FOXA3 regulates cholesterol metabolism to compensate for low uptake during the progression of lung adenocarcinoma.

Cholesterol metabolism is vital for multiple cancer progression, while how cholesterol affects lung, a low-cholesterol tissue, for cancer metastasis and the underlying mechanism remain unclear. In this study, we found that metastatic lung adenocarcinoma cells acquire cellular dehydrocholesterol and cholesterol by endogenous cholesterol biosynthesis, instead of uptake upon cholesterol treatment. Besides, we demonstrated that exogenous cholesterol functions as signaling molecule to induce FOXA3, a key transcription factor for lipid metabolism via GLI2. Subsequently, ChIP-seq analysis and molecular studies revealed that FOXA3 transcriptionally activated Hmgcs1, an essential enzyme of cholesterol biosynthesis, to induce endogenous dehydrocholesterol and cholesterol level for membrane composition change and cell migration. Conversely, FOXA3 knockdown or knockout blocked cholesterol biosynthesis and lung adenocarcinoma metastasis in mice. In addition, the potent FOXA3 inhibitor magnolol suppressed metastatic gene programs in lung adenocarcinoma patient-derived organoids (PDOs). Altogether, our findings shed light onto unique cholesterol metabolism and FOXA3 contribution to lung adenocarcinoma metastasis.

Patient-derived tumor-like cell clusters for personalized chemo- and immunotherapies in non-small cell lung cancer.

Many patient-derived tumor models have emerged recently. However, their potential to guide personalized drug selection remains unclear. Here, we report patient-derived tumor-like cell clusters (PTCs) for non-small cell lung cancer (NSCLC), capable of conducting 100-5,000 drug tests within 10 days. We have established 283 PTC models with an 81% success rate. PTCs contain primary tumor epithelium self-assembled with endogenous stromal and immune cells and show a high degree of similarity to the original tumors in phenotypic and genotypic features. Utilizing standardized culture and drug-response assessment protocols, PTC drug-testing assays reveal 89% overall consistency in prospectively predicting clinical outcomes, with 98.1% accuracy distinguishing complete/partial response from progressive disease. Notably, PTCs enable accurate prediction of clinical outcomes for patients undergoing anti-PD1 therapy by combining cell viability and IFN-γ value assessments. These findings suggest that PTCs could serve as a valuable preclinical model for personalized medicine and basic research in NSCLC.

Perioperative outcomes of bi-pigtail catheter drainage strategy versus conventional chest tube after uniportal video-assisted thoracic lung surgery.

OBJECTIVES: Chest tube (CT) drainage is a main cause of postoperative pain in lung surgery. Here, we introduced a novel drainage strategy with bi-pigtail catheters (PCs) and conducted a randomized controlled trial to compare with conventional CT drainage after uniportal video-assisted thoracic surgery lung surgery. METHODS: A single-centre, prospective, open-labelled, randomized controlled trial (ChiCTR2000035337) was conducted with a preplanned sample size of 396. The primary outcome was the numerical pain rating scale (NPRS) on the first postoperative day. Secondary outcomes included other indicators of postoperative pain, drainage volume, duration of drainage, postoperative hospital stay, incidence of postoperative complications, CT reinsertion and medical costs. RESULTS: A total number of 396 patients were randomized between August 2020 and January 2021, 387 of whom were included in the final analysis. The baseline and clinical characteristics of the patients were well balanced between 2 groups. The NPRS on the first postoperative day was significantly lower in the PC group than in the CT group (2.40 ± 1.27 vs 3.02 ± 1.39, p < 0.001), as well as the second/third-day NPRS, the incidence of sudden severe pain (9/192, 4.7% vs 34/195, 17.4%, P < 0.001) and pain requiring intervention (19/192, 9.9% vs 46/195, 23.6%, P < 0.001). In addition, the medical cost in the PC group was lower (US$7809 ± 1646 vs US$8205 ± 1815, P = 0.025). Univariable and multivariable analyses revealed that the drainage strategy was the only factor influencing the incidence of pain requiring intervention. CONCLUSIONS: The drainage strategy with bi-PCs in patients undergoing uniportal video-assisted thoracic surgery lung surgery alleviates postoperative pain with adequate safety and efficacy.

