Mutation of TP53 Confers Ferroptosis Resistance in Lung Cancer Through the FOXM1/MEF2C Axis.

Ferroptosis is a highly regulated tumor suppressor process. Loss or mutation of TP53 can cause changes in sensitivity to ferroptosis. Mutations in TP53 may be associated with the malignant or indolent progression of ground glass nodules in early lung cancer, but whether ferroptosis may also be involved in determining this biological process has not yet been determined. Using in vivo and in vitro gain- and loss-of-function approaches, this study used clinical tissue for mutation analysis and pathological research to show that wild-type TP53 inhibited the expression of forkhead box M1 (FOXM1) by binding to peroxisome proliferator-activated receptor-γ coactivator 1α, maintaining the mitochondrial function and thus affecting the sensitivity to ferroptosis. This function was absent in mutant cells, resulting in overexpression of FOXM1 and ferroptosis resistance. Mechanistically, FOXM1 activated the transcription level of myocyte-specific enhancer factor 2C in the mitogen-activated protein kinase signaling pathway, leading to stress protection when exposed to ferroptosis inducers. This study provides new insights into the mechanism of association between TP53 mutation and ferroptosis tolerance, which can aid a deeper understanding of the role of TP53 in the malignant progression of lung cancer.

Association of phthalate exposure with pulmonary function in adults: NHANES 2007-2012.

BACKGROUND: Epidemiological evidence for the adverse effect of phthalate exposure on respiratory health is on the rise, but cross-sectional studies regarding its effects on lung function are limited and contradictory, especially in adults. OBJECTIVE: To assess the associations between individual and a mixture of urinary phthalate metabolites and adult pulmonary function in the United States, and to identify which ones were primarily responsible for impaired respiratory function. METHODS: We obtained a cross-sectional data on 3788 adults aged 20 years and older from the National Health and Nutrition Examination Survey (2007-2012). Respiratory function was evaluated using spirometry, and phthalate exposure was assessed by measuring the levels of ten urinary phthalate metabolites. The effects of individual and mixed phthalate metabolites exposure on lung function were assessed using multivariate linear regression models and the repeated holdout weighted quantile sum (WQS) regression models, respectively, after adjusting for potential confounders including age, gender, family poverty income ratio, body mass index, and serum cotinine. RESULTS: When modeled as continuous variables or quantiles, urinary phthalate metabolites, including mono-ethyl phthalate (MEP), mono-n-butyl phthalate, mono-iso-butyl phthalate, mono-benzyl phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(3-carboxypropyl) phthalate, and mono-carboxyoctyl phthalate, were identified to be negatively associated with forced vital capacity in percent predicted values (ppFVC) and forced expiratory volume in the first second in percent predicted values (ppFEV1). In addition, per each decile increase in the WQS index, ppFVC (ß = -2.87, 95% CI: -3.56, -2.08) and ppFEV1 (ß = -2.53, 95% CI: -3.47, -1.54) declined significantly, primarily due to the contribution of MEP and MECPP. Furthermore, there were no significant interactions between co-exposure to urinary phthalate metabolites and each covariate. CONCLUSION: Our findings reveal that urinary phthalate metabolites are significantly associated with adult respiratory decrements, with diethyl and di-(2-ethylhexyl) phthalate contributing the most to the impaired lung function.

Thermal ablation versus radiotherapy for inoperable stage III non-small cell lung cancer: a propensity score matching analysis.

OBJECTIVE: To compare the survival benefits of thermal ablation (TA) and radiotherapy in inoperable patients with stage III non-small cell lung cancer (NSCLC). METHOD: A retrospective analysis was conducted using the data from the Surveillance, Epidemiology, and End Results (SEER) program. Propensity score matching (PSM) was conducted to balance potential baseline confounding factors. Survival analyses were conducted using Kaplan-Meier and Cox regression methods. RESULTS: The present study included 33,393 inoperable patients with stage III NSCLC, including 106 patients treated with TA and 33,287 patients treated with radiotherapy. No statistical difference in overall survival (OS) (p = .065) or cancer-specific survival (CSS) (p = .996) was found between the patients treated with TA and those treated with radiotherapy. Using 1:3 matching, a matched cohort of 420 patients (105 patients treated with TA, 315 patients treated with radiotherapy) was identified. The differences in OS (p = .177) and CSS (p = .605) were still not significant between the radiotherapy and TA groups after PSM. According to subgroup analyses, TA showed comparable survival benefits in almost all subgroups compared to radiotherapy. CONCLUSION: For inoperable stage III NSCLC, the survival benefit of TA was comparable to radiotherapy. TA may be a potential therapeutic modality for inoperable stage III NSCLC.

