Marker For Non-small Cell Lung Cancer Patients Research Articles

Extracellular vesicles miR-574-5p and miR-181a-5p as prognostic markers in NSCLC patients treated with nivolumab

Immune checkpoint inhibitors (ICIs) have revolutionized the management of advanced non-small cell lung cancer (NSCLC), although patient survival is still unsatisfactory. Accurate predictive markers capable of personalizing the treatment of patients with NSCLC are still lacking. Circulating extracellular vesicles involved in cell-to-cell communications through miRNAs (EV-miRs) transfer are promising markers. Plasma from 245 patients with advanced NSCLC who received nivolumab as second-line therapy was collected and analyzed. EV-miRnome was profiled on 174/245 patients by microarray platform, and selected EV-miRs were validated by qPCR. A prognostic model combining EV-miR and clinical variables was built using stepwise Cox regression analysis and tested on an independent patient cohort (71/245). EV-PD-L1 gene copy number was assessed by digital PCR. For 54 patients with disease control, EV-miR changes at best response versus baseline were investigated by microarray and validated by qPCR. EV-miRNome profiling at baseline identified two EV-miRs (miR-181a-5p and miR-574-5p) that, combined with performance status, are capable of discriminating patients unlikely from those that are likely to benefit from immunotherapy (median overall survival of 4 months or higher than 9 months, respectively). EV-PD-L1 digital evaluation reported higher baseline copy number in patients at increased risk of mortality, without improving the prognostic score. Best response EV-miRNome profiling selected six deregulated EV-miRs (miR19a-3p, miR-20a-5p, miR-142-3p, miR-1260a, miR-1260b, and miR-5100) in responding patients. Their longitudinal monitoring highlighted a significant downmodulation already in the first treatment cycles, which lasted more than 6 months. Our results demonstrate that EV-miRs are promising prognostic markers for NSCLC patients treated with nivolumab.

The Effect of Microwave Ablation Combined with Anti-PD-1 Monoclonal Antibody on T Cell Subsets and Long-Term Prognosis in Patients Suffering from Non-Small-Cell Lung Cancer.

Objective This research is aimed at studying the effect of microwave ablation combined with the antiprogrammed death- (PD-) 1 monoclonal antibody on T cell subsets and long-term prognosis in patients suffering from non-small-cell lung cancer (NSCLC). Methods Employing the random number table technique, a total of 122 NSCLC patients who received treatment at our hospital between May 2015 and June 2019 were selected and assigned to the observation group and the control group, and each group comprised 61 patients (n = 61). While the control group received only anti-PD-1 monoclonal antibody treatment, the observation group received microwave ablation in combination with anti-PD-1 monoclonal antibody. The clinical efficacy was observed for both groups. The levels of T cell subsets (CD3+, CD4+, and CD8+), serum tumor markers (squamous cell carcinoma antigen (SCCA), cytokeratin Ig fragment (CYFRA21-1), and serum carcinoembryonic antigen (CEA)), nuclear factor kappa B (NF-κB), protease C (PKC), and mitogen-activated protein kinase (MAPK) mRNA expression between the two groups were compared. The frequency of adverse reactions was observed in both groups. The survival time of both the groups was recorded over the course of three years of follow-up. The Kaplan-Meier method was employed for analyzing the survival of both the control and the observation group. Results The response rate (RR) of the observation group (80.33%) was considerably greater in comparison to that of the control group (62.30%) (P < 0.05). Following treatment, the observation group's levels of CD3+, CD4+, CD8+, SCCA, CyFRA21-1, and CEA and the mRNA expressions of NF-κB, PKC, and MAPK were superior to those of the control group, with statistical significances (all P < 0.05). Between the two groups, there was no significant difference in the occurrence of adverse reactions (P > 0.05). The observation group had greater 1-, 2-, and 3-year survival rates (57.38%, 39.34%, and 29.51%) than the control group (32.79%, 18.03%, and 8.20%), with statistically significant differences (all P < 0.05). Conclusion Microwave ablation in combination with an anti-PD-1 monoclonal antibody could effectively improve the level of T cell subsets and serum tumor markers in NSCLC patients, resulting in a long-term prognosis of patients with good therapeutic effect and safety.

