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Anoikis, a form of programmed cell death induced by loss of cell contact, is closely associated with tumor invasion and metastasis, making it highly significant in lung cancer research. We examined the expression patterns and prognostic relevance of Anoikis-related genes (ARGs) in lung adenocarcinoma (LUAD) using the TCGA-LUAD database. This study identified molecular subtypes associated with Anoikis in LUAD and conducted functional enrichment analyses. We constructed an ARG risk score using univariate least absolute shrinkage and selection operator (LASSO) Cox regression, validated externally with GEO datasets and clinical samples. The clinical applicability of the prognostic model was evaluated using nomograms, calibration curves, decision curve analysis (DCA), and time-dependent AUC assessments. We identified four prognostically significant genes (PLK1, SLC2A1, CDKN3, PHLDA2) and two ARG-related molecular subtypes. ARGs were generally upregulated in LUAD and correlated with multiple pathways including the cell cycle and DNA replication. The prognostic model indicated that the low-risk group had better outcomes and significant correlations with clinicopathological features, tumor microenvironment, immune therapy responses, drug sensitivity, and pan-RNA epigenetic modification-related genes. Patients with low-risk LUAD were potential beneficiaries of immune checkpoint inhibitor (ICI) therapy. Prognostic ARGs' distribution and expression across various immune cell types were further analyzed using single-cell RNA sequencing. The pivotal role of CDKN3 in LUAD was confirmed through qRT-PCR and gene knockout experiments, demonstrating that CDKN3 knockdown inhibits tumor cell proliferation, migration, and invasion. Additionally, we constructed a ceRNA network involving CDKN3/hsa-miR-26a-5p/SNHG6, LINC00665, DUXAP8, and SLC2A1/hsa-miR-218-5p/RNASEH1-AS1, providing new insights for personalized and immune therapy decisions in LUAD patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC) and is characterized by its heterogeneity and poor prognosis. The role of ribosomal proteins RPLP0, RPLP1 and RPLP2 in multiple cancers has been implicated. However, their function in LUAD and their correlation with the poor prognosis of LUAD remains elusive. In this study, we performed a comprehensive bioinformatic analysis of the impact of these ribosomal proteins on LUAD. Our findings reveal that RPLP0, RPLP1 and RPLP2 are overexpressed in LUAD, which are likely attributed to abnormal copy number variations and decreased methylation levels of their promoters. LUAD patients with high expression of RPLP0, RPLP1 or RPLP2 have worse clinical outcomes in terms of overall survival (OS), first progression (FP) and post-progression survival (PPS), indicating poor prognosis. Moreover, the expression of RPLP0, RPLP1 and RPLP2 affects immune cell infiltration in LUAD tissues. Finally, we identified multiple existing drugs that may inhibit the expression of RPLP1 and RPLP2. Collectively, our data implicate the oncogenic role of RPLP0, RPLP1 and RPLP2 in LUAD and underscore their prognostic value in LUAD patients., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: The purpose of this study was to investigate the effect of tumor size and differentiation grade on long term survival in patients with early-stage lung adenocarcinoma (LUAD) after lobectomy and segmentectomy., Patients and Methods: Patients with stage T1-2N0M0 LUAD who underwent lobectomy and segmentectomy were identified from the Surveillance, Epidemiology, and End Results database. Patients were stratified as grade I (well differentiated), grade II (moderately differentiated), and grade III/IV (poorly differentiated/undifferentiated) carcinomas. The effect of tumor size on overall survival (OS) and lung cancer-specific survival (LCSS) was evaluated using the multivariate Cox regression model, including the interaction between tumor size, type of surgery, and tumor differentiation grade. The inverse probability of treatment weighting method was used to adjust for bias between the groups., Results: A total of 19,857 patients were identified, including 18,759 (94.4%) who underwent lobectomy and 1098 (5.5%) who underwent segmentectomy. A three-way interaction among tumor size, differentiation grade, and type of surgery was observed in the overall cohort. After stratifying by differentiation grade, plots of interaction revealed that lobectomy was associated with improved survival compared with segmentectomy when the tumor size exceeded 23 mm for grade I LUAD and 14 mm for grade II LUAD. No interaction was observed between the studied factors in grade III/IV carcinomas., Conclusions: This study interpreted the interaction between tumor size and type of surgery on long-term survival in patients with early stage LUAD and established a tumor size threshold beyond which lobectomy provided survival benefits compared with segmentectomy., (© 2024. Society of Surgical Oncology.)

Background: Although visceral pleural invasion, lymphovascular invasion, tumor spread through air spaces, and poor differentiation are pathological risk factors associated with unfavorable prognosis in patients with lung adenocarcinoma, the cumulative impact of these factors on prognosis remains unclear., Methods: We enrolled 1532 patients with stage I lung adenocarcinoma. Patients were divided according to the number of risk factors as follows: Group A (without risk factors), Group B (one risk factor), and Group C (multiple risk factors). Moreover, we stratified patients into two subgroups based on tumor size (≤ 3 cm, 3-4 cm). Kaplan-Meier analysis was used to evaluate 5-year disease-free survival (DFS) and overall survival (OS)., Results: Overall, 949, 404, and 179 patients were included in Groups A, B, and C, respectively. Group C had a larger tumor size and more cases of extrathoracic recurrence than the other groups. The 5-year DFS and OS gradually decreased across Groups A to C (DFS: 94.3%, 80.6%, and 64.3%, respectively, p < 0.001; OS: 97.2%, 92.7%, and 77%, respectively, p < 0.001). A similar trend was observed for tumors ≤ 3 cm in size (DFS: 95.2%, 83.2%, and 68.5%, respectively, p < 0.001; OS: 97.6%, 94.1%, and 79.6%, respectively, p < 0.001), but a less pronounced trend was observed for tumors between 3 and 4 cm in size (DFS: 72.1, 60.8, and 43.3%, respectively, p = 0.054; OS: 85.7, 82.1, and 64.7%, respectively, p = 0.16)., Conclusions: Postoperative survival worsened with increasing pathological risk factors in patients with stage I lung adenocarcinoma, especially those with tumor size ≤ 3 cm., (© 2024. Society of Surgical Oncology.)

Background: The aim of this study is to explore the prognostic value and immune signature of ITGB4 expression in lung adenocarcinoma (LUAD) brain metastasis., Methods: We comprehensively screened genes associated with LUAD brain metastasis by integrating datasets from the GEO database and TMT-based quantitative proteomics profiles. Univariable survival and Multivariate Cox analysis was used to compare several clinical characteristics with survival, and a risk model was constructed. The biological functions were explored via GO and KEGG analysis. Gene set enrichment analysis (GSEA) was performed using the TCGA dataset. In addition, we use TIMER to explore the collection of ITGB4 Expression and Immune Infiltration Level in LUAD. The ability of ITGB4 to regulate tumor metastasis was further assessed by migration, invasion assay and Western-blot in H1975-BrM4 cells., Results: We found that ITGB4 was the only gene with high clinical diagnostic and prognostic value in LUAD. Enrichment analysis indicated that ITGB4 is associated with brain metastasis, infiltration of immune cells, and the response to immunotherapy. ITGB4 expression can effectively predict the outcomes of patients with LUAD who are receiving anti-PD-1 therapy. ITGB4 knockdown inhibited the invasion, migration of H1975-BrM4 brain metastasis cells, as well as epithelial-mesenchymal transition (EMT) abilities. The heightened expression of ITGB4 protein was shown to promote EMT and enhance the metastatic potential. ITGB4 promotes the progression in H1975-BrM4 cells via MEK/ERK signaling pathway., Conclusions: Our findings indicate that the expression of ITGB4 is linked to the occurrence of brain metastasis and infiltration of immune cells, suggesting that ITGB4 might be a clinical treatment target for LUAD., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no conflict of interest., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Background: Cluster of differentiation (CD) 155 is a transmembrane protein that belongs to the nectin-like molecule family, which is widely overexpressed in several types of cancer. However, the clinical significance of CD155 in pathologic stage I lung adenocarcinoma remains poorly understood., Methods: We analyzed 320 patients diagnosed with pathologic stage I lung adenocarcinoma who underwent surgical treatment at Kyushu University Hospital between 2006 and 2015. The number of tumor cells expressing CD155 was assessed by immunohistochemistry, and patients were categorized into high and low CD155 expression groups. We compared the clinical and pathologic characteristics and clinical outcomes between these groups., Results: Mutation status of the epidermal growth factor receptor gene (EGFR) was determined in 237 patients. A total of 106 patients (33.1%) had EGFR wild-type, and 131 patients (40.9%) had EGFR mutant-type. CD155 expression was classified as high in 77 patients (24.1%) and as low in 243 (75.9%) as low. Multivariate analysis identified pleural invasion and EGFR wild-type as independent predictors of high CD155 expression. The Kaplan-Meier plot demonstrated significantly poorer recurrence-free survival and overall survival in the high CD155 group compared with the low CD155 group. Multivariate analysis showed high CD155 expression was an independent poor prognostic factor for recurrence-free and overall survival. Subgroup analyses revealed that a prognostic difference related to CD155 expression was observed only in patients with EGFR wild-type but not in those with EGFR mutant-type., Conclusions: Our findings suggest that high expression of CD155 is associated with EGFR wild-type and could serve as a valuable prognostic marker in pathologic stage I lung adenocarcinoma, particularly in cases without EGFR mutation., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Non-small cell lung cancer (NSCLC) is histologically classified into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LSCC). However, some tumors are histologically ambiguous and other pathophysiological features or microenvironmental factors may be more prominent. Here we report integrative multiomics analyses using data for 229 patients from a Korean NSCLC cohort and 462 patients from previous multiomics studies. Histological examination reveals five molecular subtypes, one of which is a NSCLC subtype with PI3K-Akt pathway upregulation, showing a high proportion of metastasis and poor survival outcomes regardless of any specific NSCLC histology. Proliferative subtypes are present in LUAD and LSCC, which show strong associations with whole genome doubling (WGD) events. Comprehensive characterization of the immune microenvironment reveals various immune cell compositions and neoantigen loads across molecular subtypes, which predicting different prognoses. Immunological subtypes exhibit a hot tumor-enriched state and a higher efficacy of adjuvant therapy., Competing Interests: Competing interests: Kwang Pyo Kim is the CEO of NioBiopharmaceuticals, Inc. Se Jin Jang is the chief technology officer of SG Medical, Inc. All other authors declare no competing interests., (© 2024. The Author(s).)