Comprehensive characterization of genomic and radiologic features reveals distinct driver patterns of RTK/RAS pathway in ground-glass opacity pulmonary nodules.

Ground-glass opacity (GGO)-associated pulmonary nodules have been known as a radiologic feature of early-stage lung cancers and exhibit an indolent biological behavior. However, the correlation between driver genes and radiologic features as well as the immune microenvironment remains poorly understood. We performed a custom 1021-gene panel sequencing of 334 resected pulmonary nodules presenting as GGO from 262 Chinese patients. A total of 130 multiple pulmonary nodules were sampled from 58 patients. Clinical-pathologic and radiologic parameters of these pulmonary nodules were collected. Immunohistochemistry (IHC) and multiplex immunofluorescent staining (mIF) were applied to analyze proliferation and immune cell markers of GGO-associated pulmonary nodules. Compared with pure GGO nodules, mixed GGO nodules were enriched for invasive adenocarcinoma (IAC) (182/216 vs 73/118, P < .001). Eighty-eight percent (294/334) of GGO-associated nodules carried at least one mutation in EGFR/ERBB2/BRAF/KRAS/MAP2K1 of the RTK/RAS signaling pathway, and the alterations in these driver genes were mutually exclusive. The analysis of multifocal pulmonary nodules from the same patient revealed evidence of functional convergence on RTK/RAS pathways. Nodules with ERBB2/BRAF/MAP2K1 mutations tended to be more indolent than those with EGFR and KRAS mutations. IHC and mIF staining showed that KRAS-mutant GGO nodules displayed higher infiltration of CD4+ T cell and CD8+ T cell as well as stronger proliferation and immune inhibitory signals. Our study demonstrates a driver landscape of radiologically detectable GGO-associated pulmonary nodules in Chinese patients and supports that different driver patterns in RTK/RAS pathway are corresponding to different radiologic features.

Establishment of Thoracic Surgical Difficulty Assessment Scale based on Delphi method. / 基于德尔菲法构建胸外科手术难度评价量表.

OBJECTIVES: The difficulty of surgery, which is related to surgical safety, has only been mentioned as a subjective perception for a long time. There are few studies to quantitatively and systematically evaluate the difficulty of thoracic surgery. This study aims to establish a quantitative evaluation index system for thoracic surgical difficulty, and to evaluate its reliability and validity. METHODS: During the 2 national thoracic surgery academic conferences, the factors that may affect the difficulty of thoracic surgery were evaluated by the thoracic surgeons via semi open questionnaires, and then the evaluation item pool of thoracic surgery difficulty was established. The importance of each indicator in the evaluation item pool was graded by 2 rounds of Delphi method. The average score, full score rate and coefficient of variation of each index were calculated, and the composite index method was used to decide whether to delete the indicator.Finally, the difficulty evaluation scale of thoracic surgery was constructed. The surgical data of patients with thoracic tumors were collected. The scale was used to evaluate the difficulty of thoracic surgery for lung, esophageal, and mediastinal tumors. The reliability and validity of the scale were evaluated by the commonly used difficulty evaluation indexes: Operation time, intraoperative estimated blood loss, Visual Analog Scale (VAS), side injury rate, and blood transfusion rate as standards. RESULTS: A total of 230 questionnaires were distributed in the 2 rounds of survey, and 149 valid questionnaires were collected after eliminating duplicate questionnaires. Through 2 rounds of Delphi consultation with 20 experts, the difficulty evaluation indexes were scored and screened, and the difficulty evaluation scale of thoracic surgery was established. It included 5 main indexes (surgical decision-making, operation space, separation interface, reconstruction method, and surgical materials) and 16 secondary indexes [American Society of Anesthesiologists (ASA) classification, surgical trauma, operator experience, space size, space depth, space source, space adjacent, interface content, anatomical gap, visual field, interface size, reconstruction complexity, reconstruction scope, autologous materials, artificial biomaterials and instruments]. After weighting, the total score of Thoracic Surgery Difficulty Evaluation Scale was from 1 to 3. A Score at 1 standed for simplicity, and score at 3 standed for difficulty. Further data were collected for 127 cases of thoracic tumor surgery. The difficulty scores of surgery for lung, esophageal, and mediastinal tumor were 1.69±0.26, 1.86±0.18, and 1.56±0.31, respectively, and the Cronbach's α coefficients of the scale in 3 tumor surgeries were 0.993, 0.974, and 0.989, repectively, and the Spearman Brown coefficients were 0.996, 0.984, and 0.996, respectively. The Spearman correlation coefficients of operation difficulty score with operation time, estimated blood loss, and VAS were 0.360 and 0.634, 0.632 and 0.578, 0.696 and 0.875, respectively (all P<0.05). The incidence of postoperative complications in the difficult operation group (difficulty score >1.85) was higher than that in the non-difficult operation group (P=0.02). CONCLUSIONS: The quantitative Thoracic Surgical Difficulty Assessment Scale has been successfully established, which shows good reliability and validity in thoracic tumor surgery. The Thoracic Surgical Difficulty Assessment Scale has broad application prospects in reducing the difficulty of the surgery, controlling surgical complications, and training surgeons.

