Background: Circulating tumor DNA (ctDNA) is valuable for detecting minimal residual disease (MRD). However, studies involving long-term blood sampling are required to comprehensively interpret the clinical use of ctDNA analyses. Methods: We conducted a prospective multicenter cohort study (LUNGCA) for dynamic ctDNA monitoring in lung cancer patients receiving curative-intent surgery. ctDNA analysis was conducted on preoperative plasma samples, at postoperative 3 days and 1 month, and then every 3-6 months for up to 3 years. Results: In total, 233 non-small cell lung cancer (NSCLC) patients and 2336 longitudinal plasma samples were included; the median follow-up was 51.4 months. Post-comprehensive treatment (after radical surgery + necessary adjuvant therapy) MRD status was better at predicting relapse than postoperative MRD status (positive predictive value: 100% vs 90.0%; negative predictive value: 90.3% vs 90.1%). Patients with positive pre-adjuvant ctDNA and targetable mutations in tumor tissues had improved recurrence-free survival (RFS) with corresponding adjuvant tyrosine kinase inhibitor (TKI) treatment (hazard ratio [HR] = 0.01, P = .005), but adjuvant chemotherapy failed to improve RFS (HR = 0.6, P = .491). Of patients receiving adjuvant therapies, patients with a negative- or positive-negative ctDNA change pattern had favorable and similar RFS (P = .419), whereas patients with a positive- or negative-positive pattern had worse RFS (P < .001). TKI therapy was more effective than chemotherapy in clearing ctDNA. Post-relapse ctDNA negativity was associated with favorable OS (HR = 0.4; P = .029). Conclusions: Comprehensive interpretation of dynamic ctDNA monitoring data can inform precise whole-course postsurgical management of NSCLC patients.

Small extracellular vesicles (sEVs) carry molecular information from their source cells and are desired biomarkers for cancer diagnosis. We establish a machine learning-assisted dual-marker detection method to analyze the expression of epidermal growth factor receptor (EGFR) and C-X-C chemokine receptor 4 (CXCR4) in serum sEVs for the diagnosis and prognosis prediction of non-small cell lung cancer (NSCLC). We find that the serum sEV EGFR and CXCR4 are significantly higher in advanced stage NSCLC (A/NSCLC) patients compared to early stage NSCLC (E/NSCLC) patients and the healthy donors (HDs). A receiver operating characteristic curve (ROC) analysis demonstrates that the combination of EGFR and CXCR4 in serum sEVs as an efficient diagnostic index and malignant degree indicator for NSCLC. Machine learning further shows a diagnostic accuracy of 97.4% for the training cohort and 91.7% for the validation cohort based on the combinational marker. Moreover, this machine leaning-assisted serum sEV analysis successfully predicts the possibility of tumor relapse in three NSCLC patients by comparing their serum sEVs before and three days after surgery. This study provides an intelligent serum sEV-based assay for the diagnosis and prognosis prediction of NSCLC, and will benefit the precision management of NSCLC.

Localization of multiple small pulmonary nodules is the major obstacle in surgical resection. Here, we report a novel noninvasive localization technique based on a life‐size 3D printed “emulation pulmonary nodule localization model” which is simple and efficient. In the case reported here of a patient with synchronous multiple pulmonary nodules, the nodules were successfully and conveniently localized without any trauma by navigation of the emulation localization model. All 12 nodules were resected precisely and thoroughly, while normal lung tissues were considerably well preserved. Pathological examination confirmed malignancy of the major nodule and some other small nodules.

The progression of lung adenocarcinoma (LUAD) involves multiple molecular determinants, among which Oxysterol-binding protein-like 3 (OSBPL3) has been suggested to contribute to tumorigenesis, though its functional significance in LUAD remains poorly characterized. In this study, we elucidate the oncogenic functions and underlying mechanisms of OSBPL3 in LUAD pathogenesis. Analysis of clinical specimens revealed upregulated OSBPL3 expression in LUAD, which correlated with unfavorable patient outcomes. Genetic depletion of OSBPL3 in vitro impeded cellular proliferation, migratory capacity, and cell cycle progression, while inducing apoptotic cell death. Mechanistically, OSBPL3 was found to interact with the transcription factor NFE2L2, promoting its nuclear translocation and enhancing the transcriptional activation of PLAU, a downstream target gene. Upregulation of PLAU subsequently stimulated expression of key glycolytic enzymes through PI3K/AKT pathway activation, resulting in increased glucose consumption and lactate secretion. This metabolic reprogramming toward aerobic glycolysis facilitated malignant progression. Both genetic inhibition of PLAU and pharmacological blockade of AKT signaling abrogated the tumor-promoting phenotypes induced by OSBPL3. In vivo, OSBPL3 silencing significantly attenuated tumor growth and promoted apoptosis. Collectively, these findings identify an OSBPL3-NFE2L2-PLAU-AKT signaling axis that drives glycolytic metabolism and LUAD progression, showing its potential as a therapeutic target.

Background: Lung resections and stereotactic body radiation therapy (SBRT) are primary treatments for clinical stage I non-small cell lung cancer (NSCLC). The aim of this network meta-analysis is to compare the differences in effectiveness between SBRT and specific lung resections, including lobectomy, segmentectomy, and wedge resection for clinical stage I NSCLC. Methods: PubMed, EMBASE, Cochrane Library, and the ClinicalTrials.gov registry were searched. Random-effects model was conducted to assess differences in survival outcomes and treatment-related complication incidence between SBRT and three specific lung resections (lobectomy, segmentectomy, wedge resection). Subgroup analyses were performed according to clinical stages, regions, and publication years. Results: A total of 30 studies were enrolled for network meta-analysis. All three lung resections demonstrated superior overall survival (OS) compared with SBRT [lobectomy: hazard ratio (HR) 0.65, 95% confidence interval: 0.53–0.79; segmentectomy: HR 0.64, 95% confidence interval: 0.50–0.82); wedge resection: HR 0.72, 95% confidence interval: 0.55–0.93]. The recurrence-free survival (RFS) of patients in lobectomy and segmentectomy groups was significantly better than that of patients in the SBRT group, with no significant difference between the wedge resection and SBRT groups. Patients with clinical stage IA NSCLC showed no significant difference in OS between SBRT and three lung resections (lobectomy: HR 0.99, 95% confidence interval: 0.85–1.16; segmentectomy: HR 0.98, 95% confidence interval: 0.83–1.16; wedge resection: HR 1.71, 95% confidence interval: 0.91–3.26). Conclusions: For clinical stage I NSCLC patients, lobectomy and segmentectomy are superior to SBRT. Wedge resection is associated with similar RFS but better OS to SBRT. In clinical stage IA NSCLC, SBRT may provide comparable OS to lung resections.