Objective We aimed to investigate the accuracy of a circulating exosome-based gene panel for predicting spread through air spaces (STAS). Methods A training cohort of 700 patients with stage I LUAD and a validation cohort of 178 patients were evaluated. Multivariable logistic regression was performed to identify exosome-derived genes and computed tomography (CT) features associated with STAS. The predictive performance of the gene panel, frozen sections (FS), and CT features was compared. Combined prediction models incorporating multiple diagnostic modalities were subsequently constructed and validated. Results STAS-positive tumors exhibited distinct exosome-derived gene signatures, including ALK rearrangement and elevated expression of MTA1, Twist, Slug, and β-Catenin. In the training cohort, the five-gene panel achieved an AUC of 0.802 (95 % CI: 0.770–0.834), with a sensitivity of 0.847 and a specificity of 0.666—superior to both FS (P < 0.001) and CT imaging features (P < 0.001). The AUC of the combined model integrating the gene panel with FS was 0.856 (95 % CI: 0.827–0.884), comparable to the model integrating the gene panel with radiology (AUC 0.846, 95 % CI 0.817–0.875; P = 0.471), and significantly higher than the combination of FS with radiology (AUC 0.803, 95 % CI: 0.767–0.840; P = 0.008 and P = 0.043, respectively). Similar results were also observed in the validation cohort. Conclusion ALK rearrangement and elevated expression of MTA1, Twist, Slug and β-Catenin in circulating exosomes were independent predictors of STAS. The five-gene panel serves as a promising adjunct to radiology and frozen sections for preoperative identification of STAS, potentially guiding optimal surgical decision-making.

Objective:We aimed to comprehensively assess the accuracy of patient-derived organoids to recapitulate the genomic features of patient tumors, and to quantify the reliability of patient-derived organoid-based drug screening, by pooling the available evidence and the validation using our patient-derived lung cancer organoids (LCOs). Methods:A comprehensive online search was conducted to identify eligible studies. A total of 20 LCOs harvested from surgical samples were also established as our internal validation cohort, with whole-exome sequencing and transcriptomic sequencing performed, respectively. Pooled concordance in genetic profiles between LCOs and original tumors was calculated, along with the overall accuracy of LCOs for drug profiling. Results:The pooled concordance in mutational landscape between LCOs and original tumors reached 74% (95% confidence interval [CI]: 61%-84%) in overall populations without heterogeneity (I 2 = 0%, p = 0.918), and that in gene expression achieved 70% (95% CI: 51%-84%; I 2 = 8.5%, p = 0.437). Subgroup analyses of our internal LCOs by morphologic patterns suggested that LCOs retained genetic fidelity regardless of intratumoral histologic heterogeneity and pathologic features. The accuracy of LCOs for predicting drug sensitivity achieved 90.7% (95% CI: 77.4%-9.2%) in the pooled populations with mild heterogeneity (I 2 = 30.2%, p = 0.231). Conclusions:Our study indicates that LCOs can stably recapitulate the genomic features of patient tumors irrespective of histologic heterogeneity and be a promising precision medicine tool for anticancer drug screening or for predicting drug responses.