Background: This study aimed to evaluate the prognostic value of the newly revised International Association for the Study of Lung Cancer (IASLC) grading system (2020) on the 5-year overall survival (OS) and recurrence-free survival (RFS) in patients with lung adenocarcinoma (LADC)., Methods: Clinical studies that investigated the prognostic value of revised IASLC staging system in patients with LADC were retrieved from the PubMed, Web of Science, ScienceDirect, and Cochrane Library databases. This study was conducted in accordance to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and checklists., Results: Based on inclusion and exclusion criteria, we included 12 studies for analysis. The grade of LADC was assessed by revised IASLC system, which included three grades. Compared to Grade 3 LADC, grade 1 (total [95% CI]: 1.38 [1.19, 1.60]) and grade 2 (total [95% CI]: 1.29 [1.15, 1.44]) LADC had higher 5-year OS rates. Similarly, Grade 1 (total [95% CI]: 1.76 [1.42, 2.18]) and Grade 2 (total [95% CI]: 1.51 [1.28, 1.77]) had higher 5-year RFS rates Grade 3 LADC. However, 5-year OS and RFS had no significant difference between Grade 1 and Grade 2 patients., Conclusion: This systematic review and meta-analysis provides evidence that the newly revised IASLC grading system is significantly associated with the prognosis of patients with LADC, where Grade 3 indicated unfavorable prognosis., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of The First People’s Hospital of Jiande. Written informed consent was obtained from all the participants. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Long non-coding RNAs (lncRNAs) have a notable role in the diagnosis and prognosis of cancer. However, the associations between lncRNA-related hub genes (LRHGs) expression and the corresponding outcomes have not been fully understood in lung adenocarcinoma (LUAD). Here, a total of 71 patients diagnosed with LUAD and 60 healthy volunteers at The First Affiliated Hospital of Huzhou University from April, 2023 to December, 2023 were enrolled in the present study. A LRHGs model was established using least absolute shrinkage and selection operator analyses of The Cancer Genome Atlas-LUAD datasets. The underlying mechanisms of the LRHGs were investigated via Gene Set Enrichment Analysis and Gene Set Variation Analysis. Additionally, the diagnostic role of serum HOXD cluster antisense RNA 2 (HOXD-AS2) was assessed by receiver operating characteristic (ROC) curve analysis. Lastly, TCGA-LUAD samples were divided into high- and low-HOXD-AS2 expression groups based on the median expression. The associations between HOXD-AS2 expression and miR-4538 as well as Calmodulin-Dependent Protein Kinase Type II subunit Beta (CAMK2B) levels were conducted through Pearson correlation analysis. A comprehensive analysis identified 141 differentially expressed lncRNAs between 539 LUAD tissues and 59 normal samples. A prognostic marker for overall survival was established by constructing a predictive signature consisting of 9 LRHGs. Subsequently, 474 LUAD samples were categorized into a high or low-risk group based on the median of the risk score. An independent prognostic model was constructed to confirm the validity of this categorization. Further comparisons of the clinicopathological features and LRHG-related pathways were performed between the two groups. Examinations of LRHG expression in two LUAD clusters and of the association between LRHG expression and immune infiltration were also conducted. HOXD-AS2 expression was shown to be elevated in LUAD tissues compared with matched normal tissues, and the serum HOXD-AS2 level was also notably increased in LUAD samples compared with healthy controls. The results of the ROC analysis indicated that the sensitivity and specificity of HOXD-AS2 were higher than that of cytokeratin-19 fragment (CYFRA21-1), which is a serum marker for LUAD. Pearson analyses indicated that miR-4538 level was negatively associated with HOXD-AS2 expression, but CAMK2B level showed positive correlation in LUAD. The results of the present study therefore indicated that the constructed LRHG model, particularly HOXD-AS2, could independently diagnose and predict the prognosis of LUAD, which suggested the underlying mechanism of the HOXD-AS2/miR-4538/CAMK2B, and might offer efficient strategies for LUAD treatment., (© 2024. The Author(s).)

Objective: Recent evidence suggests that elevated levels of PD-L1 expression may be linked to early resistance to TKI and reduced survival in NSCLC with EGFR mutations. This study aimed to characterize the clinical and molecular features of EGFR-mutated lung adenocarcinomas and determine the prognostic significance associated with high PD-L1 expression., Materials and Methods: We conducted a retrospective chart review of 103 consecutive patients with advanced EGFR-mutated NSCLC, who received treatment between 01/01/2016 and 30/12/2020, at our institution., Results: Among the tumors, 17% (n = 18) exhibited high PD-L1 expression (≥50% tumor proportion score), which was associated with a lower prevalence of common EGFR mutations (56% vs. 82%, p = 0.03) and a higher frequency of complex EGFR mutations (28% vs. 7%, p = 0.02). Univariate analysis did not reveal any significant differences in first-line response, progression-free survival, or overall survival between the PD-L1 ≥50% and <50% groups. However, multivariate analysis demonstrated that PD-L1 ≥50% was independently associated with shorter survival (HR = 2.57; 95%CI[1.20-5.55]; p = 0.02), along with male gender (HR = 2.77; 95%CI[1.54-4.19]; p<0.005), presence of liver metastases (HR = 5.80; 95%CI[2.86-11.75]; p<0.005) or brain metastases (HR = 1.99; 95%CI[1.13-3.52]; p = 0.02), and poor general condition at diagnosis (ECOG 3 and 4) (HR = 10.69; 95% CI[4.42-25.85]; p<0.005). Additionally, a trend towards a higher frequency of de novo resistance was observed in the PD-L1 >50% group (7% vs. 17%, p = 0.19)., Conclusion: High PD-L1 expression was more commonly found in lung adenocarcinomas with uncommon and complex EGFR mutations. Furthermore, high PD-L1 expression independently predicted poor survival. These findings warrant validation through prospective studies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Slomka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

With increasing life spans, breast cancer (BC) survivors may face the possibility of developing second primary cancer (SPC), which can considerably shorten survival. Lung cancer (LC) is a common SPC among BC survivors. This study explored the association between these two cancers through Mendelian randomization (MR) analysis. A bidirectional two-sample MR analysis was conducted with BC genome-wide association study (GWAS) data from the Breast Cancer Association Consortium (BCAC) included 228,951 individuals and the GWAS summary statistics from the Transdisciplinary Research in Cancer of the Lung (TRICL) of LC included 112,781 individuals. The IVW method and MR-RAPS method showed a causal effect of overall BC on lung adenocarcinoma (LUAD) (IVW: OR = 1.060, 95% CI = 1.008-1.116, P = 0.024; MR-RAPS: OR = 1.059, 95% CI = 1.005-1.116, P = 0.033), which indicated that patients with BC had an increased risk of LUAD. However, there is no strong evidence for a causal effect of LUAD on BC. Our study revealed a causal effect of BC on second primary LUAD, suggesting that we should intensify screening for second primary LC in BC survivors. Early intervention and treatment for patients with second primary LC are needed to reduce mortality in BC survivors., (© 2024. The Author(s).)

Objectives: This study aimed to evaluate the predictive and prognostic factors in clinical stage I, anaplastic lymphoma kinase (ALK)-rearranged lung adenocarcinoma following radical surgery. Additionally, it sought to compare these factors with an external cohort of ALK wild-type patients., Methods: A multicentric, retrospective, case-control analysis was conducted on patients with clinical T1-2 N0 ALK-rearranged lung adenocarcinoma who underwent anatomical resection and radical lymphadenectomy. Data were collected from 5 high-volume oncological centres. An external cohort of ALK wild-type patients was also analysed for comparison. Survival analyses were performed using the Kaplan-Meier method, and multivariable Cox regression analysis was used to identify prognostic factors., Results: From January 2016 to December 2022, 63 patients with ALK-rearranged lung adenocarcinoma were included. High-grade tumours (G3) significantly associated with upstaging (odds ratio = 3.904, P = 0.04). Disease-free survival (DFS) and overall survival were significantly improved in upstaged patients receiving adjuvant treatment [hazard ratio (HR) = 0.18, P = 0.0042; HR = 0.24, P = 0.0004, respectively]. The solid or micropapillary histological subtypes were independently associated with worse DFS (HR = 3.41, P = 0.022). Comparison with 435 ALK wild-type patients showed worse DFS in the ALK-rearranged group (HR = 2.09, P = 0.0003). ALK-rearranged patients had higher rates of nodal upstaging, systemic and brain recurrences., Conclusions: Clinical T1-2 N0 ALK-rearranged lung adenocarcinoma is an aggressive disease with a specific tropism for lymph nodes and the brain. High-grade tumours are predictive of nodal upstaging. Adjuvant treatment significantly improves DFS and overall survival in upstaged patients, highlighting the need for personalized preoperative staging and post-surgical management in this cohort., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: To analyse impact of segmentectomy on oncological outcomes of different peripheral early-stage lung adenocarcinoma patterns., Methods: Retrospective multicentre study including patients who underwent either lobectomy or segmentectomy in 6 European centres from 2015 to 2021, for ≤2 cm pathological peripheral lung adenocarcinoma. Overall and disease-free survivals were assessed by cox-regression and lung cancer-specific survival by competing regression analyses to adjust for patient- and tumour-related factors both in the entire dataset and the in aggressive adenocarcinoma patterns dataset., Results: Lobectomy and segmentectomy were performed in 481 (71%) and 193 (29%) patients, respectively. Propensity score matching was performed (n = 191). One hundred and 8 patients had a least an aggressive pattern. Five-year disease-free, overall and lung cancer-specific survivals were similar between patients who underwent lobectomy or segmentectomy in both entire and aggressive pattern datasets. In patients with aggressive pattern, 5-year disease-free (lobectomy 87.3%; segmentectomy 86.6%, P = 0.62), overall (lobectomy 86.4%; segmentectomy 95.6%, P = 0.61) and lung cancer-specific (lobectomy 100%; segmentectomy 95.6%, P = 0.13) survivals did not differ. Segmentectomy was not an independent risk factor for disease-free survival, neither for overall survival nor for lung cancer-specific survival in any of the 2 datasets. In patients with aggressive pattern, loco-regional recurrence (linearized risks: lobectomy 8.21; segmentectomy 11.3) was higher in patients who underwent segmentectomy., Conclusions: Resection should not be extended (to lobectomy) on patients who underwent segmentectomy for pathologically proven early-stage adenocarcinoma with aggressive patterns., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Non-small cell lung adenocarcinoma (LUAD) is the predominant form of lung cancer originating from lung epithelial cells, making it the most prevalent pathological type. Currently, reliable indicators for predicting treatment efficacy and disease prognosis are lacking. Despite extensive validation of autophagy-dependent cell death (ADCD) in solid tumor studies and its correlation with immunotherapy effectiveness and cancer prognosis, systematic research on ADCD-related genes in LUAD is limited. We utilized AddModuleScore, ssGSEA, and WGCNA to identify genes associated with ADCD across single-cell and bulk transcriptome datasets. The TCGA dataset, comprising 598 cases, was randomly divided into training and validation sets to develop an ADCD-related LUAD prediction model. Internal validation was performed using the TCGA validation set. For external validation, datasets GSE13213 (119 LUAD samples), GSE26939 (115 LUAD samples), GSE29016 (39 LUAD samples), and GSE30219 (86 LUAD samples) were employed. We evaluated the model's accuracy and effectiveness in predicting prognostic risk. Additionally, CIBERSORT, ESTIMATE, and ssGSEA techniques were used to explore immunological characteristics, drug response, and gene expression in LUAD. Real-time RT-PCR was conducted to assess variations in mRNA expression levels of the gene XCR1 between cancerous and normal tissues in 10 lung cancer patients. We identified 249 genes associated with autophagy-dependent cell death (ADCD) at both single-cell and bulk transcriptome levels. Univariate COX regression analysis revealed that 18 genes were significantly associated with overall survival (OS). Using LASSO-Cox analysis, we developed an ADCD signature based on five genes (BIRC3, TAP1, SLAMF1, XCR1, and HLA-DMB) and created the ADCD-related risk scoring system (ADCDRS). Validation of this model demonstrated its ability to predict disease prognosis and its correlation with clinical characteristics, immune cell infiltration, and the tumor microenvironment. To enhance clinical applicability, we integrated an ADCDRS nomogram. Furthermore, we identified potential drugs targeting specific risk subgroups. We successfully identified a model based on five ADCD genes to predict disease prognosis and treatment efficacy in LUAD, as well as to assess the tumor immune microenvironment. An efficient and practical ADCDRS nomogram was designed., (© 2024. The Author(s).)

