pulmonary metastasectomy after their LNM diagnosis. Patients with LNM had poorer OS after first metastasectomy (log-rank p = .027), DFS after first metastasectomy (p = .018), and RFS after diagnosis (p = .039) than patients with pulmonary parenchymal metastasis without LNM. Patients who underwent metastasectomy after their LNM diagnosis had improved OS after LNM diagnosis than patients who did not undergo metastasectomy (pairwise log-rank test with Bonferroni correction p = .015). Conclusions: Pediatric patients with osteosarcoma metastatic to the lung with LNM had poorer OS, DFS, and RFS compared to patients without LNM. These results confirm the importance of attention to the presence of nodal involvement in patients with pulmonary metastatic osteosarcoma. Despite their poor prognosis, these results suggest a persistent survival benefit to surgical intervention. Total N = 39 No LMN N = 26 LMNN = 13 p Age 13.7 (9.5, 16.1) 13.9 (9.0, 15.9) 13.7 (10.7, 16.5) .777 Female 15 (38%) 10 (38%) 5 (38%) > .999 Histology Chondroblastic Osteoblastic Telangiectatic 11 (39%)16 (57%)1 (3.6%) 9 (50%)8 (44%)1 (5.6%) 2 (20%)8 (80%)0 (0%) .162 Primary tumor site Chest wall Femur Humerus Pelvis Radius Tibia 2 (5.1%)24 (62%)5 (13%)2 (5.1%)1 (2.6%)5 (13%) 2 (7.7%)14 (54%)3 (12%)2 (7.7%)1 (3.8%)4 (15%) 0 (0%)10 (77%)2 (15%)0 (0%)0 (0%)1 (7.7%) .821 Lung metastases present at time of diagnosis 20 (51%) 13 (50%) 7 (54%) .821 Treatment protocol AOST0331 AOST06P1 CCG 7921 P9754 30 (81%)2 (5.4%)4 (11%)1 (2.7%) 19 (79%)1 (4.2%)3 (13%)1 (4.2%) 11 (85%)1 (7.7%)1 (7.7%)0 (0%) > .999 Lung nodules removed during first metastasectomy 3 (2, 6) 3 (2, 5) 6 (1, 20) .567

Late hematological toxicity after chemotherapy: Exome analysis with long-term follow-up in Mexican population.

e24145 Background: Genomic alterations chemotherapy-induced are associated with cytopenias, myelodysplasia, or acute leukemia. Methods: Patients with cancer who achieved a complete response after chemotherapy, had a normal blood cytology and thereafter developed a cytopenia (group 2), + myelodysplasia or acute leukemia (group 3, G-3) were included. Control group (group 1): cases with the same malignancy, age, treatment, and follow-up, except for the development of a late cytopenia. Samples: The genomic DNA (gDNA) was extracted from peripheral blood by standard methods. Thereafter, the Whole Exome Sequencing (WES) libraries were prepared using Illumina DNA Prep with Exome 1.0 Enrichment (Illumina, San Diego CA, United States). All libraries were quantified with the Qubit dsDNA BR Assay Kit (Invitrogen, Carlsbad, CA, USA), libraries size was analysed in S2 Standard DNA Cartridge for Sep 400 (BiOptic, New Taipei City, Taiwan), and sequencing was performed in a NovaSeq 6000 (Illumina, San Diego CA, United States) in a 150 bp pair-end configuration. Computational Analysis: As an initial step, the raw sequence was pre-processed using Trimmomatic 0.40. Pre-processed sequences were aligned to the human reference sequence (hg38) using the Illumina-Dragen Enrichment pipeline (lllumina, San Diego CA, United States). The BAM files resulting from the enrichment were removed from PCR duplicates using Picard Tools (http://broadinstitute.github.io/picard.). Each BAM file was used to obtain the somatic variants using the GATK pipeline, and variants were annotated using ANNOVAR the following databases: Clinvar, gnomAD, refGene, cytoBand, exac03, avsnp147, dbnsfp30a. The somatic variants were then transformed to MAF using Funkotator from the GATK. Additionally, converted annotated variant files were analyzed with the Maftools package from the R programming language to visualize the landscape of critical mutations. Results: After comparing the 3 groups: The 10 top genes with mutations and allelic variants were: MUC12,HLA-DRB1, MUC 16, TTN, HLA-B, HLA-A, HLA-C, FLG, ZNF717, MUC6 & FLG . A greater dispersion in the MUC6, MUC 12, HLA-A, FLG, and TTN genes was found in G-3. The gen MUC6 had the highest number of mutations, including shallow amplification, deep deletion, and amplification. Most of the mutations in G-3 included missense mutations, in frame deletions, and shallow amplification. After analyzing with Oncogenic Signaling pathways in TCGA cohorts, the main pathway involved was RTK-RAS. No statistical difference was found between the level of mutations and the ratio of SNP’s. Conclusions: Mutations and allelic variants vary between patients with cytopenias and secondary myelodysplasia/leukemia. A deeper analysis of these changes is required.