The learning curve on uniportal video-assisted thoracoscopic lobectomy with the help of postoperative review of videos.

Objectives: Video-assisted thoracoscopic lobectomy has become the preferred surgical approach in experienced centers, and uniportal approaches are becoming increasingly used. But the uniportal approach is still not widely applied presumably due to the learning difficulties of this complex procedure. The use of surgical videos may be helpful to accelerate the learning of this new techniques as in other fields. In this study, we aimed to analyze the learning curve of uniportal video-assisted thoracoscopic lobectomy with the help of postoperative review of videos. Methods: 114 patients with early-stage lung cancer who underwent uniportal video-assisted thoracoscopic lobectomy performed from 2020 to 2021 were reviewed in this study. We recorded the operation video for each patient and reviewed all the videos after surgery. The learning curves were assessed using cumulative sum analysis and the collected data of perioperative outcomes were assessed. Results: The CUMSUM curve showed its inflection points were around case 38 and 53. It was less compared with previous studies, which about 57-140 cases are needed to attain the proficient phase. The perioperative outcomes were similar in each phase, which included intraoperative blood loss (79.00 ± 26.70 vs 70.67 ± 26.64 vs 70.56 ± 27.23, p=0.0119), the length of hospital stay (3.60 ± 1.52 days vs. 3.23 ± 0.90 days vs. 3.06 ± 0.88 days, p=0.053), the rate of prolonged air leak and conversion to open thoracotomy. There was also no significant difference in the numbers and station of lymph node dissection among the three phases. Conclusions: Uniportal video-assisted thoracoscopic lobectomy is a safe and reliable approach. Recording and reviewing the operation video could help the surgeon to improve deficiencies and refine the procedure.

The application of patient-derived organoid in the research of lung cancer.

Lung cancer is the most common cancer and the leading cause of cancer-related death worldwide. However, mechanisms of its progression remained unclear and new treatments against this disease are rapidly emerging. As a novel preclinical model, patient-derived organoid (PDO) can also be established from the patient's tumor tissue and cultured in the laboratory, which preserves the key biological characteristics of the original tumor. Compared to the patient-derived xenograft (PDX) model of lung cancer, the culture success rate is improved, and the time and cost of model establishment are largely reduced. PDO is also expected to provide a more individual model to predict the efficacy of anti-cancer treatment in vitro. This paper summarizes the current application of PDO in the translational research of lung cancer.

Bioinformatic analysis of single-cell RNA sequencing dataset dissects cellular heterogeneity of triple-negative breast cancer in transcriptional profile, splicing event and crosstalk network.

BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high tumoral heterogeneity, while the detailed regulatory network is not well known. METHODS: Via single-cell RNA-sequencing (scRNA-seq) data analysis, we comprehensively investigated the transcriptional profile of different subtypes of TNBC epithelial cells with gene regulatory network (GRN) and alternative splicing (AS) event analysis, as well as the crosstalk between epithelial and non-epithelial cells. RESULTS: Of note, we found that luminal progenitor subtype exhibited the most complex GRN and splicing events. Besides, hnRNPs negatively regulates AS events in luminal progenitor subtype. In addition, we explored the cellular crosstalk among endothelial cells, stromal cells and immune cells in TNBC and discovered that NOTCH4 was a key receptor and prognostic marker in endothelial cells, which provide potential biomarker and target for TNBC intervention. CONCLUSIONS: In summary, our study elaborates on the cellular heterogeneity of TNBC, revealing that NOTCH4 in endothelial cells was critical for TNBC intervention. This in-depth understanding of epithelial cell and non-epithelial cell network would provide theoretical basis for the development of new drugs targeting this sophisticated network in TNBC.