Backgrounds: Advanced lung adenocarcinoma (LUAD) patient with EGFR mutations often experience resistance to first-line epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) therapy. Nonetheless, the mechanism and biomarkers of primary resistance remain unclear. Further exploration of independent prognostic factors will help clinicians identify patients who may not respond to EGFR-TKIs and select appropriate treatment strategies., Methods: A retrospective study involving 124 patients with stage IV LUAD harboring a common sensitizing EGFR mutation (exon 19 deletion or L858R mutation) who received EGFR-TKIs as first-line therapy was performed. All participants were tested by DNA-targeted sequencing in baseline samples, and there were 19 patients with progression-free survival (PFS) ≤ 3 months (cohort 1, C1, primary resistance), 22 patients with 3 < PFS < 8 months (cohort 2, C2, poor response) without known mutations associated with resistance, and 83 patients with PFS ≥ 8 months (cohort 3, C3, normal)., Results: The most commonly mutated genes at baseline in patients prior to treatment within the entire study population. were TP53 (65 %), MYC (19 %), CDKN2A (12 %), MUC16 (12 %) and RBM10 (12 %). The baseline characteristics, except for the proportions of patients with EGFR L858R mutation and exon 19 deletion in C1 plus C2 compared to C3 (p = 0.036), were not significantly different among the cohorts. The frequencies of PIK3C2G, STK11, EPAS1, RARA and BTG2 variation were significantly higher in C1, the primary resistance group. Multivariate Cox analysis revealed that PIK3C2G (HR 15.70 95 % CI 3.24-76.05, p < 0.001), STK11 (HR 17.04, 95 % CI 3.68-78.92, p < 0.001), EPAS1 (HR 11.99, 95 % CI 2.57-56.03, p = 0.002), and BTG2 amplification (HR 9.53, 95 % CI 1.67-54.28, p = 0.011) were significantly associated with shorter PFS., Conclusions: The genomic landscape varies significantly among patients with LUAD, which should be considered when making personalized treatment decisions. This information could provide insights into molecular changes and their effects on clinical treatment in diverse patients with LUAD harboring sensitizing EGFR mutations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: The enhancer of rudimentary homolog (ERH) is significant in cancers, but its role in lung cancer is understudied., Methods: We divided lung cancer patients into high and low ERH expression groups based on tumour tissue levels. Using the log-rank test, we analysed the correlation between ERH expression and patient prognosis. The effects of high ERH expression on lung cancer cell proliferation, migration, and invasion were assessed using CCK8, EDU, transwell, and wound healing assays., Results: ERH expression was significantly higher in cancerous versus normal lung tissue ( p  < 0.05), including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Patients with high ERH expression had worse overall survival (HR = 1.37, p  = 2.5 × 1 0 -7 ) and first progression survival (HR = 1.38, p  = 0.00065) in lung cancer. However, while high ERH expression predicts an unfavourable prognosis in LUAD, it does not hold true for LUSC. Furthermore, knockdown of ERH inhibited lung cancer cell proliferation, migration, and invasion. ERH expression was linked to immune cell infiltration. High ERH expression in LUAD and LUSC samples correlated with higher CD8 T cell, T cells CD4 memory activated, and M1 macrophages abundance, while low ERH expression correlated with higher T cells CD4 memory resting abundance., Conclusion: Upregulation of ERH in lung cancer tissue is associated with poor prognosis and immune cell infiltration.

Lung adenocarcinoma (LUAD), the predominant subtype of lung cancer, has a high incidence and annual mortality worldwide. Members of the cadherin-related (CDHR) family are associated with many malignant tumor types. However, their role and clinical significance in LUAD have not been clarified. We analyzed the association of CDHRs mRNA expression profiles with prognostic significance, immune infiltration, and potential biological functional signatures in several public databases. We constructed a co-expressed mRNA network, and performed an intrinsic molecular structure and function enrichment analysis. Our results showed that CDHR2 mRNA expression was upregulated in LUAD, whereas CDHR1, CDHR3, CDHR4, and CDHR5 mRNAs were downregulated. Upregulation of CDHR2 mRNA is associated with a poor prognosis in patients with LUAD. Next, the correlation between CDHR family members and immune infiltration was observed. A receiver operating characteristic curve showed that the CDHR family is valuable for diagnosing LUAD. In this study, we found that CDHR2 mRNA expression was upregulated in LUAD. Upregulation of CDHR2 mRNA was associated with a poor prognosis in patients with LUAD., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The clinical outcomes of patients with anaplastic lymphoma kinase-positive (ALK+) advanced lung adenocarcinoma vary according to real-world data., Objective: In this study, we aimed to investigate the treatment discontinuation (TTD) and overall survival (OS) of patients with ALK+ advanced lung adenocarcinoma treated with first-line ALK-TKIs in Taiwan., Patients and Methods: This retrospective study evaluated all advanced lung adenocarcinoma patients registered in the National Taiwan Cancer Registry from 2017 to 2020 who had ALK rearrangement and received ALK-TKI treatment, using data from Taiwan's National Health Insurance Research Database (NHIRD). The TKI treatment sequences were classified into first generation (G1: crizotinib), second generation (G2: ceritinib, alectinib, brigatinib), and third generation (G3: lorlatinib)., Results: A total of 587 patients were analyzed, with a median age of 60.0 years, 91 (15.5%) aged ≥ 74 years, 293 (49.9%) female, 397 (67.6%) never smoked, and 534 (91.0%) with stage IV disease. Patients who received next-generation ALK-TKIs during the treatment course had longer median time to ALK-TKI TTD and OS. The TTD of the G1, G1+2, G1+2+3, G2, and G2+3 groups was 7.5 (5.4-11.1), 40.6 (29.4-not calculated (NC)), 50.3 (41.3-NC), 34.3 (29.2-43.0), and 36.3 (22.4-NC) months, respectively (p < 0.001). The median OS of the patients in the G1, G1+2, G1+2+3, G2, and G2+3 groups was 10.6 (7.5-14.6), not reached (NR) (NC-NC), NR (NC-NC), 43.0 (36.3-NC), and NR (30.3-NC) months, respectively (p < 0.001). Compared with treatment with crizotinib alone, the multivariate analysis revealed that treatment with next-generation TKIs was independently associated with longer TTD (G1+2 (hazard ratio (HR), 0.24; 95% CI 0.17-0.33; p < 0.001), G1+2+3 or G1+3 (HR, 0.17; 95% confidence interval (CI), 0.10-0.28; p < 0.001), G2 (HR, 0.26; 95% CI 0.19-0.36; p < 0.001), and G2+3 (HR, 0.25; 95% CI 0.14-0.44; p < 0.001)) and median OS (G12 (HR, 0.24; 95% CI 0.17-0.35; p < 0.001), G1+2+3 or G1+3 (HR, 0.09; 95% CI 0.04-0.21; p < 0.001), G2 (HR, 0.22; 95% CI 0.15-0.31; p < 0.001), and G2+3 (HR, 0.20; 95% CI 0.10-0.42; p < 0.001))., Conclusions: For patients with ALK+ NSCLC, treatments including next-generation ALK-TKIs were independently associated with longer survival outcomes., Competing Interests: Declarations Funding This study was funded by Pfizer (tracking no. 75046155), the Ministry of Health and Welfare (MOHW112-TDU-B-222-124019), and Formatting the Risk Prediction Models for Never-Smoking Lung Cancer (FORMOSA). Conflict of interest Zhe-Rong Zheng, Jia-Jun Wu, Chun-Ju Chiang, Tzu-I Chen, Kun-Chieh Chen, Cheng-Hsiang Chu, Sheng-Yi Lin, Sung-Liang Yu, Wen-Chung Lee, Tsang-Wu Liu, and Gee-Chen Chang declare that they have no conflicts of interest that might be relevant to the contents of this manuscript. Ethics approval The study was approved by the Institutional Review Board (IRB) of CSMUH, Taiwan (IRB no. CS1-22160). Consent to participate Not applicable. Consent for publication All authors reviewed the manuscript and approved the version for publication. Availability of data and material The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Code availability Not applicable. Author contributions Zhe-Rong Zheng, Jia-Jun Wu, Chun-Ju Chiang, and Gee-Chen Chang contributed to the study conception and design. Material preparation and data collection were performed by Jia-Jun Wu and Chun-Ju Chiang. The analysis of the data was done by Jia-Jun Wu, Chun-Ju Chiang, Tzu-I Chen, Kun-Chieh Chen, and Gee-Chen Chang. The writing of the original draft was performed by Zhe-Rong Zheng, Jia-Jun Wu, Chun-Ju Chiang, Tzu-I Chen, Kun-Chieh Chen, Cheng-Hsiang Chu, Sheng-Yi Lin, Sung-Liang Yu, Wen-Chung Lee, Tsang-Wu Liu, and Gee-Chen Chang. Jia-Jun Wu and Gee-Chen Chang revised the manuscript critically for important intellectual content., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

This article aimed to investigate the correlations among SKA3 expression and prognosis, clinical relevance, tumor immunity, and RNA-binding protein (RBP)-involved mechanisms for overall survival (OS) in lung adenocarcinoma (LUAD). To explore the SKA3 expression level in LUAD by analyzing the genomic data as well as related clinical characteristics from the database of TCGA. Nomogram and gene set enrichment analysis (GSEA) were applied, respectively, to evaluate the performance of SKA3 in LUAD. Correlations between SKA3 and immunity and RBP-involved mechanisms were also performed. SKA3 had a higher expression level in LUAD samples than in adjacent normal lung samples, with shorter survival times in the high-SKA3-expressed LUAD subgroup (P < 0.05). qRT-PCR results remained consistent (P < 0.05). Uni-/multivariate Cox analyses revealed that SKA3 could have independent prognostic ability for LUAD (both P < 0.05). The nomogram model constructed with clinical pathological parameters and SKA3 expression levels predicted OS rates for LUAD and GSEA revealed SKA3-related pathways. In aspects of tumor immunity, SKA3 was significantly involved with tumor neoantigen burden, tumor mutational burden, immune cell pathways, and immune checkpoint inhibitor (ICI) molecules (all P < 0.05). The CellMiner database also found significant correlations between SKA3 and the antitumor drug sensitivity of chemotherapy, fenretinide, and PX-316. Besides, a total of nine LncRNA/RBP/SKA3 networks were revealed in LUAD for their RBP-involved mechanisms. SKA3 could serve as a potential biomarker for OS prognosis and immunotherapy in LUAD. LncRNA/RBP/SKA3 networks were identified in LUAD for their RBP-involved mechanisms, paving the way for further experimental verifications.