Advancing career-focused training: Program leader perspectives on professional development pathways in hematology/oncology fellowships.

9008 Background: Hematology/Oncology (H/O) fellows have diverse career opportunities post-graduation. Many fellowship programs have created specialized training pathways for trainees to support career-aligned skill development, defined here as professional development pathways (PDPs). These may include specific training for careers in laboratory/translational research, medical education, and quality improvement. There is limited data regarding utilization and perception of PDPs in H/O fellowship programs. Methods: We conducted a national cross-sectional survey of United States (US) H/O fellowship program leaders (PLs) to assess: (1) prevalence of PDPs, (2) perceived value of PDPs, and (3) barriers to implementation. The survey underwent content validation by three experts – program directors (PDs) in different fellowship subspecialties – who reviewed the instrument for clarity, relevance, and comprehensiveness. The survey was distributed electronically to 180 US H/O fellowship programs; responses were anonymous. Results: 72 responding PLs completed the survey (40% response rate). Program size ranged from 2 to 16 fellows per year. Programs from all US geographic regions were represented; 78% were affiliated with academic hospitals and 17% with academically affiliated community hospitals. Less than half (45%) report offering PDPs. The majority (78%) of PLs agree/strongly agree that PDPs provide fellows with more focused career-concordant training. Among the 32 programs with PDPs, 84% report PDPs align with fellows’ post-graduation careers. Most (66%) have fellows select their PDP during the first year of fellowship; PDP selection is mandatory in 56%. Eleven distinct PDPs were described, most commonly clinical research (84%), clinical practice (69%), and basic science research (63%). Core PDP components include clinical experiences (100%), scholarly projects (88%), and structured mentorship (82%). Among the 40 programs without PDPs, 63% perceive value in adding them. Reported barriers include difficulty integrating PDPs into current fellowship structure (60%), lack of appropriate faculty mentors (55%), and lack of PD bandwidth (53%). Resources identified that would support implementation include dedicated time or support for mentorship (68%), sample curricular or implementation tools (68%), access to non-clinical infrastructure (e.g. research, quality improvement, education) (63%), and funding (45%). Conclusions: While most US H/O fellowship PLs view PDPs as valuable for trainee career development, less than half of responding programs currently use them. Addressing institutional and programmatic barriers and providing curricular resources, dedicated time for faculty mentors, and funding may enable wider implementation. Future studies should explore existing PDP structures and define best practices for PDP utilization.

Clonal hematopoiesis in head and neck carcinomas receiving immunotherapy.

6064 Background: Clonal hematopoiesis (CH) is an age-related accumulation of somatic genetic alterations in hematopoietic stem cells. It is implicated in the evolution of myeloid neoplasms and has been associated with poor prognosis in patients with solid tumors. Immunotherapy (ITx) has become the standard of care in the treatment of recurrent/metastatic head and neck cancer (R/M HNSCC), however, response rate corresponds to 20% of total population and relies in a robust innate host immunity. This study aims to identify the presence of CH among ITx-treated R/M HNSCC patients and its potential association with treatment outcomes. Methods: Matched pre-treatment peripheral blood (PB) and tumor tissue samples of 32 ITx-treated R/M HNSCC patients were used for DNA extraction. The ten most commonly mutated CH genes were sequenced using a custom NGS Qiagen panel with unique molecular identifiers. Low confidence and synonymous variants were excluded. Pathogenic, likely pathogenic and conflicting with moderate or high annotation impact variants based on the ClinVar database were investigated for associations with progression-free (PFS) and overall survival (OS) as well as for differences in expression between blood and tissue. The same gene alterations and their correlation with survival in HNSCC were also explored in three public datasets (TCGA, GENIE, MSKCC) as an external validation of our findings. Results: A total of 2,088 variants were detected with 1,222 silent variants. After filtering,105 pathogenic, likely pathogenic and conflicting interpretation variants were retained. Mutations in CH related genes were identified in 18 out of 32 PB samples (56%). In tissue samples, (excluding TP53 ) mutations were identified in 12 out of 32 samples (37%). TP53 mutations were significantly higher in tissue samples versus PB ( P =0.028). PPM1D mutations in PB were correlated with shorter PFS ( P =0.003) and OS ( P =0.0116), while TP53 mutations in tissue showed a trend for decreased OS ( P =0.097). TCGA and MSKCC analysis confirmed a negative association of TP53 mutations in tissue with OS ( P =0.0020, P =0.0001, respectively). Conclusions: CH was frequently detected in PB and tumor tissue of R/M HNSCC patients. CH-related PPM1D mutations in PB and TP53 in tumor tissue, were associated with shorter PFS and OS to ITx, suggesting a potential association between both peripheral and intratumoral immune contexture and clinical outcomes.