A modified approach of port-access lymphadectomy for locally advanced non-small cell lung cancer: A single center experience. / ä¸€ç§å±€éƒ¨æ™šæœŸéžå°ç»†èƒžè‚ºç™Œå¾®åˆ›æ·‹å·´ç»“æ¸ æ‰«çš„æ”¹è‰¯æœ¯å¼­­å•ä¸­å¿ƒç»éªŒ.

OBJECTIVES: Systematic nodal dissection (SND) is an important component of locally advanced non-small cell lung cancer (NSCLC), but modification of this procedure is rarely reported. In this paper, we reported a modified technique of systematic mediastinal lymph node dissection (MLND) of operable lung cancer by video-assisted thoracic surgery (VATS). Parallel upward dissection (the PUD technique) was named due to this modification and the efficacy of the PUD technique was evaluated as well. METHODS: We summarized the tips of the PUD technique and its version was updated in surgical aspect. The design and procedure sequence of the PUD technique were introduced in detail as well as its pros and cons. A retrospective study was performed on 998 cases of locally advanced NSCLC which accepted the PUD procedure in Department of Thoracic Surgery, Second Xiangya Hospital, Central South University, from 2012 to 2020. The perioperative mortality and the incidence of general and serious complications (such as recurrent laryngeal nerve injury, bronchopleural fistula) were analyzed. RESULTS: All the 998 cases were operated successfully with the PUD technique and few post-operation complications were found. There was no perioperative mortality and severe complication such as recurrent laryngeal nerve injury and bronchopleural fistula. CONCLUSIONS: The PUD technique is safe and convenient and it can be a good supplement to the existing surgical techniques for locally advanced lung cancer.

Resectable lung lesions malignancy assessment and cancer detection by ultra-deep sequencing of targeted gene mutations in plasma cell-free DNA.

BACKGROUND: Early detection of lung cancer to allow curative treatment remains challenging. Cell-free circulating tumour (ct) DNA (ctDNA) analysis may aid in malignancy assessment and early cancer diagnosis of lung nodules found in screening imagery. METHODS: The multicentre clinical study enrolled 192 patients with operable occupying lung diseases. Plasma ctDNA, white cell count genomic DNA (gDNA) and tumour tissue gDNA of each patient were analysed by ultra-deep sequencing to an average of 35 000× of the coding regions of 65 lung cancer-related genes. RESULTS: The cohort consists of a quarter of benign lung diseases and three quarters of cancer patients with all histopathology subtypes. 64% of the cancer patients are at stage I. Gene mutations detection in tissue gDNA and plasma ctDNA results in a sensitivity of 91% and specificity of 88%. When ctDNA assay was used as the test, the sensitivity was 69% and specificity 96%. As for the lung cancer patients, the assay detected 63%, 83%, 94% and 100%, for stages I, II, III and IV, respectively. In a linear discriminant analysis, combination of ctDNA, patient age and a panel of serum biomarkers boosted the overall sensitivity to 80% at a specificity of 99%. 29 out of the 65 genes harboured mutations in the patients with lung cancer with the largest number found in TP53 (30% plasma and 62% tumour tissue samples) and EGFR (20% and 40%, respectively). CONCLUSION: Plasma ctDNA was analysed in lung nodule assessment and early cancer detection, while an algorithm combining clinical information enhanced the test performance. TRIAL REGISTRATION NUMBER: NCT03081741.