Purpose: The purpose of this study was to assess whether single-site and multi-site radiomics could improve the prediction of overall survival (OS) of patients with metastatic lung adenocarcinoma compared to clinicopathological model., Materials and Methods: Adults with metastatic lung adenocarcinoma, pretreatment whole-body contrast-enhanced computed tomography examinations, and performance status (WHO-PS) ≤ 2 were included in this retrospective single-center study, and randomly assigned to training and testing cohorts. Radiomics features (RFs) were extracted from all measurable lesions with volume ≥ 1 cm 3 . Radiomics prognostic scores based on the largest tumor (RPS largest ) and the average RF values across all tumors per patient (RPS average ) were developed in the training cohort using 5-fold cross-validated LASSO-penalized Cox regression. Intra-patient inter-tumor heterogeneity (IPITH) metrics were calculated to quantify the radiophenotypic dissimilarities among all tumors within each patient. A clinicopathological model was built in the training cohort using stepwise Cox regression and enriched with combinations of RPS average , RPS largest and IPITH. Models were compared with the concordance index in the independent testing cohort., Results: A total of 300 patients (median age: 63.7 years; 40.7% women; median OS, 16.3 months) with 1359 lesions were included (200 and 100 patients in the training and testing cohorts, respectively). The clinicopathological model included WHO-PS = 2 (hazard ratio [HR] = 3.26; P < 0.0001), EGFR, ALK, ROS1 or RET mutations (HR = 0.57; P = 0.0347), IVB stage (HR = 1.65; P = 0.0211), and liver metastases (HR = 1.47; P = 0.0670). In the testing cohort, RPS average , RPS largest and IPITH were associated with OS (HR = 85.50, P = 0.0038; HR = 18.83, P = 0.0082 and HR = 8.00, P = 0.0327, respectively). The highest concordance index was achieved with the combination of clinicopathological variables and RPS average , significantly better than that of the clinicopathological model (concordance index = 0.7150 vs. 0.695, respectively; P = 0.0049) CONCLUSION: Single-site and multi-site radiomics-based scores are associated with OS in patients with metastatic lung adenocarcinoma. RPS average improves the clinicopathological model., Competing Interests: Declaration of competing interest A.I.: Research grant: AMGEN, AstraZeneca, Bayer, BMS, Merck, MSD, Novartis, CHUGAI, Par-thenon, Roche; Advisory board: Bayer, BMS, Merck, MSD, Novartis, CHUGAI, Parthenon, Roche. S.C.: Advisory board: Amgen, Lilly, Roche, Astrazeneca, Abbvie, BMS The other authors declare no actual or potential conflict of interest related to this study., (Copyright © 2024 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Lung cancer is a leading cause of cancer-related deaths, with its incidence continuing to rise. Chromatin remodeling, a crucial process in gene expression regulation, plays a significant role in the development and progression of malignant tumors. However, the role of chromatin regulators (CRs) in lung adenocarcinoma (LUAD) remains underexplored., Methods: This study developed a chromatin regulator-related signature (CRRS) using a 429-combination machine learning approach to predict survival outcomes in LUAD patients. The CRRS model was validated across multiple independent datasets. We also investigated the impact of CRRS on the immune microenvironment, focusing on immune cell infiltration. To identify potential therapeutic targets, TFF1, a chromatin regulator, was knocked down using siRNA in LUAD cells. We assessed its impact through apoptosis analysis, proliferation assays, and in vivo tumor growth studies. Additional validation was performed using Ki67 expression and TUNEL assays., Results: The CRRS accurately predicted survival outcomes and was shown to modulate immune cell infiltration in the tumor microenvironment. High-risk patients demonstrated increased activity in cell cycle regulation and DNA repair pathways, along with distinct mutation profiles and immune responses compared to low-risk patients. TFF1 emerged as a key therapeutic target. Knockdown of TFF1 significantly inhibited LUAD cell proliferation, induced apoptosis, and suppressed in vivo tumor growth. Ki67 and TUNEL assays confirmed the role of TFF1 in regulating tumor growth and cell death., Discussion: These findings highlight the potential of chromatin regulators in prognostic modeling and immune modulation in LUAD. TFF1 was identified as a promising therapeutic target, suggesting that targeting TFF1 could provide new treatment strategies. Further research is warranted to explore its full potential and therapeutic applicability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fan, Chen, Wu, Liang, Shen and Miao.)

Although the initial research focused on glycolysis, mitochondrial oxidative phosphorylation has become a major target of cancer cells. Cytochrome C oxidase assembly factor 6 (COA6) is a conserved assembly factor necessary for complex IV biogenesis. Nevertheless, the clinical predictive value of COA6, especially its correlation with immune cell infiltration in lung adenocarcinoma (LUAD), has not yet been elucidated. COA6 exhibited higher expression levels in LUAD cells and tumor tissues compared to normal tissues. Additionally, heightened COA6 expression was associated with reduced overall survival (OS) and advanced tumor stage. Apart from its role in mitochondrial respiratory processes, COA6 may be involved in the process of antigen binding, immunoglobulin receptor binding. Interestingly, we observed a positive correlation between COA6 expression and tumor mutational burden (TMB), as well as a significant association with decreased immune cell infiltration. COA6 was linked to resistance against gemcitabine and etoposide. We verified that COA6 was highly expressed in LUAD experimentally and cell proliferation was inhibited after COA6 knockdown. Thus, we conclude that the expression of COA6 was correlated with reduced immune cell infiltration. Additionally, COA6 functioned as a biomarker for drug sensitivity and the prognosis of lung adenocarcinoma., (© 2024. The Author(s).)

Background: Surgery is the optimal choice for early invasive mucinous lung adenocarcinoma (IMA). A systematic review and meta-analysis were conducted to explore the prognostic factors for resected IMA., Methods: We systematically reviewed the prognostic role of clinicopathological and genomic factors in resected IMA patients. Eligible studies on the treatment of IMA following the systematic search of PubMed, Embase and the Cochrane Library from January 2015 to January 2024 were identified. Outcomes of interest were overall survival (OS) and disease-free survival/recurrence-free survival (DFS/RFS). The hazard ratio (HR) and 95% confidence interval (CI) were used as impact indicators for systematic review and meta-analysis., Results: Sixteen studies involving 3,484 patients with IMA were included. The results of the combined analysis showed that male and smoking were associated with a worse prognosis. Furthermore, advanced clinical stage, poor differentiation grade, presence of visceral pleural invasion (VPI) and spread through air spaces (STAS), and presence of KRAS mutations were also associated with worse prognosis., Conclusions: Gender, smoking, clinical stage, tumor size, differentiation grading, VPI, STAS and KRAS mutation affect DFS/RFS and OS of IMA patients after surgery. Identifying these factors may aid physicians in developing more individualized treatment plans for resectable IMA patients., (© 2024. The Author(s).)

Background: Altered expression and activity of solute carrier family 4 member 4 (SLC4A4) could affect the growth, survival and metastasis of tumor cells. Currently, the role of SLC4A4 in lung adenocarcinoma (LUAD) immunotherapy and prognosis was not entirely clear., Methods: We analyzed SLC4A4 expression in LUAD tissues and cell lines using quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. The effects of SLC4A4 overexpression on angiogenesis, cell migration, invasion, and epithelial-mesenchymal transition were examined. Public databases helped construct a risk model evaluating SLC4A4's expression on LUAD prognosis and immunotherapy response. Additionally, a xenograft model, flow cytometry, and enzyme-linked immunosorbent assay further explored SLC4A4's role in tumor immune microenvironment infiltration., Results: Upregulation of SLC4A4 promoted apoptosis in the LUAD cell line and significantly inhibited the migration and invasive ability of cancer cells (P<0.01). A total of 10 key genes (including SIGLEC6, RHOV, PIR, MOB3B, MIR3135B, LPAR6, KRT8, ITGA2, CPS1, and C6) were screened according to SLC4A4 expression, immune score and stromal score, and a prognostic model with good outcome was constructed (AUC values of which in the training cohort at 1,3, and 5 years reached 0.73, 0.73, and 0.72, respectively). Importantly, we demonstrated that high expression of SLC4A4 was able to increase the proliferation level and cytokine secretion of CD8+ T cells for the purpose of promoting the immune system response to LUAD., Conclusion: Our study revealed that SLC4A4 can serve as a prognostic indicator for LUAD, providing new insights into the treatment and diagnosis of LUAD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: There is a growing interest in utilizing a combination of brain radiotherapy (RT) and tyrosine kinase inhibitors (TKIs) for patients diagnosed with brain metastases (BM) in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma (LAC). The current status of this treatment strategy remains a subject of debate., Methods: We initiated our study by conducting a comprehensive literature search using the SCI-expanded database of Web of Science Core Collection (WoSCC). We utilized the VOSPviewer software to analyze various aspects of the research, including the year of publication, authorship, keywords, and country.Subsequently, we performed an extensive and systematic literature search on popular online databases. Our primary outcome measures were overall survival (OS) and intracranial progression-free survival (iPFS), both quantified by hazard ratios (HRs). Additionally, for data verification, we included data from patients in non-small cell lung cancer with brain metastasis who underwent therapeutic intervention at the Cancer Prevention and Treatment Center of Sun Yat-sen University and the Radiotherapy Department of Hanzhong Central Hospital between August 2012 and November 2021., Results: The bibliometric analysis revealed an increasing trend in research focused on the combination of RT and TKIs for the management of lung cancer brain metastases over the previous decade. Then, nine studies consistent with the research direction were included for meta-analysis. The meta-analysis showed that the OS (HR = 0.81, 95% confidence interval: 0.69-0.94; P = 0.007) and iPFS (HR = 0.71, 95% confidence interval: 0.61-0.82; P < 0.001) of the combination therapy were significantly prolonged. Finally, 168 EGFR-mutated BM advanced LAC patients in the real world were verified, and the median iPFS of the combination therapy (n = 88 and EGFR-TKIs alone (n = 80) were 16.0 and 9.0 months, respectively, (P < 0.001). The median OS was 29.0 and 27.0 months, respectively, with no dramatic difference (P = 0.188)., Conclusions: Research on EGFR-mutant LAC brain metastasis has turned towards exploring optimal treatment strategies for this condition. Our meta-analysis and real-world data analysis consistently demonstrate that combination therapy offers a substantial improvement in patient survival compared to EGFR-TKI monotherapy. Notably, among patients undergoing salvage radiotherapy (RT), our subgroup analysis reveals that those initially treated with third-generation TKIs experience more significant benefits than those treated with first- or second-generation TKIs., (© 2024. The Author(s).)

