Survival Of Non-small Cell Lung Cancer Patients Research Articles

Treating non-small cell lung cancer with selumetinib: an up-to-date drug evaluation

ABSTRACT Introduction RAS-RAF-MEK-ERK signaling is implicated in tumor development by promoting cell proliferation and other cancer hallmarks. MEK1/2 kinases are up-regulated in the majority of human cancers due to activation of tyrosine kinase receptors, RAS proteins, BRAF kinase, or some other members of the MAPK pathway. Targeting of MEK1/2 kinases may counterbalance cancer progression. Areas covered The authors analyze the scientific publications relevant to selumetinib (AZD6244, ARRY-142886) systematically and provide their expert opinion. Expert opinion Selumetinib is an oral selective allosteric inhibitor of MEK1 and MEK2 kinases. Single-agent selumetinib is usually administered in hydrogen sulfate capsules 75 mg twice a day; combination with other therapeutic compounds may or may not require reduced dosing of this drug. The established dose for pediatric patients is 25 mg per square meter twice a day. Selumetinib was extensively evaluated in non-small cell lung cancer (NSCLC) patients. Studies utilizing this drug as a monotherapy did not confirm its efficacy toward NSCLC. A phase II trial showed that the addition of selumetinib to docetaxel improved response rates and progression-free survival (PFS) in chemotherapy-pretreated KRAS-mutated NSCLC patients; however, a subsequent phase III study did not confirm these findings. There are several highly successful non-NSCLC selumetinib trials involving, e.g., patients with neurofibromatosis type 1 related tumors and children with low-grade BRAF-driven gliomas.

Long-Noncoding RNA CASC9 Promotes Progression of Non-Small Cell Lung Cancer by Promoting the Expression of CDC6 Through Binding to HuR.

ObjectiveThe long-noncoding RNAs (lncRNAs) have been identified as key players in diverse cellular processes in non-small cell lung cancer (NSCLC). However, the understanding of biological functions and detailed mechanisms of lncRNAs is still limited. Herein, the lncRNA cancer susceptibility candidate 9 (CASC9) on NSCLC progression is investigated.Materials and MethodsExpressions of CASC9, HuR and cell division cycle 6 (CDC6) in NSCLC tissues were detected with quantitative real-time polymerase chain reaction (qRT-PCR). The cell counting kit-8, transwell assays, and flow cytometry were used to examine cell proliferation, migration, and the cell cycle. Tumor growth in vivo was evaluated by xenograft tumor experiments and immunohistochemistry. RNA-binding protein immunoprecipitation (RIP) was used to identify the interaction between HuR and CDC6, and CASC9 and HuR.ResultsCASC9, CDC6 and HuR expression were found significantly upregulated in NSCLC tissues, which predicted poorer 5-year overall survival in NSCLC patients. Inhibition of CASC9 significantly reduced the malignancy of NSCLC cells, such as proliferation, migration and cell cycle. In vivo experiments further demonstrated that CASC9 knockdown reduced the tumor growth and the Ki-67 expression. Moreover, CASC9 knockdown inhibited the expression of CDC6 which was detected overexpressed in NSCLC tumor tissues. Then, up-regulation of CDC6 could partly reverse the negative effects of CASC9 on cell proliferation, migration and cell cycle. RIP assay and rescue experiment showed that CASC9 regulated CDC via binding to HuR.ConclusionOur results indicate that CASC9 conferred an aggressive phenotype in NSCLC and might be a pivotal target for this disease.

1219P AI-powered prediction of 2-year relapse-free survival in operable NSCLC patients using peritumoral radiomic features according to tumour size in chest CT images

To evaluate the ability of radiomic features inside and outside the tumor and the effect of the external range according to the size of the tumor in predicting 2-year relapse-free survival of operable non-small cell lung cancer (NSCLC) patients from chest CT images.