Clinical Laboratory Results as Prognosis Marker in Advanced Stage Non-small Cell Lung Cancer (NSCLC) in Indonesia.

Background: Lung cancer is the most common cause of cancer-related death among men in the world. Given the very high mortality caused by lung cancer, a biological marker to determine a more sensitive therapy among non-small cell lung cancer (NSCLC) patients is needed. This study aims to demonstrate that the clinical laboratory result can be a prognosis marker in NSCLC patients in Indonesia.Methods: This study was a retrospective cohort study. The sample was obtained from the patient's serum and the examined routine blood test (hemoglobin, leukocyte, platelets), hemostasis (fibrinogen and D-dimers), blood chemistry test (aspartate transaminase [AST], alanine transaminase [ALT], albumin, urea, creatinine, and blood glucose), electrolyte (sodium, potassium, chloride, and calcium) and tumor markers (carcinoembryonic antigen [CEA] and Cyfra 21-1). Data were analyzed and interpreted using SPSS (IBM Corp., Armonk, NY, USA). Analysis of the data was done to find the survival rate of sociodemographic variables, clinicopathologic variables, and clinic laboratory variables.Results: The study findings showed statistically significant results that were poor prognosis for these following conditions: performance status (PS) 3-4 median survival (MS):26 days, p=<0.001; TNM stage IVb MS:58 days, p=0.001; high leukocyte MS:69 days, p=0.018; low platelet MS:50 days, p=0.013; high D-dimer MS:69 days, p=0.020; low albumin MS:56 days, p=0.001; high sodium MS:15 days, low sodium MS:50 days, p=<0.001; high chloride MS:15 days, low chloride MS:27 days, p=<0.001.Conclusion: In the advanced stage NSCLC, these findings indicate poorer prognoses; PS 3-4, IVb clinical stage, leukocytosis, thrombocytopenia, hyper-coagulopathy, hypoalbuminemia, hyper-hyponatremia, and hyper-hypochloremia. Further studies regarding the correlation between clinical laboratory and survival rate are needed.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio as Prognostic Markers for Advanced Non-Small-Cell Lung Cancer Treated with Immunotherapy: A Systematic Review and Meta-Analysis.

Background and Objectives: Advanced non-small-cell lung cancer (NSCLC) has led to a high number of mortalities. Immunotherapy, as a first-line treatment in advanced NSCLC, currently has no clarity regarding its prognostic markers to assess the treatment outcome. This systematic review aimed to evaluate neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic markers in advanced NSCLC patients treated with immunotherapy. Materials and Methods: This systematic review was conducted using the PRISMA guidelines, starting from screening for relevant studies from several databases. Each included cohort study was further assessed by using the Newcastle–Ottawa Quality Assessment Scale, and the available data were extracted for qualitative and quantitative synthesis in pooled and subgroup analysis. Results: A total of 1719 patients were included in this meta-analysis. Hazard ratio (HR) outcomes for progression-free survival (PFS) and overall survival (OS) for NLR and PLR showed significant results, supporting NLR and PLR as prognostic markers (NLR: HR PFS 2.21 [95% CI: 1.50–3.24; p < 0.0001] and HR OS 2.68 [95% CI: 2.24–3.6; p < 0.0001]; PLR: HR PFS 1.57 [95% CI: 1.33–1.84; p < 0.00001] and HR OS 2.14 [95% CI: 1.72–2.67; p < 0.00001]). Subgroup analysis with a cut-off value of 5 for NLR and 200 for PLR also demonstrated notable outcomes. Higher NLR and PLR levels are associated with poor prognostic. Conclusions: There is considerable evidence regarding both markers as prognostic markers in NSCLC patients treated with immunotherapy. However, further studies with more homogeneous baseline characteristics are required to confirm these findings.

Prognostic impact of the pre-treatment controlling nutritional status score in patients with non-small cell lung cancer: A meta-analysis.