Pyroptosis plays an important role in lung adenocarcinoma (LUAD). In this study, we aimed to explore the pyroptosis-related gene (PRG) expression pattern and to identify promising pyroptosis-related biomarkers to improve the prognosis of LUAD. The gene expression profiles and clinical information of LUAD patients were downloaded from the Cancer Genome Atlas (TCGA), and validation cohort information was extracted from the Gene Expression Omnibus database. Gene expression data were analyzed using the limma package and visualized using the ggplot2 package as well as the pheatmap package in R software. Functional enrichment analysis was also performed for the 44 differentially expressed PRGs (DEPRGs). Then, consensus clustering revealed pyroptosis-related tumor subtypes, and differentially expressed genes (DEGs) were screened according to the subtypes. Next, univariate Cox and multivariate Cox regression analyses were used to identify independent prognostic PRGs. After overlapping DEGs and the Lasso regression analysis-based prognostic genes, the predictive risk model was established and validated. Correlation analysis between PRGs and clinicopathological variables was also explored. Finally, the TIMER and TISIDB databases were used to further explore the correlation analysis between immune cell infiltration levels, the risk score, and clinicopathological variables in the predictive risk model. A total of 52 genes from the PubMed were identified as PRGs, and 44 of the 52 genes were pooled as DEPRGs. The most significant GO term was "collagen trimer" (P = 2.46E-13), and KEGG analysis results indicated that 44 DEPRGs were significantly enriched in Salmonella infection (P < 0.001). Then, consensus clustering analysis divided LUAD patients into two clusters, and a total of 79 DEGs were identified according to these cluster subtypes. Subsequently, univariate and multivariate Cox regression analyses were used to identify 12 genes that could serve as independent prognostic indicators and we also performed Lasso regression analysis and screened 23 DEGs. After overlapping 23 DEGs and 12 genes, only 4 (KLRG2, MAPK4, C6 and SFRP5) of 12 genes were selected for the further exploration of the prognostic pattern. Survival analysis results indicated that this risk model effectively predicted the prognosis (P < 0.001). Combined with the correlation analysis results between the 4 genes and clinicopathological variables, C6 and KLRG2 were screened as prognostic genes. In this study, we constructed a predictive risk model and identified two pyroptosis subtype-related gene expression patterns to improve the prognosis of LUAD. Understanding the subtypes of LUAD is helpful for accurately characterizing the LUAD and developing personalized treatment., (© 2024. The Author(s).)

Background: Aberrant fatty acid metabolism (FAM) plays a critical role in the tumorigenesis of human malignancies. However, studies on its impact in lung adenocarcinoma (LUAD) are limited., Methods: We developed a prognostic signature comprising 10 FAM-related genes (GPR115, SOAT2, CDH17, MOGAT2, COL11A1, TCN1, LGR5, SLC34A2, RHOV, and DKK1) using data from LUAD patients in The Cancer Genome Atlas (TCGA). This signature was validated using six independent LUAD datasets from the Gene Expression Omnibus (GEO). Patients were classified into high- and low-risk groups, and overall survival (OS) was compared by Kaplan-Meier analysis. The signature's independence as a prognostic indicator was assessed after adjusting for clinicopathological features. Receiver operating characteristic (ROC) analysis validated the signature. Tumor immune microenvironment (TIME) was analyzed using ESTIMATE and multiple deconvolution algorithms. Functional assays, including CCK8, cell cycle, apoptosis, transwell, and wound healing assays, were performed on MOGAT2-silenced H1299 cells using CRISPR/Cas9 technology., Results: Low-risk group patients exhibited decreased OS. The signature was an independent prognostic indicator and demonstrated strong risk-stratification utility for disease relapse/progression. ROC analysis confirmed the signature's validity across validation sets. TIME analysis revealed higher infiltration of CD8+ T cells, natural killers, and B cells, and lower tumor purity, stemness index, and tumor mutation burden (TMB) in low-risk patients. These patients also showed elevated T cell receptor richness and diversity, along with reduced immune cell senescence. High-risk patients exhibited enrichment in pathways related to resistance to immune checkpoint blockades, such as DNA repair, hypoxia, epithelial-mesenchymal transition, and the G2M checkpoint. LUAD patients receiving anti-PD-1 treatment had lower risk scores among responders compared to non-responders. MOGAT2 was expressed at higher levels in low-risk LUAD patients. Functional assays revealed that MOGAT2 knockdown in H1299 cells promoted proliferation and migration, induced G2 cell cycle arrest, and decreased apoptosis., Conclusions: This FAM-related gene signature provides a valuable tool for prognostic stratification and monitoring of TIME and immunotherapy responses in LUAD. MOGAT2 is identified as a potential anti-tumor regulator, offering new insights into its role in LUAD pathogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fu, Zhang, Fan, Zeng, Feng and Wang.)

Wnt/β-Catenin pathway plays an important role in the occurrence and progression of malignant tumors, especially PD-L1-mediated tumor immune evasion. However, the role of TCF/LEF, an important member of the Wnt/β-catenin pathway, in the tumor immunosuppressive microenvironment of lung adenocarcinoma (LUAD) remains unknown. LUAD tissue-coding RNA expression data from The Cancer Genome Atlas and TIMER databases were used to analyze the expression of TCF/LEF transcription factors and their correlation with various immune cell infiltration. Immunohistochemistry and immunofluorescence were used to detect tissue protein staining in 105 patients with LUAD. LEF1, TCF7, TCF7L1 and TCF7L2 were all aberrantly expressed in the tumor tissues of LUAD patients with the data from The Cancer Genome Atlas (TCGA) database, tumor immune estimation resource (TIMER) database and results of immunohistochemistry, but only LEF1 expression was associated with 5-year overall survival in LUAD patients. LEF1 protein expression was associated with advanced tumor node metastasis (TNM) stage, lymphatic metastasis and local invasion in 105 cases LUAD patients. At the same time, LEF1 mRNA expression was also associated with immunosuppressive microenvironment in LUAD patients with the data from TCGA database and TIMER database. Results of immunohistochemistry and immunofluorescence in tumor tissues of 105 cases LUAD patients showed that there was a positively correlation between LEF1 protein expression and the infiltration of M2 macrophages and Treg cells. LEF1 was highly expressed in tumor tissues of LUAD patients, and highly expressed LEF1 was associated with the immunosuppressive microenvironment of LUAD patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Although advances in immune checkpoint inhibitor (ICI) research have provided a new treatment approach for lung adenocarcinoma (LUAD) patients, their survival is still unsatisfactory, and there are issues in the era of response prediction to immunotherapy., Methods: Using bioinformatics methods, a prognostic signature was constructed, and its predictive ability was validated both in the internal and external datasets (GSE68465). We also explored the tumor-infiltrating immune cells, mutation profiles, and immunophenoscore (IPS) in the low-and high-risk groups., Results: As far as we are aware, this is the first study which introduces a novel prognostic signature model using BIRC5, CBLC, S100P, SHC3, ANOS1, VIPR1, LGR4, PGC, and IGKV4.1. According to multivariate analysis, the 9-immune-related genes (IRGs) signature provided an independent prognostic factor for the overall survival (OS). The low-risk group had better OS, and the tumor mutation burden (TMB) was significantly lower in this group. Moreover, the risk scores were negatively associated with the tumor-infiltrating immune cells, like CD8 + T cells, macrophages, dendritic cells, and NK cells. In addition, the IPS were significantly higher in the low-risk group as they had higher gene expression of immune checkpoints, suggesting that ICIs could be a promising treatment option for low-risk LUAD patients., Conclusion: The combination of these 9-IRGs not only could efficiently predict overall survival of LUAD patients but also show a powerful association with the expression of immune checkpoints and response to ICIs based on IPS; hoping this model paves the way for better stratification and management of patients in clinical practice., (© 2024. The Author(s).)

Angiogenesis, metastasis, and resistance to therapy are all facilitated by cancer-associated fibroblasts (CAFs). A CAF-based risk signature can be used to predict patients' prognoses for Lung adenocarcinoma (LUAD) based on CAF characteristics. The Gene Expression Omnibus (GEO) database was used to gather signal-cell RNA sequencing (scRNA-seq) data for this investigation. The GEO and TCGA databases were used to gather bulk RNA-seq and microarray data for LUAD. The scRNA-seq data were analyzed using the Seurat R program based on the CAF markers. Our goal was to use differential expression analysis to discover differentially expressed genes (DEGs) across normal and tumor samples in the TCGA dataset. Pearson correlation analysis was utilized to discover prognostic genes related with CAF, followed by univariate Cox regression analysis. Using Lasso regression, a risk signature based on CAF-related prognostic genes was created. A nomogram model was created based on the clinical and pathological aspects. 5 CAF clusters were identified in LUAD, 4 of which were associated with prognosis. From 2811 DEGs, 1002 genes were found to be significantly correlated with CAF clusters, which led to the creation of a risk signature with 8 genes. These 8 genes were primarily connected with 41 pathways, such as antigen paocessing and presentation, apoptosis, and cell cycle. Meanwhile, the risk signature was significantly associated with stromal and immune scores, as well as some immune cells. Multivariate analysis revealed that risk signature was an independent prognostic factor for LUAD, and its value in predicting immunotherapeutic outcomes was confirmed. A novel nomogram integrating the stage and CAF-based risk signature was constructed, which exhibited favorable predictability and reliability in the prognosis prediction of LUAD. CAF-based risk signatures can be effective in predicting the prognosis of LUAD, and they may provide new strategies for cancer treatments by interpreting the response of LUAD to immunotherapy., (© 2024. The Author(s).)