Smoking signature as used to define a genomically distinct subset of class I BRAF-mutant NSCLC.

8538 Background: Class I BRAF mutant ( BRAF mut) non–small cell lung cancer (NSCLC) is biologically heterogeneous, occurring in both smokers and never-smokers with disparate benefits from immunotherapy (IO). Genomically defined tobacco-induced damage may better identify biologically and clinically distinct subsets than self-reported smoking history. We evaluated COSMIC mutational signature-SBS4 as a genomic surrogate of smoking exposure and examined its association with molecular features, tumor microenvironment (TME) and outcomes in BRAF mut NSCLC. Methods: Retrospective review of 33,217 NSCLC specimens that underwent whole exome and whole transcriptome sequencing at Caris Life Sciences. Mutation profiles of specimens were deconvolved using the COSMIC SBS4 signature to estimate tobacco-associated mutational exposure (filter: total mutation count>=200, Nfiltered=26448; BRAF mut = 276). TME was estimated using QuanTIseq method. Overall survival (OS) and survival on IO (IO-OS) were obtained from insurance claims and calculated from date of tumor biopsy (for OS) or initiation of IO (for IO-OS) to last contact using Kaplan-Meier estimates and Cox proportional hazards models. Statistical significance was determined by Fishers Exact, chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons ( P <0.05). Results: Among 6,405 patients with smoking history and SBS4 data, SBS4+ (SBS4>0) was strongly associated with smoking (OR 11.2, P <0.001). SBS4+ tumors exhibited elevated TMB (mean:13 vs 9 mut/Mb, and TMB-High [>=10 mut/Mb], P <0.05, Table). SBS4+ BRAF mut tumors had a lower prevalence of mutations in SETD2 (OR 0.33), PIK3CA (OR 0.26) and SMAD4 (OR 0.25, all P <0.05). Regardless of SBS4 status, BRAF mut tumors were more often PD-L1+ (OR 3.2, TPS>=1), while mutations in STK11, KEAP1 , and SMARCA4 were less frequent (OR 0.07-0.37, all P <0.05). Evaluation of the TME revealed that SBS4+ BRAF mut were enriched for regulatory T cells (vs. SBS4-,1.44 fold, P <0.05). In metastatic disease, BRAF mut showed improved OS (HR 0.8[0.66-0.97], P =0.03) and IO-OS (HR 0.8[0.66-0.99], P =0.04) compared to WT. The OS benefit was preserved in the SBS4+ tumors (HR 0.64[0.43-0.95], P =0.03), but not in SBS4- tumors. No difference in IO-OS was observed in SBS4+ subgroups likely due to small size. Conclusions: SBS4 identifies biologically distinct subsets in class I BRAF mut NSCLC, with differences in mutational landscape, TMB, and TME. SBS4+ tumors show a survival benefit over WT disease, whereas SBS4- tumors do not. These findings support SBS4 as a genomic marker of smoking-related biology and a potential tool to refine therapeutic decision-making between targeted therapy and IO in NSCLC and potentially other smoking-associated cancers. Smoking signature in BRAF mut NSCLC (% prevalence and OS). Characteristics SBS4 + SBS4 - SETD2 20 43 PIK3CA 6 19 SMAD4 3 12 TMB-high 41 18 OS (months) 29.9 vs. 11.9 ( P =0.03) 16.0 vs. 10.9 ( P =0.47)

Which evolutionary game-theoretic model best captures NSCLC dynamics?

