Prognosis Of Non-small Cell Lung Cancer Research Articles

PP4R1 accelerates the malignant progression of NSCLC via up-regulating HSPA6 expression and HSPA6-mediated ER stress

Protein phosphatase 4 (PP4) plays an indispensable regulatory part in the development and malignant progression of multifarious tumors. Nevertheless, the function of protein phosphatase 4 regulatory subunit 1 (PP4R1), a vital regulatory subunit of PP4, in tumors especially in lung cancer remains blurred. Therefore, this study aimed to investigate the function and mechanism of PP4R1 in the development of non-small cell lung cancer (NSCLC). We analyzed the clinical correlation of PP4R1 based on the TCGA database by UALCAN (https://ualcan.path.uab.edu/index.html) and found that hyper-expression of PP4R1 mRNA was related to the severe prognosis in NSCLC. The subsequent cellular experiments confirmed that the proliferation, colony growth, migration as well as invasion of H1299 and HCC827 were significantly enhanced after PP4R1 overexpression treatment in vitro. Results from animal experiments pointed out that tumors exhibited stronger growth and lung metastatic capacities due to the overexpression of PP4R1. The bioinformatics analysis, including RNA-seq, showed us that PP4R1 significantly promoted the expression of several HSP70 family member genes, with a particularly marked increase in HSPA6, and the enrichment analyses illustrated that the differentially expressed genes (DEGs) were enriched in those pathways related to protein folding. More importantly, the overexpression of HSPA6 resulted in the same malignant progression of NSCLC as PP4R1 overexpression, and both concomitant with the activation of endoplasmic reticulum (ER) stress. In aggregate, PP4R1 contributed to the malignant progression of NSCLC via up-regulating HSPA6 expression and then activating ER stress.

Comparative analysis of methodologies for predicting overall survival in patients with non-small cell lung cancer based on the number and rate of resected positive lymph nodes: A study based on the SEER database for 2010 through 2019.

Lymph node (LN) metastasis is crucial in non-small cell lung cancer (NSCLC) prognosis and treatment, but the TNM system lacks LN quantity consideration. Our goal is to investigate the role of positive LNs (nPLN) and positive LN rate (LNR) in overall survival (OS) and assess whether they offer higher value in prognostic assessment of NSCLC than N-stage. Patients were stratified into four subgroups using X-Tile software. Statistical analysis was conducted using the Kaplan-Meier method, univariate analysis, and multivariate Cox regression analysis. Model performance was evaluated using the Harrell consistency index (C-index), Akaike information criterion (AIC), and Bayesian information criterion (BIC). The prognostic performance of the nodal classification was validated using overall survival as the endpoint. The survival curves demonstrate distinct disparities between each nPLN and LNR category. A pronounced trend toward deteriorating overall survival from N-PLN 1 to N-PLN 2+ was observed across all tumor size categories. However, the differences between each LNR category were only significant for tumors ≤3cm and 5-7cm. Notably, both nPLN and LNR classifications displayed a higher C-index, lower AIC, and lower BIC compared with the N staging. Furthermore, the LNR classification provided superior prognostic stratification when compared with the nPLN classification. Our results demonstrate that nPLN and LNR classifications may offer improved prognostic performance compared with the current N classification for LN-positive NSCLC patients. Nonetheless, more studies are needed to assess the feasibility of incorporating these classifications into the next TNM staging system.

Relationship between plasma circulating cell-free DNA concentration and treatment outcomes including prognosis in patients with advanced non-small cell lung cancer

BackgroundSome research found that elevated plasma cell-free DNA (cfDNA) concentrations and poor prognosis are associated in non-small cell lung cancer (NSCLC). However, more studies need to be carried out to verify this conclusion. Therefore, this study investigated the relationship between cfDNA concentration and treatment outcomes including prognosis in patients with advanced NSCLC.MethodsWe retrospectively collected medical records and cfDNA data from 160 patients with advanced NSCLC. Progression-free survival (PFS) were calculated using the Kaplan-Meier method and were compared between groups using the log rank test. Cox regression analysis was used for estimating the independent predictors of PFS. And we used logistic regression to evaluate the relationship between baseline biomarkers and efficacy. In our study, BT1 cfDNA, BT2 cfDNA, and BT3 cfDNA were defined as cfDNA concentration before the first treatment (baseline cfDNA concentration), cfDNA concentration before the second treatment, and cfDNA concentration before the third treatment, respectively.ResultsPatients with low cfDNA (BT1 cfDNA < 15 (ng/mL)) were reported a significantly prolonged median progression-free survival (mPFS) compared with patients with patients with high cfDNA (BT1 cfDNA ≥ 15(ng/mL)) (mPFS: 14.6 vs. 8.3 months, P = 0.002), as well as patients with neutrophil/lymphocyte ratio (NLR)<2.98 (mPFS: 13.1 vs. 7.9 months, P = 0.023). In addition, Cox proportional hazards regression analysis identified independent indicators associated with PFS including BT1 cfDNA ≥ 15 (ng/mL), NLR ≥ 2.98 and extrapulmonary metastasis. The best cut-off value for BT3 cfDNA for predicting disease progression is 41.46 (ng/mL) (Area Under the Curve (AUC): 0.652, 95%CI: 0.516–0.788), achieving 90.7% sensitivity and 37.5% specificity for the prediction of disease progression. BT3 cfDNA (OR = 6.08, 95% CI: 1.94–19.57, P = 0.002) was an independent factor for disease progression in patients with advanced NSCLC.ConclusionsBT1 cfDNA may be a biomarker to assess the prognosis of advanced NSCLC. Patients with advanced NSCLC with lower cfDNA and NLR before treatment had a better prognosis. Increased BT3 cfDNA concentration was an independent factor of disease progression in advanced NSCLC patients. These findings may assist in identifying high-risk patients and guiding treatment strategies.