Clinical Significance of PIK3CA Gene in Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Aim To explore the clinicopathological and prognostic role of PIK3CA gene mutation and expression in non-small-cell lung cancer (NSCLC) patients. Methods A systematic and comprehensive literature search was conducted through EMBASE (via OVID), Web of Science, and PubMed. Relative risks (RRs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were combined to evaluate the relationship of the PIK3CA gene with clinicopathological parameters and the survival of NSCLC patients, respectively. Results A total of 13 studies involving 3908 patients were analyzed in our study. Only lymph node metastasis status had an association with PIK3CA mutation (RR = 2.823; 95% CI: 1.128-7.065; P = 0.029). The results indicated that PICK3CA mutation was related with overall survival (OS) (HR = 1.55; 95% CI: 1.13-2.13; P = 0.007), progression-free survival (PFS) (HR = 1.48; 95% CI: 1.06-2.08; P = 0.023), and cancer-specific survival (CSS) (HR = 2.63; 95% CI: 1.00-6.92; P = 0.005). Furthermore, PIK3CA high expression was more prevalent in NSCLC patients with smoking history (RR = 2.42; 95% CI: 1.04-5.61; P = 0.040). However, no significant relation between PIK3CA expression and OS was found (HR = 0.80; 95% CI: 0.58-1.12; P = 0.193). Conclusion PIK3CA mutation may affect lymph node metastasis and serve as a promising prognostic factor, and smoking may be related with PIK3CA high expression in NSCLC patients. However, more well-designed prospective researches are needed to verify the abovementioned findings.

A fourteen-lncRNA risk score system for prognostic prediction of patients with non-small cell lung cancer.

Growing evidence has underscored long non-coding RNAs (lncRNAs) serving as potential biomarkers for cancer prognosis. However, systematic tracking of a lncRNA signature for prognosis prediction in non-small cell lung cancer (NSCLC) has not been accomplished yet. Here, comprehensive analysis with differential gene expression analysis, univariate and multivariate Cox regression analysis based on The Cancer Genome Atlas (TCGA) database was performed to identify the lncRNA signature for prediction of the overall survival of NSCLC patients. A risk-score model based on a 14-lncRNA signature was identified, which could classify patients into high-risk and low-risk groups and show poor and improved outcomes, respectively. The receiver operating characteristic (ROC) curve revealed that the risk-score model has good performance with high AUC value. Multivariate Cox’s regression model and stratified analysis indicated that the risk-score was independent of other clinicopathological prognostic factors. Furthermore, the risk-score model was competent for the prediction of metastasis-free survival in NSCLC patients. Moreover, the risk-score model was applicable for prediction of the overall survival in the other 30 caner types of TCGA. Our study highlighted the significant implications of lncRNAs as prognostic predictors in NSCLC. We hope the lncRNA signature could contribute to personalized therapy decisions in the future.

Abstract 1416: Long non-coding RNA GAN1 inhibits tumor progression by regulating the mir-26a/PTEN axis in lung cancer

Abstract Background: Long non-coding RNA has been reported to be involved in many cancers. To explore the role of lncRNA in non-small-cell lung cancer (NSCLC), we detected lncRNA expression profile with a custom microarray and found that lnc-GAN1 was significantly downregulated in NSCLC. In this study, we aimed to explore the clinical significance, biological function and mechanism of lnc-GAN1 in NSCLC. Methods: We firstly analyzed relationship between the lncGAN1 expression and clinical features and survival in NSCLC patients from two medical centers. We secondly examined the biological function of lncGAN1 in lung cancer cells with Cell viability, colony formation, migration, invasion, cell cycle and apoptosis assays. Then, we localized the distribution of lnc-GAN1 in lung cancer cells using RNA-FISH and analyzed the interaction between lnc-GAN1 and mir-26a-5p with Dual luciferase reporter and RNA immunoprecipitation (RIP) assay. Finally, the xenograft tumor model was employed to assess tumor suppression role of GAN1. Results: lnc-GAN1 is notably downregulated in NSCLC tissues compared with normal lung tissues and associated with small tumor size, poor overall survival (OS) and disease-free survival in NSCLC patients. In vitro experiments, lnc-GAN1 expression suppresses proliferation, colony formation, cell cycle progression and apoptosis of lung cancer cells. lnc-GAN1 was mainly observed in cytoplasm of lung cancer cells with FISH and subcellular fraction analysis. RNA-seq analysis showed that the genes in cell cycle pathway were changed obviously when lnc-GAN1 was overexpressed. Mechanistically, lnc-GAN1 functions as a sponge of miR-26a-5p, which directly targets PTEN. Ectopically expressed lnc-GAN1 increased the mRNA and protein levels of PTEN and decreased miR-26a-5p level in lung cancer cells. Furthermore, mir-26a-5p mimics caused a decrease in both lnc-GAN1 and PTEN expressions while mir-26a-5p inhibitors led to an increase in both lnc-GAN1 and PTEN levels. Finally, In vivo experiments demonstrated that lnc-GAN1 could suppress tumor growth compared with control vector in nude mice. Conclusions: our study discovered that lnc-GAN1 is significantly downregulated and associated with survival in NSCLC patients, and plays a tumor suppressor role by inhibiting miR-26a-5p and upregulating PTEN expression in lung cancer, which suggest that lnc-GAN1 is a potential prognostic biomarker and innovative therapeutic target in NSCLC. Citation Format: Rui-qi Wang, Xiao-Ran Long, Mei-Yin Zhang, Dong-Ni Chen, Zhe-Sheng Wen, Shi-Juan Mai, Hui-Yun Wang. Long non-coding RNA GAN1 inhibits tumor progression by regulating the mir-26a/PTEN axis in lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1416.