Metastasis remains the primary cause of mortality in lung adenocarcinoma (LUAD) patients. However, the molecular mechanisms underlying LUAD cell metastasis are only partially elucidated. Here, by performing integrated bioinformatic analysis of clinical data, RNA-binding protein (RBP) NOVA2 is identified as a pivotal LUAD metastasis-associated regulator. NOVA2 expression is elevated in metastatic LUAD tissues and correlates with poor prognosis of LUAD patients. Functionally, NOVA2 depletion suppresses epithelial-mesenchymal transition (EMT), migration, and invasion in vitro, and attenuates LUAD cell metastasis in vivo. Mechanistically, histone acetyltransferase p300 augments H3K27 acetylation level and facilitates the binding of STAT3 to the NOVA2 promoter, which in turn promotes NOVA2 transcription. Increased NOVA2 expression induces exon skipping (exons 6-7) in SMAD4 to generate a truncated splicing isoform (termed Δ-SMAD4). The resulting Δ-SMAD4 isoform evades E3 ubiquitin ligase β-TrCP-mediated ubiquitination, maintaining its ability to form complex with SMAD3 (R-SMAD) and sustain TGF-β/SMAD signaling. Moreover, in NOVA2-overexpressing LUAD cells, Δ-SMAD4 knockdown has stronger inhibitory effects on TGF-β-induced EMT and invasion than does SMAD4 knockdown. In summary, our findings identify a novel mechanism by which STAT3-mediated transcriptional upregulation of NOVA2 promotes SMAD4 splicing in metastatic LUAD, and suggest that the STAT3-NOVA2-Δ-SMAD4 axis drives EMT and LUAD metastasis, which may be a promising therapeutic target for treating LUAD.

It remains undetermined regarding the impact of neoadjuvant therapy on immunogenic cell death (ICD) and subsequent tumor microenvironment (TME) remodeling in esophageal squamous cell carcinoma (ESCC). And it is of paramount significance to identify beneficiaries from neoadjuvant therapy in treatment-naïve ESCC. In this study, 88 ESCC samples undergoing neoadjuvant therapy plus surgery (NA+S) or surgery alone (SA) were subjected to bulk-RNA sequencing. A five-gene RINscore incorporating ICD-related signature genes with TME-based hub genes was established to predict clinical outcomes and pharmacological responses, in which SLAMF7 and IL1R1 were selected out as co-expressed genes. The regulatory mechanism of the repressive co-transcription factor BATF of SLAMF7 and IL1R1 was further demonstrated. Our data demonstrated that NA+S led to high abundance in kinds of T helper cells, nature killer T cells and M1-like macrophages with increased CD8+T cells infiltration compared with SA. ICD phenotypes were further characterized in treatment-naïve ESCC to determine their differences in TME and potential benefits from NA. Our findings not only offered novel insights into the distinct TME and ICD profiles of ESCC undergoing different therapeutic modes, but also provided the RINscore, which may aid oncologists in determining individualized (neo)adjuvant immunotherapy regimen.

It has not been determined which descriptor spread through air spaces (STAS) should be incorporated into the context of the ninth Tumor, Node and Metastasis (TNM) staging system: the T or the uncertain resection [R(un)] category. A multicenter retrospective cohort of 807 patients with pathological stage I lung adenocarcinoma was included in this study to assess the feasibility of incorporating STAS into the T descriptor or the R(un) category by analyzing recurrence-free survival (RFS) and overall survival (OS). Decision curve analysis (DCA) was performed to evaluate the standardized net benefit of the proposed T (nT) and that of the proposed residual tumor classification (nR) versus the current staging systems. Log-rank tests indicated that patients with pT1/STAS-positive lung adenocarcinoma had similar RFS and OS to patients with pT2a disease irrespective of R status. Regarding STAS as an indicator for upgrading R0 to R(un), comparable survival was observed between pT1-2a/STAS-positive patients undergoing R0 segmentectomy and pT1-2a patients undergoing R(un) segmentectomy. We further assessed the effects of the combination of STAS with either T or R category on survival in a validation cohort. Subgroup analyses stratified by surgical procedures further identified the consistency of the nT category in discriminating RFS and OS. However, the separation of nR0 and nR(un) disease in pT2a tumors treated by lobectomy or segmentectomy was not sufficiently distinguished. DCA further corroborated a greater predictive capability of nT versus the current T category. In conclusion, STAS might be preferentially considered as an indicator for upgrading pT1 disease into pT2a in the future TNM staging system.