Background:The influence of pre-treatment controlling nutritional status (CONUT) score on the prognosis of non-small cell lung cancer (NSCLC) patients is inconclusive. We performed this meta-analysis to evaluate the prognostic significance of CONUT score in NSCLC patients.Methods:A systematic literature review was conducted using PubMed, Embase, and the Cochrane Library databases. The hazard ratio (HR) and 95% confidence interval (CI) were extracted to assess the correlation between the CONUT score and the overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS), as well as the cancer-specific survival.Results:A total of 11 studies with 3029 patients were included in the analysis. Pooled results indicated that a high CONUT score was positively correlated with poor OS (HR: 1.63, 95%CI: 1.40–1.88, P < .001) and shortened DFS/RFS (HR: 1.65, 95%CI: 1.35–2.01, P < .001), but no significant relationship with the cancer-specific survival (HR: 1.28, 95%CI: 0.60–2.73, P = .517) was identified. The negative effect of high CONUT score on the OS and DFS/RFS was detected in every subgroup with varying treatment methods, cancer stage, CONUT cut-off values, sample size, and analysis methods of HR. Additionally, preoperative high CONUT score was an independent predictor of postoperative complications (odds ratio: 1.58, 95%CI: 1.21–2.06, P = .001) in NSCLC. Last but not least, high CONUT score was not significantly correlated with the patients’ sex, smoking status, cancer stage, lymphatic invasion, vascular invasion, pleural invasion, and pathological cancer type.Conclusion:These results demonstrate that high CONUT score is positively related to poor prognoses. The CONUT score may therefore be considered as an effective prognostic marker in NSCLC patients.

Prognostic and Predictive Significance of PD-L1 Expression in Non-Small Cell Lung Cancer Patients: A Single-Center Experience.

To investigate the prognostic and predictive value of PD-L1 expression in operated non-small cell lung cancer (NSCLC) patients and to analyze its relationship with clinicopathological factors. A total of 90 patients with operable NSCLC were included in this retrospective single center study. Tumor blocks of patients were stained immunohistochemically with PD-L1 polyclonal antibody. When evaluated immunohistochemically and statistically, patients with tumor staining percentage of ≥5%, those with +2 and +3 membranous staining intensity, and those with ≥50% H-Score were considered positive. The relationship between PD-L1 expression status and clinicopathological features in addition to the prognostic effect of PD-L1 on survival were statistically analyzed. The frequency of PD-L1 expression was 37%, 15% and 5% according to the staining percentage, staining intensity, and the H-Score, respectively. There was no significant relationship between PD-L1 expression and age, gender, smoking, tumor stage and histological subtype (p > 0.05). However, PD-L1 expression was relatively higher in patients < 65 years of age, men, smokers, patients with advanced tumor stage, and squamous cell subtype. Based on the analysis of the H-Score, no significant difference was noted regarding disease-free survival time between PD-L1 positive and PD-L1 negative patients (median 20 [95% CI 1.2-38.7] months vs. median 27 [95% CI 17.5-36] months, p=0.208). However, overall survival time was significantly shorter in PD-L1 positive compared to PD-L1 negative patients (median 24 months [95% CI 9.9-38] vs. median 48 months [95% CI 33.6-62.3], p=0.049). In patients with high PD-L1 expression, the biological behavior of the cancer was more aggressive, and the life expectancy was shorter. PD-L1 expression seems to be a poor prognostic marker in NSCLC patients.

Significance of inflammatory indexes in atezolizumab monotherapy outcomes in previously treated non-small-cell lung cancer patients

Cancer immunotherapy, including atezolizumab monotherapy, is a promising alternative strategy for patients with advanced non-small-cell lung cancer (NSCLC). Several inflammatory indices have been reported as potential biomarkers regarding the effectiveness of various treatments. This study aimed to analyze the efficacy of atezolizumab monotherapy using baseline inflammatory markers in NSCLC patients. We retrospectively enrolled 81 NSCLC patients who received atezolizumab monotherapy at six different medical institutions in Japan. The Cox proportional hazards model was used to assess the impact of the clinical variables, including inflammatory indexes, on clinical outcomes. Median progression-free survival (PFS) and overall survival (OS) were 60 days and 252 days, respectively. The objective response rate was 7.4%, and the disease control rate was 54.3%. Patients with high neutrophil to lymphocyte ratio (NLR), low lymphocyte to monocyte ratio (LMR), and/or high platelet to lymphocyte ratio (PLR), at baseline, demonstrated substantially shorter PFS and OS compared to those with a low NLR, high LMR, and/or low PLR. The multivariate analysis demonstrated that a high baseline NLR was substantially associated with short PFS and short OS. Our retrospective observations suggest that inflammatory indices may be a potential negative prognostic factor of atezolizumab monotherapy outcomes in NSCLC patients.

