BACKGROUND:Multiplex nucleic acid amplification tests (NAATs) are essential for managing respiratory viral infections. To robustly confirm the capability of laboratories for multiplex respiratory viral detection, a well-designed, large-scale external quality assessment study incorporating in-depth analysis was conducted. METHODS:Laboratories performing multiplex viral NAATs in China were publicly recruited and provided with a reference panel to assess their testing performance. Multivariate analysis was performed on the collected results and detailed methodological data to identify potential sources of errors. RESULTS:Among 914 participating laboratories, overall concordance was 81.6% (746/914). False-positives (FPs) were concentrated in 13 laboratories, suggesting the occurrence of laboratory contamination. False-negatives (FNs) were more prevalent, primarily occurring in samples with low viral loads. Multivariate analysis identified capillary electrophoresis-based multiplex PCR assay (aOR = 2.1, 95% CI: 1.1-3.8), certain commercial kit (Flu/RSV kit [Autobio], aOR = 102.2, 95% CI: 13.4-776.0), and laboratory-developed tests (aOR = 6.59, 95% CI: 2.2-19.8) as independent risk factors for FNs. Suboptimal laboratory performance also increased the odds of FNs. CONCLUSIONS:This study demonstrates the advances and limitations of multiplex viral NAATs: high adoption and acceptable concordance reflect the technology's maturity, yet the occurrence of FNs and FPs highlights a need for continued assay optimization, strengthened laboratory quality management, and increased clinician awareness of testing limitations.

Although tumor immunotherapy has shown significant efficacy against solid tumors, it frequently causes cutaneous and follicular adverse events resulting from disruption of the hair follicle immune microenvironment. This microenvironment is maintained through careful regulation by immune cells and cytokine networks to support normal hair cycling. Immune checkpoint inhibitors disturb this balance by activating T cells, promoting macrophage polarization toward pro-inflammatory phenotypes, upregulating inflammatory cytokines such as tumor necrosis factor-alpha, and activating Toll-like receptor/nuclear factor-kappa B signaling pathways, ultimately leading to follicular toxicity including alopecia. Encompass relies mainly on topical corticosteroids and other immunomodulatory agents. A deeper understanding of these mechanisms is essential to identify key regulatory nodes for future targeted interventions.

Metformin exhibits immunomodulatory properties in cancer treatment, but the underlying mechanisms remain elusive. Using genome-wide CRISPR screening, we identified SLC5A11 as an essential mediator of metformin sensitivity. Molecular docking and dynamics simulations revealed direct metformin-SLC5A11 binding at the pocket containing Asn78 and Glu102 residues. Metformin suppressed PD-L1 expression across multiple cancer models through SLC5A11-dependent activation of AMPK and subsequent JAK2-STAT1-IRF1 downregulation. SLC5A11 knockout abolished these effects, while reconstitution restored metformin responsiveness. In syngeneic mouse models of lung and pancreatic cancer, combining metformin with anti-PD1 therapy produced synergistic antitumor effects, enhanced T cell infiltration, and potentiated immunotherapy efficacy. Metformin pretreatment significantly enhanced PBMC-mediated cytotoxicity against tumor cells and patient-derived organoids in ex vivo co-culture systems. Our findings establish the SLC5A11-AMPK-PD-L1 axis as a novel mechanism linking metformin to tumor immunity, providing a molecular rationale for combining metformin with checkpoint inhibitors in cancer immunotherapy.