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with a dismal prognosis. Hitherto, little has been known regarding the clinical implications of tertiary lymphoid structures (TLS) and its biological mechanisms of antitumor effect on treatment-naïve ESCC. We herein identified the presence of TLS as an independent factor for favorable survival. By characterizing the immune infiltration and genomic profiles based on transcriptomic datasets, we found TLS abundant in enriched B cells with IRF4 as a signature gene. Increased expression of IRF4 and its positive correlation with STING in activating tumor-infiltrating B cells were also investigated using a single-cell RNA sequencing dataset. CD40 as a co-regulator of IRF4 and TLS formation, in vitro experiments were conducted to further demonstrate the competitive binding relationships between CD40 and STING with TRAF2 in promoting IRF4 expression and B cell activation via the non-canonical NF-kB signaling pathway, in which CD40 reduced STING ubiquitination while promoting its phosphorylation. Our data provided deeper insights into the potential role of activated B cells and TLS in ESCC, with implications for the development of biomarkers and therapeutic targets.

Background The purpose of this study was to assess the prognostic factors for non-lepidic invasive adenocarcinoma presenting as subsolid nodules. The feasibility of detecting non-lepidic predominant patterns on frozen section (FS) was also evaluated. Methods A multicenter retrospective cohort of 614 patients with clinical T1N0M0 non-lepidic invasive adenocarcinoma presenting as subsolid nodule was included. Two subgroups were divided based on the consolidation-to-tumor ratio (CTR) on lung window: ground glass opacity (GGO)-dominant subgroup (CTR<0.5), solid-dominant subgroup (CTR≥0.5). Kaplan-Meier approach and multivariable Cox models were used to identify risk factors for recurrence-free survival (RFS) and overall survival (OS). FS and final pathology (FP) of 100 specimens were also reviewed by five pathologists for tumor grading synchronously. Results Multivariate analysis indicated that segmentectomy was a risk factor for shortened RFS and OS in the solid-dominant subgroup rather than in the GGO-dominant one. Subset analysis demonstrated survival disadvantages of segmentectomy for high-grade adenocarcinoma but not for intermediate-grade one in the solid-dominant subgroup. However, segmentectomy exhibited non-inferiority to lobectomy in the GGO-dominant subgroup irrespective of tumor grade. The overall accuracy of identifying non-lepidic patterns was 84 % with a good interobserver agreement. Multivariable logistic analysis identified presence of complex glandular pattern and acinar pattern as independent predictors of the discrepancy between FS and FP. Conclusions Segmentectomy should be cautiously performed for patients with radiologically solid-dominant non-lepidic invasive adenocarcinoma, especially for those with high-grade patterns. FS had high diagnostic accuracy and satisfactory interobserver agreement for tumor grading, which might aid surgeons in determining the appropriate surgical procedure.

BACKGROUND:This study aims to investigate the prognostic value of baseline and absolute changes of inflammatory markers in thymic epithelial tumors (TETs). METHODS:This real-world study enrolled 147 patients. Inflammatory markers, including baseline and absolute changes of platelet-to-lymphocyte (PLR), platelet-to-monocyte (PMR), lymphocyte-to-monocyte (LMR), and neutrophil-to-lymphocyte ratio (NLR), were retrospectively collected. Survival analysis was conducted using Kaplan-Meier analysis. Lasso and multivariate Cox regression were conducted to assess the relationship between disease-free survival (DFS), overall survival (OS) and inflammatory markers. Predictive nomograms were constructed by variables identified in Cox regression. RESULTS:Higher baseline NLR and PLR, lower baseline LMR and PMR, a greater change in PLR and smaller changes in LMR, PMR, and PNR related to inferior DFS and OS. Multivariate Cox regression identified higher baseline PLR and advanced Masaoka Stage were risk, while higher baseline PMR was protective OS factors. Age, higher baseline PLR, and advanced Masaoka Stage were risk DFS factors. A greater absolute PLR change and metastasis were risk, while a lower absolute PMR change was protective OS factors. Age and a greater absolute PLR change were risk, while a greater absolute LMR change was favorable DFS factors. CONCLUSIONS:The present study is the first to reveal the prognostic role of the baseline and absolute changes of inflammatory markers in TETs. The prognostic models based on these inflammatory markers offer promising tools for predicting the prognosis of TET patients.

