Search Results (1,960)

The incidence of peripheral lung squamous cell carcinoma (p-LUSC) has increased in recent years, but the clinical features of early-stage p-LUSC remain unclear. In the present study, we aim to elucidate the general clinical features of p-LUSC by comparing it with peripheral lung adenocarcinoma (p-LUAD). Patients with p-LUSC or p-LUAD who were at an early imaging stage and underwent complete lobectomy with systematic lymph node dissection were included. The clinical characteristics of p-LUSC were elucidated through comparative analysis with p-LUAD, and independent prognostic factors for recurrence-free survival were identified. A total of 103 patients with p-LUSC and 600 patients with p-LUAD were included. Compared with p-LUAD, all p-LUSC cases appeared as solid nodules (SDNs) on imaging, and p-LUSC was associated with the male sex, older age, smoking history, lobulation sign, interstitial pneumonia, and a shorter volume doubling time. In terms of malignant aggressiveness, p-LUSC demonstrated a significantly lower lymph node metastasis rate than SDNs of p-LUAD in the >2.0 to ≤3.0 cm group, while no statistically significant difference was observed between the two groups in the 0–2.0 cm group. As for prognosis, tumor size and lymph node metastasis were found as independent risk factors for tumor recurrence. Full article

Background: Lung adenocarcinoma in non-smoking women represents a distinct clinical entity that cannot be fully explained by traditional exposure-centered carcinogenic models. Although ambient air pollution is a recognized risk factor, sex-specific vulnerability suggests the involvement of additional biological modulators shaping inflammatory, immune, and proliferative responses. Main body: In this conceptual review, we integrate epidemiological, experimental, and mechanistic evidence to propose a multisystem framework of lung carcinogenesis in non-smoking women. We delineate a central carcinogenic spine encompassing lung epithelial injury, chronic inflammation, growth factor signaling activation—particularly epidermal growth factor receptor (EGFR) pathways—and tumor microenvironment remodeling. Within this framework, three interacting domains function as biological modulators that amplify carcinogenic processes: chemosensory–neural–immune modulation, hormonal–endocrine signaling including estrogen–EGFR crosstalk, and psychosocial stress–hypothalamic–pituitary–adrenal (HPA) axis dysregulation. These domains converge through feedback mechanisms that reinforce systemic dysregulation and tumor-promoting microenvironments. Implications: This integrative model provides a biologically grounded perspective on female-specific vulnerability to lung adenocarcinoma and informs precision prevention, risk stratification, and ESG-informed public health strategies beyond conventional exposure reduction. Full article

Background/Objectives: Lung adenocarcinoma (LUAD), the predominant subtype of non-small cell lung cancer (NSCLC), is frequently diagnosed at advanced stages with distant metastasis, underscoring the need for effective prognostic biomarkers. Fibroblast growth factor 2 (FGF2), a multifunctional regulator, has shown to play contradictory roles in cancer progression. Methods: We analyzed three independent Gene Expression Omnibus (GEO) datasets (GSE19804, GSE18842, and GSE19188) to identify consistently dysregulated genes in LUAD. Functional enrichment (GO, KEGG, and cancer hallmark analysis), protein–protein interaction (PPI) network construction, and hub gene prioritization were performed using public bioinformatic tools. Survival analyses were conducted via the Kaplan–Meier Plotter. The expression of FGF2 was validated across multiple platforms, including TCGA, CPTAC, TNMplot, LCE, and the Human Protein Atlas. Functional assays (Transwell migration and wound healing) demonstrated that exogenous FGF2 significantly suppressed LUAD cell motility in vitro. Results: A total of 949 differentially expressed genes (DEGs) were commonly identified across datasets, with enrichment in cell adhesion and metastasis-related pathways. Among the 11 hub genes identified, FGF2 was consistently downregulated in LUAD tissues across all datasets and stages. Higher FGF2 expression was associated with longer overall and progression-free survival. In vitro, FGF2 treatment significantly suppressed the migration and wound healing abilities of LUAD cell lines. Conclusions: FGF2 is downregulated in LUAD and inversely associated with metastatic progression and poor prognosis. The observed reduction in cancer cell motility upon FGF2 treatment in vitro, together with its expression pattern, supports a potential tumor-suppressive role and suggests that FGF2 may serve as a candidate non-invasive biomarker for monitoring LUAD metastasis. Full article