Abstract Background Adenocarcinomas often exhibit a poor response to immunotherapy due to their "cold tumor" nature and immunosuppressive microenvironment. Cancer-testis antigens (CTAs), which are selectively expressed in tumors but absent in most normal tissues, represent ideal targets for tumor-specific therapies. Despite promising individual CTAs like MAGE-A, MSLN, and PRAME, a systematic analysis of their role across various adenocarcinomas is lacking. Methods In this study, we explored the expression profiles, prognostic significance, and immunomodulatory roles of cancer-testis antigens (CTAs) across various types of adenocarcinomas. By integrating data from The Cancer Genome Atlas (TCGA) with a validation cohort of 198 patients, comprising cases of colon, rectal, and lung adenocarcinomas, we analyzed six CTAs (CT83, MAGEA1, MAGEA4, MAGEA10, MSLN, and PRAME) utilizing survival analysis and immunohistochemistry techniques. Results Our findings revealed that CTAs exhibit tumor type-specific expression profiles. Notably, MSLN was highly expressed in colon adenocarcinoma (COAD, 73%), rectal adenocarcinoma (READ, 69%), and lung adenocarcinoma (LUAD, 72%), whereas PRAME was exclusively expressed in LUAD (24%). Elevated levels of CT83 ( p = 0.026) and MAGEA10 ( p = 0.036) in COAD, MAGEA1 ( p = 0.028) in READ, MAGEA1 ( p = 0.008) and MAGEA4 ( p = 0.009) in LUAD, were significantly associated with shorter progression-free survival (PFS). Additionally, exploratory CTA-count analysis showed that the prognostically relevant cutoff differed across tumor types, with more than one CTA-positive marker associated with poorer progression-free survival in COAD and more than two CTA-positive markers associated with poorer progression-free survival in READ and LUAD (COAD: p = 0.008; READ: p = 0.012; LUAD: p = 0.045). In LUAD, CT83 and MAGEA1 expression were significantly associated with lower infiltration of B cells, CD4 + T cells, and dendritic cells (all p < 0.01), and with higher infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs, p < 0.001) and FOXP3 + regulatory T cells (Tregs, p < 0.05). These effects were corroborated in the validation cohort of COAD (MAGEA4-Tregs, p < 0.05) and LUAD (CT83-Tregs, p < 0.05). Conclusions We found that CTA expression was highly tumor-type-specific in adenocarcinomas. These findings provide preliminary evidence for the potential relevance of CTA-based stratification in adenocarcinomas and may inform future mechanistic studies and prospective evaluation of precision immunotherapeutic strategies.

e20590 Background: Elderly patients (≥70 years) with metastatic non-small cell lung cancer (NSCLC) face challenges with standard chemotherapy due to poor performance status, comorbidities, and limited social support. Metronomic chemotherapy (MCT), using low-dose continuous cytotoxic agents, shows promising safety and anti-angiogenic, immunomodulatory effects. This phase II study updates efficacy and safety of PD-1 inhibitors combined with metronomic oral vinorelbine (mOV) as first-line therapy in elderly metastatic NSCLC patients. Methods: Elderly patients (≥70 years) with untreated locally advanced or metastatic NSCLC, without EGFR mutations, ALK fusions, or ROS1 fusions, and ECOG performance status 0-1, received PD-1 inhibitors combined with mOV (30 mg, three times weekly on days 1, 3, and 5), followed by PD-1 inhibitor maintenance until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results: From March 2021 to November 2025, 54 patients (median age 79 years, 79.6% male) were enrolled. After a median follow-up of 10.1 months, median PFS was 8.37 months (95% CI, 5.47–22.90) and median OS was 22.87 months (95% CI, 12.93–NR). The ORR was 25.9% (95% CI, 14.96%–39.65%) and DCR was 75.9% (95% CI, 62.36%–86.51%). Thirty-nine patients (72.2%) experienced at least one AE, with immune-related pneumonitis being the most frequent (18.5%). Grade 3–4 AEs occurred in 5 patients (9.3%), mainly immune-related pneumonitis, myocarditis, hepatitis, enteritis, and myositis, and bone marrow suppression. PD-L1-positive patients (TPS ≥1, 28 patients, 51.9%) had similar PFS (8.40 vs. 8.37 months) but significantly improved OS (30.17 months, 95% CI, 21.10–NR) compared to PD-L1-negative patients (20 patients, 37%), whose median OS was 13.13 months (95% CI, 8.60–NR). Patients with high PD-L1 expression (TPS ≥50%, 11 patients, 20.4%) showed the greatest benefit, with a median PFS of 25.83 months (95% CI, 20.30–NR) and a median OS not reached, along with ORR of 36.4%. Among patients aged ≥80 years (n = 22), median PFS was 8.97 months (95% CI, 3.53–NR) and median OS was 13.13 months (95% CI, 5.60–NR), with ORR of 18.2%. Sixteen patients (72.7%) experienced at least one AE, with grade 3-4 AEs observed in one patient (4.5%, myelosuppression). Conclusions: PD-1 inhibitors combined with mOV as first-line therapy provided significant survival benefits and acceptable tolerability in elderly patients with driver gene–negative metastatic NSCLC, particularly those with high PD-L1 expression. Similar efficacy and safety were observed in patients aged ≥80 years. Research Sponsor: National High-Level Hospital Clinical Research Funding (BJ-2023-073) and Beijing Medical Award Foundation Grant (YXJL-2020-0785-0251). Clinical trial information: ChiCTR2300074586;ChicTR21000 49487.