Research Progress of Immune Checkpoint Inhibitor Therapy for BRAF Mutation in Non-small Cell Lung Cancer

在非小细胞肺癌（non-small cell lung cancer, NSCLC）患者中，约2%-4%有BRAF基因突变，该型肿瘤恶性程度高、化疗有效率低、预后差。尽管BRAF抑制剂及MEK抑制剂联合治疗在BRAF V600E突变的晚期NSCLC患者中成效显著，已被写入美国国家综合癌症网络（National Comprehensive Cancer Network, NCCN）指南，但两药联合副作用发生率高，耐药之后尚无有效治疗策略，且针对非V600E突变患者仍缺乏靶向治疗方案。本文将针对BRAF突变型NSCLC免疫标志物表达情况以及免疫检查点抑制剂（immune checkpoint inhibitor, ICI）疗效相关研究做一综述，为延长患者生存提供更多选择方案。

Sphingosine kinase-1 predicts overall survival outcomes in non-small cell lung cancer patients treated with carboplatin and navelbine.

Sphingosine 1-phosphate (S1P) is a bioactive lipid metabolite associated with cancer cell proliferation, survival, migration and regulation of tumor angiogenesis in various cellular and animal models. Sphingosine kinase-1 (SphK1) and S1P lyase are the main enzymes that respectively control the synthesis and degradation of S1P. The present study analyzed the prognostic and predictive value of SphK1 and S1P lyase expression in patients with non-small cell lung cancer (NSCLC), treated with either surgery alone or in combination with adjuvant carboplatin and navelbine. Formalin-fixed, paraffin-embedded tissue samples from 176 patients with NSCLC were stained immunohistochemically using antibodies against SphK1 and S1P lyase, and their expression was correlated with all available clinicopathological factors. Increased expression of SphK1 was significantly associated with shorter overall and disease free survival in patients treated with adjuvant platinum-based chemotherapy. No prognostic relevance for S1P lyase expression was observed. Collectively, the results suggest that the immunohistochemical detection of SphK1 may be a promising predictive marker in NSCLC patients treated with adjuvant platinum-based chemotherapy.

Cul4A Modulates Invasion and Metastasis of Lung Cancer Through Regulation of ANXA10.

Cullin 4A (Cul4A) is overexpressed in a number of cancers and has been established as an oncogene. This study aimed to elucidate the role of Cul4A in lung cancer invasion and metastasis. We observed that Cul4A was overexpressed in non-small cell lung cancer (NSCLC) tissues and the overexpression of Cul4A was associated with poor prognosis after surgical resection and it also decreased the expression of the tumor suppressor protein annexin A10 (ANXA10). The knockdown of Cul4A was associated with the upregulation of ANXA10, and the forced expression of Cul4A was associated with the downregulation of ANXA10 in lung cancer cells. Further studies showed that the knockdown of Cul4A inhibited the invasion and metastasis of lung cancer cells, which was reversed by the further knockdown of ANXA10. In addition, the knockdown of Cul4A inhibited lung tumor metastasis in mouse tail vein injection xenograft models. Notably, Cul4A regulated the degradation of ANXA10 through its interaction with ANXA10 and ubiquitination in lung cancer cells. Our findings suggest that Cul4A is a prognostic marker in NSCLC patients, and Cul4A plays important roles in lung cancer invasion and metastasis through the regulation of the ANXA10 tumor suppressor.