Background and Objectives: Lung cancer in never-smokers (LCINS) has become a major global health concern, ranking as the fifth leading cause of cancer-related mortality. Unlike smoking-related lung cancer, LCINS arises from complex interactions between environmental carcinogens and distinct genomic alterations. This review summarizes current evidence on environmental risks, molecular features, and therapeutic progress shaping lung cancer management. Methods: A narrative review was conducted to examine risk factors for lung cancer in non-smokers. Studies reporting driver mutations in never-smokers and smokers were identified across major lung cancer histological subtypes, including small-cell lung cancer (SCLC), lung adenocarcinoma (LUAD), squamous cell carcinoma (SCC), and large-cell carcinoma (LCC). In addition, PubMed was searched for phase III trials and studies on targeted therapies related to driver mutations published between 2016 and 2025. Results: Environmental factors such as cooking oil fumes, radon, asbestos, arsenic, and fine particulate matter (PM_2.5) are strongly associated with LCINS through oxidative stress, DNA damage, and chronic inflammation. EGFR, PIK3CA, OS9, MET, and STK11 mutations are characteristic of never-smokers, in contrast to TP53 mutations, which are more common in smokers. Recent advances in targeted therapy and immunotherapy have improved survival and quality of life, emphasizing the importance of molecular profiling for treatment selection. Conclusions: LCINS represents a distinct clinical and molecular entity shaped by complex interactions between environmental exposures and genetic susceptibility. Genetic alterations promote tumor immune evasion, facilitating cancer development and progression. Continued advances in air quality control, molecular diagnostics, and precision therapies are essential for prevention, early detection, and reduction of the global disease burden. Full article

Objective: To determine the optimal layer thickness for multi-planar volume reconstruction (MPVR) in differentiating invasive adenocarcinoma from non-invasive and minimally invasive lesions in pulmonary nodules (≤ 15 mm). Materials and Methods: This retrospective study enrolled a total of 601 solitary pulmonary nodules (≤15 mm) between June 2020 and February 2024, including 404 invasive adenocarcinomas (IAC), 80 micro-invasive adenocarcinomas (MIAs), 96 adenocarcinomas in situ (AISs), and 21 atypical adenomatous hyperplasias (AAHs). Thin-section computed tomography (TSCT) images with lung window settings and MPVR images with varying layer thicknesses (ranging from 2 to 14 mm with intervals of 2 mm) were analyzed for their morphological characteristics. Multivariate logistic regression analysis was employed to develop models for differentiating invasive adenocarcinoma from non-invasive and minimally invasive lesions. The model’s performances were further evaluated and compared to identify the optimal thickness for diagnosis. Results: The 10 mm MPVR model exhibited the best performance (AUC: 0.910, 95% CI [confidence interval]: 0.905–0.914; sensitivity: 0.906; specificity: 0.753; accuracy: 0.856; PPV: 0.883; and NPV: 0.796). As the MPVR layer thickness increased from 2 mm to 10 mm, model performance improved, with sensitivity rising from 0.870 to 0.906, specificity rising from 0.519 to 0.753, and accuracy increasing from 0.755 to 0.856. However, for layer thicknesses of 12 mm to 14 mm, all of them decreased. Furthermore, the overall performance of the 10 mm MPVR model surpassed that of the lung window model (AUC: 0.841, 95% CI: 0.831–0.844; sensitivity: 0.787; specificity: 0.760; accuracy: 0.778; PPV: 0.871; and NPV: 0.634). Conclusions: MPVR images with varying layer thicknesses can effectively distinguish invasive adenocarcinoma from non-invasive and minimally invasive lesions in pulmonary nodules ≤ 15 mm. Notably, the diagnostic performance of the 10 mm model was superior to model built with TSCT images, showing great potential as a precise and non-invasive tool for assessing the invasiveness of adenocarcinomas ≤ 15 mm. Full article