Lung adenocarcinoma (LUAD) is a study that examines the prognostic value of lactate metabolism genes in tumor cells, which are associated with clinical prognosis. We analyzed the expression and clinical data for LUAD from The Cancer Genome Atlas database, using the GSE68465 dataset from the Gene Expression Omnibus and the MSigDB database. LASSO Cox regression and stepwise Cox regression were used to identify the optimal lactate metabolism gene signature. Differences in immune infiltration, tumor mutation burden (TMB), and response to immune checkpoint blockade (ICB) therapy were evaluated between groups. LASSO and Cox regression analyses showed an eight-lactate metabolism gene signature for model construction in both TCGA cohort and GSE68465 data, with higher survival outcomes in high-risk groups. The lactate metabolism risk score had an independent prognostic value (hazard ratio: 2.279 [1.652-3.146], P < .001). Immune cell infiltration differed between the risk groups, such as CD8+ T cells, macrophages, dendritic cells, mast cells, and neutrophils. The high-risk group had higher tumor purity, lower immune and stromal scores, and higher TMB. High-risk samples had high tumor immune dysfunction and exclusion (TIDE) scores and low cytolytic activity (CYT) scores, indicating a poor response to ICB therapy. Similarly, most immune checkpoint molecules, immune inhibitors/stimulators, and major histocompatibility complex (MHC) molecules were highly expressed in the high-risk group. The 8-lactate metabolism gene-based prognostic model predicts patient survival, immune infiltration, and ICB response in patients with LUAD, driving the development of therapeutic strategies to target lactate metabolism., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Lactate dehydrogenase is dysregulated in several cancer types. However, the mechanism of its dysregulation in lung cancer is not fully understood. We utilized web-based computational databases to conduct gene expression analysis on LDHA, identified its regulator, and explored their role in the prognosis of lung cancer., Methods: We used various web-based computational tools, including the UALCAN, TIMER2.0, ENCORI, TCGA Portal, OncoDB, and GEPIA2 datasets for lung cancer analysis in this study. We also performed survival, biological processes, and metastasis analysis using various computational tools. We also carried out co-expression functional enrichment analysis using the Enrichr and TIMER databases, multivariate analysis of survival and pathological stage, and transcriptional regulation analysis using the ENCORI and OncoDB datasets. Furthermore, LDHA inhibitor binding of withanolides was analyzed using Auto Dock Tools 1.5.6, LigPlot+, and Pymol., Results: The study found that the higher levels of LDHA gene expression were associated with poor prognosis and overall survival in lung cancer patients. We identified 11 key genes co-expressed with LDHA; out of them, two genes, MKI67 and PGK1, showed a strong positive correlation with LDHA and associated poor survival outcomes in LUAD patients. Furthermore, we also identified hsa-let-7c-5p and TMPO-AS1 as potential regulators of LDHA in LUAD. It might be possible that the TMPO-AS1- hsa-let-7c-5p-LDHA ceRNA network could serve as a potential regulator of aerobic glycolysis in LUAD and can serve as prognostic biomarkers. Further, Withanolides can inhibit the activity of LDHA and can be tested as an adjuvant treatment., Conclusion: We conclude that LDHA is overexpressed in LUAD, and the patients with high expression of LDHA exhibit poor prognosis. Further, the TMPO-AS1-hsa-let-7c-5p-LDHA ceRNA network can regulate aerobic glycolysis, thereby facilitating tumor growth in lung cancer.

Objective: Disulfidptosis was stimulated in high SLC7A11 expression cells starving to glucose. We attempted to identify disulfidptosis-related lncRNAs (DRLs), built a prognostic model to predict survival, and analyzed the tumor microenvironment., Methods: The TCGA database was utilized to procure the pertinent data. By utilizing both Cox regression and the least absolute shrinkage and selection operator (LASSO) method, a risk model based on DRLs was formulated for prognostic evaluation. The ability of survival prediction was validated by multiple approaches. The biological functions were screened through GO, KEGG, and GSEA. Various methods were employed to evaluate the tumor immune environment, which included ESTIMATE, tumor mutation burden (TMB) score, CIBERSORT algorithm, and tumor immune dysfunction and exclusion (TIDE) score., Results: Ninety-one DRLs were recognized, and lncRNA AC092718.4, AL365181.2, AL606489.1, EMSLR, and ENTPD3-AS1 were involved in the risk model. The GEO database was used to verify the influence of these lncRNAs on survival. The following analyses showed that survival could be predicted excellently by the DRLs risk model. The results of enrichment analyses pointed toward the involvement of the cell cycle and IgA production pathways. In the low-risk patient group, there was a notable surge in stromal, immune, and ESTIMATE scores, while the TMB scores took a tumble. Conversely, the high-risk patient group displayed a converse trend. Notably, the group of patients with lower risk scores and higher TMB scores showed the most favorable survival outcomes, underscoring the importance of considering both risk score and TMB in predicting the response to immune checkpoint blockade therapy. Furthermore, patients classified as high-risk might display resistance to both chemotherapy and targeted therapy. Cellular biological experiments proved that lncRNA AC092718.4 promoted invasion, migration, and proliferation abilities in vitro. These results provided valuable insights into the role of DRLs in LUAD and presented a possible effective treatment approach for LUAD., Conclusions: We developed a disulfidptosis-related risk model with 5 lncRNAs that enables survival prediciton for LUAD patients and aids cilinical decisions by forecasting the TME, TMB, and drug sensitivity, making it a valuable tool for outcomes prediction., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The role of solute carrier family 35 member F3 (SLC35F3) in lung adenocarcinoma (LUAD) remains unclear. To address this gap, we conducted a study employing bioinformatics analysis and experimental validation., Methods: This study aimed to examine the expression patterns of SLC35F3 in various cancer types, particularly focusing on LUAD, by analyzing data from the Cancer Genome Atlas (TCGA) database to evaluate its clinical relevance. The research also explored potential regulatory mechanisms of SLC35F3, including its interactions with immune infiltration, tumor mutational burden (TMB), and drug sensitivity in LUAD. The investigation included analyzing SLC35F3 expression in single-cell sequencing of LUAD cells, examining genetic variations of SLC35F3 in LUAD, and assessing SLC35F3 expression in cell lines using quantitative real-time PCR (qRT-PCR)., Results: The aberrant expression of SLC35F3 was observed in both pan-cancer and LUAD. In LUAD patients, a statistically significant increase in SLC35F3 expression was correlated with gender (p < 0.001) and was associated with poorer overall survival (OS) (p = 0.020). The expression of SLC35F3 was identified as an independent prognostic determinant in patients with LUAD (p = 0.032). SLC35F3 exhibited associations with various pathways, including cell cycle and more. SLC35F3 expression demonstrated correlations with immune infiltration, TMB, and some drugs in LUAD. Results indicated significant upregulation of SLC35F3 in both LUAD tissues and cell lines., Conclusions: SLC35F3 may serve as a prognostic biomarker and immunotherapeutic target for patients with LUAD., Clinical Trial Registration: Not applicable., (© 2024 The Author(s). The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Background: Lung cancer, on a global scale, leads to the most common cases of cancer mortalities. Novel therapeutic approaches are urgently needed to disrupt this lethal disease. The rapid development of tumor immunology combining breakthroughs involving fatty acid metabolism brings possibilities. Directing fatty acid metabolism is supposed to help discover potential prognostic biomarkers and treatment targets for lung cancer., Methods: Through searching the GSE140797 dataset, we identified genes related to fatty acid metabolism as well as fatty acid metabolism-related differentially expressed genes (DEGs). We applied various methods to ascertain the independent prognostic value of the DEGs. The methods we utilized entail prognostic analysis, differential expression analysis, as well as univariate and multivariate Cox regression analyses. The lasso Cox regression model was utilized in examining how DEGs correlate with the immune score, immune checkpoint, ferroptosis, methylation, and OCLR score. The expression levels of ACAT1 and ACSL3 in tissues derived from normal lung and lung adenocarcinoma (LUAD) tissues were compared by qRT-PCR., Results: In this study, ACSL3 and ACAT1 were identified as fatty acid metabolism-related genes utilizing independent prognostic value and as a result, the risk prognostic model was built using these factors. qRT-PCR results implied that ACSL3 and ACAT1 expressions were upregulated and downregulated, correspondingly in tumor tissues. Additional evaluations suggested that ACSL3 and ACAT1 were affirmed to be remarkably correlated with the immune score, methylation, immune checkpoint, OCLR score, and ferroptosis., Conclusions: ACSL3 and ACAT1 were effective prognostic biomarkers and potential immunotherapeutic targets in LUAD., (© 2024 The Author(s). The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Various forms of programmed cell death (PCD) collectively regulate the occurrence, development and metastasis of tumors. Nevertheless, a comprehensive analysis of the diverse types of PCD in lung adenocarcinoma (LUAD) is currently lacking. The study encompassed a total of 1481 genes associated with the regulation of 13 distinct PCD patterns. Ten machine learning algorithms were amalgamated into 101 combinations, from which the optimal algorithm was chosen to formulate an artificial intelligence-derived prognostic signature based on the average C-index across four multicenter cohorts. The established optimal cell death index (CDI) model emerged as an independent risk factor for overall survival, demonstrating robust and consistent performance. Notably, CDI exhibited significantly higher accuracy compared to traditional clinical variables and molecular features. It exhibited superior performance than other published models. By integrating CDI with relevant clinical features, a nomogram with excellent predictive performance was developed. LUAD patients with low CDI score had a higher immune modulators, TIDE scores and immune scores, indicating a better immunotherapy benefit. More importantly, we found that the regulation of antigen presentation is the crucial mechanism of PCD. SCG2 is a key molecule that inhibits the malignant progression of LUAD. CDI holds great potential as a robust and promising tool for enhancing clinical outcomes in patients with LUAD., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: This study evaluates the prognostic impact of the new grading system for lung adenocarcinoma, stratified by lymphadenectomy extent., Materials and Methods: We analyzed 1258 lung adenocarcinoma patients who underwent curative resections between 2006 and 2017. We analyzed overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) across tumor grades and lymphadenectomy extent, categorized as IASLC-R0 (complete resection) or R(un) (uncertain resection)., Results: The median age of cohort was 63 and 41.9 % were male. The majority had undergone lobectomy. The distribution of tumors was 274 grade 1, 558 grade 2, and 426 grade 3 cases. After a median follow-up time of 102 months, the 10-year OS/CSS/RFS rates worsened significantly across grade 1-3: 92.4/99.3/92.3 %, 77.8/87.5/71.7 %, and 63.6/70.2/52.0 %, respectively (p < 0.001). Multivariate Cox regression analysis identified grade 3, R(un) lymphadenectomy, higher Charlson Comorbidity Index, smoking history, thoracotomy, higher pathology stage, and angiolymphatic invasion as independent prognostic factors for lower OS, CSS, and RFS. Furthermore, grade 3 patients benefited significantly from IASLC-R0 lymphadenectomy, showing significantly better OS and RFS than those who underwent R(un) lymphadenectomy (p = 0.007 for OS, p = 0.001 for RFS, post-propensity score matching). Among grade 3 tumors underwent R0 or R(un) resections found the incidence rates of local, distant, and simultaneous local and distant recurrence were 8.5 % vs 13.7 %, 11.0 % vs 12.2 %, and 11.0 % vs 20.6 %, respectively., Conclusion: Surgical outcomes for lung adenocarcinoma have declined across grades 1-3. IASLC-R(un) treatment worsens OS and RFS in grade 3. Intensive monitoring and adjuvant therapy should be considered when patients with grade 3 lung adenocarcinoma undergo R(un) lymphadenectomy., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Lepidic-type adenocarcinomas (LPAs) can be multifocal, and treatment is often deferred until growth is observed. This study investigated the potential downside of that strategy by evaluating the relationship of nodal involvement with tumor size and survival., Methods: The impact of tumor size on lymph node involvement and survival was evaluated for National Cancer Database patients who underwent surgery without induction therapy as primary treatment for cT1-3 N0 M0 histologically confirmed LPA from 2006 to 2019 by using logistic regression, Kaplan-Meier, and Cox analyses., Results: Positive nodes occurred in 442 of 8286 patients (5.3%). The incidence of having positive nodes approximately doubled with each 1-cm increment increase in size. Patients with positive nodes were more likely to have larger tumors (27 mm vs 20 mm, P < .001) and clinical ≥T2 disease (40.7% vs 26.8%, P < .001) compared with node-negative patients. However, tumor size was the only significant independent predictor of having positive nodal disease in logistic regression analysis, and this association grew stronger with each incremental centimeter increase in size. Patients with positive nodes were more likely to undergo adjuvant radiotherapy (23.5% vs 1.1%, P < .001) and chemotherapy (72.9% vs 7.9%, P < .001), and expectedly, had worse survival compared with the node-negative group in univariate (5-year overall survival, 50.9% vs 81.1%, P < .001) and multivariable (hazard ratio, 2.56; 95% CI, 2.14-3.05; P < .001) analyses., Conclusions: Nodal involvement is relatively uncommon in early-stage LPAs but steadily increases with tumor size and is associated with dramatically worse survival. These data can be used to inform treatment decisions when evaluating LPA patients., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: We aimed to validate the prognostic implication of uncertain resection, R(un), proposed by International Association for the Study of Lung Cancer (IASLC) and evaluate the prognostic value of spread through air spaces (STAS) in reclassifying the R classification among patients with lung adenocarcinoma after segmentectomy., Methods: We enrolled 1007 patients who underwent segmentectomy for c-stage IA lung adenocarcinoma between 2014 and 2017. Recurrence-free survival (RFS) and overall survival (OS) were compared to evaluate the prognostic value of IASLC-R(un) and STAS. Whether STAS would skip into complementary lobectomy was evaluated in a prospective cohort., Results: The current IASLC-R(un) failed to significantly stratify the RFS (P = .078) in segmentectomy, and STAS was a stronger risk factor of poor prognosis for both RFS and OS (P < .001). Moreover, the presence of STAS was associated with increased locoregional recurrence in patients undergoing segmentectomy (P < .001) but not in those treated with lobectomy (P = .187), indicating that only STAS-positive segmentectomy was consistent with the concept of R(un) in relapse pattern. After reclassifying STAS-positive segmentectomy into the R(un) category, the proposed R(un) showed an improvement in prognosis stratification. In addition, 2 of 30 patients (6.2%) in the prospective cohort who underwent initial segmentectomy and complementary lobectomy had STAS clusters in the complementary lobectomy specimens., Conclusions: Unfavorable prognosis, relapse patterns consistent with R(un), and pathologic verification that saltatory spread of STAS observed in complementary lobectomy specimens supported reclassifying STAS-positive segmentectomy as R(un). STAS is a critical concern for the surgical completeness evaluation after segmentectomy., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Despite advances in science and technology, lung cancer remains a major public health issue. The discovery of early diagnostic and prognostic markers is still needed to reduce the mortality rate of lung cancer, which is the highest among all cancer types. Aberrations in the DNA methylation system have an important role in human cancer and are promising for the development of early diagnostic and prognostic markers. The present study focused on zinc finger protein (ZNF)577, whose encoding gene was indicated to exhibit promoter hypermethylation together with 9 other genes in lung adenocarcinoma (LADC) in a previous study by our group. ZN577 is a member of the ZNG family and its functional role has so far remained elusive. LADC tissue samples surgically resected at Tokushima University Hospital (Tokushima, Japan) between April 1999 and November 2013 were collected. A total of 73 tumors and 27 paired tumor-adjacent normal tissues were examined for DNA methylation and mRNA expression of ZNF577. A total of 149 LADC tissue samples were collected and evaluated by immunohistochemistry (IHC) for the tissue expression of ZNF577. High methylation (n=27, P<0.0001) and low mRNA expression levels (n=27, P<0.031) of ZNF577 were identified in LADC tissues, and it was demonstrated that methylation levels were inversely correlated with mRNA expression levels (P=0.0116, ρ=-0.2515). Among the LADC tissues, lepidic-patterned samples had lower methylation levels of ZNF577 than other pathological types. In addition, mRNA expression levels of ZNF577 were significantly higher in females, non-smokers and stage I samples. Overall survival [P<0.0001; area under curve (AUC)=0.8658] and disease-free survival (DFS; P<0.0004; AUC=0.7232) rates were significantly higher in the ZNF577 high mRNA expression group than in the ZNF577 low mRNA expression group. Among the 149 LADC samples examined by IHC, 105 were negative and 44 were positive for the tissue expression of ZNF577. Cox regression analysis showed poorer DFS (hazard ratio: 3.917; P=0.023) in patients with lower expression of ZNF577. In conclusion, higher methylation levels of ZNF577 were observed in LADC tissues than in normal lung tissue and low mRNA expression of ZNF577 was associated with unfavorable prognosis.