CHST11 Promotes Lung Cancer Metastasis through Changing Intracellular Iron Metabolism

Non‐small‐cell lung cancer (NSCLC) is one of the most lethal cancers, for it often develops metastasis after therapy. Cancer metastasis usually begins from epithelial‐to‐mesenchymal transition (EMT), and metabolic disorder is a key mediator of lung cancer EMT. The linkage between metabolic disorder and NSCLC EMT is still unclear. Here, we compared gene expression signatures from both TGFb induction EMT model of NSCLC cells and the EMT score from clinical NSCLC patients' cohort. We found several chondroitin sulfate (CS) biosynthesis genes were highly correlated to NSCLC EMT status. CHST11, the key enzyme of this pathway, was selected for further functional studies. Enforced CHST11 expression promoted NSCLC cells migration, invasion and increasing M‐type markers, such as Slug, N‐cadherin and Vimentin expression and vise versa. Deplete the final product of CS biosynthesis by chondroitinase ABC or enzyme‐dead CHST11 could abolish the NSCLC EMT ability from TGFb and CHST11, respectively. Moreover, we found the CHST11 expression changing the iron metabolic status in NSCLC cells and promoting the NSCLC EMT.In the end, immunohistochemistry showed that CHST11 was a poor prognostic marker of overall survival and disease‐free survival in clinical NSCLC patients. In conclusion, our findings implicated that 1) The chondroitin sulfate biosynthesis pathways is crucial for NSCLC EMT; 2) A novel CHST11‐CP‐Fe3+ pathway is involved in NSCLC EMT. 3) CHST11 is a poor prognostic marker in NSCLC patients. These results might help us to understand the role of aberrant cancer metabolism in NSCLC EMT.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

ALDH1 expression correlates with an epithelial-like phenotype and favorable prognosis in lung adenocarcinoma: a study based on immunohistochemistry and mRNA expression data.

Cancer stem cells (CSC) and epithelial-mesenchymal transition (EMT) pathways are crucial for cancer progression. However, synergistic interactions between CSC and EMT are not clear in non-small cell lung cancer (NSCLC). The objective of this study was to investigate CSC markers such as CD44, NANOG, and ALDH1 expression and its correlation with EMT markers in NSCLC patients. Its association with survival was also determined. CD44, NANOG, and ALDH1 protein expression was evaluated in 267 resected NSCLC and its correlation with e-cadherin, β-catenin, p120 catenin, vimentin, SNAIL, and TWIST expressions was determined based on immunohistochemical and mRNA expression data from The Cancer Genome Atlas (TCGA) database. Survival analyses also were performed based on immunohistochemistry and mRNA expression data from Gene Expression Omnibus dataset. ALDH1 expression in lung adenocarcinoma was positively correlated with the epithelial-like phenotype, low vimentin and low TWIST in immunohistochemical and mRNA expression data. NANOG and ALDH1 expressions measured by immunohistochemical and mRNA expression profiling data of adenocarcinomas were associated with a favorable prognosis. ALDH1 was an independent favorable prognostic marker for overall survival or recurrence-free survival in adenocarcinoma (P = 0.026 and P = 0.033, respectively). The epithelial-like phenotype expressing P120-catenin and beta-catenin was associated with a favorable prognosis; however, the TWIST-expressing mesenchymal-like phenotype was correlated with an unfavorable prognosis. NANOG and ALDH1 protein or mRNA expression showed improved prognosis in adenocarcinoma alone. ALDH1 expression correlated with an epithelial-like phenotype.

Establishing a detection method for CCNY: a potentially significant clinical investigative marker in NSCLC patients.

BackgroundCCNY, a novel cyclin family member, plays an increasingly important role in the progression of tumor invasion and metastasis, including lung cancer. However, the clinical significance of CCNY in non-small-cell lung cancer (NSCLC) patients is unknown.Patients and methodsWe prepared CCNY monoclonal antibodies, validated specific peptides by a peptide array, and established a double-antibody sandwich ELISA detection method. Then, we measured CCNY levels in 100 NSCLC patients and 50 healthy controls. A blinded validation was subsequently performed in 399 NSCLC patients and 150 healthy controls.ResultsWe successfully prepared two specific mouse anti-human CCNY monoclonal antibodies and established a reliable and stable detection method. In the training set, serum CCNY was markedly increased in the NSCLC patients (P<0.05) with an integrated area under the curve of 0.751. With further analysis of the CCNY levels, there were no differences in age, sex, smoking status, tumor location, histologic subtype, or tumor size, but differences were observed in lymphatic (P<0.001) and distant (P<0.001) metastases in NSCLC patients. The CCNY[+] patients had a shorter survival time and progression-free survival than CCNY[−] patients at 3-year follow-up (P<0.001). The results were confirmed by the validation set.ConclusionOur study suggests that CCNY may be useful as a latent tumor marker to facilitate diagnosis and may be an effective indicator of tumor aggressiveness, playing an important role in the prognosis of NSCLC patients.