AIM:Conflicting results have been reported about the impact of neoadjuvant therapy on anastomotic leakage (AL) after esophagectomy. We aimed to unravel the potential effect of neoadjuvant therapy on AL after esophagectomy through a network meta-analysis. METHODS:A Bayesian network meta-analysis was performed by retrieving relevant literature from PubMed, EMbase, The Cochrane Library and Web of Science Core Collection. Randomized clinical trials (RCTs) and retrospective studies (RS) comparing the following treatment modalities were included: neoadjuvant chemoradiation (nCRT), neoadjuvant chemotherapy (nCT), neoadjuvant radiotherapy (nR), neoadjuvant immunochemotherapy (nICT), and surgery alone (SA). Subgroup analyses by radiation dose, examined lymph nodes (ELN), route of reconstruction, site of anastomosis, and surgical approach were also conducted. RESULTS:A total of 62 studies with 12,746 patients were included for the present study, among which 17 were RCTs. There were no significantly statistical differences observed among the five treatment modalities in AL for both RCTs (nCRT-nICT: risk ratio 1.51, 95% confidence interval 0.52-4.4; nCT-nICT: 1.71, 0.56-5.08; nICT-nR: 0.79, 0.12-8.02; nICT-SA: 0.59, 0.2-1.84) and RS (nCRT-nICT: odds ratio 1.53, 95% confidence interval 0.84-2.84; nCT-nICT: 1.56, 0.87-2.88; nICT-SA: 0.6, 0.31-1.12; nICT-nR: 1.08, 0.09-36.02). Subgroup analysis revealed that no significant difference in AL was observed among the five treatment modalities except for the impact of nCRT versus nCT (0.21, 0.05-0.73) on AL with a radiation dose ≥41.4 Gy. CONCLUSIONS:Neoadjuvant therapy do not significantly increase the incidence of AL after esophagectomy. Administration of irradiation with a moderate dose is not associated with elevated risk in AL. Clinicians can be less apprehensive about prescribing nCRT.

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Objectives: Mediastinal neoplasms are typical but uncommon thoracic diseases with increasing incidence and unfavorable prognoses. A comprehensive understanding of their spatiotemporal distribution is essential for accurate diagnosis and timely treatment. However, previous studies are limited in scale and data coverage. Therefore, this study aims to elucidate the distribution of mediastinal lesions, offering valuable insights into this disease. Materials and methods: This multi -center, hospital -based observational study included 20 nationwide institutions. A retrospective search of electronic medical records from January 1st, 2009, to December 31st, 2020, was conducted, collecting sociodemographic data, computed tomography images, and pathologic diagnoses. Analysis focused on age, sex, time, location, and geographical region. Comparative assessments were made with global data from a multi -center database. Results: Among 7,765 cases, thymomas (30.7%), benign mediastinal cysts (23.4%), and neurogenic tumors (10.0%) were predominant. Distribution varied across mediastinal compartments, with thymomas (39.6%), benign cysts (28.1%), and neurogenic tumors (51.9%) most prevalent in the prevascular, visceral, and paravertebral mediastinum, respectively. Age-specific variations were notable, with germ cell tumors prominent in patients under 18 and aged 18 -29, while thymomas were more common in patients over 30. The composition of mediastinal lesions across different regions of China remained relatively consistent, but it differs from that of the global population. Conclusion: This study revealed significant heterogeneity in the spatiotemporal distribution of mediastinal neoplasms. These findings provide useful demographic data when considering the differential diagnosis of mediastinal lesions, and would be beneficial for tailoring disease prevention and control strategies.