Multiple factors affecting perioperative antibiotherapy in minimally invasive lung surgery: a retrospective case-control study.

Background: During the perioperative period, empiric antibiotic escalation therapy is not uncommon, leading to longer postoperative hospital stay and higher medical expenses. However, few systematic studies have investigated this issue. In this case-control study, we explored the factors affecting empiric antibiotic escalation therapy after minimally invasive lung surgery during hospitalization, with the aim to enhance recovery after surgery and rational use of antibiotics. Methods: The data of patients who underwent minimally invasive lung surgery at our center from January 2019 to December 2020 were collected from the hospital information system (HIS). A total of 1,360 cases were identified based on the inclusion and exclusion criteria. These patients were divided into 2 groups: group A (n=825), in which patients did not receive antibiotic escalation therapy after surgery; and group B (n=535), in which patients received empiric antibiotic escalation therapy after surgery. A logistic regression model was used to analyze the influencing factors of empiric antibiotherapy escalation during postoperative hospitalization. Results: Compared with group A, group B had significantly longer postoperative hospital stay (5.05±2.78 vs. 4.49±2.24 days, P<0.001) and slightly higher average total hospitalization costs (74,080.85±23,796.51 vs. 71,798.09±21,307.26 yuan, P=0.067). Multivariate analysis showed that the statistically significant factors included history of secondary lung surgery [odds ratio (OR): 3.267; 95% confidence interval (CI): 1.305-8.178; P=0.011], preoperative hemoglobin A1c (HbA1c) ≥6.5% (OR: 1.603; 95% CI: 1.143-2.249; P=0.006), postoperative fever of unknown origin [temperature (T) >38 ℃; OR: 2.494; 95% CI: 1.321-4.708; P=0.005], postoperative hypoalbuminemia (intravenous albumin administration for ≥2 days; OR: 14.125; 95% CI: 1.777-112.282; P=0.012). Conclusions: Multivariate analysis showed that history of secondary lung surgery, preoperative HbA1c ≥6.5%, postoperative fever of unknown origin (T >38 ℃), and postoperative hypoalbuminemia (<35 g/L and intravenous albumin administration ≥2 days) were the independent risk factors for empiric antibiotic escalation therapy after minimally invasive lung surgery. For preoperative risk factors, further cohort studies should be conducted to explore better intervention indicators or measures. For postoperative risk factors, perioperative dynamic monitoring of procalcitonin can guide the rational use of antibiotics, reduce the risk of drug resistance and hospitalization cost.

Impact of Lymph Node Dissection on Survival and Tumor Recurrence for Patients with Resected cT1-2N0 Small Cell Lung Cancer.

BACKGROUND: The role of lymph node (LN) dissection for early-stage small cell lung cancer (SCLC) remains unclear. Therefore, this study aimed to investigate the impact of LN dissection on patient survival and tumor recurrence for patients with cT1-2N0M0 SCLC. METHODS: Patients with cT1-2N0M0 SCLC who underwent intent-to-cure surgery at our institution between 2011 and 2019 were retrospectively reviewed. The survival outcomes of patients with systematic LN dissection (n = 112) and LN sampling (n = 35) were compared before and after propensity score-matching (PSM), as were the outcomes for patients with (pN+) and without (pN0) pathologic nodal metastasis. The prognostic impact of LN dissection was evaluated through multivariable analysis. RESULTS: The dissection group displayed significantly better overall survival (66.4% vs. 48.4%; P = 0.009) and recurrence-free survival (RFS) (63.5% vs. 37.6%;, P = 0.003) than the sampling group at 5 years. The rate of local recurrence was significantly lower in the dissection group than in the sampling group (11.6% vs. 42.9%; P < 0.001). After adjustment by multivariable analysis and PSM, LN dissection retained its independent favorable effects. The overall nodal upstaging rate was 37.6%, and the dissection group had a tendency of better RFS in both the pN0 (P = 0.05) and pN+ (P = 0.036) patients. CONCLUSION: Systematic LN dissection is associated with improved survival of patients who undergo surgery for cT1-2N0 SCLC. Further studies are warranted to verify the necessity of LN dissection in the surgery for SCLC.