Abstract 6458: Adverse recurrence prognostic implications of tumor CD47 expression in resected non-small cell lung cancer

Abstract Background: Immunotherapy is one of the most promising advances in the field of oncology. However, limited information exists regarding characterization of the tumor associated macrophages (TAMs) related immune microenvironment in patients with non-small cell lung cancer(NSCLC), by which it may possible to predict the efficacy of novel immunotherapies. Method: 191 resected NSCLC specimens were retrospectively studied for the CD47 expression & PD-L1 expression which were examined using immunohistochemistry (IHC). The infiltration of macrophages (M2-macrophages & M1-macrophages) and CD8+T-lymphocytes were evaluated using dual-IF staining. 46 cases of pulmonary infectious diseases were used as the control group. Targeted sequencing was performed on all 191 specimens using NovoSeq 6000 system. Bioinformatics analysis including somatic variant detection and statistical analysis were subsequently carried out. Finally, the pattern of immune infiltrates was depicted and their prognostic role of was assessed. Results: Using IHC 2/3+ as cutoff, the prevalence of CD47 positive (CD47pos) expression in NSCLC was 33.0% (63/191), significantly higher than that in non-tumor lung tissues (17.4%, 8/46, Chi-squared test p-val=0.038). CD47pos expression was significantly higher in female, non-smoking, and adenocarcinoma (LUAD) patients (p-val=0.020, p-val<0.001, and p-val<0.001, respectively). With somatic mutations integrated, CD47pos expression significantly correlates with EGFR mutation (p-val<0.001). When patients were stratified by LUAD and squamous cell carcinoma (LUSC), statistical correlation between EGRE mutation and CD47pos expression remains in LUAD (adjusted p-val=0.002) and LUSC patients group (adjusted p-val=0.0499). The expression of CD47 (H-score) in NSCLC was negatively correlated with both tumor PD-L1 expression (tumor proportion score, TPS) (p-val=0.0346) and tumor mutation burden (TMB) (p-val=0.0107). CD47pos expression independently correlates with worse disease free survival (DFS) for NSCLC patients in multivariate Cox regression (p-val=0.035). When CD47 and M2 were combined as combinatorial biomarkers, four groups of patients can be significantly separated with negative CD47(CD47neg) expression / absence of M2 in tumor area being best DFS and CD47pos expression / M2 in tumor area being worst DFS. To link the pattern of immune infiltrates with patient better DFS, we performed an unsupervised clustering using major immune components (CD47, PD-L1, CD8, M1 and M2). 191 patients were clustered into three groups and patient's DFS of each group was significantly differentiated (Log-rank p-val=0.041). Briefly, the group of patients with worst DFS is characterized with high infiltration of M1 and M2 in tumor area. Conclusions: To the best of our knowledge, this is the first study that extensively investigated the major immune modulators along with their association with genotype in NSCLC cohort. We elucidated the demographic characteristics, molecular characteristics, and immuno-microenvironment characteristics of CD47 expression in NSCLC. We further identified the tumor CD47pos expression as an independent adverse recurrence prognostic factor in NSCLC. Our study illustrates the idea of ‘precision medicine' by stratification of patients based on immuno-microenvironment characteristics. Citation Format: Yan Xu, Ji Li, Bing Tong, Shuang Wang, Wei Zhong, Minjiang Chen, Jing Zhao, Mengzhao Wang. Adverse recurrence prognostic implications of tumor CD47 expression in resected non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6458.

Impact of time-to-treatment on overall survival of non-small cell lung cancer patients-an analysis of the national cancer database.