ABSTRACT Immune checkpoint inhibitors (ICIs) are an important treatment option for patients with advanced non‐small cell lung cancer (NSCLC). There remains significant uncertainty regarding immunotherapy regimen selection and safety management for elderly lung cancer patients, due to the insufficient inclusion of geriatric patients in current clinical studies and the absence of specific management guidelines or consensus statements for immunotherapy in the elderly population. The consensus integrates the latest evidence‐based medical evidence worldwide with clinical practice experience in China. It provides recommendations on key challenges in immunotherapy for elderly patients with advanced NSCLC, including geriatric assessment, treatment regimen selection, management of adverse reactions, and future research directions, aiming to provide a reference for clinical practice.

OBJECTIVE:Whether hair repigmentation during cancer therapy is driven by immune checkpoint inhibitors (ICIs) or chemotherapy remains unclear. This study aimed to quantitatively identify the primary driver using a controlled design. METHODS:In this prospective study, 29 patients with thoracic malignancies were divided into an immunotherapy group (n = 18) and a chemotherapy group (n = 11). Standardized dermoscopic images were captured before and after treatment. Hair pigmentation was quantified via grayscale analysis. RESULTS:Grayscale values decreased significantly posttreatment in the immunotherapy group (p = 0.0008) but not in the chemotherapy group (p = 0.1427). The magnitude of change (ΔGrayscale) was significantly greater with immunotherapy than with chemotherapy alone (23.5 ± 24.67 vs. 4.32 ± 9.01; p = 0.0065), representing a large effect size (Cohen's d = 0.90). CONCLUSION:This controlled study provides quantitative evidence suggesting that immunotherapy, rather than chemotherapy, is closely associated with hair repigmentation. It establishes an objective methodological framework for future investigation of this phenomenon.

BACKGROUND:Immune checkpoint inhibitors (ICIs) frequently cause severe adverse events (AEs) in elderly lung cancer patients due to age-related immune decline. This study combines pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) with real-world data to explore safety profiles in geriatric lung cancer patients. METHODS:AE reports for geriatric lung cancer patients (≥ 65 years) on FDA-approved ICIs from FAERS (Q3 2014-Q3 2024) were analyzed using the Reporting Odds Ratio. Single-center retrospective data was used for clinical contextualization. RESULTS:A total of 16 062 AE reports were identified, along with 260 AE signals in the FAERS database. The median age of reports was 72 years, with a male predominance (70.8%). Median onset time was 50 days. Reports with fatal outcomes (not causally adjudicated) accounted for 27.6% of cases. The geriatric group had significantly higher odds of reported fatal outcomes compared to the non-elderly group (OR = 1.13, p < 0.001). Further analysis revealed elevated odds of fatal outcomes were associated with reports concerning male patients (OR = 1.46), those originating from Asian geographic regions (OR = 1.36), and anti-PD-1 recipients (OR = 1.22) (all p < 0.001) in geriatric patients. A complementary single-center cohort (n = 225) provided clinical context, identifying immune-mediated pneumonia (21.3%) as the most common AE, predominantly in males (89.6%) and anti - PD-1 users (93.8%). CONCLUSION:A higher reported rate of fatal outcomes was observed in geriatric lung cancer patients, especially those reports pertaining to males, Asian regions, and recipients of anti-PD-1 therapy.