Bidirectional Mendelian Randomization of Causal Relationship between Inflammatory Cytokines and Different Pathological Types of Lung Cancer.

Prior research has proposed a potential association between lung cancer and inflammatory cytokines, yet the specific causal relationship remains unclear, especially across various lung cancer pathologies. This study utilized bidirectional Mendelian randomization (MR) to explore these causal connections, unveiling novel insights. Our research revealed distinctive inflammatory cytokine profiles for each subtype of lung cancer and identified potential biomarkers that could refine diagnostic and therapeutic approaches. We applied two-sample Mendelian randomization, leveraging genetic variance data from three extensive genome-wide association studies (GWAS) focusing on different lung cancer types (lung adenocarcinoma: 1590 cases and 314,193 controls of healthy individuals of European descent; lung squamous cell carcinoma: 1510 cases and 314,193 controls of European ancestry; small cell lung cancer: 717 cases and 314,193 controls of European ancestry). A separate GWAS summary on inflammatory cytokines from 8,293 healthy participants was also included. The inverse variance weighting method was utilized to examine causal relationships, with robustness confirmed through multiple sensitivity analyses, including MR-Egger, weighted median, and MR-PRESSO. Our analysis revealed that elevated levels of IL_1RA were associated with an increased risk of lung adenocarcinoma (OR: 1.29, 95% CI: 1.02-1.64, p = 0.031), while higher MCP_1_MCAF levels correlated with a decreased risk of lung squamous cell carcinoma (OR: 0.77, 95% CI: 0.61-0.98, p = 0.031). Furthermore, IL_10, IL_13, and TRAIL levels were positively associated with lung squamous cell carcinoma risk (IL_10: OR: 1.27, 95% CI: 1.06-1.53, p = 0.012; IL_13: OR: 1.15, 95% CI: 1.06-1.53, p = 0.036; TRAIL: OR: 1.15, 95% CI: 1.06-1.53, p = 0.043). No association was found between inflammatory cytokine levels and small cell lung cancer development, whereas SDF_1A and B-NGF were linked to an increased risk of this cancer type (SDF_1A: OR: 1.13, 95% CI: 1.05-1.21, p = 0.001; B-NGF: OR: 1.13, 95% CI: 1.01-1.27, p = 0.029). No significant relationship was observed between the 41 circulating inflammatory cytokines and lung adenocarcinoma or squamous cell carcinoma development. Our findings indicate distinct associations between specific inflammatory cytokines and different types of lung cancer. Elevated IL_1RA levels are a risk marker for lung adenocarcinoma, whereas higher MCP_1_MCAF levels appear protective against lung squamous cell carcinoma. Conversely, elevated levels of IL_10, IL_13, and TRAIL are linked with an increased risk of lung squamous cell carcinoma. The relationships of SDF_1A and B-NGF with small-cell lung cancer highlight the complexity of inflammatory markers in cancer development. This study provides a nuanced understanding of the role of inflammatory cytokines in lung cancer, underscoring their potential in refining diagnosis and treatment strategies.

Efficacy and safety of microwave ablation and its synergistic potential in the treatment of early-stage non-small cell lung cancer.

Lung cancer remains the primary cause of cancer-related mortality globally. In the case of early-stage non-small cell lung cancer (NSCLC), surgical resection, such as lobectomy and sub-lobectomy, continues to be the established standard treatment. However, for patients with insufficient cardiopulmonary function and multiple comorbidities who are unable to undergo surgical resection, nonoperative local therapies, including radiotherapy and thermal ablation, are preferred. In recent years, microwave ablation (MWA) has gained popularity for treating early-stage NSCLC due to its high heating efficiency, good tissue conductance, and heat conduction capabilities. This review provides a comprehensive summary of the current efficacy and safety data regarding MWA for early-stage NSCLC and discusses the potential benefits of combining MWA with other therapies.

RBM15 drives the progression of lung adenocarcinoma by regulating N6-methyladenosine-mediated LDHA mRNA stability.