Lung cancer is a major cause accounting for cancer-related mortalities, with lung adenocarcinoma (LUAD) being the most prevalent subtype. Given the high clinical and cellular heterogeneities of LUAD, accurate diagnosis and prognosis are crucial to avoid overdiagnosis and overtreatment. Taking full advantage of scRNA-Seq data to resolve the tumor heterogeneities, we explored the overall landscape of LUAD microenvironment. Utilizing the stage-specific tumor cell markers, we have developed highly accurate diagnostic and prognostic models with elevated sensitivity and specificity. The diagnostic model, developed through random forest algorithms with a thirteen-gene signature, achieved an accuracy of 96.4% and an AUC of 0.993. These metrics were further demonstrated by benchmarking with available models and scoring systems in independent cohorts. Concurrently, the prognostic model, formulated via Cox regression with a six-gene signature, effectively predicted overall survival, with elevated risk scores associated with increased fractions of cancer-associated fibroblasts, and higher likelihood of immune escape and T-cell exclusion. Subsequently, two nomograms were developed to predict survival and drug responses, facilitating their integration into clinical practice. Overall, this study underscores the potential of our models for efficient, rapid, and cost-effective diagnosis and prognosis of LUAD, adaptable to multiple expression profiling platforms and quantification methods., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Sublobar resection offers noninferior survival vs lobectomy for ≤2 cm non-small cell lung cancer and is commonly used for subsolid tumors. Although data exist for solid tumors, the minimum adequate margin of resection for subsolid adenocarcinomas remains unclear., Methods: This was a retrospective review of 1101 adenocarcinoma resections at our institution from 2006 to 2022. Inclusion criteria were tumors ≤3 cm with ≥10% radiographic ground glass, excised by sublobar resection. Exclusions were positive nodes or positive or unreported margin. The primary outcome was the rate of local recurrence (LR) at multiple thresholds of margin distance. The relationship between margin distance and solid component size was also explored., Results: Inclusion criteria were met by 194 patients. Median (interquartile range) tumor diameter and margin distance were 12 mm (9-17 mm) and 10 mm (5-17 mm), respectively. Median follow-up was 42.5 months. There was a progressive increase in LR with diminishing margin (0.1-cm decrements) from 1.5 cm to 0.5 cm. The difference in the rate of LR between "over" (n = 143) and "under" (n = 51) was most significant at 0.5 cm (8 of 51 [15.7%] vs 6 of 143 [4.2%]; P = .01) but did not reach α adjusted for multiple comparisons. On Cox regression for LR-free survival, margin ≤0.5 cm (P = .19) and solid component percentage (P = .14) trended to significance. Combining these using a ratio of margin distance-to-solid component size, a ratio of ≤1 showed a significantly higher rate of LR (7 [14.3%] vs 2 [2.0%], P = .009). Treatment of LRs provided at least intermediate-term survival in 87% of recurrences (median postrecurrence follow-up was 44 months)., Conclusions: During sublobar resection of subsolid lung adenocarcinomas, a margin distance-to-solid component size ratio of >1.0 appears to be a more reliable factor than margin distance alone to minimize local recurrence. Local recurrence, however, may not impact survival in patients with subsolid adenocarcinomas if timely treatment is administered., Competing Interests: Disclosures Joseph Shrager reports a relationship with Merck & Co Inc that includes: consulting or advisory; with Becton Dickinson and Company that includes: consulting or advisory; and with Varian Medical Systems Inc that includes: funding grants. Leah Backhus reports a relationship with Johnson and Johnson that includes: consulting or advisory; with Bristol-Myers Squibb Co that includes: consulting or advisory; with AstraZeneca that includes: consulting or advisory; and with Genentech that includes: consulting or advisory. Natalie Lui reports a relationship with Intuitive Surgical Inc that includes: consulting or advisory and with Centese that includes: consulting or advisory. The other authors have no conflicts of interest to disclose., (Published by Elsevier Inc.)

