BackgroundHypoxia within the tumor microenvironment contributes to the progression of non-small cell lung cancer (NSCLC), yet the extent to which tumor growth alters regional pulmonary ventilation and its prognostic significance remains unclear.MethodsThis retrospective study included 365 patients with pathologically confirmed NSCLC diagnosed between 2009 and 2020. Tumor location and bilateral pulmonary ventilation were assessed using VPS. Ipsilateral ventilation impairment was defined by reduced relative ventilation compared with the contralateral lung. Subgroup analyses were conducted by histological subtype, tumor size, and anatomical location. ResultsQuantitative VPS demonstrated significantly lower ventilation in the tumor-bearing lung compared with the contralateral side (χ² = 17.74, p < 0.001). This pattern was observed in both lung squamous cell carcinoma (LSCC; χ² = 16.30, p < 0.001) and lung adenocarcinoma (LUAD; χ² = 4.81, p = 0.028). Ventilation was reduced by 4.08% in right-sided tumors (52.74% vs. 56.82%, p = 0.003) and by 4.07% in left-sided tumors (43.19% vs. 47.26%, p = 0.003). Significant impairment was evident in LSCC, while LUAD showed a similar but non-significant trend. Ventilation decline persisted across tumor size strata, and correlation analysis indicated that impairment was not solely attributable to tumor volume. Patients with tumors in the lower-ventilated lung had significantly worse survival (HR = 2.40, 95% CI: 1.28–4.51, p = 0.017).ConclusionPulmonary ventilation is significantly reduced in the tumor-bearing lung in NSCLC, independent of tumor size, and is associated with poorer prognosis. Ventilation metrics may serve as functional biomarkers for risk stratification.

Background Accurate detection of MET amplification is essential for guiding targeted therapy in lung adenocarcinoma (LUAD). Conventional methods such as FISH are limited by tissue availability, and ctDNA–based liquid biopsy shows limited sensitivity for amplification detection. DNA methylation profiling offers a promising alternative. Objectives To identify MET amplification-associated DNA methylation features and develop a diagnostic model for MET amplification detection in LUAD. Design A retrospective cohort study. Methods Targeted DNA methylation sequencing (Illumina TruSeq Methyl Capture EPIC) was performed on 38 LUAD tissue samples at our institution. MET amplification was defined based on NGS-derived copy number (CN) using two thresholds: CN3 and CN5. DNA methylation data from 443 LUAD cases in TCGA were integrated with the institutional cohort to identify high-confidence differentially methylated positions (DMPs). Random Forest models were constructed and validated internally and in the TCGA cohort. Subgroup analyses were performed by EGFR mutation status and sample type. GO and KEGG analyses were conducted for functional relevance. Results A total of 20,661 (CN3) and 13,303 (CN5) DMPs were identified, of which 241 and 107, respectively, overlapped with TCGA-derived DMPs. The CN3-based model achieved AUCs of 0.92 (95% CI: 0.84–1.00) in the test cohort and 0.69 (95% CI: 0.64–0.74) in the TCGA cohort, whereas the CN5-based model yielded AUCs of 0.93 (95% CI: 0.81–1.00) and 0.77 (95% CI: 0.70–0.84), respectively. A simplified CN5-based model using the top five DMPs maintained comparable performance (AUC 0.89, 95% CI: 0.72–1.00). Diagnostic performance remained stable in EGFR-mutant patients and in biopsy specimens. Functional enrichment analyses indicated that DMPs were significantly involved in kinase regulation and MET downstream signaling pathways, including the PI3K–Akt signaling pathway. A hypermethylated MET amplification-associated DMP at Chr7:116367600 was consistently observed under both CN thresholds in the institutional cohort. Conclusion This study identifies MET amplification–associated DNA methylation features in LUAD. The CN5-based diagnostic model demonstrated promising accuracy. These findings suggest a novel approach for predicting NGS-defined MET amplification and warrant further validation in larger cohorts and prospective liquid biopsy studies.