Background: Advances in molecular pathology have transformed NSCLC (Non-Small Cell Lung Cancer) diagnosis, prognosis, and treatment by enabling precise tumor characterization and targeted therapeutic strategies. We review key genomic alterations in NSCLC, including EGFR (epidermal growth factor receptor) mutations, ALK (anaplastic lymphoma kinase) and ROS1 (ROS proto-oncogene 1) rearrangements, BRAF (B-Raf proto-oncogene serine/threonine kinase) mutations, MET (mesenchymal–epithelial transition factor) alterations, KRAS (Kirsten rat sarcoma) mutations, HER2 (human epidermal growth factor receptor 2) alterations and emerging NTRK (neurotrophic receptor tyrosine kinase) fusions and AXL-related pathways. Methods: A total of 48 patients with NSCLC was analyzed, including 22 women and 26 men (mean age 70 years, range 44–86). Tumor specimens were classified histologically as adenocarcinomas (n = 81%) or squamous cell carcinomas (n = 19%). Smoking history, PD-L1 (programmed death-ligand 1) expression, and genetic alterations were assessed. NGS (Next-generation sequencing) identified genomic variants, which were classified according to ACMG (American College of Medical Genetics and Genomics) guidelines. Results: The cohort consisted of 29 former smokers, 13 current smokers, and 5 non-smokers (12%), with a mean smoking burden of 33 pack years. PD-L1 TPS (tumor proportion score) was ≥50% in 10 patients, ≥1–<50% in 22, and <1% in 15 patients. In total, 120 genomic variants were detected (allele frequency ≥ 5%). Of these, 52 (43%) were classified as likely pathogenic or pathogenic, 48 (40%) as variants of unknown significance, and 20 (17%) as benign or likely benign. The most frequently altered genes were TP53 (tumor protein p53) (31%), KRAS and EGFR (15% each), and STK11 (serine/threonine kinase 11) (12%). Adenocarcinomas accounted for 89% of all alterations, with TP53 (21%) and KRAS (15%) being most common, while squamous cell carcinomas predominantly harbored TP53 (38%) and MET (15%) mutations. In patients with PD-L1 TPS ≥ 50%, KRAS mutations were enriched (50%), particularly KRAS G12C and G12D, with frequent co-occurrence of TP53 mutations (20%). No pathogenic EGFR mutations were detected in this subgroup. Conclusions: Comprehensive genomic profiling in NSCLC revealed a high prevalence of clinically relevant mutations, with TP53, KRAS and EGFR as the dominant drivers. The strong association of KRAS mutations with high PD-L1 expression, irrespective of smoking history, highlights the interplay between genetic and immunological pathways in NSCLC. These findings support the routine implementation of broad molecular testing to guide precision oncology approaches in both adenocarcinoma and squamous cell carcinoma patients. Full article

Background: Radiomics can provide quantitative descriptors of tumor phenotype, but translation is often limited by feature instability across scanners and protocols. We aimed to develop and internally validate a protocol-specific CT-radiomics model using preoperative imaging to predict 5-year recurrence in patients with stage I lung adenocarcinoma after complete surgical resection. Methods: The retrospective study included 270 patients with completely resected stage I lung adenocarcinoma from January 2010–December 2021, among whom 23 (8.5%) experienced recurrence within five years. Radiomic features were extracted from routine preoperative CT scans. After preprocessing to remove highly constant and highly correlated features, the Synthetic Minority Over-sampling Technique addressed class imbalance in the training set. Recursive Feature Elimination identified the most predictive radiomic features. An XGBoost classifier was trained using optimized hyperparameters identified through RandomizedSearchCV with cross-validation. Model performance was evaluated using the ROC curve and predictive metrics. Results: Five radiomic features differed significantly between recurrence groups (p = 0.007 to <0.001): Shape Sphericity, first-order 90Percentile, GLCM Autocorrelation, GLCM Cluster Shade, and GLDM Large Dependence Low Gray Level Emphasis. The radiomics model showed excellent discriminatory ability with AUC values of 0.99 (95% CI: 0.98–1.00), 0.97 (95% CI: 0.91–1.00), and 0.96 (95% CI: 0.85–1.00) on the training, validation, and test sets, respectively. On the test set, the model achieved sensitivity of 100% (95% CI: 51–100%), specificity of 94% (95% CI: 81–98%), PPV of 67% (95% CI: 30–90%), NPV of 100% (95% CI: 90–100%), and overall accuracy of 95% (95% CI: 83–99%). Conclusions: Under protocol-homogeneous imaging conditions, CT radiomics accurately predicted recurrence in patients with completely resected stage I lung adenocarcinoma. External multi-vendor validation is needed before broader deployment. Full article