Understanding and predicting the eco-evolutionary dynamics of cancer requires identifying mathematical models that best capture tumor growth and treatment response. In this study, we fit a family of two-population models to in-vitro data from non-small cell lung cancer (NSCLC), tracking drug-sensitive and drug-resistant cells under varying environmental conditions. The dataset, originally presented by Kaznatcheev et al., includes conditions with and without the drug Alectinib and cancer-associated fibroblasts (CAFs). We compare combinations of growth models (logistic, Gompertz, and von Bertalanffy) and drug efficacy terms (Norton–Simon, linear, and ratio-dependent) to identify which best explains the observed dynamics. Our models incorporate density dependence, frequency-dependent competition, and drug response, enabling mechanistic interpretation of tumor cell interactions. The logistic model with ratio-dependent drug efficacy best fits monoculture data. Using growth parameters from monocultures, we estimate inter-type competition coefficients in co-cultures. We find that growth rate and carrying capacity are stable across CAF conditions, while competition and drug efficacy parameters shift, altering interaction dynamics. Notably, CAFs promote coexistence between resistant and sensitive cells, whereas Alectinib results in competitive exclusion. Our results underscore the need to evaluate both model fit and biological plausibility to guide therapeutic modeling of cancer.

Radical Cascade Combining Cross‐Olefin Coupling with the Smiles‐Truce Rearrangement

ABSTRACT Radical cascade reactions enable the swift and efficient assembly of complex molecular architectures. These transformations are especially valuable when initiated from readily available substrates bearing native functionalities. In this work, we describe the development of a cascade reaction that selectively combines two alkene starting materials, forming three new bonds in a single step. This transformation is initiated by polarity‐matched, catalytic hydrogen atom transfer from a cobalt catalyst to an electron‐rich styrene double bond. Subsequent Giese‐addition of the carbon‐centred radical occurs and, when using N ‐sulfonyl acrylamides as the Michael acceptors, a radical cascade reaction is triggered to yield α,γ‐diarylated amides via Smiles‐Truce rearrangement. This allows for the construction of complex organic molecules with sterically hindered aryl substituents in a swift manner under mild conditions.

Phytofabrication and characterization of ZnO NPs using Eucalyptus globulus leaves extract for remediation of heavy metal ions

Decoding THz‐Driven Dynamic Fingerprints of Ferroelectric Nanotwin Networks

ABSTRACT Ultrafast polarization dynamics in ferroelectrics are of considerable interest for high‐speed tunable dielectrics and electro‐optics. Extended domain wall networks formed in ferroelectric twin nanodomains can support collective dynamics in the terahertz regime but require techniques that track polarization and strain evolution driven by ultrafast stimulus. Here, we use multi‐modal probing of THz‐pulse‐driven excitations in PbTiO 3 /SrTiO 3 superlattices by combining X‐ray free electron laser measurements that directly tracks lattice changes, with optical second harmonic generation that tracks the electronic potential coupled with the lattice potential. Dynamical phase‐field modeling enables fingerprinting of these collective modes as superpositions of domain “breathing” through wall oscillations and polarization “rotations” with still walls. Ultrafast domain wall motion at 0.1–0.5 THz is observed at practical fields of 100 kV/cm with wall velocities of >4000 m/s, approaching typical speed of sound in PbTiO 3 . A unique “charging” mode is discovered that can electrically charge and discharge domain walls on ∼4 ps time scale thus dynamically tuning wall conductivity. Integrated experimental and theoretical fingerprinting of the dynamical landscape presented here enables ultrafast control of ferroics for high‐speed microelectronics and optical applications.

Synaptic Functionality and Neuromorphic Information Processing in Membrane Ion Channel Junctions

ABSTRACT The human brain performs complex memory and computational tasks with high energy efficiency by regulating ion transport through membrane channels. These signaling mechanisms have been inspiring the development of nanofluidic memristors that emulate synaptic behavior. Here, we describe a membrane ion channel synapse (MICS), constructed from aqueous droplets linked by gramicidin A channels, that achieves neuromorphic functionality. MICS exhibits memristive ion transport with hysteretic current–voltage behavior arising from voltage‐dependent channel formation and ion transport dynamics. MICS emulates a range of synaptic behaviors including associative learning. We further demonstrate its application in reservoir computing by performing handwritten digit classification and tic‐tac‐toe game and explore the system parameters that improve the computational performance. This droplet‐based biomimetic synapse offers a potentially scalable and energy‐efficient platform for next‐generation neuromorphic computing systems.