Background and Objective:In 2025, lung cancer research advanced rapidly across the disease continuum, from population-level risk assessment and screening to mechanistic studies of early carcinogenesis and therapeutic innovation in perioperative and metastatic settings. A key shift moved beyond a smoking-centred paradigm toward a multidimensional risk framework reflecting the growing burden among never-smokers and the roles of air pollution, occupational exposures, and systemic metabolic-inflammatory states. This narrative review aims to synthesize influential 2025 evidence across prevention, diagnosis, treatment, and survivorship, and to identify convergent themes and translational gaps relevant to clinical practice and policy. Methods:We performed a narrative synthesis of influential lung cancer studies published in major international journals in 2025. Evidence was organized along a clinically oriented pathway spanning carcinogenesis and screening, precision diagnosis, treatment optimization in resectable and advanced disease, and survivorship, emphasizing practice-informing trials, high-impact translational research, and implementation-relevant technologies. Key Content and Findings:Lineage tracing, single-cell and spatial omics, and evolutionary inference refined concepts of field cancerization, clonal selection, and copy-number-driven fitness. In small-cell lung cancer, evidence further supported neuronal coupling and synapse-like programs as potentially tractable vulnerabilities. Clinically, low-dose computed tomography (CT) strategies and data-informed nodule thresholds aimed to balance under-detection against over-surveillance harms. In diagnostics, artificial intelligence (AI) models increasingly inferred molecular features from routine histopathology ("virtual molecular testing") and should be regarded as decision support requiring prospective validation, population calibration, and explicit failure-mode reporting. Multimodal approaches integrating imaging with circulating tumor DNA (ctDNA) improved feasibility in tissue-limited settings, but clinical utility remains contingent on assay standardization and pathway-level implementation. In resectable disease, longer follow-up consolidated neoadjuvant chemo-immunotherapy for selected patients, while ctDNA kinetics emerged as a candidate biomarker for response-adaptive escalation and de-escalation. In advanced non-small cell lung cancer (NSCLC), phase III evidence for antibody-drug conjugates and bispecific antibodies began reshaping sequencing, while highlighting challenges in toxicity, access, affordability, and immature overall survival in several programs. Conclusions:The 2025 landscape reflects coordinated progress in risk conceptualization, biology, diagnostics, and therapeutics, yet gaps in validation, standardization, and real-world deliverability persist. Priorities include prospective evaluation of AI- and ctDNA-enabled pathways, toxicity-informed sequencing, and equitable implementation aligned with health-system capacity.

BACKGROUND:Evidence suggests that the hypoxic tumor microenvironment (TME) contributes to the initiation and progression of non-small cell lung cancer (NSCLC). However, the degree to which tumor growth affects ventilation in the ipsilateral lung, and the clinical significance of this functional change, is not well understood. This study aimed to measure ventilation impairment on the tumor-bearing side using ventilation-perfusion scintigraphy (VPS) and to evaluate its association with patient survival. METHODS:This retrospective study included 365 patients with pathologically confirmed NSCLC diagnosed between 2009 and 2020. Tumor location and bilateral pulmonary ventilation were evaluated using VPS. Ipsilateral ventilation impairment was determined by comparing the relative ventilation contributions of each lung. Subgroup analyses were performed by histological subtype, tumor size, and anatomical location. Survival outcomes were assessed using Kaplan-Meier analysis and univariate Cox regression. RESULTS:Quantitative VPS analysis showed that pulmonary ventilation on the tumor-bearing side was significantly lower than on the contralateral side (χ2 = 17.74, p < 0.001), a pattern consistently observed in both LSCC (χ2 = 16.30, p < 0.001) and LUAD (χ2 = 4.81, p = 0.028) subgroups. Further analysis confirmed an association between tumor presence and reduced ipsilateral ventilation: in patients with right-sided tumors, ventilation was 4.08% ± 1.34% lower than in unaffected right lungs (52.74% vs. 56.82%, p = 0.003); a similar difference was observed in left-sided tumors (43.19% vs. 47.26%, p = 0.003). Subgroup analysis indicated significant impairment in LSCC (left lung: 42.51% vs. 49.02%, p = 0.002; right lung: 50.97% vs. 57.50%, p = 0.002), while LUAD showed a similar but non-significant trend (p > 0.05). Stratified analysis by tumor size demonstrated a consistent decline in ventilation across different tumor volumes. Spearman correlation analysis suggested that ipsilateral ventilation impairment was not solely explained by space-occupying effects (left lung: ρ = -0.225, p = 0.011; right lung: ρ = -0.322, p < 0.001). Survival analysis showed that patients with tumors in the lower-ventilated lung had a significantly higher risk of mortality (HR = 2.40, 95% CI: 1.28-4.51, p = 0.017). CONCLUSION:This study is the first to systematically demonstrate that pulmonary ventilation is significantly reduced in the tumor-bearing lung of patients with NSCLC. This reduction is not solely explained by the space-occupying effect of the tumor, but may also reflect a more complex interaction between tumor biology and regional pulmonary function. In addition, the presence of a tumor in the lower-ventilated lung was associated with worse prognosis. These findings support the potential value of functional imaging in prognostic assessment and suggest that ventilation metrics may serve as functional biomarkers for risk stratification in NSCLC.