Background: Durvalumab consolidation following radiochemotherapy is now the standard treatment for unresectable stage III non-small cell lung cancer (NSCLC). [¹⁸F]FDG PET/CT offers valuable insights not just for staging but also for tumor characterization via radiomics, which can potentially predict histology, immunophenotype, and prognosis. Methods: We conducted a retrospective analysis of [¹⁸F]FDG PET/CT scans from stage IIIA–IIIB NSCLC patients treated at the Clinical Centre, University of Pécs. All biopsy samples were classified histologically (squamous vs. adenocarcinoma) and tested for PD-L1. Lung tumors were segmented using MEDISO InterViewTM FUSION software (version 3.12.002.0000). with an SUVmax threshold of four. Imaging features were extracted and compared based on histology, PD-L1 status, and neutrophil-to-lymphocyte ratio (NLR)-based prognosis groups. Statistical analyses were performed with Jamovi (v2.6.44), using Shapiro–Wilk, t-test/ANOVA, Mann–Whitney/Kruskal–Wallis, or Chi-square tests as appropriate. Results: Fifty-six patients were included (38 PD-L1-positive, 18 -negative). Among PD-L1-positive cases, poor versus good NLR prognosis groups differed in maximum diameter (p = 0.046), short-zone emphasis (p = 0.026), and zone-length non-uniformity (p = 0.027). Focusing on PD-L1-positive squamous carcinoma, maximum diameter, metabolic tumor volume, busyness, and coarseness showed significant differences (all p < 0.05). SUVmax, mean SUV, SUVpeak, and complexity were higher in squamous than in adenocarcinoma subtypes. PD-L1-positive and -negative squamous tumors differed in zone percentage (p = 0.039) and long-zone high gray-level emphasis (p = 0.024), while no significant differences were observed among adenocarcinomas. Conclusions: [¹⁸F]FDG PET/CT radiomics showed potential for differentiating NSCLC histological subtypes and for identifying PD-L1-associated imaging patterns in squamous cell carcinoma. In addition, certain metabolic features were associated with NLR-based prognostic groups in PD-L1-positive patients. Full article

Breast cancer and lung adenocarcinoma share common features, including female predominance and the expression of estrogen receptor (ER) and epidermal growth factor receptor (EGFR) during carcinogenesis. Patients with breast cancer have a significantly higher risk of developing second primary lung cancer than those without breast cancer. ER beta expression is associated with resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung adenocarcinoma, indicating a potentially important interaction between ER and EGFR. However, the mechanisms underlying this crosstalk remain poorly understood. Our clinical data showed a significant correlation between antiestrogen treatment for breast cancer and mutant EGFR expression (p = 0.021) in lung adenocarcinoma patients. In vitro, tamoxifen upregulated phosphorylated EGFR (p-EGFR) in EGFR-mutant lung adenocarcinoma cell lines. Heparin-binding EGF-like growth factor was identified as a key mediator from the ER pathway that stimulates p-EGFR. Tamoxifen counteracts estrogen’s effect and restores p-EGFR upregulation. Furthermore, coadministration of tamoxifen and the EGFR TKI gefitinib potentially inhibited p-EGFR expression in EGFR-mutant lung adenocarcinoma. Regular follow-up with chest computed tomography is recommended for patients with breast cancer. For those diagnosed with both ER-positive breast cancer and EGFR-mutant lung adenocarcinoma, combined tamoxifen and EGFR TKI therapy may offer an effective targeted treatment strategy. Full article

Alternative splicing (AS) is a fundamental mechanism governing transcriptomic diversity and cellular identity. Although 293T (human embryonic kidney) and A549 (human lung adenocarcinoma) cell lines are widely used, cell-type-specific splicing dynamics—including responses to receptor overexpression—remain incompletely characterized. To address this, we integrated Oxford Nanopore long-read sequencing with BGI short-read data to profile transcriptomes under both basal and GPCR-overexpressing conditions (ADORA3 in 293T; P2RY12 in A549). Full-length isoform analysis using FLAIR and SQANTI3 revealed extensive transcriptomic complexity, including 18.02% novel isoforms in 293T and 19.52% in A549 cells. We found that 293T cells exhibited a stable transcriptome architecture enriched in splicing-related pathways, whereas A549 cells underwent broader transcriptional remodeling linked to tumorigenic processes. These findings suggest that 293T cells may be a suitable model for investigating splicing regulation, while A549 cells could serve as a relevant system for exploring tumor-related transcriptome dynamics. Our work elucidates context-dependent AS regulation and underscores the value of integrating long-read sequencing with FLAIR/SQANTI3 for dissecting cell-state-specific transcriptome dynamics. Full article