A Meta Analysis on Prognostic Value of Patients with Non-Small Cell Lung Cancer

Nuclear factor kappa B (NF-κB), a key nuclear transcription factor, is associated with prognosis in a variety of human cancers. However, the clinical value of NF-κB in non-small cell lung cancer (NSCLC) is still controversial. Therefore, the aim of this meta-analysis was to obtain an accurate evaluation of the relationship between NF-κB expression and survival prognosis of NSCLC patients based on published articles. PubMed, EMBASE and Web of Science databases were systematically searched for potential articles. A total of 1159 patients from 7 eligible studies comparing prognostic significance of NF-κB expression levels in NSCLC were included in our meta-analysis. I2 statistic and P value were performed to evaluate heterogeneity using Review Manager version 5.3. The results of analysis were presented as hazard ratio (HR) or odds ratios with 95% confidence interval (95% CI). Subgroup analysis based on ethnicity of NSCLC patients was conducted to illustrate the potential discrepancy. Significant heterogeneity was considered at I2 &gt; 50% and P &lt; 0.05, and random-effects model was used. The combined results indicated that higher NF-κB expression was associated with shorter overall survival of NSCLC patients (HR = 2.78, 95% CI = 1.51–5.12, P = 0.001). Moreover, NF-κB expression was closely associated with tumor stage (HR = 0.32, 95% CI = 0.18–0.57, P &lt; 0.0001) and lymph node metastasis (HR = 0.56, 95% CI = 0.38–0.83, P = 0.004). We conclude that NF-κB expression may be a potential unfavorable prognostic marker for NSCLC patients.

Cell cycle‐related and expression‐elevated protein in tumor overexpression is associated with proliferation behaviors and poor prognosis in non‐small‐cell lung cancer

The cell cycle‐related and expression‐elevated protein in tumor (CREPT) is overexpressed in several human malignancies. However, the clinical relevance of CREPT expression and its biological role in non‐small‐cell lung cancer (NSCLC) remains unclear. In this study, we detected the expression of CREPT in both NSCLC tissues and cell lines by immunohistochemistry, Western blot analysis, and RT‐PCR. The correlation between CREPT expression and clinicopathologic features was analyzed in 271 NSCLC patients. The prognostic value of CREPT expression was evaluated by Kaplan–Meier analysis and Cox regression analysis. CREPT was overexpressed in Calu‐1 cell lines by using plasmid vector and its biological function was explored both in vitro and in vivo. We found that CREPT was significantly overexpressed in NSCLC compared with paired adjacent non‐tumor tissues, and the expression level of CREPT was correlated with tumor differentiation, lymph node metastasis, and clinical stage. Kaplan–Meier analysis showed that the recurrence‐free survival and overall survival of high CREPT expression groups were significantly shorter than those of the low CREPT expression group. Multivariate analysis identified that CREPT might be an independent biomarker for the prediction of NSCLC prognosis. Overexpression of CREPT increased cell proliferation and enhanced the migration and invasion ability of Calu‐1 cells (a human NSCLC cell line with relative low CRPET expression) in vitro. Moreover, CREPT overexpression promoted tumor growth in a nude mice model. These results suggest that CREPT is closely relevant to the proliferation of NSCLC cells and it might be a potential prognostic marker in NSCLC patients.