Background:Epidermal growth factor receptor (EGFR) mutations are the most common oncogenic subtype in non-small cell lung cancer (NSCLC) among Asians. EGFR tyrosine kinase inhibitors (TKIs) have become the mainstay of therapy, significantly improving survival outcomes. However, prognostic factors influencing survival in real-world settings among patients treated with EGFR-TKIs remain underexplored. This study aims to identify prognostic factors in EGFR-TKI-treated patients using data from a nationwide registry. Methods:Patient data were sourced from the "Meina Xinsheng" registry, with survival metrics provided by the China Center for Disease Control. We analyzed the impact of sex, age, disease stage, histology, gene mutation type, and Karnofsky Performance Status (KPS) score on duration of treatment (DoT), overall survival (OS), and the incidence of long-term survival (>5 years), using both univariate and multivariate analyses. A reference cohort of EGFR wild-type patients receiving EGFR-TKI therapy was also included. Results:Among 231,699 patients registered for EGFR-TKI treatment across 3,445 hospitals nationally, 221,788 cases of advanced NSCLC were analyzed. Within the subset of 83,791 patients eligible for survival analysis spanning 2012 to 2018, the median OS was 3.2 years [95% confidence interval (CI): 3.18-3.3], and the median lung cancer-specific survival (LCSS) was 4.1 years (95% CI: 4.02-4.1). At least 7.7% of patients achieved a survival milestone of more than 5 years. Factors associated with improved OS and higher long-term survival rates included female sex, stage IIIb disease, adenocarcinoma histology, EGFR exon 19 deletion, superior KPS scores, prolonged DoT, receiving EGFR-TKI as first-line treatment, and achieving a complete response (CR). Younger patients (<40 years) exhibited better OS, albeit with a shorter DoT. Notably, patients maintaining disease control for 22 months had significantly higher long-term survival (12.8%) compared with those who did not (2.7%). Conclusions:In this large real-world cohort of advanced NSCLC patients treated with EGFR-TKI, female sex, stage IIIb (vs. stage IV) disease, adenocarcinoma histology, EGFR exon 19 deletion, and the use of EGFR-TKI as first-line therapy were independently associated with longer DoT and/or OS. These factors may help identify patients more likely to derive durable benefit from EGFR-TKIs and support risk stratification and treatment optimization in EGFR-mutant NSCLC.

Background:Pulmonary ground-glass opacity (GGO) is often considered to have inert biological behavior. However, whether the clinicopathological features and aggressiveness of GGO associated with cystic airspace (GGO-A) differ from GGO associated without cystic airspace (GGO-nA) remains unknown. This study aimed to compare the clinicopathological features and aggressiveness of GGO-A with GGO-nA. Methods:This retrospective study included patients with GGOs [lesion size: 0.5-2.0 cm, consolidation-to-tumor ratio (CTR) ≤50%] from 2017 to 2021. Patients were divided into GGO-As and GGO-nAs. Chi-squared, Mann-Whitney test, Kaplan-Meier analyses and Logistic regression were utilized for data analysis. Results:A total of 818 patients (266 with GGO-As and 552 with GGO-nAs) were enrolled. Compared to patients with GGO-nAs, patients with GGO-As had distinct clinical features: male [odds ratio (OR) =5.588, P<0.001], without family history of cancer (OR =5.121, P<0.001), with emphysema pulmonum (OR =3.228, P=0.003) and with pulmonary bullae (OR =2.634, P<0.001). Compared to GGO-nAs, GGO-As had more invasive adenocarcinomas (IAs) (75.8% vs. 39.3%, P<0.001) and micropapillary subtypes (17.0% vs. 5.7%, P=0.09). In addition, KRAS mutated more frequently in GGO-As than GGO-nAs (15.5% vs. 2.5%, P=0.07). Among patients followed up, there were higher frequency of GGO growth (28.9% vs. 17.0%, P=0.02) and shorter median time from baseline to GGO growth (24.0 months vs. not reached, log rank P<0.001) in GGO-As than GGO-nAs. Furthermore, among pure-GGOs and non-smokers, GGO-As were still associated with higher aggressiveness. Conclusions:GGO-A showed higher aggressiveness compared to GGO-nA, with more invasive histological subtypes, a higher frequency of KRAS mutations, and faster radiological progression. These findings suggested more proactive surveillance and potentially aggressive clinical management for GGO-As.