An event-based resilient consensus algorithm for secure and low-carbon operation of cyber-physical smart grids

A functional SNP rs12718466 in APOA1 promoter modulates gene expression via interaction with SOX7

Associated antitumor effects of oncoytic vaccinia virus expressing a tethered IL-12/IL-2 fusion cytokine.

e14557 Background: Cancer immunotherapy has revolutionized cancer treatment, but many solid tumors remain non-inflamed and resistant to current approaches. This necessitates strategies to convert "cold" tumors into "hot" (immune-inflamed) ones. Oncolytic viruses (OVs), especially those engineered to deliver immunostimulatory molecules like cytokines, offer a promising solution. Cytokines, however, face limitations such as short half-lives, high dose requirements, and systemic toxicities in clinical use. Our previous work showed that intratumoral delivery of tethered IL-2 or IL-12 via oncolytic vaccinia viruses (oVV) achieved strong antitumor effects without systemic toxicity. This study hypothesized that an oVV expressing a tethered fusion cytokine of IL-12 and IL-2 could achieve superior antitumor effects compared to single-cytokine viruses. Methods: We engineered two oncolytic vaccinia viruses: one expressing a single-chain IL-12 (vvDD-scIL-12-FG) and another expressing a tethered fusion cytokine of IL-12 and IL-2 (vvDD-scIL-12-R-IL-2-RG) via homologous recombination. Transgene expression was confirmed by RT-qPCR, and membrane association was validated by flow cytometry. We evaluated the antitumor efficacy across multiple murine tumor models and investigated the underlying mechanisms of action using RT-qPCR and flow cytometry. Results: Our data confirm successful expression and membrane tethering of the IL-12/IL-2 fusion cytokine without impairing viral replication or cytotoxicity. Treatment with vvDD-scIL-12-R-IL-2-RG demonstrated robust antitumor activity in Lewis lung carcinoma, renal adenocarcinoma Renca, and murine colon adenocarcinoma MC38 models. Notably, in a late-stage MC38 colon cancer model, 85% of mice achieved complete tumor regression without systemic toxicity. Critically, vvDD-scIL-12-R-IL-2-RG outperformed viruses expressing tethered IL-2 or IL-12 alone. Mice cured by vvDD-scIL-12-R-IL-2-RG resisted rechallenge with MC38 cells but not unrelated B16 melanoma cells, indicating durable, tumor-specific immunity. Mechanistically, vvDD-scIL-12-R-IL-2-RG treatment elevated intratumoral Th1 chemokines and IFN-γ, alongside increased infiltration of IFN-γ⁺ CD8⁺ T cells. Peripheral lymphocyte depletion did not significantly attenuate these superior antitumor effects, suggesting reliance on pre-existing tumor-infiltrating lymphocytes. These changes effectively converted non-inflamed tumors into immune-inflamed ones, driving superior responses. Conclusions: Our findings indicate that an oVV-delivered, tethered IL-12/IL-2 fusion cytokine is both safe and effective, making it a promising candidate for clinical translation in cancer immunotherapy.

Proton or photon? Comparative survival and toxicity outcomes in lung cancer radiotherapy: A systematic review and meta-analysis.