A Review of Biomarkers and Their Clinical Impact in Resected Early-Stage Non-Small-Cell Lung Cancer.

The postoperative survival of early-stage non-small-cell lung cancer (NSCLC) patients remains unsatisfactory. In this review, we examined the relevant literature to ascertain the prognostic effect of related indicators on early-stage NSCLC. The prognostic effects of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), mesenchymal-epithelial transition (MET), C-ros oncogene 1 (ROS1), or tumour protein p53 (TP53) alterations in resected NSCLC remains debatable. Kirsten rat sarcoma viral oncogene homologue (KRAS) alterations indicate unfavourable outcomes in early-stage NSCLC. Meanwhile, adjuvant or neoadjuvant EGFR-targeted agents can substantially improve prognosis in early-stage NSCLC with EGFR alterations. Based on the summary of current studies, resected NSCLC patients with overexpression of programmed death-ligand 1 (PD-L1) had worsening survival. Conversely, PD-L1 or PD-1 inhibitors can substantially improve patient survival. Considering blood biomarkers, perioperative peripheral venous circulating tumour cells (CTCs) and pulmonary venous CTCs predicted unfavourable prognoses and led to distant metastases. Similarly, patients with detectable perioperative circulating tumour DNA (ctDNA) also had reduced survival. Moreover, patients with perioperatively elevated carcinoembryonic antigen (CEA) in the circulation predicted significantly worse survival outcomes. In the future, we will incorporate mutated genes, immune checkpoints, and blood-based biomarkers by applying artificial intelligence (AI) to construct prognostic models that predict patient survival accurately and guide individualised treatment.

The Incidence and Effect of Different Organ Metastasis on the Prognosis of NSCLC.

The aim of this study was to explore the effect of different organ metastasis on the prognosis of non-small cell lung cancer (NSCLC). Patients with distant metastatic NSCLC were selected from Surveillance, Epidemiology, and End Results database during 2016 to 2019. The incidence of different organ metastasis and their association with clinicopathological factors were explored. Overall survival (OS) and lung cancer-specific survival (LCSS) for metastatic NSCLC were calculated, and multivariate Cox regression analysis was performed with a nomogram for OS being constructed based on Cox regression. Total 26,210 patients with distant metastatic NSCLC were included in this study. Around 48.9% of the metastatic NSCLC were multiple-organ metastasis and bone was the most commonly involved organ (44.4%). For patients with single-organ metastasis, the prognosis for lung or distant lymph nodes (LNs) metastasis was better than others (with median OS of 15 and 16 months for lung and distant LNs metastasis, respectively), and liver metastasis resulted in the worst prognosis with median OS of 8 months. A nomogram was constructed to visualize Cox regression model, along with the receiver operating characteristic (ROC) curve demonstrated good discrimination for the predictive model with 1- and 2-year area under the curve of ROC of 0.687 and 0.702, respectively. The prognosis of NSCLC patients with distant metastasis was poor. Liver metastasis results in the worst prognosis among the single-organ metastasis. The nomogram developed based on the Cox regression model has provided a useful tool to estimate the probability of OS of the metastatic NSCLC.

The association of chest computed tomography-defined visual emphysema and prognosis in patients with nonsmall cell lung cancer.