BackgroundThe association between time-to-treatment and outcomes for lung cancer has not been conclusively established. In this study, we evaluated the effect of time-to-treatment on the overall 5-year survival of patients with non-small cell lung cancer (NSCLC) with cancer stage at diagnosis.MethodsWe analyzed data in the National Cancer Data Base for adult patients newly diagnosed with NSCLC in 2003–2011 (N=693,554). Extended Cox regression with counting process was used to model the effect of time-to-treatment on survival, adjusted for demographic and clinical factors. Multivariable analyses were performed separately for the groups with different stages at diagnosis. Time-to-treatment was defined as the interval between diagnosis and treatment initiation, with the categories of (I) 0 day, (II) 1 day–4 weeks, (III) 4.1–6.0 weeks, and (IV) >6 weeks (the 1 day–4 weeks group was considered the reference group).ResultsCompared to treatment initiated between 1 day and 4 weeks after diagnosis, time-to-treatment at 4.1–6.0 weeks was associated with a lower risk of death for patients with early-stage cancer [adjusted HR (aHR), 0.84 (95% CI, 0.82–0.85)], with locally advanced cancer [aHR, 0.82 (95% CI, 0.80–0.83)], and with metastatic cancer [aHR, 0.75 (95% CI, 0.74–0.76)]. Similarly, a lower risk of death was associated with time-to-treatment longer than 6 weeks for patients with any cancer stage at diagnosis. However, a subset analysis for early-stage patients who received surgery only showed that extended time-to-surgery was associated a higher risk of death [aHR 4.1-6.0 weeks, 1.06 (95% CI, 1.03–1.09); aHR>6 weeks 1.17 (95% CI, 1.14–1.20)].ConclusionsThe findings show that, although time-to-treatment should not be compromised, it is imperative to ensure that patients receive optimal pre-treatment assessments rather than rushing the treatment. Future research should focus on examining clinical characteristics to determine an optimal time-to-treatment to achieve the best possible survival for NSCLC patients.

Circ_0000376, a Novel circRNA, Promotes the Progression of Non-Small Cell Lung Cancer Through Regulating the miR-1182/NOVA2 Network.

BackgroundHypoxia has been shown to induce the malignant progression of cancer, including non-small cell lung cancer (NSCLC). Circular RNA (circRNA) is considered to be an important regulator of cancer progression. However, the role of a newly discovered circRNA, circ_0000376, in the progression of NSCLC is unclear.MethodsThe relative expression levels of circ_0000376, miR-1182 and neuro-oncological ventral antigen 2 (NOVA2) were detected via quantitative real-time polymerase chain reaction (qRT-PCR). Glucose consumption and lactate production were determined using Glucose Assay Kit and Lactate Assay Kit, respectively. Moreover, the protein levels of glycolysis markers and NOVA2 were measured using Western blot (WB) analysis. Furthermore, 3-(4, 5-dimethyl-2 thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay was performed to assess cell viability, and transwell assay was employed to evaluate cell migration and invasion. The interaction between miR-1182 and circ_0000376 or NOVA2 was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. In addition, animal experiments were conducted to assess the influence of circ_0000376 silencing on NSCLC tumor growth in vivo.ResultsCirc_0000376 was upregulated in NSCLC, and its high expression was related to the poor overall survival of NSCLC patients. Hypoxia could enhance circ_0000376 expression and promote the glycolysis, viability, migration, and invasion of NSCLC cells. However, silencing of circ_0000376 could inhibit the glycolysis, viability, migration, and invasion of hypoxia-induced NSCLC cells. Additionally, circ_0000376 could sponge miR-1182, and miR-1182 could target NOVA2. MiR-1182 silencing could reverse the inhibitory effect of circ_0000376 knockdown on NSCLC progression, and NOVA2 overexpression also could reverse the suppressive effect of miR-1182 overexpression on NSCLC progression. Meanwhile, miR-1182 inhibitor could invert the negative regulation effect of circ_0000376 silencing on NOVA2 expression. In addition, circ_0000376 knockdown inhibited the NSCLC tumor growth via regulating the miR-1182 and NOVA2 expression in vivo.ConclusionCirc_0000376 promoted NSCLC progression by regulating the miR-1182/NOVA2 axis, suggesting that circ_0000376 might be a potential biomarker for NSCLC treatment.

Comparison of Metabolic and Morphological Response Criteria for Early Prediction of Response and Survival in NSCLC Patients Treated With Anti-PD-1/PD-L1.