Background: Lung adenocarcinoma (LUAD) exhibits pronounced cellular and molecular heterogeneity that shapes tumor progression and therapeutic response. Although nucleotide metabolism is essential for sustaining tumor proliferation and coordinating immune interactions, its single-cell heterogeneity and clinical implications remain incompletely defined. Methods: We integrated a publicly available scRNA-seq dataset derived from independent LUAD patients to construct a comprehensive LUAD cellular atlas, identified malignant epithelial cells using inferCNV, and reconstructed differentiation trajectories via Monocle2. Cell–cell communication patterns under distinct nucleotide metabolic states were assessed using CellChat. A nucleotide metabolism-related signature (NMRS) was subsequently developed across TCGA-LUAD and multiple GEO cohorts using 101 combinations of machine learning algorithms. Its prognostic and immunological predictive value was systematically evaluated. The functional relevance of the key gene ENO1 was further verified through pan-cancer analyses and in vitro experiments. Results: We identified substantial nucleotide metabolic heterogeneity within malignant epithelial cells, closely linked to elevated proliferative activity, glycolytic activation, and increased CNV burden. Pseudotime analysis showed that epithelial cells gradually acquire enhanced immune-modulatory and complement-related functions along their differentiation continuum. High-metabolism epithelial cells exhibited stronger outgoing communication—particularly via MIF, CDH5, and MHC-II pathways—highlighting their potential role in shaping an immunosuppressive microenvironment. The NMRS built from metabolism-related genes provided robust prognostic stratification across multiple cohorts and surpassed conventional clinical parameters. Immune profiling revealed that high-NMRS tumors displayed increased T-cell dysfunction, stronger exclusion, higher TIDE scores, and lower IPS, suggesting poorer responses to immune checkpoint blockade. ENO1, markedly upregulated in high-NMRS tumors and functioning as a risk factor in several cancer types, was experimentally shown to promote invasion in LUAD cell lines. Conclusions: This study delineates the profound impact of nucleotide metabolic reprogramming on epithelial cell states, immune ecology, and malignant evolution in LUAD. The NMRS provides a robust predictor of prognosis and immunotherapy response across cohorts, while ENO1 emerges as a pivotal metabolic–immune mediator and promising therapeutic target. Full article

A collection of 40 derivatives of 1,2-diphenyl-2-[1,2,3]triazol-1-yl-ethanol was obtained through a sequence of reactions, starting with benzoin as the initial raw material and using the CuAAC reaction as the key step in this process. The structure of a pair of these compounds was ultimately corroborated by single-crystal X-ray diffraction studies, which also reveals important O-H···N interactions. The antimicrobial activity of synthesized 1,2,3-triazoles was assessed against strains that include Candida albicans and Staphylococcus aureus. The antiproliferative properties of some of these novel compounds were also tested using a variety of tumor cell lines, including U251 (human glioblastoma), PC-3 (human prostate cancer cell line), K562 (human leukemia), HCT-15 (human colorectal adenocarcinoma), MCF-7 (human breast adenocarcinoma), and SKLU (human lung adenocarcinoma). Full article

Lineage plasticity, the ability of cancer cells to alter their differentiated state through transcriptional and epigenetic reprogramming, has emerged as a key mechanism of therapeutic resistance across cancers. This adaptive process can manifest in multiple ways, including epithelial–mesenchymal transition, acquisition of stem-like features, and histological transformation, the most striking and clinically apparent example. In EGFR-mutant lung adenocarcinoma (LUAD), lineage plasticity is increasingly recognized as a prevalent mechanism of acquired resistance to tyrosine kinase inhibitors (TKIs). Among its visible manifestations, histologic transformation into small-cell lung cancer (SCLC) is the most frequent, while squamous transformation and other phenotypic shifts also occur. Transformed tumors typically retain the initiating EGFR mutation but lose EGFR dependence, acquire neuroendocrine features, and display aggressive clinical behavior with poor clinical outcomes compared with both de novo SCLC and non-transformed LUAD. Recent studies show that plasticity arises through combined genomic, transcriptomic, and epigenetic reprogramming, often foreshadowed by molecular alterations before overt histological change. Spatial and single-cell profiling reveal heterogeneous trajectories and intermediate states, while functional models and multi-omics approaches have begun to identify therapeutic vulnerabilities distinct from both de novo EGFR-mutated SCLC and classical EGFR-mutated LUAD. Thus, lineage plasticity, whether manifested as histologic transformation or through more subtle epigenetic reprogramming, represents a formidable resistance mechanism in NSCLC. Defining its molecular basis and temporal dynamics will be essential for early detection, prognostication, and the development of tailored therapies. Full article