Abnormal N6-methyladenosine (m6A) methylation in RNA plays a pivotal role in the pathogenesis of many types of tumors by influencing mRNA metabolism, alternative splicing, translocation, stability and translation. However, the specific regulators and underlying mechanisms of m6A modification in the progression of lung adenocarcinoma are not well understood. In this study, we analyzed the RNA-seq transcriptome data downloaded from The Cancer Genome Atlas (TCGA) database, and identified "m6A writer" RNA binding motif protein 15 (RBM15) expression was significantly elevated in lung adenocarcinoma (LUAD) biopsies, and the higher RBM15 levels were correlated with the poorer overall survival (OS) of LUAD patients. Further study confirmed RBM15 was prominently expressed in LUAD tissues and cell lines. Moreover, silencing RBM15 in PC9 and H1299 cells reduced cell proliferation both in vitro and in vivo, while overexpression of RBM15 in A549 cells promoted cell growth. Mechanistically, lactate dehydrogenase A (LDHA) acted as a downstream target of RBM15. RBM15-mediated m6A modification of LDHA mRNA enhanced its stability to exert an oncogenic role in LUAD. Taken together, our findings suggest that the RBM15/LDHA axis might be a novel and promising therapeutic target for LUAD.

Clinical and Genetic Characteristics of Early-Onset Lung Adenocarcinoma in a Large Chinese Cohort.

BACKGROUND: The characteristics of early-onset lung adenocarcinoma (EOLA) have not been extensively studied. Our research aimed to comprehensively assess the clinical and genetic features of EOLA. METHODS: We conducted a retrospective analysis of surgically resected lung adenocarcinoma patients, categorizing them into the EOLA group (aged <40 years) and the late-onset lung adenocarcinoma (LOLA) group (aged >60 years). A comparative investigation of clinical, germline, and genomic features was conducted. Propensity score matching was used to balance baseline characteristics for gene mutation analysis. RESULTS: We enrolled 487 EOLA and 2507 LOLA patients. EOLA patients exhibited a higher female-to-male ratio (2.55 vs 1.19) and a higher proportion of family history of lung cancer in the ground-grass opacity subgroup (12.7% vs 8.9%). The EOLA group exhibited higher rates of earlier stage in the ground-grass opacity subgroup and solid subgroup. Preinvasive adenocarcinoma was the dominant histologic subtype in the EOLA group within the ground-glass opacity subgroup (73.8% vs 25.6%). After propensity score matching, we analyzed 241 stage 0/I patients with available genetic test results. Significant disparities in gene mutation rates emerged between the EOLA and LOLA patients, including Erb-B2 receptor tyrosine kinase 2 (ERBB2; 38.0% vs 2.8%), epidermal growth factor receptor (EGFR; 36.0% vs 64.5%), MET (0.0% vs 7.1%), neurofibromin 1 (NF1; 0.0% vs. 5.7%), and anaplastic lymphoma kinase (ALK) fusion (10.0% vs 1.4%). CONCLUSIONS: EOLA patients exhibited distinct clinical and genetic characteristics compared with LOLA patients.

Robotic-assisted thoracoscopic lobectomy for synchronous pulmonary sequestration and adenocarcinoma: A case report.

BACKGROUND: Pulmonary sequestration (PS) is a congenital pulmonary malformation. Adenocarcinoma arising in PS is extremely rare. METHODS AND RESULTS: We present the first reported case of synchronous intralobar PS and lung adenocarcinoma in the right lower lobe, which was successfully treated using robotic-assisted thoracic surgery (RATS). The robotic system allowed for easy identification, clipping, and dissection of the abnormal artery, highlighting its benefits over traditional surgical approaches. CONCLUSIONS: This case underscores the importance of considering the possibility of coexisting lung cancer in patients with a clinical diagnosis of PS and demonstrates the safety and efficacy of RATS in managing this rare condition.

Real-world comprehensive diagnosis and "Surgery + X" treatment strategy of early-stage synchronous multiple primary lung cancer.