Aims Conflicting data were provided regarding the prognostic impact and genomic features of lung adenocarcinoma (LUAD) with lepidic growth pattern (LP+A). Delineation of the genomic and immune characteristics of LP+A could provide deeper insights into its prognostic implications and treatment determination. Methods We conducted a search of articles in PubMed, EMBASE and the Cochrane Library from inception to January 2024. A domestic cohort consisting of 52 LUAD samples was subjected to whole-exome sequencing as internal validation. Data from The Cancer Genomic Atlas and the Gene Expression Omnibus datasets were obtained to characterise the genomic and immune profiles of LP+A. Pooled HRs and rates were calculated. Results The pooled results indicated that lepidic growth pattern was either predominant (0.35, 95% CI 0.22 to 0.56, p<0.01) or minor (HR 0.50, 95% CI 0.36 to 0.70, p<0.01) histological subtype was associated with favourable disease-free survival. Pooled gene mutation rates suggested higher EGFR mutation (0.55, 95% CI 0.46 to 0.64, p<0.01) and lower KRAS mutation (0.14, 95% CI 0.02 to 0.25, p=0.02) in lepidic-predominant LUAD. Lepidic-predominant LUAD had lower tumour mutation burden and pooled positive rate of PD-L1 expression compared with other subtypes. LP+A was characterised by abundance in resting CD4+memory T cells, monocytes and gamma delta T cells, as well as scarcity of cancer-associated fibroblasts. Conclusions LP+A was a unique histological subtype with a higher EGFR mutation rate, lower tumour mutation burden and immune checkpoint expression levels. Our findings suggested potential benefits from targeted therapy over immunotherapy in LP+A.

Radiotherapy is the most predominant treatment strategy for lung squamous cell carcinoma (LUSC) patients, but radioresistance is the major obstacle to therapy effectiveness. The mechanisms and regulators of LUSC radioresistance remain unclear. Here, lactotransferrin (LTF) is found to be significantly upregulated in radioresistant LUSC cell lines (H226R and H1703R) and clinical samples and promotes radioresistance of LUSC both in vitro and in vivo. Comprehensive enrichment analyses suggested that LTF potentially modulates autophagy in LUSC. Interestingly, the level of autophagy was raised in the radioresistant cells, and suppression of autophagy sensitized LUSC to irradiation. Functional experiments showed that LTF deficiency inhibits cellular autophagy through the AMPK pathway, ultimately leading to radiosensitization. Mechanistically, LTF can directly interact with AMPK to facilitate its phosphorylation and activate autophagy signaling. Moreover, NEAT1 functions as a ceRNA that targets miR-214-5p resulting in an increased LTF expression. Intriguingly, SP2, a transcription factor regulated by AMPK, induced NEAT1 expression by directly binding to its promoter region and thus forming a LTF/AMPK/SP2/NEAT1/miR-214-5p feedback loop. Our work reveals for the first time that LTF induces radioresistance by promoting autophagy and enhancing its self-expression via forming a positive feedback loop, suggesting that LTF is an appealing radiosensitization target for treating LUSC.