Background: Durvalumab, a PD-L1 inhibitor used as consolidation therapy after chemoradiation in unresectable stage III non–small cell lung cancer (NSCLC), can induce immune-related adverse events, among which immune-mediated pneumonitis represents one of the most severe. Differentiating checkpoint inhibitor pneumonitis (CIP) from infectious pneumonia is challenging due to overlapping clinical and radiologic findings. Case presentation: We describe a 67-year-old woman with stage III lung adenocarcinoma treated with chemotherapy, radiotherapy, and durvalumab, who presented with progressive dyspnea and extensive bilateral ground-glass opacities on CT imaging. Laboratory tests revealed leukopenia and elevated inflammatory markers. Despite broad-spectrum antibiotic and antiviral therapy, her condition worsened, requiring high-flow nasal cannula oxygen therapy. Multiplex molecular testing on sputum identified human metapneumovirus (HMPV), while blood cultures and urinary antigens for Streptococcus pneumoniae and Legionella pneumophila were negative. A pulmonology consultation raised suspicion for severe durvalumab-induced pneumonitis exacerbated by viral infection. High-dose methylprednisolone (2 mg/kg/day) followed by a four-week taper led to gradual clinical and radiologic resolution. Durvalumab was permanently discontinued. Discussion: To our knowledge, this is the first reported case of HMPV-associated pneumonitis in a patient receiving durvalumab. This case highlights the potential synergistic interplay between viral infection and immune checkpoint blockade, resulting in severe lung injury. Comprehensive microbiologic evaluation, including molecular diagnostics, is essential to guide therapy and distinguish infectious from immune-mediated causes. Conclusions: Early recognition of mixed infectious and immune-mediated pneumonitis, and timely corticosteroid therapy are critical to achieving favorable outcomes and preventing irreversible pulmonary damage. Full article

Background/Objectives: This study aimed to evaluate the prognostic effects of tumor spread through air spaces (STAS) and other clinical and pathological risk factors on disease-free survival (DFS) in patients with non-small cell lung cancer (NSCLC) who underwent curative lobectomy and had tumors measuring 4 cm or less. Methods: NSCLC patients who underwent surgery between March 2015 and May 2024 and had at least 12 months of follow-up were retrospectively analyzed. Patients with tumors measuring 4 cm or less who underwent R0 resection, lobectomy, and STAS assessment on intraoperative frozen sections were included in the study. Clinicopathological features of all patients were restaged according to the 9th edition of the TNM staging system. The Kaplan–Meier method, log-rank test, and univariate Cox regression analysis were used to determine the factors affecting DFS. Results: 88 patients were included in the study. The median age of the patients was 61 years, 77.3% were male, and 72.7% had adenocarcinoma histology. According to TNM 9, 23.9% of the cases were staged T1b, 18.2% T1c, and 58.0% T2a. STAS positivity was detected in 45 patients (51.1%). The rates of lymphovascular invasion (LVI) (40.0% vs. 18.6%; p = 0.028) and visceral pleural invasion (VPI) (57.8% vs. 27.9%; p = 0.005) were significantly higher in the STAS-positive group than in the STAS-negative group. Recurrence was observed in a total of 31 patients (35.2%) during a median follow-up period of 68.1 months. In Kaplan–Meier analysis, the median DFS was not reached for the entire cohort. The estimated median DFS in STAS-positive patients was 52.7 months, while the median was not reached in the STAS-negative group (p = 0.001). The median DFS was 52.3 months in those with lymph node positivity, while the median was not reached in those with lymph node negativity (p = 0.031). According to TNM 9, the difference in DFS between stage IA/IB and stage IIAB groups was not statistically significant (p = 0.080). In univariate Cox analysis, STAS positivity (HR = 3.79; 95% CI: 1.69–8.51; p = 0.001), lymph node positivity (HR = 2.58; 95% CI: 1.05–6.31; p = 0.038) and VPI (HR = 2.28; 95% CI: 1.07–4.86; p = 0.032) were found to be significant prognostic factors adversely affecting DFS. Age, gender, histological type, tumor location, T stage, LVI, perineural invasion (PNI), and adjuvant chemotherapy had no significant effect on DFS. Conclusions: STAS is a strong negative prognostic indicator for recurrence in patients with operated NSCLC with tumor size ≤ 4 cm. It is believed that STAS should be integrated into risk-based staging and adjuvant treatment decision-making processes in early-stage NSCLC, particularly when evaluated in conjunction with VPI and lymph node positivity. Full article