Background:Chest computed tomography (CT) examinations became more frequent during and after the coronavirus disease 2019 (COVID-19) pandemic, increasing incidental pulmonary nodule detection and concern about surveillance burden and lung cancer risk. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause persistent focal pulmonary abnormalities that may resemble nodules on CT. Population-level evidence on changes in pulmonary nodule detection or progression after vaccination and widespread infection remains limited. We aimed to determine whether COVID-19 vaccination phases and the late-2022 SARS-CoV-2 infection wave were associated with abrupt changes in pulmonary nodule detection or CT-based progression. Methods:We conducted a retrospective cohort study using records from The First Affiliated Hospital of Guangzhou Medical University and the Guangzhou Cadre Health Management Center in Guangzhou, China. We analyzed 772,506 chest CT scans acquired from January 2013 to December 2023, including 627,164 inpatient scans, 46,411 hospital health-examination scans, and 98,931 cadre health-examination scans. Monthly pulmonary nodule detection and progression rates were calculated using 6-30 mm as the main nodule-size criterion and 0-30 mm as a secondary criterion. Regression discontinuity-in-time (RDiT) analyses examined four prespecified calendar time points: the first, second, and third COVID-19 vaccination phases in December 2020, June 2021, and September 2021, respectively, and the concentrated SARS-CoV-2 infection wave beginning in December 2022 after China's late-2022 policy restructuring. Results:The cohorts included 328,223 inpatients, 29,279 hospital health examinees, and 46,587 cadre health examinees. Median ages were 55 [interquartile range (IQR), 43-65], 46 (IQR, 36-54), and 50 (IQR, 43-57) years, respectively. Male proportions were 53.57%, 47.69%, and 66.81%. From 2013 to 2023, detection rates for 6-30 mm nodules increased from 25.85% to 31.19% in the inpatient cohort, from 12.11% to 21.64% in the hospital health-examination cohort, and from 18.38% to 29.49% in the cadre health-examination cohort. Nodules smaller than 6 mm accounted for an increasing share of detections over time. RDiT analyses showed no reproducible abrupt increase in 6-30 mm nodule detection around the three vaccination phases or the late-2022 SARS-CoV-2 infection wave. Detection P values ranged from 0.06 to 0.85, and progression P values, where estimable, ranged from 0.058 to 0.94. Secondary analyses using the 0-30 mm criterion and sex-specific inpatient analyses showed consistent patterns. Conclusions:In these Guangzhou cohorts, the gradual increase in pulmonary nodule detection from 2013 to 2023 primarily reflected greater ascertainment of nodules smaller than 6 mm. COVID-19 vaccination phases and the late-2022 SARS-CoV-2 infection wave were not accompanied by consistent abrupt increases in 6-30 mm nodule detection or progression.

Detecting lung cancer effectively in the general population is essential for optimizing treatment outcomes and improving the 5-year survival rate. While low-dose computed tomography (LDCT) is the current standard, it has limitations in broader populations. We developed a blood-based multi-omics model using whole-genome cell-free DNA (cfDNA) features to distinguish lung cancer from non-cancer individuals. This study included 1600 patients and an equal number of non-cancer controls, divided into training and validation cohorts. The model achieved an area under the curve (AUC) of 95.59% for the training cohort and 95.74% for the validation cohort. The model consistently performed well across various cancer stages and histological subtypes. To further validate the performance of the model, an external validation cohort was utilized. Notably, it also effectively differentiated non-cancer samples from cancer samples in the external validation cohort, with 85.9% sensitivity and 94.78% specificity. Importantly, in simulated population screenings, our ctDNA assay outperformed both LDCT and a previously established method. This suggests its potential utility in wider lung cancer screening programs, possibly complementing the LDCT approach. In conclusion, our ctDNA assay emerges as a promising and highly sensitive tool for the early detection and categorization of lung cancer.