Introduction/Aim: Immunotherapy with immune checkpoint inhibitors (ICIs) has positively changed the history of several malignant tumors. In parallel, new challenges have emerged in the evaluation of treatment response as a result of their peculiar anticancer effect. In the current study, we aimed to compare different response criteria, both morphological and metabolic, for assessing response and outcome in patients with advanced non-small cell lung cancer (NSCLC) treated with ICI.Materials and Methods: Overall, 52 patients with advanced NSCLC candidate to ICI were prospectively evaluated. Inclusion criteria comprised whole-body contrast-enhanced CT and 18F-FDG PET/CT at baseline and at the first response evaluation 3 or 4 cycles after ICI. Response assessment on CT was performed according to RECIST 1.1 and imRECIST criteria, whereas metabolic response on PET was computed by EORTC, PERCIST, imPERCIST, and PERCIMT criteria. The concordance between the different tumor response criteria and the performance of each criterion to predict progression-free survival (PFS) and overall survival (OS) were calculated.Results: Inclusion criteria were fulfilled in 35 out of 52 patients. We observed a low agreement between imRECIST and imPERCIST (κ = 0.143) with discordant response in 20 patients, particularly regarding stable disease and progressive disease groups. Fair agreement between imRECIST and EORTC (κ = 0.340), and PERCIST (κ = 0.342), and moderate for PERCIMT (κ = 0.413) were detected. All criteria were significantly associated with PFS, while only PERCIMT and imPERCIST were associated with OS. Of note, in patients classified as immune stable disease (iSD), imPERCIST, and PERCIMT well-differentiated those with longer PFS (p < 0.001, p = 0.009) and OS (p = 0.001, p = 0.002). In the multivariate analysis, performance status [hazard ratio (HR) = 0.278, p = 0.015], imRECIST (HR = 3.799, p = 0.026), and imPERCIST (HR = 4.064, p = 0.014) were predictive factors for PFS, while only performance status (HR = 0.327, p = 0.035) and imPERCIST (HR = 3.247, p = 0.007) were predictive for OS.Conclusions: At the first evaluation during treatment with ICI, imPERCIST criteria correctly evaluated treatment response and appeared able to predict survival. Moreover, in patients with iSD on CT, imPERCIST were able to discriminate those with longer survival. This advantage might allow for earlier therapy modification based on metabolic response.

Management of Non–Small-Cell Lung Cancer Patients Initially Diagnosed With 1 to 3 Synchronous Brain-Only Metastases: A Retrospective Study

BackgroundThe treatment options for newly diagnosed non–small-cell lung cancer (NSCLC) patients with 1 to 3 synchronous brain metastases (BM) remain controversial. The current study aimed to comprehensively analyze the characteristics, local treatment paradigms, and survival outcomes in these populations. Patients and MethodsA total of 252 NSCLC patients initially diagnosed with 1 to 3 synchronous brain-only metastases were enrolled onto this study. Local therapy (LT) to primary lung tumors (PLT) and BM included surgery, radiotherapy, or both. Median overall survival (mOS) was measured among patients who received LT to both PLT and BM (all-LT group), patients who were treated with LT to either PLT or BM (part-LT group), and patients who did not receive any LT (non-LT group). ResultsThe mOS for all-LT (n = 70), part-LT (n = 113), and non-LT (n = 69) groups was 33.2, 18.5, and 16.8 months, respectively (P = .002). The OS rates at 5 years for the all-LT, part-LT, and non-LT groups were 25.5%, 16.2%, and 0, respectively. Multivariable analysis revealed that all-LT versus non-LT, pretreatment Karnofsky performance status > 70, histology of adenocarcinoma, thoracic stage I-II, EGFR mutation, ALK positive, and second-line systemic therapies were independent prognostic factors for improved mOS. ConclusionsThe current study showed that LT for both PLT and BM is associated with superior OS in appropriately selected NSCLC patients initially diagnosed with 1 to 3 synchronous BM. Prospective trials are urgently needed to confirm this finding.

Evaluation of Postoperative Radiotherapy Effect on Survival of Resected Stage III-N2 Non-small Cell Lung Cancer Patients