Retraction Note: The microRNA-1246 promotes metastasis in non-small cell lung cancer by targeting cytoplasmic polyadenylation element-binding protein

The microRNAs present a class of non-coding RNAs which are usually implicated in tumor biology. Recent report has unraveled that a novel member of microRNA family called miR-1246. However, the functional role and molecular mechanisms of miR-1246 in non-small cell lung cancer (NSCLC) is still elusive. Using RT-PCR, luciferase reporter, mRNA microarrays, invasion and migration assays, we investigated the potential role of miR-1246 in the pathogenesis of NSCLC. In this study, we showed that miR-1246 markedly promoted NSCLC cell migration and invasion. Meanwhile, we found that cytoplasmic polyadenylation element binding protein 4 (CPEB4) might be involved and serve as a direct target of miR-1246 in NSCLC. CPEB4 knockdown substantially enhanced NSCLC migration and invasion resembling the effect of miR-1246 in NSCLC. CPEB4 is also frequently downregulated in NSCLC and decreased CPEB4 expression correlated with poor survival. These results suggested that the miR-1246 may promote cell metastasis by targeting CPEB4. Meanwhile, the level of CPEB4 could be used as a potential marker in NSCLC patients. Our findings unraveled novel functions of miR-1246 in lung cancer cells and shed light on NSCLC prognosis.

Prognostic significance of ABCB1 in stage I lung adenocarcinoma.

Cancer stem cell (CSC) properties have been recently proposed to explain tumor carcinogenesis and multidrug resistance in several human cancers, including non-small cell lung cancer (NSCLC). The present study examined the protein expression of three CSC-associated markers, namely ATP binding cassette subfamily B member 1 (ABCB1), aldehyde dehydrogenase 1 family member A1 (ALDH1A1) and cluster of differentiation (CD) 44, by immunohistochemistry in 194 NSCLC patients who underwent complete resection of NSCLC tumors. The association between the expression of these proteins and patient prognosis was evaluated to clarify the prognostic significance of CSC-associated markers in NSCLC patients. Positive staining for ABCB1 demonstrated a trend toward worse survival compared with negative staining in stage I-III NSCLC. Negative staining for ALDH1 or CD44 exhibited a trend toward worse survival compared with positive staining in stage I-III NSCLC. It was observed that patients with stage I lung adenocarcinoma (ADC) showing positivity for ABCB1 expression had significantly poorer survival than those with negative ABCB1 staining (P=0.03). Furthermore, stage I ADC patients with wild-type epidermal growth factor receptor (EGFR) who exhibited positive staining for ABCB1 had significantly shorter disease-free survival (DFS) compared with patients with negative staining for ABCB1 (P<0.01). Analyses by univariate and multivariate Cox proportional hazards models revealed that ABCB1-positive staining was significantly associated with DFS and was an independent prognostic factor (hazard ratio, 3.49; P<0.05) in these patients. These results suggest that ABCB1 protein expression is useful for predicting prognosis and selecting patients for post-operative therapy in stage I lung ADC patients, particularly those harboring wild-type EGFR.

Diagnostic and prognostic values of endothelial-cell-specific molecule-1 with malignant pleural effusions in patients with non-small cell lung cancer.

Over-expressed endothelial-cell-specific molecule-1 (ESM-1) in tumor vascular endothelium contributes to tumor angiogenesis, metastasis, and poor prognosis. However, the content of ESM-1 in pleural effusion is unclear. A retrospective study was carried out to investigate the diagnostic and prognostic values of ESM-1 with malignant pleural effusions in patients with non-small cell lung cancer (NSCLC). ESM-1 levels in malignant pleural effusion (MPE) from 70 patients with NSCLC and 50 cases of benign pleural effusion (BPE) were measured using enzyme-linked immunosorbent assay. Receiver operating characteristic (ROC) curve was calculated to assess the diagnostic value of ESM-1. Survival curves were performed by Kaplan-Meier method and survival characteristics were compared by log-rank test. Univariable and multivariate Cox proportional hazards model were carried out to analysis the significance of different prognostic factors for overall survival (OS). ESM-1 levels were significantly higher in MPE than those in BPE (p < 0.001). By ROC curve analysis, with a cutoff level of 19.58 ng/ml, the accuracy, sensitivity, and specificity for ESM-1 diagnosis MPE were 82.5%, 81.4%, and 84.0%, respectively. Moreover, NSCLC patients with pleural fluid ESM-1 levels below 19.58 ng/ml had significant longer OS than those patients with higher levels (22.09 months vs. 11.49 months, p = 0.003). Multivariate survival analysis showed that high MPE ESM-1 level was an independent prognostic factor (HR, 1.007; p = 0.039) for the OS of NSCLC patients. This study showed that ESM-1 level in pleural effusion could be a potential diagnostic and prognostic marker in NSCLC patients with MPE.