Expert consensus on multi-disciplinary treatment, whole-course pulmonary rehabilitation management in patients with lung cancer and chronic obstructive lung disease.

Comorbidity of lung cancer and chronic obstructive pulmonary disease (COPD) is very common. Surgical operation is the initial treatment of lung cancer. But surgery operation will aggravate the symptoms of COPD, such as shortness of breath, chest tightness. On the other side, the COPD also increase the perioperative complications. Besides, the COPD may also influence the anti-cancer treatment and long-term survival of lung cancer patients. At present, there are guidelines for pulmonary rehabilitation (PR) of COPD or lung cancer respectively, but there is no reference expert consensus on the PR of patients with lung cancer who are comorbidity of COPD. Primary care has to satisfy the patient's complex needs holistically, and single-disease guidelines are unsuitable. In view of this, we organized experts from respiratory department, thoracic surgery department, oncology department, nursing department, etc., to write the expert consensus. We discussed the contents of the expert consensus through literature review, expert correspondence, expert meeting and discussion. This expert consensus contain five parts: introduction, respiratory assessment, timing of PR, PR strategies, perioperative PR management strategies in lung cancer patients with COPD. This expert consensus focuses on patients with COPD comorbid lung cancer and undergoing surgery operation, highlighting the concept of whole process management. For clinical medical staff, this expert consensus will promote the practice of PR in and out the hospital for this specific patient; for patients, this expert consensus is helpful to better understand PR and improve the enthusiasm of participating in PR in the whole process.

Homologous recombination deficiency (HRD) can predict the therapeutic outcomes of immuno-neoadjuvant therapy in NSCLC patients.

BACKGROUND: Neoadjuvant immunotherapy is emerging as novel effective intervention in lung cancer, but study to unearth effective surrogates indicating its therapeutic outcomes is limited. We investigated the genetic changes between non-small cell lung cancer (NSCLC) patients with varied response to neoadjuvant immunotherapy and discovered highly potential biomarkers with indicative capability in predicting outcomes. METHODS: In this study, 3 adenocarcinoma and 11 squamous cell carcinoma NSCLC patients were treated by neoadjuvant immunotherapy with variated regimens followed by surgical resection. Treatment-naive FFPE or fresh tissues and blood samples were subjected to whole-exome sequencing (WES). Genetic alternations were compared between differently-responded patients. Findings were further validated in multiple public cohorts. RESULTS: DNA damage repair (DDR)-related InDel signatures and DDR-related gene mutations were enriched in better-responded patients, i.e., major pathological response (MPR) group. Besides, MPR patients exhibited provoked genome instability and unique homologous recombination deficiency (HRD) events. By further inspecting alternation status of homology-dependent recombination (HR) pathway genes, the clonal alternations were exclusively enriched in MPR group. Additionally, associations between HR gene alternations, percentage of viable tumor cells and HRD event were identified, which orchestrated tumor mutational burden (TMB), mutational intratumor heterogeneity (ITH), somatic copy number alteration (SCNA) ITH and clonal neoantigen load in patients. Validations in public cohorts further supported the generality of our findings. CONCLUSIONS: We reported for the first time the association between HRD event and enhanced neoadjuvant immunotherapy response in lung cancer. The power of HRD event in patient therapeutic stratification persisted in multifaceted public cohorts. We propose that HR pathway gene status could serve as novel and additional indicators guiding immune-neoadjuvant and immunotherapy treatment decisions for NSCLC patients.

[Research on "Augmented Reality" Assisted Precise Thoracoscopic Resection of Pulmonary Nodules].