Section-specific labels automatically extracted from radiology reports encode structured information and are widely used as supervision targets or evaluation references for tasks such as abnormality classification, report generation, and label refinement. However, the information-selection regularities embedded in these labels have rarely been treated as the primary research object. This study aimed to characterize Findings-to-Impression concept-retention regularities in radiology reports and evaluate whether these recovered regularities are clinically plausible and can support downstream information-selection tasks. We analyzed 48,171 paired Findings and Impression studies from the CheXpert Plus dataset and treated the section-specific concept annotations as large-scale observational evidence for recovering reproducible Findings-to-Impression information-selection regularities. The dataset was randomly split at the patient level into 80% training and 20% held-out test sets. The recovered regularities were explicitly represented using our proposed framework. Predictive utility was evaluated using four progressively specified feature sets implemented with three supervised learning models, whereas transferability was assessed through progressively informed prompting across three LLMs (GPT-5.5, Med42-8B, and OpenBioLLM-8B). Clinical plausibility was assessed through independent review of 200 studies by two radiologists. The recovered section-specific information-selection regularities demonstrated predictive utility for traditional models and LLM-guided concept selection. Model discrimination improved with the progressive incorporation of contextual features, reaching its highest performance after the addition of stable directional pair associations (area under the receiver operating characteristic curve 0.707; average precision 0.798). In the LLM experiments, prompting informed by baseline and complexity-specific retention tendencies significantly improved concept-selection precision across all evaluated models compared with zero-shot. Med42-8B showed the broadest overall performance improvement, whereas OpenBioLLM-8B exhibited the greatest increase in precision and the most conservative selection behavior. However, adding directional pair association information did not provide further improvement in LLM performance. Automatically extracted section-specific radiology labels provide large-scale observational evidence for reproducible section-aware concept-selection regularities. These regularities provide an interpretable basis for downstream applications and a reusable representation of information-selection knowledge.

Immune checkpoint inhibitors frequently cause severe immune-related adverse events (irAEs) in elderly lung cancer patients due to age-related immune decline. This study conducted a pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) to investigate the safety profile in this vulnerable population and explore influencing factors of irAEs based on retrospective real-world data. We obtained adverse event reports for elderly lung cancer patients (≥ 65 years) treated with FDA-approved immune checkpoint inhibitors from the FAERS database, covering the period from the third quarter of 2014 to the third quarter of 2025. The reporting odds ratio was used to identify significant adverse event signals. A retrospective single-center cohort of 250 patients was used to develop a random forest model for predicting grade ≥ 2 irAEs. Analysis of 19,681 reports revealed a higher reporting proportion of fatal outcomes in elderly patients (ROR = 1.09, 95

Lung cancer remains a leading cause of cancer-related mortality owing to its aggressiveness and pronounced heterogeneity. Cancer stem cells (CSCs) have been implicated in tumor progression and therapeutic resistance; however, their transcriptional programs and spatial organization in non-small cell lung cancer (NSCLC) are not fully characterized. Here, we integrated single-cell RNA sequencing with spatial transcriptomics to systematically define CSC-associated phenotype in NSCLC. Weighted gene co-expression network analysis identified a 127-gene CSC signature enriched for stemness-related pathways, with DSG2 emerging as a dominant marker. Elevated DSG2 expression was associated with chemotherapy resistance and predicted response to EGFR tyrosine kinase inhibitors based on independent clinical proteomic datasets. Spatial mapping revealed preferential enrichment of DSG2+CSCs at tumor margins, where they co-localized with FAP+myofibroblasts (myCAFs). Multiplex immunofluorescence demonstrated that FAP+myCAFs expressed MMP9 and MMP12, consistent with a microenvironment supportive of epithelial-mesenchymal transition and CSC maintenance. Functional co-culture assays showed that myCAFs enhanced CSC-associated phenotypes in DSG2^high tumor cells in an MMP-dependent manner. Collectively, these findings delineate a spatially organized DSG2+CSC-myCAF niche that contributes to therapeutic resistance in NSCLC.