BACKGROUND: Diagnosing and treating synchronous multiple primary lung cancers (sMPLC) are complex and challenging. This study aimed to report real-world data on the comprehensive diagnosis and treatment of patients with early-stage sMPLC. MATERIALS AND METHODS: A single-center cohort study was carried out and a large number of patients with early-stage sMPLC were included. A single- or two-stage surgery was performed to remove the primary and co-existing lesions. The "X" strategies, including ablation, SBRT, and EGFR-TKIs treatment, were applied to treat the high-risk residual lesions. Wide panel-genomic sequencing was performed to assess the genetic heterogeneity of the co-existing lesions. RESULTS: A total of 465 early-stage sMPLC patients with 1198 resected lesions were included. Despite most patients being histologically different or harboring different genetic alternations, about 7.5% of the patients had the same histological type and driver gene mutation changes, comprehensive re-evaluation is thus needed. The "Surgery + X" strategy showed remarkable efficacy and safety in treating multiple lesions. Follow-up data revealed that the T2 stage (p = 0.014) and the solid presence of a primary lesion (p < 0.001) were significantly related to tumor recurrence. And a T2-stage primary tumor had a significantly higher rate of developing new lesions after the initial surgery (p < 0.001). CONCLUSIONS: In real-world practice, histopathological and radiological evaluation combined with genetic analyses could be a robust diagnostic approach for sMPLC. The "Surgery + X" treatment strategy showed remarkable efficacy, superiority, and safety in the clinical treatment of early-stage sMPLC.

Spatial heterogeneity of T cell repertoire across NSCLC tumors, tumor edges, adjacent and distant lung tissues.

Background: A better understanding of T cells in lung cancer and their distribution across tumor-adjacent lungs and peripheral blood is needed to improve efficacy and minimize toxicity from immunotherapy to lung cancer patients. Methods: Here, we performed CDR3ß TCR sequencing of 136 samples from 20 patients with early-stage NSCLC including peripheral blood mononuclear cells, tumors, tumor edges (<1 cm from tumor), as well as adjacent lungs 1 cm, 2 cm, 5 cm, and 10 cm away from the tumor to gain insight into the spatial heterogeneity of T cells across the lungs in patients with NSCLC. PD-L1, CD4, and CD8 expression was assessed using immunohistochemical staining, and genomic features were derived by targeted sequencing of 1,021 cancer-related genes. Multiplex immunohistochemistry against PD-1, CTLA4, LAG3, and TIM3 was performed on four patients to assess T cell exhaustion. Results: Our study reveals a decreasing gradient in TIL Tumor Infiltrating Lymphocytes homology with tumor edge, adjacent lungs, and peripheral blood but no discernible distance-associated patterns of T cell trafficking within the adjacent lung itself. Furthermore, we show a decrease in pathogen-specific TCRs in regions with high T cell clonality and PD-L1 expression. Conclusions: Exclusion in T exhaustion cells at play across the lungs of patients with NSCLC may potentially be the mechanism for lung cancer occurrence.

Development and validation of a radiomics-based nomogram for predicting a major pathological response to neoadjuvant immunochemotherapy for patients with potentially resectable non-small cell lung cancer.

Introduction: The treatment response to neoadjuvant immunochemotherapy varies among patients with potentially resectable non-small cell lung cancers (NSCLC) and may have severe immune-related adverse effects. We are currently unable to accurately predict therapeutic response. We aimed to develop a radiomics-based nomogram to predict a major pathological response (MPR) of potentially resectable NSCLC to neoadjuvant immunochemotherapy using pretreatment computed tomography (CT) images and clinical characteristics. Methods: A total of 89 eligible participants were included and randomly divided into training (N=64) and validation (N=25) sets. Radiomic features were extracted from tumor volumes of interest in pretreatment CT images. Following data dimension reduction, feature selection, and radiomic signature building, a radiomics-clinical combined nomogram was developed using logistic regression analysis. Results: The radiomics-clinical combined model achieved excellent discriminative performance, with AUCs of 0.84 (95% CI, 0.74-0.93) and 0.81(95% CI, 0.63-0.98) and accuracies of 80% and 80% in the training and validation sets, respectively. Decision curves analysis (DCA) indicated that the radiomics-clinical combined nomogram was clinically valuable. Discussion: The constructed nomogram was able to predict MPR to neoadjuvant immunochemotherapy with a high degree of accuracy and robustness, suggesting that it is a convenient tool for assisting with the individualized management of patients with potentially resectable NSCLC.

Survival benefit of thermal ablation therapy for patients with stage II-III non-small cell lung cancer: A propensity-matched analysis.