Background: Chest CT increasingly identifies pulmonary nodules outside organised screening, but national data on prevalence, trends, and management demand in health-examination populations are lacking. Methods: In this retrospective multicentre study, we analysed electronic records from Guangzhou Ping An Healthcare Diagnostic Center’s nationwide health-examination network in China (Jan 1, 2018–Dec 31, 2025) using a validated natural language processing algorithm. We estimated CT use, scan-level nodule frequency, and annual prevalence. Clinically relevant nodules were 5.0–30.0-mm solid or part-solid nodules or 8.0–30.0-mm pure ground-glass nodules. Annual prevalence was age-, sex-, and macroregion-standardised. Findings: During 2018–2025, 1,223,402 participants underwent at least one chest CT. The proportion undergoing CT increased from 8.0% in 2018 to 65.5% in 2025, peaking at 71.1% in 2024. Any pulmonary nodules and clinically relevant nodules were reported on 786,575 (59.2%) and 208,397 (15.7%) examinations and in 714,884 (58.4%) and 190,744 (15.6%) participants, respectively. Annual prevalence per 1000 participants increased from 98.3 (95% CI 52.4–144.2) to 669.2 (610.9–727.5) for any nodule and from 26.2 (14.7–37.7) to 184.4 (165.1–203.7) for clinically relevant nodules. Increases were concentrated in solid and pure ground-glass nodules and those smaller than 10.0 mm. Nodules smaller than 5.0 mm and those measuring 5.0–9.9 mm accounted for 56.0% and 42.6% of the prevalence increase, respectively. Pulmonary tuberculosis and bronchiectasis were associated with higher clinically relevant nodule prevalence. Interpretation: Rising clinically relevant nodule prevalence among health-examination participants, together with expanding CT use, indicates growing potential demand for surveillance and diagnostic assessment.

Background:Polygenic susceptibility and modifiable lifestyle behaviors contribute to lung cancer, but their interaction and combined impact on lung cancer hazard and potential biological correlations remain incompletely characterised. This study aimed to evaluate the independent and combined associations of polygenic risk and healthy lifestyle with lung cancer hazard and to explore potential biological correlations underlying these associations. Methods:We analyzed data of 254,874 UK Biobank (UKB) participants. A five-component lifestyle score (smoking, alcohol intake, diet, physical activity and sedentary behavior) was summed [0-5] and categorized as unfavorable (0-1 factors), intermediate [2] and favorable [3-5]. An 18-single nucleotide polymorphism (SNP) polygenic risk score (PRS) was standardized and categorized into tertiles (low/intermediate/high). Cox proportional hazards models estimated associations with lung cancer hazard; additive interaction was assessed using the relative excess risk due to interaction (RERI). Mediation analyses of peripheral markers and circulating proteins were exploratory. Results:Among 254,874 UKB participants, 2,021 lung cancers occurred over a median of 11.69 years. A favorable lifestyle was associated with lower lung cancer hazard [hazard ratio (HR) 0.34; 95% confidence interval (CI): 0.30-0.38; P<0.001], while high PRS was associated with higher hazard (HR 1.62, 95% CI: 1.45-1.81; P<0.001). In the high PRS group, favorable lifestyle remained protective (HR 0.36, 95% CI: 0.30-0.44; P<0.001), whereas intermediate lifestyle was not statistically significant (HR 0.85, 95% CI: 0.68-1.05; P=0.13). The global multiplicative interaction between lifestyle class and PRS category was not significant (P for global interaction =0.49), although selected additive interaction signals were observed, including high PRS combined with intermediate lifestyle (RERI 0.92, 95% CI: 0.31-1.55). Exploratory mediation suggested partial signals for inflammatory markers and proteins (WFDC2, PIGR, PRSS8). Conclusions:This large-scale prospective study confirms the protective association of a healthy lifestyle with a lower lung cancer hazard. Importantly, in individuals with high genetic susceptibility, moderate lifestyle improvements may not fully offset the elevated hazard, underscoring the need for more comprehensive lifestyle interventions in this high genetic-susceptibility population. Mediation findings provide hypothesis-generating clues for future mechanistic work.