Objective: The role of postoperative radiotherapy (PORT) in resected stage IIIA-N2 non-small cell lung cancer (NSCLC) patients remains controversial. This study aimed to explore the effect of PORT on survival of resected stage IIIA-N2 NSCLC patients.Methods: Resected stage IIIA-N2 NSCLC patients aged 18 years or older were identified from the SEER (Surveillance, Epidemiology, and End Results) database from 2010 to 2015. Cox regression analysis was used to identify factors including PORT associated with survival time. A subgroup analysis of patients stratified by number of lymph node metastases was also performed. Overall survival (OS) and overall mortality were compared among the different groups.Results: A total of 3,445 patients were included in the study. Multivariate Cox analysis showed that PORT had no significant impact on survival of patients with <6 positive lymph node [hazard ratio (HR) = 1.012, P = 0.858, 95% CI: 0.886–1.156]. Postoperative chemotherapy (POCT) (HR = 0.605, P < 0.001, 95% CI: 0.468–0.783) and PORT (HR = 0.724, P = 0.007, 95% CI: 0.574–0.914) are both favorable prognostic factors for stage IIIA-N2 patients with ≥6 positive lymph nodes. In 2,735 patients who featured <6 number of positive regional lymph nodes, patients who received PORT had better survival and lower 3-years and 5-years overall mortality rate than patients who underwent surgery only (41 vs. 28 months, P < 0.015). There was no significant difference in the survival of postoperative patients who underwent POCT in view of whether received PORT (44 vs. 53 months, P = 0.176). A total of 710 patients who featured ≥6 number of positive regional lymph node metastasis were divided into two groups by PORT. PORT did not prolong survival for postoperative patients who did not receive chemotherapy (12 vs. 15 months, P = 0.632). PORT showed a significant advantage in influencing OS in patients who received PORT combined with POCT as compared with those who received POCT only (32 vs. 25 months, P = 0.006).Conclusions: For IIIA-N2 patients with <6 lymph node metastases, use of PORT can be encouraged to improve survival. For patients with ≥6 positive lymph nodes, PORT combined with POCT significantly improved OS and decreased overall mortality.

TAF15 contributes to the radiation-inducible stress response in cancer.

Resistance to radiation therapy is a significant problem in the treatment of non-small cell lung cancer (NSCLC). There is an unmet need to discover new molecular targets for drug development in combination with standard of care cancer therapy. We found that TAF15 was radiation-inducible using phage-displayed peptide libraries. In this study, we report that overexpression of TAF15 is correlated with worsened survival in NSCLC patients. Radiation treatment led to surface induction of TAF15 in vitro and in vivo. We genetically silenced TAF15 which led to a significant reduction in proliferation of NSCLC cells. Cells depleted of TAF15 exhibited cell cycle arrest and enhanced apoptosis through activation and accumulation of p53. In combination with radiation, TAF15 knockdown led to a significant reduction in the surviving fraction of NSCLC cell lines. To determine the importance of TAF15 surface expression, we targeted TAF15 with an antibody. In combination with radiation, the anti-TAF15 antibody led to a reduction in the surviving fraction of cancer cells. These studies show that TAF15 is a radiation-inducible molecular target that is accessible to anti-cancer antibodies and enhances cell viability in response to radiation.

SMYD3 overexpression indicates poor prognosis and promotes cell proliferation, migration and invasion in non‑small cell lung cancer.

SET and MYND domain-containing protein 3 (SMYD3) is a lysine methyltransferase, and its aberrant expression has been implicated in several malignancies. However, its clinical and biological roles in non-small cell lung cancer (NSCLC) remain unclear. In the present study, it was revealed that SMYD3 was significantly upregulated in NSCLC tissues, as compared with paired adjacent normal tissues. A high SMYD3 expression was associated with aggressive clinicopathological characteristics, as well as poor disease-free survival and overall survival (OS) in NSCLC patients. Multivariate analysis revealed that SMYD3 overexpression was an independent predictor of poor OS in NSCLC patients. In addition, SMYD3 knockdown inhibited cell proliferation, triggered apoptosis, and blocked migration and invasion in NSCLC cells in vitro, whereas stable SMYD3 overexpression promoted NSCLC cell proliferation. Furthermore, the SMYD3-silenced NSCLC cells became more sensitive, whereas the SMYD3-overexpressed NSCLC cells became more resistant to the apoptosis induced by cisplatin. Mechanistic analysis revealed that SMYD3 knockdown led to the upregulation of Bim, Bak and Bax, and the downregulation of Bcl-2, Bcl-xl, MMP-2 and MMP-9 in NSCLC cells. In combination, the present findings indicated that SMYD3 has oncogenic potential in the context of NSCLC, providing evidence that may be exploited for both prognostic and therapeutic purposes in the future.

CircMET promotes NSCLC cell proliferation, metastasis, and immune evasion by regulating the miR-145-5p/CXCL3 axis.