Background: Thermal ablation (TA) is considered a safe alternative to surgical resection for the treatment of non-small cell lung cancer (NSCLC). While previous studies have shown that TA is beneficial for stage I NSCLC patients, however, few have reported on TA efficacy in patients with stage II-III NSCLC. The current study investigated the impact of TA on the overall survival (OS) and cancer-specific survival (CSS) of patients with stage II-III NSCLC. Methods: Data on patients with stage II-III NSCLC who did not undergo surgical resection between 2004 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM), Kaplan-Meier survival curves, and Cox regression were used for statistical analyses. Results: A total of 57,959 stage II-III NSCLC patients who did not undergo surgical resection were included in this study, 261 of whom received TA. Overall, TA was associated with a longer OS (p = 0.035) and CSS (p = 0.005) than non-ablation. After 1:3 PSM, 252 patients receiving TA and 732 patients not receiving ablation were enrolled in the matched cohort. The OS (p = 0.047) and CSS (p = 0.029) remained higher in the TA group than in the non-ablation group after PSM. Cox regression analysis showed that age, sex, primary tumor site, pathological type, tumor size, radiotherapy, chemotherapy, and thermal ablation were independently associated with OS and CSS (p <0.05). Subgroup analysis found that the advantages of TA were more pronounced among individuals ≥70 years of age, with tumor size ≤3.0 cm, or who did not receive radiotherapy. Conclusion: TA could be an effective alternative treatment for stage II-III NSCLC patients unsuitable for surgical resection, particularly those ≥70 years of age, with tumor size ≤3.0 cm, or who have not received radiotherapy.

Single-Cell RNA Sequencing Unravels Distinct Tumor Microenvironment of Different Components of Lung Adenocarcinoma Featured as Mixed Ground-Glass Opacity.

Lung adenocarcinoma featured as mixed ground-glass opacity (mGGO) doubled its volume half of the time in comparison with that featured as pure ground-glass opacity (pGGO). The mechanisms underlying the heterogeneous appearance of mGGO remain elusive. In this study, we macro-dissected the solid (S) components and ground-glass (GG) components of mGGO and performed single-cell sequencing analyses of six paired components from three mGGO patients. A total of 19,391 single-cell profiles were taken into analysis, and the data of each patient were analyzed independently to obtain a common alteration. Cancer cells and macrophages were the dominant cell types in the S and GG components, respectively. Cancer cells in the S components, which showed relatively malignant phenotypes, were likely to originate from both the GG and S components and monitor the surrounding tumor microenvironment (TME) through an intricate cell interaction network. SPP1hi macrophages were enriched in the S components and showed increased activity of chemoattraction, while macrophages in the GG components displayed an active antimicrobial process with a higher stress-induced state. In addition, the CD47-SIRPA axis was demonstrated to be critical in the maintenance of the GG components. Taken together, our study unraveled the alterations of cell components and transcriptomic features between different components in mGGOs.

A Machine-Learning Approach to Developing a Predictive Signature Based on Transcriptome Profiling of Ground-Glass Opacities for Accurate Classification and Exploring the Immune Microenvironment of Early-Stage LUAD.

Screening for early-stage lung cancer with low-dose computed tomography is recommended for high-risk populations; consequently, the incidence of pure ground-glass opacity (pGGO) is increasing. Ground-glass opacity (GGO) is considered the appearance of early lung cancer, and there remains an unmet clinical need to understand the pathology of small GGO (<1 cm in diameter). The objective of this study was to use the transcriptome profiling of pGGO specimens <1 cm in diameter to construct a pGGO-related gene risk signature to predict the prognosis of early-stage lung adenocarcinoma (LUAD) and explore the immune microenvironment of GGO. pGGO-related differentially expressed genes (DEGs) were screened to identify prognostic marker genes with two machine learning algorithms. A 15-gene risk signature was constructed from the DEGs that were shared between the algorithms. Risk scores were calculated using the regression coefficients for the pGGO-related DEGs. Patients with Stage I/II LUAD or Stage IA LUAD and high-risk scores had a worse prognosis than patients with low-risk scores. The prognosis of high-risk patients with Stage IA LUAD was almost identical to that of patients with Stage II LUAD, suggesting that treatment strategies for patients with Stage II LUAD may be beneficial in high-risk patients with Stage IA LUAD. pGGO-related DEGs were mainly enriched in immune-related pathways. Patients with high-risk scores and high tumor mutation burden had a worse prognosis and may benefit from immunotherapy. A nomogram was constructed to facilitate the clinical application of the 15-gene risk signature. Receiver operating characteristic curves and decision curve analysis validated the predictive ability of the nomogram in patients with Stage I LUAD in the TCGA-LUAD cohort and GEO datasets.