Although computed tomography (CT)-defined emphysema is considered a predictor of lung cancer risk, it is not fully clear whether CT-defined emphysema is associated with the prognosis of lung cancer. We aimed to assess the clinical impact of CT-defined emphysema on the survival of lung cancer. In the prospective cohort study of nonsmall cell lung cancer (NSCLC), the correlation between CT-defined emphysema and clinical variables was analysed. A multivariable Cox regression model was built to assess the association between CT-defined emphysema and overall survival (OS) for up to 8.8 years. The differences in survival analyses were derived by Kaplan-Meier analysis and log-rank testing. Low attenuation area (LAA%) was defined as the per cent of voxels below -950 HU. 854 patients were included and CT-defined emphysema was present in 300 (35.1%) at diagnosis. Epidermal growth factor receptor (EGFR) wild-type (OR 1.998; p<0.001) and anaplastic lymphoma kinase (ALK) wild-type (OR 2.277; p=0.004) were associated with CT-defined emphysema. CT-defined emphysema remained a significant predictor of prognosis adjusting for age, sex, smoking history, tumour histology and Eastern Cooperative Oncology Group Performance Status (ECOG PS), whether in I-IIIA stage (adjusted hazard ratio (HR) 1.745; p=0.017) or in IIIB-IV stage (adjusted HR 1.291; p=0.022). Stratified analyses showed that OS rate among the driver oncogene groups with different CT-defined emphysema status differed significantly (log-rank p<0.001). Furthermore, patients with centrilobular emphysema (CLE) with LAA% >17% displayed poorer survival than those with LAA% ≤17% (median 432 versus 670 days; HR 1.564; p=0.020). CT-defined emphysema, especially CLE with LAA%>17%, is an independent predictor of NSCLC prognosis. Moreover, prospective studies are needed to further explore this association.

Drug-eluting beads bronchial arterial chemoembolization/bronchial arterial infusion chemotherapy with and without PD-1 blockade for advanced non-small cell lung cancer: a comparative single-center cohort study.

Drug-eluting beads bronchial arterial chemoembolization (DEB-BACE)/bronchial artery infusion chemotherapy (BAI) have been investigated as treatment options for advanced non-small cell lung cancer (NSCLC), especially for those patients who develop refractoriness to or are intolerant to systemic chemotherapy. This retrospective study aimed to compare the outcomes of DEB-BACE/BAI with and without programmed cell death protein 1 (PD-1) blockade for advanced NSCLC, and to investigate the effectiveness and safety of combination regimens. This retrospective cohort study included advanced NSCLC patients who were intolerant to or were resistant to systemic chemotherapy, radiotherapy, or molecular targeted therapy and underwent DEB-BACE/BAI between October 2016 and October 2021 in Beijing Hospital, National Center of Gerontology. A total of 84 advanced NSCLC patients (DEB-BACE/BAI + PD-1 blockade group: group A, n=27; DEB-BACE/BAI: group B, n=57) were enrolled finally. The embolic agent CalliSpheres (100-300, 300-500, or 500-700 µm) loaded with gemcitabine (800 mg) was administered during the DEB-BACE procedure. The adverse events (AEs) and outcomes were compared. Of these, the median progression-free survival (PFS) and overall survival (OS) were compared via Kaplan-Meier (KM) methods. Univariate and multivariate Cox regression analyses were used to investigate the predictors of PFS and OS. KM methods showed that group A had longer median PFS (12.0 vs. 3.0 months, P<0.001) and OS (27.0 vs. 8.0 months, P<0.001) than group B. The predictors of PFS for DEB-BACE/BAI included tumor diameter (P=0.013), immunotherapy (P<0.001), and DEB-BACE/BAI cycles (P=0.012), whereas the predictors of OS included tumor diameter (P=0.021), extrapulmonary metastases (P=0.041), immunotherapy (P<0.001), and DEB-BACE/BAI cycles (P=0.020). The incidence rates of overall AEs in groups A and B were 40.7% (11/27) and 36.8% (21/57), respectively, and no significant difference was found (P=0.731). Group A had an incidence rate of 11.1% for grade 3 immunotherapy-related AEs (irAEs). There were no incidences of ectopic embolization or spinal artery injury. Compared with DEB-BACE/BAI, PD-1 blockade plus DEB-BACE/BAI could improve the prognosis for advanced NSCLC despite the associated risk of grade 3 irAEs. The combination regimens are promising and safe approaches for advanced NSCLC.

Prognostic impact of soluble PD-L1 derived from tumor-associated macrophages in non-small-cell lung cancer.