In recent years, circular RNAs (circRNAs) have been increasingly reported to play a crucial role in the proliferation, migration, and invasion of non-small-cell lung cancer (NSCLC) cells. However, the circRNA MET (circMET) oncogenic mechanism that drives NSCLC development and progression remains largely unknown. In this study, the present results demonstrated that circMET expression was significantly higher in NSCLC tissues than in peritumoral tissues using quantitative real-time polymerase chain reaction. Notably, NSCLC patients with a large tumor diameter, poor differentiation and lymphatic metastasis had high RNA levels of circMET. Moreover, high circMET expression served as an independent risk factor for short overall survival (OS) and progression-free survival (PFS) in NSCLC patients. Next, we validated that circMET overexpression can enhance NSCLC cell proliferation, metastasis, and immune evasion in vitro. Mechanistically, our study uncovers that circMET acts as a miR-145-5p sponge to upregulate CXCL3 expression. Collectively, circMET regulates the miR-145-5p/CXCL3 axis and serves as a novel, promising diagnostic and prognostic biomarker in patients with NSCLC.

MiR-1299 Impedes the Progression of Non-Small-Cell Lung Cancer Through EGFR/PI3K/AKT Signaling Pathway.

BackgroundNon-small-cell lung cancer (NSCLC) is one of the most malignant tumors. In which, numerous miRNAs had been reported to participate in the pathogenesis. However, the expression and function of miR-1299 in NSCLC are not clear.MethodsTo explore the roles of miR-1299 in NSCLC, we detected the levels of miR-1299 in clinical samples of NSCLC and investigated the role of miR-1299 in the regulation of the NSCLC cells proliferation, metastasis, and EMT. Luciferase reporter assay was employed to verify the target of miR-1299. Additionally, the proliferation, metastasis, and EMT of A549 and H1299 cells were analyzed after the overexpression and knockdown of miR-1299.ResultsWe found that the miR-1299 expression negatively corresponded with the clinical stage and overall survival in NSCLC patients. Overexpression of miR-1299 inhibited the migration, invasion, and EMT of A549 and H1975 cells. Meanwhile, we proved that miR-1299 is the sponge of EGFR. Besides, our results suggested that miR-1299 inhibits the progression of NSCLC cells through the PI3K/Akt signal pathway.ConclusionWe demonstrated that miR-1299 inhibits the progression of NSCLC through the EGFR/PI3K/Akt signal pathway. Therapeutic intervention targeting the miR-1299 may provide a potential strategy for the treatment of NSCLC.

Bevacizumab for non-small cell lung cancer patients with brain metastasis: A meta-analysis.

This study evaluates the efficacy and safety of bevacizumab (BEV) in the treatment of non-small cell lung cancer (NSCLC) patients with brain metastases (BM) by performing meta-analyses of response and survival indices. Seventeen studies were included. BEV treatment was associated with a lower new BM incidence (hazard ratio: 0.30 [95% confidence interval (CI): 0.14, 0.46]) during follow-up. Disease control rate (DCR) of BEV-treated patients with BM was 91% [95% CI: 85, 95]. However, intracranial DCR was relatively higher (94% [95% CI: 87, 98]) than extracranial DCR (86% [95% CI: 74, 96]). DCR of NSCLC patients with BM was significantly better with BEV than with control therapies (odds ratio: 2.71 [95% CI: 1.26, 5.86], P = 0.01). Progression-free survival (PFS) of BEV-treated patients with and without BM was 7.1 months [95% CI: 6.2, 8.0] and 7.4 months [95% CI: 6.3, 8.4], respectively. Intracranial PFS of BEV-treated patients with BM was 8.0 months [95% CI: 6.0, 10.0]. Overall survival of BEV-treated NSCLC patients with and without BM was 13.5 months [95% CI: 11.4, 15.6] and 12.5 months [95% CI: 10.2, 14.8], respectively. The incidence of bleeding/hemorrhage in the central nervous system was 1% with BEV treatment.

An Artificial Intelligence Model for Predicting 1-Year Survival of Bone Metastases in Non-Small-Cell Lung Cancer Patients Based on XGBoost Algorithm.