Background and objective: Traditional biopsy methods often limit diagnostic accuracy and treatment options due to inadequate tissue samples. En-bloc biopsy (EB), a minimally invasive technique, offers adequate tissue for both pathological and genetic analysis while reducing tumor burden. This study evaluates the clinical applicability and survival benefits of EB in advanced lung cancer. Methods: We retrospectively reviewed advanced lung cancer patients with pulmonary tumors and distant metastases confirmed by PET-CT, who underwent EB via video-assisted thoracoscopic surgery (VATS) at our center from 2010 to 2020. Clinical characteristics, pathological and genetic results, surgical details, and survival data were analyzed. Kaplan-Meier and Log-Rank tests were used to compare overall survival (OS) between: (1) targeted vs. non-targeted therapies within the EB group, and (2) EB vs. traditional biopsy, with further subgroup analysis focusing on targeted therapy recipients and stage IVA patients. Results: Among 142 patients (majority male, non-smokers, under 65, ECOG 0–1), 128 (90.1 ​%) had adenocarcinoma. No severe perioperative complications or early postoperative deaths occurred. All 132 genetic samples were valid; 62.9 ​% were EGFR-positive. Median follow-up was 52.0 months; median OS, 66.0 months. In the EB group, targeted therapy was linked to longer OS than non-targeted (80.0 vs. 43.0 months, p ​= ​0.0445). EB outperformed traditional biopsy in OS (66.0 vs. 28.0 months, p ​= ​0.0025). Subgroups receiving targeted therapy (HR ​= ​0.55, p ​= ​0.0260) and with stage IVA disease (HR ​= ​0.66, p ​= ​0.0338) showed survival benefit. Conclusion: VATS-based EB is safe and feasible in advanced lung cancer, improves access to precision therapy, and significantly prolongs survival.

BACKGROUND:Depression is are often insufficiently managed in cancer patients globally. To address this, we conducted a comprehensive systematic review and network meta-analysis to evaluate and compare the effectiveness of pharmacological and non-pharmacological interventions in alleviating depressive symptoms in adult cancer patients. METHODS:We searched PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov from inception until 31 July 2024, with an updated search conducted on 10 January 2025. Eligible studies were randomised controlled trials evaluating pharmacological or non-pharmacological interventions for depressive symptoms in adult patients with cancer (aged ≥18 years). Studies involving paediatric populations, lacking complete outcome data, or not reporting intervention outcomes were excluded. A Bayesian network meta-analysis was undertaken to compare the effectiveness of included interventions. The review protocol was prospectively registered in PROSPERO (CRD42023465056). FINDINGS:A total of 95 RCTs involving 17,260 participants were included. Several non-pharmacological interventions indicated potential benefit compared with usual care, notably massage and touch therapy (standardised mean difference [SMD]: -0.76, 95% CI: -1.37 to -0.16; low certainty), relaxation therapy (SMD: -0.59, 95% CI: -1.06 to -0.11; low certainty), psychotherapy (SMD: -0.43, 95% CI: -0.56 to -0.30; low certainty), and education and support of person with cancer (SMD: -0.30, 95% CI: -0.45 to -0.14; low certainty). Among pharmacological approaches, preliminary findings suggest the combination of mirtazapine and methylphenidate may offer benefits compared with placebo (SMD: -2.46, 95% CI: -4.24 to -0.70; low certainty). However, the overall evidence quality was low, reflecting substantial variability and limited data. INTERPRETATION:Non-pharmacological interventions such as massage, relaxation therapies, and psychotherapy show promise in alleviating depressive symptoms in cancer patients. Limited preliminary evidence also suggests possible benefits of combined pharmacological treatment (mirtazapine plus methylphenidate). More rigorous research is required to strengthen these findings and better inform clinical practice.