Programmed cell death-ligand 1 (PD-L1) on tumor cells can be degraded to soluble form (sPD-L1) and enter circulation, however, the clinical significances of sPD-L1 in peripheral blood remains to be elucidated in non-small-cell lung cancer (NSCLC). We monitored plasma sPD-L1 levels during perioperative periods and evaluated PD-L1-positive cells in tumor tissues in patients with operable NSCLC. Then the correlation between preoperative plasma sPD-L1 levels and relapse-free survival (RFS) was analyzed retrospectively. In patients who underwent radical surgery (n = 61), plasma sPD-L1 levels (median; 63.5pg/mL) significantly increased 1month after surgery (72.2pg/mL, P < 0.001). The combined score of PD-L1-positive cells including tumor cells and tumor-associated macrophages (TAMs) was significantly associated with preoperative plasma sPD-L1 levels. In patients with high levels of preoperative plasma sPD-L1, the probability of 5-year RFS was significantly poor for patients with low PD-L1 expression intensity of tumor cells (tcPD-L1) compared with those with high tcPD-L1 (33.3% vs. 87.5%, respectively, P = 0.016; 95% CI, 0.013-0.964). In former group, PD-L1-positive TAMs were markedly infiltrating compared with those from latter group (246.4 vs. 76.6 counts/mm2, respectively, P = 0.003). In NSCLC, plasma sPD-L1 can reflect the accumulation of PD-L1-posotive TAMs, not just PD-L1-positive tumor cells. In patients with high levels of preoperative plasma sPD-L1, the prognoses after surgery depends on which PD-L1-positive cells, tumor cells or TAMs, are the primary source of the sPD-L1. Thus, measuring both plasma sPD-L1 levels and PD-L1 expression status of tumor cells and TAMs is of benefit for assessment of postoperative prognosis in operable NSCLC.

Tumor-associated macrophages mediate resistance of EGFR-TKIs in non-small cell lung cancer: mechanisms and prospects.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the first-line standard treatment for advanced non-small cell lung cancer (NSCLC) with EGFR mutation. However, resistance to EGFR-TKIs is inevitable. Currently, most studies on the mechanism of EGFR-TKIs resistance mainly focus on the spontaneous resistance phenotype of NSCLC cells. Studies have shown that the tumor microenvironment (TME) also mediates EGFR-TKIs resistance in NSCLC. Tumor-associated macrophages (TAMs), one of the central immune cells in the TME of NSCLC, play an essential role in mediating EGFR-TKIs resistance. This study aims to comprehensively review the current mechanisms underlying TAM-mediated resistance to EGFR-TKIs and discuss the potential efficacy of combining EGFR-TKIs with targeted TAMs therapy. Combining EGFR-TKIs with TAMs targeting may improve the prognosis of NSCLC with EGFR mutation to some extent.

Prognostic Factors for Survival of Stage IB Non-small Cell Lung Cancer Patients: A 10-Year Follow-Up Retrospective Study.

This study aimed to determine the prognostic factors for the long-term outcome of stage IB non-small cell lung cancer (NSCLC). Surgically resected patients with stage IB NSCLC diagnosed (based on TNM 8th edition) between April 2008 and December 2013 were retrospectively reviewed. The prognosis and possible risk factors among the stage IB NSCLC patients were evaluated. Of the 349 patients identified for the study, 80 (22.9%) received post-surgery adjuvant chemotherapy (ACT). The median follow-up time after surgery was 123.3 months. The 10-year overall survival (OS) rate was 69.6%, and the 10-year recurrence-free survival (RFS) rate was 62.8%. The patients in this cohort were divided into three groups (T1 with visceral pleural invasion [VPI], T2a without VPI, and T2a with VPI), and no significant differences in OS or RFS were found among the groups. Furthermore, survival analysis indicated that the absence of ground-glass opacity (GGO) components portends an adverse long-term OS and RFS. In a subgroup of patients with solid nodules, age older than 65 years (hazard ratio [HR] 1.987; 95% confidence interval [CI] 1.312-3.010; p = 0.001) and ACT (HR 0.392; 95% CI 0.225-0.684; p < 0.001) were independent prognostic factors for OS, whereas lymphovascular invasion (HR 1.792; 95% CI 0.995-3.227; p = 0.052) should be considered as an independent unfavorable prognostic factor for RFS. As an upstaging factor, VPI did not further stratify prognosis for the stage IB patients in our cohort. The presence of GGO components had a notable impact on a favorable prognosis in stage IB NSCLCs.

Radiomics-Clinical AI Model with Probability Weighted Strategy for Prognosis Prediction in Non-Small Cell Lung Cancer.