Non-small-cell lung cancer (NSCLC) patients often develop bone metastases (BM), and the overall survival for these patients is usually perishing. However, a model with high accuracy for predicting the survival of NSCLC with BM is still lacking. Here, we aimed to establish a model based on artificial intelligence for predicting the 1-year survival rate of NSCLC with BM by using extreme gradient boosting (XGBoost), a large-scale machine learning algorithm. We selected NSCLC patients with BM between 2010 and 2015 from the Surveillance, Epidemiology, and End Results database. In total, 5973 cases were enrolled and divided into the training (n = 4183) and validation (n = 1790) sets. XGBoost, random forest, support vector machine, and logistic algorithms were used to generate predictive models. Receiver operating characteristic curves were used to evaluate and compare the predictive performance of each model. The parameters including tumor size, age, race, sex, primary site, histological subtype, grade, laterality, T stage, N stage, surgery, radiotherapy, chemotherapy, distant metastases to other sites (lung, brain, and liver), and marital status were selected to construct all predictive models. The XGBoost model had a better performance in both training and validation sets as compared with other models in terms of accuracy. Our data suggested that the XGBoost model is the most precise and personalized tool for predicting the 1-year survival rate for NSCLC patients with BM. This model can help the clinicians to design more rational and effective therapeutic strategies.

LncRNA ELF3-AS1 Promotes Non-Small Cell Lung Cancer Cell Invasion and Migration by Downregulating miR-212.

LncRNA ELF3-AS1 has been characterized as an oncogenic lncRNA in bladder cancer and oral cancer, whereas its role in non-small cell lung cancer (NSCLC) is unknown. In this study, the authors observed that ELF3-AS1 was upregulated in NSCLC tissues in comparison with that in paired nontumor tissues collected from 68 NSCLC patients. High expression levels of ELF3-AS1 predicted the poor survival of NSCLC patients. Expression levels of miR-212 were inversely and significantly correlated with the expression levels of ELF3-AS1 across NSCLC tissue samples. In NSCLC cells, overexpression of ELF3-AS1 led to downregulated miR-212 and increased methylation of miR-212 gene. In addition, overexpression of ELF3-AS1 inhibited the role of miR-212 in suppressing cancer cell invasion and migration. Therefore, ELF3-AS1 is upregulated in NSCLC and promotes cancer cell invasion and migration by downregulating miR-212 through methylation.

Pretreatment Neutrophil-to-Lymphocyte Ratio (NLR) May Predict the Outcomes of Advanced Non-small-cell Lung Cancer (NSCLC) Patients Treated With Immune Checkpoint Inhibitors (ICIs).

Background: Recent studies have demonstrated the predictive value of pretreatment neutrophil-to-lymphocyte ratio (NLR) in advanced cancers; however, the role of NLR in patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) remained to be explored. Thus, we aimed to investigate whether pretreatment NLR was associated with the outcomes of advanced NSCLC patients treated with ICIs.Methods: A comprehensive literature research was first conducted in PubMed, the Cochrane Central Library, and Embase for studies that evaluated the association between pretreatment NLR and survival of advanced NSCLC patients with ICIs treatment. We then conducted a retrospective study in Chinese People's Liberation Army (PLA) General Hospital (Beijing, China) to validate these findings.Results: A total of 17 eligible studies with 2,106 patients were included in our meta-analysis, of which, 12 studies reported progression-free survival (PFS), and 13 studies reported overall survival (OS). The pooled results showed that high pretreatment NLR was significantly associated with poorer PFS (HR = 1.44, 95% CI 1.26–1.65; P < 0.001) and OS (HR = 2.86, 95% CI 2.11–3.87; P < 0.001) compared with those with low pretreatment NLR. Subgroup analysis demonstrated that the association between baseline NLR and PFS remained significant except that the cut-off value of NLR was 3 (HR = 1.48, 95% CI 0.93–2.37; P = 0.098) and region of Asia (HR = 1.55, 95% CI 1.00–2.39; P = 0.051). These results were further validated in our retrospective study that patients with pretreatment NLR ≥ 6.0 had shorter PFS (median: 5.0 vs. 9.1 months, HR = 1.39; 95% CI 1.01–1.91; P = 0.02) and OS (median: 10.0 vs. 17.3 months, HR = 1.71; 95% CI 1.18–2.46; P < 0.001) compared with those with NLR < 6.0. The associations between NLR and survival were consistent in subgroup analysis stratified by age, gender, ECOG PS, histology, stage, smoking history, treatment, and prior lines of therapy. Dynamics of NLR (dNLR) that increased ≥3.0 from baseline was also significantly associated with worse PFS (median: 3.1 vs. 9.1 months; P = 0.01) and OS (median: 6.8 vs. 17.0 months; P < 0.0001).Conclusions: Our study demonstrates that pretreatment NLR and dNLR from baseline are associated with the outcomes of advanced NSCLC patients treated with ICIs; however, it warrants further prospective studies.