BACKGROUND:Mediastinal neoplasms are typical thoracic diseases with increasing incidence in the general global population and can lead to poor prognosis. In clinical practice, the mediastinum's complex anatomic structures and intertype confusion among different mediastinal neoplasm pathologies severely hinder accurate diagnosis. To solve these difficulties, we organised a multicentre national collaboration on the basis of privacy-secured federated learning and developed CAIMEN, an efficient chest CT-based artificial intelligence (AI) mediastinal neoplasm diagnosis system. METHODS:In this multicentre cohort study, 7825 mediastinal neoplasm cases and 796 normal controls were collected from 24 centres in China to develop CAIMEN. We further enhanced CAIMEN with several novel algorithms in a multiview, knowledge-transferred, multilevel decision-making pattern. CAIMEN was tested by internal (929 cases at 15 centres), external (1216 cases at five centres and a real-world cohort of 11 162 cases), and human-AI (60 positive cases from four centres and radiologists from 15 institutions) test sets to evaluate its detection, segmentation, and classification performance. FINDINGS:In the external test experiments, the area under the receiver operating characteristic curve for detecting mediastinal neoplasms of CAIMEN was 0·973 (95% CI 0·969-0·977). In the real-world cohort, CAIMEN detected 13 false-negative cases confirmed by radiologists. The dice score for segmenting mediastinal neoplasms of CAIMEN was 0·765 (0·738-0·792). The mediastinal neoplasm classification top-1 and top-3 accuracy of CAIMEN were 0·523 (0·497-0·554) and 0·799 (0·778-0·822), respectively. In the human-AI test experiments, CAIMEN outperformed clinicians with top-1 and top-3 accuracy of 0·500 (0·383-0·633) and 0·800 (0·700-0·900), respectively. Meanwhile, with assistance from the computer aided diagnosis software based on CAIMEN, the 46 clinicians improved their average top-1 accuracy by 19·1% (0·345-0·411) and top-3 accuracy by 13·0% (0·545-0·616). INTERPRETATION:For mediastinal neoplasms, CAIMEN can produce high diagnostic accuracy and assist the diagnosis of human experts, showing its potential for clinical practice. FUNDING:National Key R&D Program of China, National Natural Science Foundation of China, and Beijing Natural Science Foundation.

Non-small cell lung cancer(NSCLC) is one of the most common malignancies worldwide. Not only the complex molecular components but also the cellular heterogeneity in NSCLC tissues pose a great barrier for its clinical treatment. Recent years has witnessed the widespread application of single-cell sequencing in the studies regarding tumor heterogeneity. However, the disadvantages of single-cell sequencing technology itself could not be neglected. Spatial transcriptome(ST) technology allows in situ transcriptome sequencing of tissues to achieve high-throughput transcriptomic information of tissue cells with their spatial information available. In other words, ST makes it possible to acquire cellular composition and gene expression patterns without breaking intercellular communication network, which distinguishes itself from conventional single-cell sequencing, since mechanical separation and enzymatic digestion of tissue cells into single-cell suspension used to be inevitable during the performance of single-cell sequencing. To gain new insights into the spatial heterogeneity of NSCLC, we reviewed and summarized the latest progress in ST technology which has been applied to tumor sample analysis, especially to the field of NSCLC.

We investigated the clinical implications and molecular features of TLS in stage I lung adenocarcinoma (LUAD).

OBJECTIVES:To determine the impact of recurrent laryngeal nerve (RLN) lymph node (LN) dissection on survival and postoperative complications in patients with oesophageal squamous cell carcinoma (ESCC). METHODS:Patients with cT1-4N0-3M0 thoracic ESCC who underwent oesophagectomy and two-field lymphadenectomy from three institutions were included. The entire cohort was divided into three groups that underwent the total two-field lymphadenectomy (T-2FL), standard two-field lymphadenectomy (S-2FL) or unilateral RLN-LN dissection plus S-2FL (U-2FL) based on the extent of RLN-LN dissection. Subgroup analyses were also performed and were stratified by treatment modality. RESULTS:Both the U-2FL and T-2FL groups had significantly superior outcomes compared with the S-2FL group (overall survival: U-2FL versus S-2FL: P = 0.002; T-2FL versus S-2FL: P < 0.001; recurrence-free survival: U-2FL versus S-2FL: P = 0.01; T-2FL versus S-2FL: P < 0.001). Moreover, no significant differences were observed between U-2FL and T-2FL regarding overall survival (P > 0.05) and recurrence-free survival (P > 0.05), irrespective of administration of neoadjuvant therapy plus oesophagectomy or upfront oesophagectomy. Additionally, the extent of RLN-LN dissection was not an independent predictor of stage migration (P = 0.14) but was for postoperative nodal upstaging (P = 0.02). Notably, S-2FL brought significantly lowered risk in postoperative complications, especially for RLN palsy, when compared with T-2FL (P = 0.002) but not U-2FL (P = 0.72). CONCLUSIONS:Adequacy of RLN-LN dissection is an important prognosticator for improved overall survival and recurrence-free survival in patients with thoracic ESCC. U-2FL may serve as an alternative to T-2FL in selected populations.