To break with traditional preoperative localization, a porcine animal model to evaluate the safety of augmented reality (AR) assisted localization of solitary pulmonary nodules (SPN) was used. Before the experiment, Microsoft HoloLens AR system was used to bring the CT image into the laboratory after 3D reconstruction. The virtual model was fitted with real body surface markers, and the virtual positioning auxiliary line and auxiliary locator were used to perform puncture positioning before surgery. Data related to actual puncture path and expected planned path were recorded in the experiment. SPSS 26.0 was used to calculate the puncture accuracy under AR assisted positioning, and the results obtained were acceptable in segmentectomy or wedge pneumonectomy. Its feasibility in animal models will also be evaluated, and its safety and efficacy will need to be further studied in clinical trials.

A uniportal right upper lobectomy by three-arm robotic-assisted thoracoscopic surgery using the da Vinci (Xi) Surgical System in the treatment of early-stage lung cancer.

Minimally invasive techniques, typified by video-assisted thoracoscopic surgery, are widely practiced in the treatment of thoracic diseases all around the world, and video-assisted thoracoscopic surgery has been recognized as a standard treatment method for early staged lung cancer. Among them, robotic-assisted thoracoscopic surgery, which has the advantages of providing a three-dimensional view and better maneuverability, has emerged as a next-generation technique in the field of minimally invasive surgery and is also gaining its popularity with the idea of Enhanced Recovery After Surgery deeply rooted in patients' minds. Up to now, robotic-assisted thoracoscopic surgery usually requires 3 or 4 ports with 1 or 2 additional access incisions. Meanwhile, traditional video-assisted thoracoscopic surgery can now be completed with uniportal method, with less postoperative pain and higher patient satisfaction with respect to the number of incisions in comparison with the multi-port technique. To inform the integration of these new minimally invasive techniques, here, we present a case in which uniportal right upper lobectomy was performed using the 4th generation da Vinci Robotic Surgical System (Xi). With continuous innovation in robotic minimally invasive techniques and improvements in surgical skills, we believe more patients will benefit from robotic-assisted thoracoscopic surgery with single port in the near future.

Remote monitoring of patient recovery following lung cancer surgery: a messenger application approach.

BACKGROUND: Repeated assessment of patient recovery after discharge is challenging. This study used a popular messenger application to remotely collect patient self-reported symptoms and their severity so as to monitor patient recovery and identify the factors affecting the recovery of symptoms following lung cancer surgery. METHODS: This prospective observational study was conducted at a single tertiary lung cancer center in China between November 2018 and June 2019. Participants received demonstration videos and repeated symptom surveys regarding pain and cough severity (assessed using numeric rating scores of 0-10 for pain and 0-6 for cough) at 2, 4, 6, 8, and 12 weeks after discharge via a smartphone program bound to the WeChat application. Patients who responded to at least 3 of the 5 post-discharge surveys were included in this study. The data were analyzed to investigate the symptom recovery and its related factors. RESULTS: Of the 826 patients enrolled, 589 (71.3%) responded to at least three surveys. The average pain score reduced from 4.1±2.5 at 2 weeks to 2.2±2.0 at 12 weeks (P<0.001). Factors associated with higher pain severity included the female gender, age over 60 years, thoracotomy, longer operation time (>90 minutes), and prolonged chest tube drainage (>7 days). The average cough score decreased from 2.34±1.30 at 2 weeks to 1.93±1.26 at 12 weeks (P<0.001). Being female and a prolonged operation time (>90 min) were related to increased cough severity. Sublobar resection and limited lymphadenectomy may contribute to lower cough severity post-surgery. CONCLUSIONS: The messenger application-based remote monitoring successfully collected post-discharge symptom information and identified factors associated with recovery following lung surgery.

Augmented reality-assisted localization of solitary pulmonary nodules for precise sublobar lung resection: a preliminary study using an animal model.