18F-fludrodeoxyglucose maximal standardized uptake value and metabolic tumor burden are associated with major chemotherapy-related tumor markers in NSCLC patients.

ObjectiveMetabolic activity and tumor burden are significant for prognosis and metastasis of non-small cell lung cancer (NSCLC), including maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Chemotherapy resistance is a great challenge for treating NSCLC patients and is also closely related with several biomarkers such as epidermal growth factor receptor (EGFR), p53, and excision repair cross-complementing group 1 protein (ERCC1). Our purpose was to determine the correlation between positron emission tomography/computed tomography (PET/CT) parameters and tumor markers-related chemotherapy resistance in NSCLC.MethodsForty-six NSCLC chemotherapy-naïve patients were enrolled. The SUVmax, MTV, and TLG were calculated by PET/CT imaging, and expression of EGFR, p53, and ERCC1 were analyzed by immunohistochemistry on tissues. SUVmax, MTV, and TLG compared for their performance in predicting the expression of EGFR, p53, and ERCC1 were illustrated with statistical analysis.ResultsSUVmax was significantly correlated with p53 expression (P=0.001), and MTV and TLG were significantly associated with ERCC1 (P=0.000; P=0.000). Furthermore, multiple stepwise regression analysis revealed that SUVmax was the primary predictor for p53, MTV and TLG was the primary predictor for ERCC1. SUVmax had a sensitivity of 91% and specificity of 50% for the detection of p53 positive. The sensitivities of MTV and TLG were 83% and 80%, and specificities were 69% and 75% for the detection of ERCC1 positive, respectively. When we suggested p53 or ERCC1 positive, the cutoff value of SUVmax, MTV, and TLG were 7.68, 23.62, and 129.65 cm3, respectively.ConclusionSUVmax, MTV, and TLG were closely associated with p53 and ERCC1’ expressions. Therefore, 18F-fludrodeoxyglucose PET/CT could be a new way of predicting p53 or ERCC1-related chemotherapy effect in NSCLC patients with more convenience.

Gene Expression of the EGF System—a Prognostic Model in Non–Small Cell Lung Cancer Patients Without Activating EGFR Mutations

OBJECTIVES: Contradicting results have been demonstrated for the expression of the epidermal growth factor receptor (EGFR) as a prognostic marker in non–small cell lung cancer (NSCLC). The complexity of the EGF system with four interacting receptors and more than a dozen activating ligands is a likely explanation. The aim of this study is to demonstrate that the combined network of receptors and ligands from the EGF system is a prognostic marker. MATERIAL AND METHODS: Gene expression of the receptors EGFR, HER2, HER3, HER4, and the ligands AREG, HB-EGF, EPI, TGF-α, and EGF was measured by quantitative polymerase chain reaction in tumor samples from 100 NSCLC patients without EGFR activating mutations. Results were dichotomized into high or low levels of target expression. Coexpression of the ligands and receptors was observed, and a score was developed based on the summed effect of receptors and ligands. Akaike’s information criteria selected the optimal score. Results were correlated with age, sex, stage, histology, performance status, and overall survival. RESULTS: Patients were randomly split 1:1 to create test and validation cohorts. In multivariate analyses, the only individual prognostic marker was EPI (hazard ratio [HR] 0.38 [0.20-0.72], P = .003). The optimal score in the test cohort was validated as a marker of inferior survival in the validation cohort and by bootstrapping. Multivariate analysis confirmed the combined score as a prognostic marker of inferior survival (HR 3.75 [2.17-6.47], P < .00001). CONCLUSION: Our study has developed a model that takes the complexity of the EGF system into account and shows that this model is a strong prognostic marker in NSCLC patients.