OBJECTIVES:This study aimed to investigate the potential of complex glandular patterns (CGP) in lymph node micrometastasis (LNMM) and to determine the clinical beneficiaries in stage I lung adenocarcinoma (LUAD) with CGP. Meanwhile, the feasibility of detecting CGP on frozen section was also evaluated. METHODS:We retrospectively analysed the clinicopathological characteristics of 848 pathologic-stage I LUADs. A logistic regression model and a Cox proportional-hazards model were conducted to define the risk factors for LNMM and survival respectively. Furthermore, 5 pathologists reviewed frozen sections of 100 LUADs independently. RESULTS:The logistic regression model indicated that CGP [odds ratio 3.89, 95% confidence interval (CI) 2.46-6.15; P < 0.001] was an independent predictor of the presence of LNMM. Subgroup analysis revealed that CGP-present/LNMM-positive LUAD had the highest risk of both loco-regional and distant recurrence. Moreover, adequate lymphadenectomy [recurrence-free survival: hazard ratio (HR) 0.61, 95% CI 0.40-0.95; P = 0.028; overall survival: HR 0.64, 95% CI 0.41-0.99; P = 0.043] and adjuvant chemotherapy (recurrence-free survival: HR 0.30, 95% CI 0.18-0.52; P < 0.001; overall survival: HR 0.33, 95% CI 0.19-0.57; P < 0.001) brought survival benefits to CGP-present patients, especially to CGP-present/LNMM-positive subgroup. Across the 5 pathologists, sensitivity ranged from 59 to 68% and specificity ranged from 79 to 83%, with moderate diagnostic agreement and high interobserver agreement for detecting CGP on frozen section. CONCLUSIONS:LNMM was more frequently observed in stage I LUAD with CGP. Adequate lymphadenectomy and adjuvant chemotherapy were associated with improved survival in CGP-present patients, especially in CGP-present/LNMM-positive subgroup. Additionally, it is feasible to identify CGP on frozen section intraoperatively.

Background: It remains undetermined whether preoperative computed tomography (CT)-guided hookwire localization would result in elevated risk of tumor spread through air spaces (STAS) in stage IA lung adenocarcinoma. Methods: A total of 1836 patients who underwent lobectomy were included. To eliminate the potential impact of confounding factors on producing STAS, propensity score–matching (PSM) was used to create two balanced subgroups stratified by implementation of hookwire localization. We also introduced an external cohort including 1486 patients to explore the effect of hookwire localization on the incidence of STAS and patient survival after sublobar resection (SR). For proactive simulation of hookwire localization, 20 consecutive lobectomy specimens of p-stage IA lung adenocarcinoma were selected. Results: Ex vivo tests revealed that mechanical artifacts presenting as spreading through a localizer surface (STALS) could be induced by hookwire localization but be distinguished by CD68 and AE1/3 antibody-based immunohistochemistry. The distance of STALS dissemination tended to be shorter compared with real STAS (P = 0.000). After PSM, implementation of hookwire localization was not associated with elevated STAS incidence, nor worse survival in p-stage IA patients undergoing lobectomy irrespective of STAS. Conclusions: CT-guided hookwire localization might induce mechanical artifacts presenting as STALS which could be distinguished by immunohistochemistry, but would not affect survival in p-stage IA disease. Surgeons can be less apprehensive about performing hookwire localization in relation to STAS on stage IA disease suitable for SR.