8622 Background: Sevabertinib, a potent, reversible, oral tyrosine kinase inhibitor, received FDA accelerated approval for pretreated patients with advanced NSCLC harboring HER2 tyrosine kinase domain-activating mutations. Sevabertinib demonstrated significant antitumor activity and manageable safety in patients with HER2 -mutant NSCLC who had previously received treatment (Cohort D) or were treatment-naïve (Cohort F) in the ongoing, open-label, multicenter, Phase I/II SOHO-01 trial (NCT05099172) (Le X et al. N Engl J Med 2025). Here, we report updated safety and efficacy data from Cohorts D and F. Methods: Patients with HER2 -mutant NSCLC received sevabertinib 20 mg twice daily in both cohorts: patients previously treated with systemic therapy but naïve to HER2-targeted therapy (Cohort D) and treatment-naïve patients (Cohort F). The primary endpoint was objective response rate (ORR) assessed by blinded independent central review (BICR) per RECIST v1.1. Other key prespecified and secondary endpoints included duration of response (DoR) and progression-free survival (PFS) assessed by BICR per RECIST v1.1, and safety per MedDRA v28.0 and CTCAE v5.0. Results: In total, 154 patients (n=81, D; n=73, F) received sevabertinib in the two cohorts; median follow-up was 19.5 (D) and 15.0 (F) months. Median age was 60 (D) and 65 (F) years; 61.7% (D) and 63.0% (F) were female; 61.7% (D) and 78.1% (F) had never smoked. As of November 17, 2025, ORR (95% CI) was 66.7% (55.3, 76.8; D) and 75.3% (63.9, 84.7; F); disease control rate (confirmed response or stable disease for ≥12 weeks; 95% CI) was 81.5% (71.3, 89.2; D) and 89.0% (79.5, 95.1; F). Median (95% CI) DoR was 9.5 (6.3, 13.5; D) and 12.2 (8.8, not estimable; F) months; median (95% CI) PFS was 8.3 (6.9, 12.3; D) and 13.5 (10.0, not estimable; F) months. Treatment-related adverse events (TRAEs) in both cohorts were consistent with previous reports. Grade 3 or higher TRAEs occurred in 39.5% (D) and 24.7% (F) of patients. Diarrhea was reported in 86.4% (D) and 87.7% (F) of patients; grade 3 diarrhea occurred in 23.5% (D) and 5.5% (F) of patients. No cases of interstitial lung disease or grade 4 diarrhea, discontinuations due to diarrhea, or new safety signals were observed. Conclusions: Sevabertinib demonstrated sustained efficacy with a manageable safety profile in treatment-naïve and pretreated patients with advanced HER2 -mutant NSCLC. These data further support the rapid and durable responses of sevabertinib for patients with HER2 -mutant NSCLC. Clinical trial information: NCT05099172 .