In this study, we propose a radiomics clinical probability-weighted model for the prediction of prognosis for non-small cell lung cancer (NSCLC). The model combines radiomics features extracted from radiotherapy (RT) planning images with clinical factors such as age, gender, histology, and tumor stage. CT images with radiotherapy structures of 422 NSCLC patients were retrieved from The Cancer Imaging Archive (TCIA). Radiomic features were extracted from gross tumor volumes (GTVs). Five machine learning algorithms, namely decision trees (DT), random forests (RF), extreme boost (EB), support vector machine (SVM) and generalized linear model (GLM) were optimized by a voted ensemble machine learning (VEML) model. A probabilistic weighted approach is used to incorporate the uncertainty associated with both radiomic and clinical features and to generate a probabilistic risk score for each patient. The performance of the model is evaluated using a receiver operating characteristic (ROC). The Radiomic model, clinical factor model, and combined radiomic clinical probability-weighted model demonstrated good performance in predicting NSCLC survival with AUC of 0.941, 0.856 and 0.949, respectively. The combined radiomics clinical probability-weighted enhanced model achieved significantly better performance than the radiomic model in 1-year survival prediction (chi-square test, p < 0.05). The proposed model has the potential to improve NSCLC prognosis and facilitate personalized treatment decisions.

Clinicopathological and prognostic significance of SMAD4 in non-small cell lung cancer: A meta-analysis and database validation.

The relationship between SMAD family member 4 (SMAD4) and the clinicopathological and prognostic significance of non-small cell lung cancer (NSCLC) patients is unclear. Our aim was to investigate the association between SMAD4 expression and clinicopathological parameters and NSCLC prognosis. We searched articles in databases from inception to July 2022 to retrieve literature related to SMAD4 expression and the clinicopathological and/or prognostic significance of NSCLC patients. Odds ratios (ORs), hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. We evaluated the expression of SMAD4 and overall survival (OS) in NSCLC using the Kaplan-Meier plotter database. Eight articles with 1461 NSCLC patients were included. SMAD4 expression was related to tumor differentiation (OR = 0.359, 95% CI: 0.238-0.543, P = .000), lymph node metastasis (OR = 0.469, 95% CI: 0.04-0.725, P = .001), tumor node metastasis stage (OR = 0.238, 95% CI: 0.156-0.362, P = .000) and good OS (HR = 0.592, 95% CI: 0.332-0.853, P = .000) in NSCLC. There was no significant association between SMAD4 expression and age (OR = 0.822, 95% CI: 0.515-1.312, P = .411) or sex (OR = 1.056, 95% CI: 0.675-1.653, P = .811). Furthermore, SMAD4 expression was lower in NSCLC, and a good prognosis in NSCLC (HR = 0.6, 95% CI = 0.51-0.72, P = 4.2 e-9) was shown to correlate with higher SMAD4 expression using the Kaplan-Meier Plotter database. SMAD4 expression is lower in NSCLC and correlated with lymph node metastasis, tumor differentiation, tumor node metastasis stage and good OS for NSCLC patients.

Segmentectomy vs Lobectomy for Early Non-Small Cell Lung Cancer With Visceral Pleural Invasion

BackgroundRecent prospective trials have demonstrated the noninferiority of segmentectomy to lobectomy in the surgical management of early non-small cell lung cancer (NSCLC). It remains unknown, however, whether segmentectomy is sufficient for treating small tumors with visceral pleural invasion (VPI), a known indicator of aggressive disease biology and poor prognosis in NSCLC. MethodsPatients in the National Cancer Database (2010-2020) with cT1a-bN0M0 NSCLC and VPI and additional high-risk features who underwent segmentectomy or lobectomy were identified for analysis. Only patients with no comorbidities were included in this analysis to reduce selection bias. Overall survival of patients who underwent segmentectomy vs lobectomy was evaluated using multivariable-adjusted Cox proportional hazards and propensity score– matched analyses. Short-term and pathologic outcomes were also evaluated. ResultsOf the 2568 patients with cT1a-bN0M0 NSCLC and VPI included in our overall cohort, 178 (7%) underwent segmentectomy and 2390 (93%) underwent lobectomy. No significant differences were found in the 5-year overall survival between patients undergoing segmentectomy vs lobectomy in multivariable-adjusted and propensity score–matched analyses (adjusted hazard ratio, 0.91 [95% CI, 0.55-1.51], P = .72; 86% [95% CI, 75%-92%] vs 76% [95% CI, 65%-84%], P = .15, respectively). There were also no differences in surgical margin positivity, 30-day readmission, and 30- and 90-day mortality between patients undergoing either surgical approach. ConclusionsIn this national analysis, no differences were found in survival or in short-term outcomes between patients undergoing segmentectomy vs lobectomy for early-stage NSCLC with VPI. Our findings suggest that if VPI is detected after segmentectomy for cT1a-bN0M0 tumors, completion lobectomy is unlikely to confer an additional survival advantage.

CircTADA2A up-regulates MAPK8 by targeting MiR-214-3p and recruiting EIF4A3 to promote the invasion and migration of non-small cell lung cancer cells.