Background:Accurate risk stratification of pulmonary nodules is critical for early lung cancer detection. This study aimed to improve malignancy classification and invasiveness prediction using machine learning models integrating low-dose computed tomography (LDCT) radiomics and plasma cell-free DNA (cfDNA) fragmentomics. Methods:This multicenter study enrolled 1356 participants across discovery (n = 1147) and external validation (n = 209) cohorts. A deep learning-based imaging model processed LDCT scans for automated lung nodule detection and malignancy classification. A parallel cfDNA model analyzed four whole-genome fragmentation features: copy number variation, fragment size ratio, fragment-based methylation, and mutation context and signature. The two models were integrated via a stacked ensemble algorithm. An invasion prediction model evaluated tumor aggressiveness. Findings:The integrated imaging-cfDNA model outperformed individual models, with an AUC of 0.950 (95% CI: 0.926-0.975) in the internal test set and 0.966 (95% CI: 0.940-0.991) in the external validation. The combined model's specificity increased to 0.60 (95% CI: 0.49-0.71) while maintaining 95% sensitivity, compared to specificities of 0.50 (95% CI: 0.41-0.59) and 0.33 (95% CI: 0.23-0.44) at equivalent sensitivity levels for the imaging and cfDNA models, respectively. The combined model consistently outperformed the other two models across nodule characteristics, with particular improvement for 10-20 mm and pure solid nodules. The invasion prediction model stratified lung cancers with an AUC of 0.884 (internal) and 0.880 (external). Prediction scores increased stepwise with tumor aggressiveness, from adenocarcinoma in situ to minimally invasive adenocarcinoma, and were highest for invasive adenocarcinoma. Interpretation:This multimodal approach enhances pulmonary nodule risk stratification by integrating radiomic and molecular biomarkers. The model significantly improves diagnostic accuracy, potentially reducing unnecessary procedures while minimizing missed diagnoses, supporting its clinical utility in lung cancer screening. Funding:Noncommunicable Chronic Diseases-National Science and Technology Major Project, National Key Research & Development Programme, China National Science Foundation, the Science and Technology Planning Project of Guangzhou, and Guangzhou National Laboratory.

This study assesses non–risk-based low-dose computed tomographic screening to assess lung cancer detection in the general population and evaluate outcomes by risk stratification.

Background:Adjuvant epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) show promising outcomes in early-stage non-small cell lung cancer (NSCLC) with EGFR mutations, but accurately identifying patients who would derive the greatest benefit remains a clinical challenge. We compared the predictive performance of clinicopathological factors and the 14-gene assay to assess postoperative prognosis and predict the potential benefit of adjuvant EGFR-TKIs in stage I NSCLC. Methods:From March 2013 to February 2019, patients with completely resected stage I NSCLC [8th edition tumor-node-metastasis (TNM) classification staging] and EGFR mutation were included. The 14-gene assay, assessed through quantitative reverse transcription polymerase chain reaction (qPCR), was developed and subsequently validated across diverse international cohorts. Clinicopathological high-risk factors included any feature indicating a higher risk of recurrence based on the National Comprehensive Cancer Network (NCCN) guidelines. The primary endpoint of this study was the 5-year disease-free survival (DFS) rate. Results:Diagnostic values were evaluated in 180 stage I NSCLC patients. The 14-gene assay demonstrated superior performance compared to clinicopathological factors in predicting recurrence events. Patients with molecular high-risk, rather than clinicopathological high-risk factors, showed a more favorable response to adjuvant EGFR-TKIs. Specifically, adjuvant EGFR-TKIs benefited molecular high-risk patients, regardless of clinicopathological high-risk (DFS rate increased from 65.9% to 95.0%, P=0.02) or low-risk subgroups (80.0% to 100%, P=0.04). Patients with molecular low risk did not show any benefit from EGFR-TKIs, regardless of clinicopathological high-risk (DFS rate increased from 93.3% to 100%, P=0.37) or low-risk subgroups (97.0% to 100%, P=0.73). Conclusions:The 14-gene assay is proven to be superior to clinicopathological factors, offering valuable guidance for adjuvant EGFR-TKIs decisions in stage I NSCLC.

Background: Lung cancer is responsible for most cancer-related deaths, and non-small cell lung cancer (NSCLC) accounts for the majority of cases. Targeted therapy has made promising advancements in systemic treatment for NSCLC over the last two decades, but inadequate drug targets with clinically proven survival benefits limit its universal application in clinical practice compared to chemotherapy and immunotherapy. There is an urgent need to explore new drug targets to expand the beneficiary group. This study aims to identify druggable genes and to predict the efficacy and prognostic value of the corresponding targeted drugs in NSCLC. Methods: Two-sample mendelian randomization (MR) of druggable genes was performed to predict the efficacy of their corresponding targeted therapy for NSCLC. Subsequent sensitivity analyses were performed to assess potential confounders. Accessible RNA sequencing data were incorporated for subsequent verifications, and Kaplan-Meier survival curves of different gene expressions were used to explore the prognostic value of candidate druggable genes. Results: MR screening encompassing 4,863 expression quantitative trait loci (eQTL) and 1,072 protein quantitative trait loci (pQTL, with 453 proteins overlapping) were performed. Seven candidate druggable genes were identified, including CD33, ENG, ICOSLG and IL18R1 for lung adenocarcinoma, and VSIR, FSTL1 and TIMP2 for lung squamous cell carcinoma. The results were validated by further transcriptomic investigations. Conclusions: Drugs targeting genetically supported genomes are considerably more likely to yield promising efficacy and succeed in clinical trials. We provide compelling genetic evidence to prioritize drug development for NSCLC.

Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1) protein significantly improve survival in patients with advanced non-small-cell lung cancer (NSCLC), but its impact on early-stage ground-glass opacity (GGO) lesions remains unclear. This is a single-arm, phase II trial (NCT04026841) using Simon’s optimal two-stage design, of which 4 doses of sintilimab (200 mg per 3 weeks) were administrated in 36 enrolled multiple primary lung cancer (MPLC) patients with persistent high-risk (Lung-RADS category 4 or had progressed within 6 months) GGOs. The primary endpoint was objective response rate (ORR). T/B/NK-cell subpopulations, TCR-seq, cytokines, exosomal RNA, and multiplexed immunohistochemistry (mIHC) were monitored and compared between responders and non-responders. Finally, two intent-to-treat (ITT) lesions (pure-GGO or GGO-predominant) showed responses (ORR: 5.6%, 2/36), and no patients had progressive disease (PD). No grade 3–5 TRAEs occurred. The total response rate considering two ITT lesions and three non-intent-to-treat (NITT) lesions (pure-solid or solid-predominant) was 13.9% (5/36). The proportion of CD8+ T cells, the ratio of CD8+/CD4+, and the TCR clonality value were significantly higher in the peripheral blood of responders before treatment and decreased over time. Correspondingly, the mIHC analysis showed more CD8+ T cells infiltrated in responders. Besides, responders’ cytokine concentrations of EGF and CTLA-4 increased during treatment. The exosomal expression of fatty acid metabolism and oxidative phosphorylation gene signatures were down-regulated among responders. Collectively, PD-1 inhibitor showed certain activity on high-risk pulmonary GGO lesions without safety concerns. Such effects were associated with specific T-cell re-distribution, EGF/CTLA-4 cytokine compensation, and regulation of metabolism pathways.

Background: Real-world data on C-MET protein overexpression in non-small cell lung cancer (NSCLC) patients, particularly among the Asian Chinese population, are limited. Objectives: This study aimed to evaluate the clinicomolecular characteristics and prognosis of C-MET overexpression in Chinese NSCLC patients, focusing on those with positive C-MET overexpression (immunohistochemistry (IHC) 3+). Design: A retrospective and observational study. Methods: Data were collected from NSCLC patients diagnosed at the First Affiliated Hospital of Guangzhou Medical University between November 2006 and April 2021. We identified C-MET overexpression using IHC and C-MET overexpression positivity was defined as IHC 3+ with ⩾50% tumor cells. Additionally, patient genotypes were collected for subgroup analysis. Results: Data from 9785 NSCLC patients were collected. C-MET (−) accounted for 5% (503/9785), C-MET (+) for 27% (2654/9785), C-MET (++) for 36% (3464/9785), and C-MET (+++) for 32% (3164/9785). Genetic testing was available for 4326 patients. Wild-type was observed in 37% (1591 cases), with epidermal growth factor receptor ( EGFR) abnormalities being the most common at 49% (2127 cases). Positive C-MET overexpression correlated significantly with women ( p < 0.001), early-stage ( p = 0.003), adenocarcinoma ( p < 0.001), and driver mutations ( p < 0.001). Patients with anaplastic lymphoma kinase ( ALK) alterations had a higher occurrence of C-MET overexpression positivity (57.1%). Positive C-MET overexpression was significantly associated with EGFR ( p < 0.001), ALK ( p < 0.001), and KRAS alterations ( p = 0.024). Compared to C-MET overexpression (IHC 0), C-MET overexpression (IHC 2+) (hazard ratio (HR) = 0.455, p < 0.001) and C-MET overexpression (IHC 3+) (HR = 0.569, p < 0.001) were correlated with better overall survival in overall NSCLC patients, especially for C-MET overexpression (IHC 2+). Conclusion: Our study elucidates the clinicomolecular characteristics and prognosis of C-MET overexpression in NSCLC patients, particularly those with positive C-MET overexpression (IHC 3+). This provides insight into the prevalence of C-MET overexpression in Chinese NSCLC patients and offers a basis for considering C-MET overexpression as a prognostic and predictive marker in NSCLC.