BACKGROUND: Accurate localization of early lung cancer, manifested as solitary pulmonary nodules (SPNs) on computed tomography (CT), is critical in sublobar lung resection. The AR-assisted localization of SPNs was evaluated using a pig animal model. METHODS: A Microsoft HoloLens AR system was used. First, a plastic thoracic model was used for the pilot study. Three female 12 months 45 kg Danish Landrace Pigs were then used for the animal study. Thirty natural pulmonary structures, such as lymphonodus and bifurcated bronchioles or bronchial vessels, were chosen as simulated SPNs. The average angle between the actual puncturing needle and the expected path, the average distance between the puncture point and the plan point, and the difference between the actual puncturing depth and expected depth were recorded, and the accuracy rate was calculated. RESULTS: The point selected in the plastic thoracic model could be hit accurately with the assistance from the AR system in the pilot study. Moreover, the average angle between the actual puncturing needle and the expected path was 14.52°±6.04°. Meanwhile, the average distance between the puncture point and the expected point was 8.74±5.07 mm, and the difference between the actual and expected depths was 9.42±7.95 mm. Puncturing within a 1 cm3 area around the SPN using a hook-wire was considered a successful hit. The puncture accuracy was calculated. The average hit rate within a spherical area with a diameter of 1 cm range was 76.67%, and within a diameter of 2 cm range was 100%. CONCLUSIONS: The HoloLens AR-assisted localization of SPNs may become a promising technique to improve the surgical treatment of early-stage lung cancer. Here, we evaluated its feasibility in an animal model. Nevertheless, its safety and effectiveness require further investigation in clinical trials.

C/EBPδ-Slug-Lox1 axis promotes metastasis of lung adenocarcinoma via oxLDL uptake.

Cancer cells undergo significant lipid metabolic reprogramming to ensure sufficient energy supply for survival and progression. However, how cancer cells integrate lipid metabolic signaling with cancer progression is not well understood. In the present study, we demonstrated that C/EBPδ, a critical lipid metabolic regulator, is a TGF-ß1 downstream gene and promotes lung adenocarcinoma metastasis. Importantly, C/EBPδ caused significant oscillations in both lipid metabolic and epithelial to mesenchymal transition (EMT) gene networks. Mechanistically, we demonstrated that C/EBPδ recruited oncogene NCOA3 to transcriptionally activate Slug, a canonical EMT transcription factor, which in turn induced oxLDL receptor-1 (Lox1) expression and enhanced oxLDL uptake to promote cancer metastasis, which could be blocked with LOX1 neutralizing antibody. In summary, our results unveiled a previously unappreciated interplay between lipid metabolic and metastatic program, as well as the existence of a pivotal C/EBPδ-Slug-Lox1 transcription axis to promote oxLDL levels and cancer metastasis.

Comprehensive circular RNA profiling identifies CircFAM120A as a new biomarker of hypoxic lung adenocarcinoma.

BACKGROUND: Hypoxia is crucial in the initiation and progression of tumor metastasis. Circular RNAs (CircRNAs) comprise a novel group of non-coding, RNase R resistant and regulatory RNAs which are generated by 'back-splicing' processes. However, the characterization and function of circRNAs in hypoxic cancer cells remain unknown. METHODS: High throughput RNA-seq assay was performed in lung adenocarcinoma cells (A549) under either normoxic or hypoxic conditions. Bioinformatic analysis of differentially expressed circRNAs was conducted and their target genes were predicted and partially confirmed. RESULTS: Hypoxia increased the expression of hypoxia-inducible factor 1 alpha (HIF-1α) and its downstream genes in A549 cells and enhanced cell migration ability. Comprehensive analysis of global circRNAs expression profiles of A549 identified a total of 558 circRNAs candidates, among which 65 circRNAs were differentially expressed (35 upregulated and 30 downregulated) in hypoxic cancer cells. The difference in their circRNA expressions were compared by computational analysis and circRNA-miRNA networks were constructed. We further characterized one circRNA (hsa_circ_0008193) derived from the FAM120A gene and renamed it as circFAM120A. The expression of circFAM120A, as validated by reverse transcription polymerase chain reaction, was significantly downregulated in both hypoxic A549 and lung cancer tissue from patients with lymph node metastasis. Gene ontology (GO) enrichment analysis and KEGG pathway analysis revealed that circFAM120A may participate in lung cancer development. CONCLUSIONS: CircRNAs profiles were altered in lung adenocarcinoma under hypoxia and circFAM120A may have the potential to be a new biomarker of lung adenocarcinoma hypoxia.