Non-small cell lung cancer (NSCLC) occupies 87% of all lung cancer cases. Due to delayed diagnosis, the prognosis of NSCLC is unfavorable. To improve the survival of patients with NSCLC, more effective therapeutic targets urgently need to be identified. Recently, circular RNAs (circRNAs) have been revealed to play a crucial role in NSCLC progression. This research focused on the influence of circTADA2A on the malignant phenotype of NSCLC cells and its in-depth regulatory mechanisms. RT-qPCR and western blot assays were done to examine the level of gene/protein of interest. Wound healing and transwell assays were conducted to monitor the migration and invasion of NSCLC cells. Bioinformatics tools and mechanistic assays were utilized to delve into the underlying mechanism of circTADA2A in NSCLC cells. The results demonstrated that circTADA2A presented a high expression in NSCLC. CircTADA2A knockdown was revealed to hamper migration and invasion of NSCLC cells. Mechanistically, circTADA2A elevated MAPK8 expression through sequestering miR-214-3p and recruiting EIF4A3. CircTADA2A enhances MAPK8 expression by serving as a miR-214-3p sponge and EIF4A3 decoy, consequently promoting invasion and migration of NSCLC cells.

Prediction of disease-free survival of N1/2 non-small cell lung cancer after adjuvant chemotherapy by the biomarker RPMB

No molecular biomarkers have been proven applicable in clinical practice to identify patients who can benefit from adjuvant chemotherapy in non-small cell lung cancer (NSCLC). In this study, we established a biomarker, RPMB, short for promotor methylation burden of DNA repair genes (DRGs), to identify the subgroup of patients who might benefit from adjuvant chemotherapy in NSCLC. Methylation profiles of 828 NSCLC primary tumors and their clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. The RPMB for each patient after radical resection was calculated and its correlation with the prognosis of NSCLC was extensively investigated. DRGs of NSCLC were much more hypomethylated than the other genes (all p＜0.001). RPMB was defined as the ratio of methylated DRGs to the total number of all the DRGs. Patients with higher RPMB values tended to be nonsmokers, had adenocarcinoma, were female and had peripheral tumors. Subgroup analysis of forest plot among different clinical factors showed that high RPMB was significantly correlated to better disease-free survival (DFS) in pathologic N-positive patients after adjuvant chemotherapy (HR = 0.404, n = 62, p = 0.034). Notably, more superior DFS was exhibited in high RPMB NSCLCs with N1 nodal stage compared with those with low RPMB values (HR = 0.348, n = 47, p = 0.043). High RPMB might be used as a potential predictor to identify suitable N-positive NSCLC patients who can benefit from adjuvant chemotherapy after radical surgery.

Serum exosomal m6A demethylase FTO promotes gefitinib resistance in non-small cell lung cancer by up-regulating FLRT3, PTGIS and SIRPα expression

This study investigates the molecular mechanism of FTO m6A demethylase in non-small cell lung cancer (NSCLC) and gefitinib resistance using GEO and TCGA databases. Differentially expressed genes (DEGs) were screened from RNA-seq data sets of serum exosomes of gefitinib-resistant NSCLC patients in the GEO database and the NSCLC data set in the GEPIA2 database. From this analysis, FTO m6A demethylase was found to be significantly upregulated in the serum exosomes of gefitinib-resistant NSCLC patients. To identify downstream genes affected by FTO m6A demethylase, weighted correlation network analysis and differential expression analysis were performed, resulting in the identification of three key downstream genes (FLRT3, PTGIS, and SIRPA). Using these genes, the authors constructed a prognostic risk assessment model. Patients with high-risk scores exhibited a significantly worse prognosis. The model could predict the prognosis of NSCLC with high accuracy measured by AUC values of 0.588, 0.608, and 0.603 at 1, 3, and 5 years respectively. Furthermore, m6A sites were found in FLRT3, PTGIS, and SIRPA genes, and FTO was significantly positively correlated with the expression of these downstream genes. Overall, FTO m6A demethylase promotes gefitinib resistance in NSCLC patients by upregulating downstream FLRT3, PTGIS, and SIRPA expression, with these three downstream genes serving as strong prognostic indicators.