Given the critical role of the cGAS-STING pathway in antitumor immunity, this study investigates the functional role of STING in head and neck squamous cell carcinoma (HNSCC) to evaluate the therapeutic potential of STING agonists. Analysis of the TCGA-HNSC dataset reveals that elevated expression of the STING-encoding gene TMEM173 is significantly correlated with increased M1 macrophage infiltration and enrichment of macrophage polarization-related signaling pathways. In vitro experiments in which RAW 264.7 cells are co-cultured with tumor cell-conditioned medium demonstrate that the STING agonist MSA-2 effectively reprograms tumor-induced M2-polarized macrophages toward the M1 phenotype. This MSA-2-induced M1 polarization is accompanied by increased expressions of IFN-α, IFN-β, IFN-γ, TNF-α, and IL-6, while the STING inhibitor H-151 reverses these effects. Flow cytometry further reveals that MSA-2 treatment reduces PD-1 and increases MHC II expression on macrophages. Immunohistochemical analysis of clinical samples confirms that high STING expression is correlated with increased numbers of CD68⁺ and CD80⁺ (M1-like) macrophages. In support of translational relevance, analysis of single-cell RNA-seq data from HNSCC patients receiving neoadjuvant immunotherapy indicates that TMEM173 is expressed primarily in T cells and macrophages and that the cGAS-STING pathway score is significantly higher in patients who respond to treatment. Collectively, these findings provide systematic clinical and experimental evidence supporting the potential of STING agonists, such as MSA-2, to enhance antitumor immunity in HNSCC, particularly when combined with immunotherapy.

Lung cancer ranks as the primary contributor to cancer-related fatalities on a global scale, hallmarked by a poor prognosis. Programmed cell death (PCD) is critically involved in regulating the onset, progression, and treatment of lung adenocarcinoma (LUAD). Existing prognostic models concerning PCD focus solely on individual mechanisms and fail to account for the intricate interaction among multiple regulatory mechanisms. In this study, the LUAD samples were sorted into low immune cell invasion subtype (C1) and high immune cell invasion subtype (C2) by clustering analysis. A PCD prognostic signature model was developed by LASSO Cox regression analysis. Tumors in the high-risk group were categorized as "cold" and characterized by immunosuppression, which was linked to an unfavorable prognosis and sensitivity to drug therapy. However, the opposite was true for the low-risk group, which was associated with a favorable prognosis and sensitivity to immunotherapy. Single-cell analysis found that the PCD signature model could activate several immune cells, thereby affecting the tumor microenvironment (TME) of LUAD. Furthermore, ENO1, could be used as a target for LUAD prognosis and immunotherapy. This study aims to comprehensively explore the functional mechanisms of various PCD regulatory patterns in LUAD to provide accurate prognosis and personalized treatment plans.

Aims/Background Myopia is highly prevalent in certain neurodegenerative diseases (NDDs), and both conditions demonstrate genetic susceptibility. This study investigated the potential bidirectional causal relationships between myopia and four NDDs, Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), using Mendelian randomization (MR). We aimed to determine whether myopia contributes to the risk of NDDs and vice versa. Methods We analyzed data from two independent, large-scale genome-wide association study (GWAS) cohorts on myopia, comprising 212,571 participants in the first cohort (finn-b-H7_MYOPIA) and 95,619 in the second (GCST009521). GWAS summary statistics for the four NDDs, encompassing 589,439 samples, were also incorporated. Bidirectional MR was employed to investigate causal relationships between myopia and each of the four NDDs. The inverse variance-weighted (IVW) method served as the primary analytical approach. Sensitivity analyses, including MR-Egger regression, weighted median, weighted mode, and simple mode, were conducted to assess the robustness of the findings. Horizontal pleiotropy was evaluated using the MR-Egger regression intercept test and the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) global test, while heterogeneity was assessed via Cochran's Q test. Leave-one-out analyses were conducted to evaluate the influence of individual single nucleotide polymorphisms (SNPs). Odds ratios (ORs) with 95% confidence intervals (CIs) were reported, and statistical significance was set at p < 0.05. Results MR analyses identified no evidence of a causal relationship between myopia and refractive error and increased risk of any of the four NDDs (all p > 0.05). Similarly, none of the NDDs were associated with an increased risk of myopia or refractive error (all p > 0.05). Sensitivity analyses revealed no SNPs with significant influence on the causal associations (all p > 0.05), supporting the robustness of the findings. Conclusion This study provides no evidence of a bidirectional causal relationship between myopia and the four NDDs among individuals of European ancestry. Future research should extend beyond direct causal inference to investigate potential mediating biological mechanisms.