Prognostic value of mean platelet volume to plateletcrit ratio in patients with osteosarcoma.

OBJECTIVE: The objective of this study was to investigate the prognostic value of preoperative mean platelet volume to plateletcrit (MPV/PCT) ratio in patients with osteosarcoma. MATERIALS AND METHODS: The retrospective study included 188 consecutive osteosarcoma patients who experienced neoadjuvant chemotherapy and surgical resection of tumor. The relationships between MPV/PCT and clinicopathological characteristics were analyzed. The Kaplan-Meier analysis and Cox regression proportional hazard model were applied to assess the prognostic value of MPV/PCT ratio. RESULTS: MPV/PCT ratio was found to be significantly associated with platelet count, platelet distribution width, and PCT (all P<0.001). Kaplan-Meier analysis showed that high MPV/PCT ratio (≥43.58) was associated with a prolonged disease-free survival (DFS, P=0.035). The multivariate Cox revealed that only good chemotherapy response was an independent predictor of better DFS in the overall population. However, the stratification analysis showed that a high MPV/PCT ratio (≥43.58) was indicated as an independent prognostic factor for a favorable DFS (HR =0.137, 95%CI =0.029-0.644, P=0.012) in the male osteosarcoma patients but not in female patients. CONCLUSION: The high preoperative MPV/PCT ratio may serve as an independent prognostic factor for a favorable prognosis in male osteosarcoma patients. Further studies are needed to confirm the findings.

Tumor histology predicts mediastinal nodal status and may be used to guide limited lymphadenectomy in patients with clinical stage I non-small cell lung cancer.

OBJECTIVE: Methods to minimize surgical trauma from mediastinal lymphadenectomy in patients with early-stage lung cancer are still immature. This study aimed to identify predictors of negative pathologic N2, which may be used to select patients for limited mediastinal lymphadenectomy. METHODS: Clinicopathologic features of 1430 patients with resected clinical stage I non-small cell lung cancer and complete mediastinal lymphadenectomy were retrospectively analyzed for variables associated with negative N2 nodal metastasis (2008-2015). Overall and recurrence-free survival in patients after complete or limited mediastinal lymphadenectomy were assessed via Kaplan-Meier survival analysis and log-rank testing. The accuracy of frozen section diagnosis for predicting final pathology was retrospectively assessed in 126 randomly selected patients after the surgery. RESULTS: Multivariable analysis revealed that tumor size ≤2 cm, negative pN1, lymphovascular invasion, and lepidic adenocarcinoma were associated with negative mediastinal nodal metastasis. Notably, none of the patients with histology of adenocarcinoma in situ, minimally invasive adenocarcinoma, or lepidic pattern-predominant adenocarcinoma on final pathology had pN2 disease, and the 5-year overall and recurrence free-survival of these patients (99.3% and 99.3%, respectively) was not different from those after limited mediastinal lymphadenectomy (98.7% and 100%, P = .582 and .511, respectively). If these subtypes were classified together as the low-risk group, the concordance rate between frozen section and final pathology diagnosis was 88.9% in the retrospective test cohort. CONCLUSIONS: Tumor histology may predict negative mediastinal metastasis in patients with early-stage lung cancer. Future prospective studies are merited to validate the feasibility of using frozen section to select patients for limited mediastinal lymphadenectomy.