HNRNPA2B1-mediated m6A modification of lncRNA MEG3 facilitates tumorigenesis and metastasis of non-small cell lung cancer by regulating miR-21-5p/PTEN axis

BackgroundAccumulating data indicate that N6-methyladenosine (m6A) RNA methylation and lncRNA deregulation act crucial roles in cancer progression. Heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) as an m6A “reader” has been reported to be an oncogene in multiple malignancies. We herein aimed to elucidate the role and underlying mechanism by which HNRNPA2B1-mediated m6A modification of lncRNAs contributes to non-small cell lung cancer (NSCLC).MethodsThe expression levels of HNRNPA2B1 and their association with the clinicopathological characteristics and prognosis in NSCLC were determined by RT-qPCR, Western blot, immunohistochemistry and TCGA dataset. Then, the role of HNRNPA2B1 in NSCLC cells was assessed by in vitro functional experiments and in vivo tumorigenesis and lung metastasis models. HNRNPA2B1-mediated m6A modification of lncRNAs was screened by m6A-lncRNA epi-transcriptomic microarray and verified by methylated RNA immunoprecipitation (Me-RIP). The lncRNA MEG3-specific binding with miR-21-5p was evaluated by luciferase gene report and RIP assays. The effects of HNRNPA2B1 and (or) lncRNA MEG3 on miR-21-5p/PTEN/PI3K/AKT signaling were examined by RT-qPCR and Western blot analyses.ResultsWe found that upregulation of HNRNPA2B1 was associated with distant metastasis and poor survival, representing an independent prognostic factor in patients with NSCLC. Knockdown of HNRNPA2B1 impaired cell proliferation and metastasis in vitro and in vivo, whereas ectopic expression of HNRNPA2B1 possessed the opposite effects. Mechanical investigations revealed that lncRNA MEG3 was an m6A target of HNRNPA2B1 and inhibition of HNRNPA2B1 decreased MEG3 m6A levels but increased its mRNA levels. Furthermore, lncRNA MEG3 could act as a sponge of miR-21-5p to upregulate PTEN and inactivate PI3K/AKT signaling, leading to the suppression of cell proliferation and invasion. Low expression of lncRNA MEG3 or elevated expression of miR-21-5p indicated poor survival in patients with NSCLC.ConclusionsOur findings uncover that HNRNPA2B1-mediated m6A modification of lncRNA MEG3 promotes tumorigenesis and metastasis of NSCLC cells by regulating miR-21-5p/PTEN axis and may provide a therapeutic target for NSCLC.

Expression Pattern and Prognostic Analysis of Branched-Chain Amino Acid Catabolism-Related Genes in Non-Small Cell Lung Cancer.

The purpose of our study is to analyze the expression pattern and prognostic value of catabolism-related enzymes of branched-chain amino acids (BCAAs) in non-small cell lung cancer (NSCLC). Differential expression analysis, mutation, copy number variation (CNV), methylation analysis, and survival analysis of BCAAs catabolism-related enzymes in NSCLC were performed using the Cancer Genome Atlas (TCGA) database. Six and seven differentially expressed genes were obtained in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), respectively. IL4I1 was located at the core regulatory nodes in the gene co-expression networks of both LUAD and LUSC. The AOX1 mutation rate was the highest in both LUAD and LUSC. For CNV, IL4I1 was up-regulated in both LUAD and LUSC with an increase in copy number, whereas AOX1 and ALDH2 were differentially regulated in the two subtypes of lung cancer. In patients with NSCLC, high expression of IL4I1 was associated with lower overall survival (OS), and low expression of ALDH2 predicted shorter disease-free survival (DFS). ALDH2 expression was related with LUSC survival. This study explored the biomarkers of BCAAs catabolism related to the prognosis of NSCLC, which provided a theoretical foundation to guide the clinical diagnosis and treatment of NSCLC.

Peripheral myeloid cells as prognostic markers in patients (pts) with non-small cell lung cancer (NSCLC) treated with cemiplimab: Pooled analysis of EMPOWER-Lung 1 and EMPOWER-Lung 3 phase 3 trials.