Objectives: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer. Understanding the molecular mechanisms underlying tumor progression is of great clinical significance. This study aims to identify novel molecular markers associated with LUAD subtypes, with the goal of improving the precision of LUAD subtype classification. Additionally, optimization efforts are directed towards enhancing insights from the perspective of patient survival analysis., Materials and Methods: We propose an innovative feature-selection approach that focuses on LUAD classification, which is comprehensive and robust. The proposed method integrates multi-omics data from The Cancer Genome Atlas (TCGA) and leverages a synergistic combination of max-relevance and min-redundancy, least absolute shrinkage and selection operator, and Boruta algorithms. These selected features were deployed in six machine-learning classifiers: logistic regression, random forest, support vector machine, naive Bayes, k-Nearest Neighbor, and XGBoost., Results: The proposed approach achieved an area under the receiver operating characteristic curve (AUC) of 0.9958 for LR. Notably, the accuracy and AUC of a composite model incorporating copy number, methylation, as well as RNA- sequencing data for expression of exons, genes, and miRNA mature strands surpassed the accuracy and AUC metrics of models with single-omics data or other multi-omics combinations. Survival analyses, revealed the SVM classifier to elicit optimal classification, outperforming that achieved by TCGA. To enhance model interpretability, SHapley Additive exPlanations (SHAP) values were utilized to elucidate the impact of each feature on the predictions. Gene Ontology (GO) enrichment analysis identified significant biological processes, molecular functions, and cellular components associated with LUAD subtypes., Conclusion: In summary, our feature selection process, based on TCGA multi-omics data and combined with multiple machine learning classifiers, proficiently identifies molecular subtypes of lung adenocarcinoma and their corresponding significant genes. Our method could enhance the early detection and diagnosis of LUAD, expedite the development of targeted therapies and, ultimately, lengthen patient survival., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled “Subclassification of Lung Adenocarcinoma through Comprehensive Multi-omics Data to Benefit Survival Outcomes”., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Lung cancer remains a leading cause of global cancer‑related deaths, therefore the identification of prognostic factors for lung cancer is critical. Casein kinase 2 alpha (CK2α) is one of the driver kinases in various cancers, and it was previously demonstrated that CK2α localization was associated with a poor prognosis in invasive breast cancer. In the present study, the importance of CK2α in the nucleolus was explored as a potential prognostic marker for surgically resected early‑stage lung adenocarcinoma. The present study included 118 patients who underwent pulmonary lobectomy between 2014 and 2018 in Fukushima Medical University Hospital (Fukushima, Japan), and in whom CK2α localization in tumor samples was assessed by immunohistochemistry. Patient and tumor characteristics, including pathological stage, histological type and histological grade, were analyzed. Recurrence‑free survival (RFS) and overall survival were evaluated in relation to nucleolar CK2α staining. CK2α staining in the nucleoli was observed in 50.8% of lung adenocarcinoma tumors. Positive nucleolar CK2α staining was independent of pathological stage, histological type and histological grade. Patients with positive nucleolar CK2α staining exhibited significantly worse RFS compared with patients with negative staining. Multivariate analysis identified nucleolar CK2α staining and lymph node metastasis as independent poor prognostic factors. The results of the present study suggested that nucleolar CK2α staining is a novel and independent prognostic factor in surgically resected early‑stage lung adenocarcinoma. These findings indicated the potential of nucleolar CK2α as a predictive biomarker for future recurrence, and a guide to treatment decisions. Further research is required, particularly in understanding the molecular mechanisms linking nucleolar CK2α to recurrence.

Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), subtypes of non-small cell lung cancer (NSCLC), exhibit distinct characteristics. The expression and prognostic significance of Protocadherin Gamma Subfamily A, 12 (PCDHGA12) in NSCLC remain unexplored. This study analyzed transcriptomic and genomic datasets from TCGA to investigate PCDHGA12 expression and its prognostic relevance in LUAD and LUSC. We found PCDHGA12 mRNA and protein levels were downregulated in both LUAD and LUSC tissues compared to adjacent non-cancerous tissues, with high PCDHGA12 expression correlating with lower overall survival in LUSC but not in LUAD. GSEA revealed a unique enrichment pattern associated with PCDHGA12 low expression in LUSC, especially in the DNA repair pathway. Co-expression analysis showed associations of PCDHGA12 with focal adhesion and the PI3K-AKT pathway in LUAD, and additionally with ECM-receptor interaction in LUSC. Hub gene prognosis analysis identified genes correlated with prognosis only in LUSC, reflecting PCDHGA12's influence. Mutation analysis linked with PCDHGA12 identified differential mutations in SPTA1, KEAP1, and TNR in LUAD, and a notable NAV3 mutation in LUSC. Additionally, immuno-infiltration analysis reveals a positive correlation between PCDHGA12 expression and immune cell infiltration. Specifically, lower PCDHGA12 expression in LUSC is associated with higher levels of CD8 T cells and DCs, lower levels of Tregs and M0 macrophages, and increased expression of HMGB1 and TNFRSF18. These genetic and immunological differences may account for the significant prognostic disparity of PCDHGA12 levels between LUAD and LUSC. Further experimental studies are essential to validate these associations and investigate potential targeted and immunotherapeutic strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The prognosis of poorly differentiated lung adenocarcinoma (PDLA) is determined by many clinicopathological factors. The aim of this study is identifying prognostic factors and developing reliable nomogram to predict the overall survival (OS) and cancer-specific survival (CSS) in patients with PDLA. Patient data from the Surveillance, Epidemiology and End Results (SEER) database was collected and analyzed. The SEER database was used to screen 1059 eligible patients as the study cohort. The whole cohort was randomly divided into a training cohort (n = 530) and a test cohort (n = 529). Cox proportional hazards analysis was used to identify variables and construct a nomogram based on the training cohort. C-index and calibration curves were performed to evaluate the performance of the model in the training cohort and test cohorts. For patients with PDLA, age at diagnosis, gender, tumor size were independent prognostic factors both for overall survival (OS) and cancer-specific survival (CSS), while race and number of nodes were specifically related to OS. The calibration curves presented excellent consistency between the actual and nomogram-predict survival probabilities in the training and test cohorts. The C-index values of the nomogram were 0.700 and 0.730 for OS and CSS, respectively. The novel nomogram provides new insights of the risk of each prognostic factor and can assist doctors in predicting the 1-year, 3-year and 5-year OS and CSS in patients with PDLA., (© 2024. The Author(s).)

The extracellular matrix (ECM) is a complex and dynamic network of cross-linked proteins and a fundamental building block in multicellular organisms. Our study investigates the impact of genes related to the ECM receptor interaction pathway on immune-targeted therapy and lung adenocarcinoma (LUAD) prognosis. This study obtained LUAD chip data (GSE68465, GSE31210, and GSE116959) from NCBI GEO. Moreover, the gene data associated with the ECM receptor interaction pathway was downloaded from the Molecular Signature Database. Differentially expressed genes were identified using GEO2R, followed by analyzing their correlation with immune cell infiltration. Univariate Cox regression analysis screened out ECM-related genes significantly related to the survival prognosis of LUAD patients. Additionally, Lasso regression and multivariate Cox regression analysis helped construct a prognostic model. Patients were stratified by risk score and survival analyses. The prognostic models were evaluated using receiver operating characteristic curves, and risk scores and prognosis associations were analyzed using univariate and multivariate Cox regression analyses. A core gene was selected for gene set enrichment analysis and CIBERSORT analysis to determine its function and tumor-infiltrating immune cell proportion, respectively. The results revealed that the most abundant pathways among differentially expressed genes in LUAD primarily involved the cell cycle, ECM receptor interaction, protein digestion and absorption, p53 signaling pathway, complement and coagulation cascade, and tyrosine metabolism. Two ECM-associated subtypes were identified by consensus clustering. Besides, an ECM-related prognostic model was validated to predict LUAD survival, and it was associated with the tumor immune microenvironment. Additional cross-analysis screened laminin subunit beta 1 (LAMB1) for further research. The survival time of LUAD patients with elevated LAMB1 expression was longer than those with low LAMB1 expression. Gene set enrichment analysis and CIBERSORT analyses revealed that LAMB1 expression correlated with tumor immune microenvironment. In conclusion, a prognostic model of LUAD patients depending on the ECM receptor interaction pathway was constructed. Screening out LAMB1 can become a prognostic risk factor for LUAD patients or a potential target during LUAD treatment., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

In addition to considering the main effects, understanding gene-environment (G × E) interactions is imperative for determining the etiology of diseases and the factors that affect their prognosis. In the existing statistical framework for censored survival outcomes, there are several challenges in detecting G × E interactions, such as handling high-dimensional omics data, diverse environmental factors, and algorithmic complications in survival analysis. The effect heredity principle has widely been used in studies involving interaction identification because it incorporates the dependence of the main and interaction effects. However, Bayesian survival models that incorporate the assumption of this principle have not been developed. Therefore, we propose Bayesian heredity-constrained accelerated failure time (BHAFT) models for identifying main and interaction (M-I) effects with novel spike-and-slab or regularized horseshoe priors to incorporate the assumption of effect heredity principle. The R package rstan was used to fit the proposed models. Extensive simulations demonstrated that BHAFT models had outperformed other existing models in terms of signal identification, coefficient estimation, and prognosis prediction. Biologically plausible G × E interactions associated with the prognosis of lung adenocarcinoma were identified using our proposed model. Notably, BHAFT models incorporating the effect heredity principle could identify both main and interaction effects, which are highly useful in exploring G × E interactions in high-dimensional survival analysis. The code and data used in our paper are available at https://github.com/SunNa-bayesian/BHAFT., (© 2024 John Wiley & Sons Ltd.)

Lung adenocarcinoma (LUAD), characterized by a low 5-year survival rate, is the most common and aggressive type of lung cancer. Recent studies have shown that tertiary lymphoid structures (TLS), which resemble lymphoid structures, are closely linked to the immune response and tumor prognosis. The functions of the tertiary lymphoid structure-related genes (TLS-RGs) in the tumor microenvironment (TME) are poorly understood. Based on publicly available data, we conducted a comprehensive study of the function of TLS-RGs in LUAD. Initially, we categorized LUAD patients into two TLS and two gene subtypes. Subsequently, risk scores were calculated, and prognostic models were constructed using seven genes (CIITA, FCRL2, GBP1, BIRC3, SCGB1A1, CLDN18, and S100P). To enhance the clinical application of TLS scores, we have developed a precise nomogram. Furthermore, drug sensitivity, tumor mutational burden (TMB), and the cancer stem cell (CSC) index were found to be substantially correlated with the TLS scores. Single-cell sequencing results reflected the distribution of TLS-RGs in cells. Finally, we took the intersection of overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) prognosis-related genes and then further validated the expression of these genes by qRT-PCR. Our in-depth investigation of TLS-RGs in LUAD revealed their possible contributions to the clinicopathological features, prognosis, and characteristics of TME. These findings underscore the potential of TLS-RGs as prognostic biomarkers and therapeutic targets for LUAD, thereby paving the way for personalized treatment strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wu, Pan, Pan, Zeng, Liang and Li.)

Lung cancer remains the leading cause of cancer-related death worldwide, and drug resistance represents the main obstacle responsible for the poor mortality and prognosis. Here, to identify a novel gene signature for predicting survival and drug response, we jointly investigated RNA sequencing data of lung adenocarcinoma patients from TCGA and GEO databases, and identified a ferroptosis-related gene signature. The signature was validated in the validation set and two external cohorts. The high-risk group had a reduced survival than the low-risk group ( P < 0.05). Moreover, the established gene signature was associated with tumor mutation burden, microsatellite instability, and response to immune checkpoint blockade. In addition, four candidate oncogenes ( RRM2 , SLC2A1 , DDIT4 , and VDAC2 ) were identified to be candidate oncogenes using in silico and wet experiments, which could serve as potential therapeutic targets. Collectively, this study developed a novel ferroptosis-related gene signature for predicting prognosis and drug response, and identified four candidate oncogenes for lung adenocarcinoma.