AI-based chest CT semantic segmentation algorithm enables semi-automated lung cancer surgery planning by recognizing anatomical variants of pulmonary vessels.

Background: The recognition of anatomical variants is essential in preoperative planning for lung cancer surgery. Although three-dimensional (3-D) reconstruction provided an intuitive demonstration of the anatomical structure, the recognition process remains fully manual. To render a semiautomated approach for surgery planning, we developed an artificial intelligence (AI)-based chest CT semantic segmentation algorithm that recognizes pulmonary vessels on lobular or segmental levels. Hereby, we present a retrospective validation of the algorithm comparing surgeons' performance. Methods: The semantic segmentation algorithm to be validated was trained on non-contrast CT scans from a single center. A retrospective pilot study was performed. An independent validation dataset was constituted by an arbitrary selection from patients who underwent lobectomy or segmentectomy in three institutions during Apr. 2020 to Jun. 2021. The golden standard of anatomical variants of each enrolled case was obtained via expert surgeons' judgments based on chest CT, 3-D reconstruction, and surgical observation. The performance of the algorithm is compared against the performance of two junior thoracic surgery attendings based on chest CT. Results: A total of 27 cases were included in this study. The overall case-wise accuracy of the AI model was 82.8% in pulmonary vessels compared to 78.8% and 77.0% for the two surgeons, respectively. Segmental artery accuracy was 79.7%, 73.6%, and 72.7%; lobular vein accuracy was 96.3%, 96.3%, and 92.6% by the AI model and two surgeons, respectively. No statistical significance was found. In subgroup analysis, the anatomic structure-wise analysis of the AI algorithm showed a significant difference in accuracies between different lobes (p = 0.012). Higher AI accuracy in the right-upper lobe (RUL) and left-lower lobe (LLL) arteries was shown. A trend of better performance in non-contrast CT was also detected. Most recognition errors by the algorithm were the misclassification of LA1+2 and LA3. Radiological parameters did not exhibit a significant impact on the performance of both AI and surgeons. Conclusion: The semantic segmentation algorithm achieves the recognition of the segmental pulmonary artery and the lobular pulmonary vein. The performance of the model approximates that of junior thoracic surgery attendings. Our work provides a novel semiautomated surgery planning approach that is potentially beneficial to lung cancer patients.

Identification of the Unique Clinical and Genetic Features of Chinese Lung Cancer Patients With EGFR Germline Mutations in a Large-Scale Retrospective Study.

BACKGROUND: Epidemiological surveys have suggested that lung cancer has inherited susceptibility and shows familial aggregation. However, the distribution and prevalence of epidermal growth factor receptor (EGFR) germline variants and their roles in lung cancer genetic predisposition in Chinese population remain to be elucidated. METHODS: In this study, EGFR germline and somatic variants were retrospectively reviewed from the next-generation sequencing results of 31,906 patients with lung cancer. Clinical information was also collected for patients with confirmed EGFR germline mutations. RESULTS: A total of 22 germline EGFR variants were identified in 64 patients with lung cancer, accounting for 0.2% of the total cases studied. Five patients were diagnosed as multiple primary carcinomas. Family history was documented in 31.3% (20/64) of patients, 55% of which were diagnosed as lung cancer. G863D was the most frequent EGFR germline mutation, followed by P848L, D1014N, and K757R. Somatic EGFR-sensitive mutations were identified in 51.6% of patients with germline EGFR mutations. The proportion of L858R mutation, exon 19 deletion, and rare sensitive mutation was 50%, 17.6%, and 32.4%, respectively. D1014N and T790M mutations were common in young patients. The family members of patients with P848L, R776H, V769M, and V774M mutations were more commonly diagnosed with cancers. A total of 19 patients were confirmed to have received EGFR tyrosine kinase inhibitors (TKIs), but the response to EGFR-TKIs differed among patients with different EGFR mutations. CONCLUSION: Chinese patients with lung cancer harbored unique and dispersive EGFR germline mutations and showed unique clinical and genetic characteristics, with varied response patterns to EGFR-TKI treatment.