9028 Background: Circulating innate and adaptive immune cells can modulate clinical responses to immune checkpoint inhibition in pts with cancer; however, there are no clear validated baseline clinical tests to guide clinicians, outside of programmed cell death-ligand 1 (PD-L1) IHC tests on limited biopsy specimens. High neutrophil/lymphocyte ratio (NLR) is associated with poor prognosis in NSCLC, but data are limited on the potential contribution of other immune cells such as monocytes and eosinophils in modulating systemic immune response. Further, previous correlative studies have not established clinically actionable immune cell cut-off values. Methods: We used multiple quantitative analytic methods including multivariable Cox regression and conditional decision trees to assess the prognostic importance of NLR and peripheral myeloid cells, including monocytes and eosinophils, in pts with NSCLC treated with cemiplimab in Phase 3 trials EMPOWER-Lung 1 (NCT03088540) and EMPOWER-Lung 3 (NCT03409614). In EMPOWER-Lung 1, pts with PD-L1 ≥50% were randomized 1:1 to cemiplimab 350 mg every 3 weeks (Q3W) or platinum-based chemotherapy (chemo). EMPOWER-Lung 3 was a 2-part study. In Part 1, pts with PD-L1 &lt; 50% were randomized 1:1:1 to chemo, cemiplimab 350 mg Q3W + chemo, or cemiplimab 350 mg Q3W + ipilimumab 50 mg Q6W + chemo. In Part 2, pts were randomized 2:1 to receive cemiplimab 350 mg or placebo Q3W + chemo. Results: Overall, 691 pts in EMPOWER-Lung 1 and 769 pts in EMPOWER-Lung 3 were included in this analysis. The results showed significant association between multiple factors including NLR and overall survival (OS) and progression-free survival (PFS). For pts with NLR &gt; 3.98 vs ≤3.98, median OS (95% CI) was 10 (9–13) vs 20 (17–24) months (HR: 2.04; 95% CI: 1.60–2.61; P&lt; 0.001) and median PFS (95% CI) was 4 (4–6) vs 6 (6–7) months (HR: 1.80; 95% CI: 1.50–2.18; P&lt; 0.001), respectively, accounting for known prognostic factors. In multivariable analyses, monocytes (OS HR: 1.72; 95% CI: 1.29–2.30; P&lt; 0.001; PFS HR: 1.37; 95% CI: 1.08–1.75; P= 0.010) and log eosinophils (OS HR: 0.90; 95% CI: 0.85–0.97; P= 0.003; PFS HR: 0.93; 95% CI: 0.88–0.98; P= 0.004) were significantly associated with OS and PFS in both studies. (Neutrophil + monocyte)/lymphocyte ratio was the top predictor of both OS and PFS in decision tree analysis. Peripheral blood cell count correlations were not affected by tumor PD-L1 levels (ρ &lt; 0.15 for all markers). Conclusions: This is a large and comprehensive prognostic analysis of data from two prospective Phase 3 clinical trials in advanced NSCLC. Clinically actionable peripheral blood cell count parameters, incorporating putative immunosuppressive myeloid cells (neutrophils and monocytes) and protective lymphocytes and eosinophils, may help predict response to anti–PD-1 therapy in advanced NSCLC. Clinical trial information: NCT03088540 , NCT03409614 .

The mortality burden of cachexia in patients with non-small cell lung cancer: A meta-analysis.

e24075 Background: Cachexia and weight loss have been linked to poor outcomes in patients with cancer. This study’s aim was to conduct a meta-analysis to estimate the risk of mortality associated with cachexia in patients with non-small cell lung cancer (NSCLC) in studies identified through a systematic literature review (SLR). Methods: A feasibility assessment was undertaken to determine the suitability of conducting a meta-analysis evaluating the impact of cachexia, defined per International Consensus criteria (ICC) or previous weight loss (WL) ≥5% (without specifying a 6-month duration), on overall survival (OS) in patients with NSCLC. The meta-analysis was conducted using a random-effects model, considering variability across studies, and using the identified studies as base case. The impact of heterogeneity was evaluated through sensitivity and subgroup analyses. Standard measures of statistical heterogeneity were calculated for each meta-analysis. Results: Of the 40 NSCLC publications identified in the SLR, 20 (50%) used the ICC definition or reported WL ≥5%. Sixteen studies (80%, n = 6,225 patients, published in 2016 to 2021) met the criteria for inclusion in the meta-analysis: 11 (69%) studies per ICC and 5 (31%) studies per WL ≥5%. Combined criteria (ICC or WL ≥5%) were associated with 82% higher mortality risk versus no cachexia or WL &lt; 5% (pooled hazard ratio [95% CI]: 1.82 [1.47, 2.25]). A subgroup analysis of studies using the ICC definition (hazard ratio [95% CI]: 2.26 [1.80, 2.83]) or WL ≥5% (hazard ratio [95% CI]: 1.28 [1.12, 1.46]) showed consistent findings. Although high statistical heterogeneity (I-square = 88%) was observed across studies, this variability could be disregarded because effect estimates (hazard ratios) from included studies were directionally aligned with considerable overlap in CIs of individual studies. A meta-influence analysis did not identify any potential outliers. Results of the sensitivity and subgroup analyses were consistent with the base case analysis. Cumulative meta-analyses by publication year or data collection midpoint identified no time-varying effect, indicating results were robust to the differing timeframes of publication or data collection. No substantial publication bias, measured via funnel plot analysis, was identified in the meta-analysis. Conclusions: Based on thorough methodologic, clinical, and statistical heterogeneity assessments, the meta-analysis results are robust. ICC-defined cachexia or WL ≥5% were associated with inferior OS in patients with NSCLC. Identifying cachexia or WL ≥5% has important implications for prognosis and treatment of NSCLC.