Background: Dysregulation of N6-methyladenosine (m6A) RNA modification plays a critical role in the development and progression of non-small cell lung cancer (NSCLC). Methods: To explore the m6A modification landscape in NSCLC, we utilized direct RNA nanopore sequencing (dRNA-seq) to compare m6A patterns between NSCLC and adjacent normal tissues. Results: Our analysis revealed distinct m6A modification differences, with tumor tissues showing reduced m6A density compared to normal tissues. Aberrantly modified genes, such as SOX2 and TOP2A, exhibited hypomethylated m6A modifications and were upregulated in NSCLC tissues. We identified 14,419 differentially methylated m6A sites, with 49.5% hypermethylated and 50.5% hypomethylated. Functional enrichment analysis showed that hypermethylated genes were involved in DNA replication and transcription regulation, while hypomethylated genes were linked to cell migration and MAPK signaling. The expression patterns of m6A regulators, including METTL3, METTL16, CBLL1, FTO, ALKBH5, and ELAVL1, were consistent across NSCLC subtypes. Furthermore, correlation with clinical data from the TCGA database revealed that m6A-associated DEGs, such as HMGA1, ERO1A, LRFN4, SNTN, SLC2A1, DNASE2B, and VSIG2, were prognostically significant in NSCLC. Conclusions: This study underscores the pivotal role of m6A modifications in NSCLC and highlights the potential of dRNA-seq for identifying RNA epigenetic changes that may serve as novel therapeutic targets.

BACKGROUND:The burden of breast cancer for older adults has been rising with the increasing population aging. This study aims to describe the burden of breast cancer in older adults worldwide, analyze the temporal trends for older breast cancer incidence, and assess the socioeconomic inequalities of breast cancer incidence and mortality with human development index (HDI) levels, which will provide valuable information in preventing and controlling the increasing breast cancer burden in older women. METHODS:The incidence and mortality rates of specific cancer types in older individuals in 2022 were sourced from the Global Cancer Today database. Trends in breast cancer incidence acquired from the Cancer Incidence in Five Continents (CI5) database. HDI and other risk factors were obtained from the United Nations. We used a generalized linear model to estimate the rate ratio and 95% confidence interval (CI) between HDI levels and breast cancer burden in older people. RESULTS:It was estimated approximately 1,058,466 newly diagnosed breast cancer cases and 383,774 breast cancer deaths in women ≥60 years, accounting for 18.9% and 12.7% of global cancer cases and deaths. The age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) were 172.9 and 57.7 per 100,000, ranking first and second among all cancer incidence and mortality in older women. The highest ASIR and ASMR were four-fold higher than the lowest, with ASIR ranging from a peak of 399.1 per 100,000 in Australia-New Zealand to a low of 90.6 per 100,000 in South Central Asia, and ASMR varying from a high of 118.6 per 100,000 in Melanesia to a low of 28.8 per 100,000 in East Asia. The largest increases in ASIR from 1998-2002 to 2013-2017 were observed in South Korea, China, and Estonia. The corresponding estimated 5-year average percentage changes (EAPC) were 6.01%, 2.89%, and 1.93%, respectively. CONCLUSIONS:The global burden of breast cancer in older women is increasing fast and varies greatly across countries. Effective prevention strategies are essential to address the increasing breast cancer burden for older women.