e20048 Background: Radiotherapy (RT) is a cornerstone in non-small cell lung cancer (NSCLC) management. Conventional photon-based RT uses high-energy X-rays to induce DNA damage in tumor cells but inevitably exposes surrounding normal tissue. Proton beam RT offers more conformal dose delivery, potentially decreasing toxicity, yet its clinical superiority remains uncertain. Methods: Pubmed, MEDLINE, and Embase were systematically searched for observational studies comparing both modalities. Random-effects meta-analysis was used to pool risk and hazard ratios (RR/HR) for toxicity, along with 95% CIs and I² for heterogeneity. The study is registered in PROSPERO (CRD420261288838). Results: A total of 7 observational studies with a pooled population of 246,267 individuals were considered, out of which 245,216 received Photon RT and 1,051 received Proton RT. 5 studies of locally advanced/Stage II-III NSCLC were pooled for OS, demonstrating a non-significant trend favoring proton therapy (HR 0.79, 95% CI 0.51-1.23; P = 0.29; I² = 60%). Two studies of early-stage/Stage I NSCLC treated with SBRT showed no significant OS benefit on the pooled analysis (HR 0.70, 95% CI 0.32-1.55; P = 0.38; I² = 85%). In centrally located early-stage NSCLC treated with SBRT, Proton RT showed comparatively less toxicity (RR 0.32, 95% CI 0.14-0.74; P = 0.008). Other toxicity endpoints are presented in table 1. Photon RT has been the standard for lung cancer for decades because of its proven tumor control and acceptable toxicity. Our pooled analysis shows that proton therapy achieves similar OS and major toxicity outcomes, aligned with prior institutional and database studies that failed to demonstrate consistent superiority of protons in unselected populations. This equivalence is biologically plausible: both the Bragg peak and reduced exit dose may benefit from this, but this benefit can be diluted by motion uncertainty, range errors, and conservative planning margins. Therefore, routine replacement of photons is not supported; however, protons remain justified in anatomically high-risk settings where normal tissue sparing becomes clinically decisive. Conclusions: Proton therapy achieves survival and toxicity outcomes comparable to photon RT in NSCLC, supporting its role as a targeted option for selected high-risk cases rather than a universal replacement. Keywords: Proton, Photon, Radiotherapy, Lung cancer. Other toxicity endpoints. Outcome Grade Effect (RR, 95% CI) p-value I² Severe pneumonitis ≥ 3 1.29 (0.69-2.41) 0.43 0% Severe esophagitis ≥ 3 1.39 (0.44-4.32) 0.57 0% Cardiotoxicity ≥ 3 0.67 (0.19-2.30) 0.52 3% Pneumonitis ≥ 2 0.79 (0.44-1.41) 0.43 61%

Cerebrovascular mortality in patients with head and neck cancer in the United States, 1999-2023: A population-based analysis.

e18106 Background: Survival gains in head and neck cancer (HNC) have increased the importance of non-cancer mortality in older adults. Cerebrovascular disease is a major competing cause of death due to shared risk factors and treatment-related vascular injury, yet long-term national and subgroup-specific mortality trends remain poorly defined. Therefore, we evaluated national and subgroup-specific cerebrovascular mortality trends in U.S. adults aged ≥55 years with HNC from 1999–2023. Methods: Death certificates from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database were examined from 1999 to 2023 for multiple causes of death using multiple causes of death (MCD) MCD-ICD-10 codes for head and neck cancer (C00–C14, C30–C32) and cerebrovascular disease (I60–I69). Age-adjusted mortality rates (AAMRs) per 100,000 persons and annual percent change (APC) were calculated for older adults (age 55+) and stratified by ten-year age group, sex, race/ethnicity, census region and state. Results: From 1999–2023, 14,255 cerebrovascular-related deaths occurred in older adults with Head and Neck Cancer. Overall mortality declined from 1999–2010 (AAMR dropped from 1.03 to 0.6; APC –4.54%, 95% CI –8.07 to –3.41,p=0.02), plateaued till 2016 (AAMR: 0.61; APC –0.24%, 95 CI -3.99 to 4.84, p = 0.89), and then increased significantly till 2023 (AAMR: 0.87; APC 6.09%, 95% CI 4.06 to 10.82, p=0.006). Among females, AAMR declined from 0.52 in 1999 to 0.26 in 2016 (APC –4.21%, 95%CI -6.3 to -3.0) and then increased to 0.41 by 2023 (APC 9.01%, 95% CI 4.40 to 20.27). For males, AAMR declined from 1.76 in 1999 to 1.0 in 2014 (APC –4.01%, 95%CI -4.98 to 3.24) and then increased to 1.44 by 2023 (APC 5.66%, 95% CI 4.14 to 7.81). In 2023, AAMRs were highest among NH Black individuals (0.97), followed by NH White (0.91) and NH Asian (0.49) populations. Regionally, South had the highest AAMR(0.96) in 2023 followed by the Midwest (0.88), West (0.81) and Northeast (0.7). State-level AAMRs peaked in Oregon (1.89), Minnesota (1.84), and Wisconsin (1.47), with lowest rates in California (0.75) and New York (0.64). Conclusions: After decades of decline, cerebrovascular mortality in Head and Neck Cancer patients has risen markedly since 2016, especially among women and Black individuals. These findings underscore the need for cerebrovascular screening and prevention strategies integrated into survivorship care.