The treatment of non-small cell lung cancer (NSCLC) lacking driver oncogenes remains a formidable challenge, particularly in cases where resistance to programmed cell death protein 1/programmed death-ligand 1 (PD-(L)1) blockade has been acquired. Metronomic chemotherapy (MCT), which involves the frequent administration of chemotherapy drugs at reduced doses, offers a more favorable safety profile, anti-tumor angiogenesis, and immune modulatory effects compared to conventional chemotherapy. In this study, we conducted a retrospective analysis to assess the efficacy and safety of combining PD-1 inhibitors with metronomic oral vinorelbine (mOV) in patients with pre-treated metastatic NSCLC. Additionally, we identified protein markers associated with this novel treatment approach through plasma proteomics testing. Methods: Patients with histologically or cytologically confirmed unresectable stage III and IV NSCLC and received at least one systematic treatment. Pts received PD-1 inhibitors combined with mOV (30mg, TIW1, day 1-3-5 per week) until disease progression or intolerable side effects. The primary endpoint was progression-free survival (PFS). Peripheral plasma was collected from 10 patients at the beginning and early stages of treatment (1-3 stages after treatment) and were analyzed using the SOMAscan Assay Kit for human serum, which measures the expression of 11000 types of human proteins using highly selective single-stranded modified Slow Off-rate Modified DNA Aptamers (SOMAmer). Results: From May 2020 to June 2023, 23 pts were evaluated for inclusion in the study. The median age was 70(range: 48-85) with 18(78%) males. Median follow-up was 35.6 months (range 27.2months-44.13months), and the median PFS was 5.63 months (95%Cl: 4.03-16.5 months). The median OS was 24.8 months (95%Cl: (13.5 months-NA). The ORR and DCR were 13% (95%C1: 1.44%-27.6%) and 69.6% (95%Cl: 49.2%-89.9%), respectively. Adverse events (AEs)with any grade were observed in 20(86.9%) pts, of which grade III-IV AEs were observed in 4 (17.4%) pts. Immune-related adverse events (irAEs) occurred in 4 (17.4%) pts, of which grade III-IV irAEs occurred in 2 (8.7%) patients with G3 interstitial pneumonia. According to the length of PFS, patients were divided into a good efficacy group and a poor efficacy group. Baseline differential protein analysis identified 321 differential proteins, and pathway enrichment results showed that they were mainly enriched in the JAK-STAT signaling pathway, AMPK signaling pathway, PI3K Akt signaling pathway, PD-1 checkpoint pathway, and other pathways. The differential protein analysis before and after treatment identified SH2D2A and HOMER3, two proteins involved in T-cell activation. The levels of these two proteins were lower in the good efficacy group before treatment and increased after treatment, while they showed the opposite trend in the poor efficacy group. Conclusions: The combination of PD-1 inhibitors plus mOV has good efficacy and safety in the postoperative treatment of elderly patients. Protein biomarkers can help accurately identify the patients that will benefit from this treatment regimen. Research Sponsor: National High Level Hospital Clinical Research Funding (BJ-2023-073) Yue Yuan, Yumeng Tian, Qian Wei, Xin Nie, Junling Ma, Lin Li. Efficacy, safety, and protein markers of PD-1 inhibitors plus metronomic oral vinorelbine in elderly metastatic non-small-cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB197.

Advanced prostate cancer (PCa) frequently develops resistance to androgen deprivation therapy through various mechanisms including lineage plasticity. Slow-cycling cells (SCCs) have emerged as key players in adaptive responses to therapy, yet their role in PCa remains unclear. Through in silico analysis of single-cell RNA sequencing (scRNA-seq) data, we discovered that SCCs are enriched during pivotal stages of PCa progression, including the transition from androgen-dependent to castration-resistant states and the emergence of neuroendocrine PCa (NEPC). Using a tetracycline-inducible H2BeGFP reporter system, we confirmed SCC enrichment following androgen deprivation in both in vitro and in vivo models. Furthermore, we identified TET2 as a key regulator of SCCs, with its expression upregulated by androgen deprivation and positively correlated with SCC signature scores in PCa. Genome-wide 5-hydroxymethylcytosine (5hmC) profiling revealed increased hydroxymethylation after androgen deprivation, while TET2 knockdown reduced 5hmC levels at specific loci. Functional studies demonstrated that TET2 governs SCC maintenance, cell cycle progression, and DNA damage repair. Targeting TET2, either alone or in combination with an ATM inhibitor, significantly suppressed tumor growth, highlighting TET2 as a promising therapeutic target. Our study provides the first single-nucleotide resolution map of 5hmC dynamics in PCa, identifies a cell state driving epigenetic rewiring, and underscores the transformative potential of novel therapeutic strategies for advanced PCa.