NRP1表达与晚期非小细胞肺癌一线含铂方案化疗敏感性及预后的相关性分析

背景与目的：神经菌毛素-1(neuropilin-1,NRP1)作为血管内皮生长因子(vascular endothelial growth factor,VEGF)受体,在肿瘤新生血管形成和肿瘤细胞迁移中发挥重要作用。本研究目的是探索NRP1表达与晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)含铂一线化疗敏感性及预后的相关性。方法：应用免疫组织化学法检测104例一线应用含铂双药方案化疗的晚期NSCLC肿瘤组织中NRP1表达,采用χ2检验及Logistic回归模型分析NRP1表达与化疗反应率的关系。采用Kaplan-Meier和Cox比例风险回归模型分析NRP1表达对生存期的影响。结果：在104例患者中,56例(53.8%)出现NRP1高表达。NRP1高表达与年龄、性别、组织类型、分化程度、行为状态和化疗方案等临床病理因素无关。NRP1低表达患者的化疗反应率高于高表达患者(43.8%vs 23.2%,P=0.026)。Logistic多因素分析结果显示,NRP1表达为化疗反应率的独立预测因素(OR=3.103,95%CI：1.320~7.290,P=0.009),NRP1低表达患者较高表达患者具有更长的无进展生存期(4.6个月vs 3.0个月,χ2=11.273,P=0.001)和总生存期(11.5个月vs 9.2个月,χ2=14.392,P=0.000),NRP1高表达是晚期NSCLC化疗反应率及总生存期的独立预测因素。结论：NRP1高表达与晚期NSCLC一线含铂联合化疗反应率和生存期相关,NRP1表达可能是预测晚期NSCLC化疗敏感性和预后的生物标志物。     

MCAM expression is associated with poor prognosis in non-small cell lung cancer

Background

MCAM has been recently identified as a biomarker for epithelial–mesenchymal transition (EMT) and is potentially involved in metastasis of cancer. The current study aimed at investigating the expression of MCAM in non-small-cell lung cancer (NSCLC) and its clinico-pathological significance.

Methods

A follow-up analysis was performed on 118 patients with NSCLC resected by lobectomy or pneumectomy with systematic lymph node dissection. All patients were followed for 6–60 months. Immunostaining of tissue sections from primary tumors and their lymph node metastasis was performed and evaluated using monoclonal antibody against MCAM, E-cadherin, and vimentin. Correlations were investigated between MCAM immunostaining in primary tumors and E-cadherin, vimentin immunostaining, lymph node metastasis, and survival.

Results

MCAM protein expression was found in 46.61 % of squamous cell carcinomas and 37.47 % of adenocarcinomas; MCAM expression positively correlated with vimentin, but inversely with E-cadherin (both P values <0.05). There were significant correlations between the MCAM immunostaining score in primary tumors and in their lymph node metastasis (P = 0.03). According to the Kaplan–Meier survival estimate, the level of MCAM expression in primary tumors was a statistically significant prognostic factor (P < 0.05).

Conclusions

MCAM expression in surgically treated NSCLC is clearly associated with lymph node metastasis and poor prognosis.     

hENT1 mRNA表达与非小细胞肺癌吉西他滨化疗临床预后的相关性

目的：探讨非小细胞肺癌（NSCLC）石蜡组织中平衡型核苷转运载体（human equilibritive nucleosidetransporter 1,hENT1）mRNA表达水平与接受吉西他滨方案化疗的患者临床病理关系及预后意义。方法：采用实时荧光定量RT-PCR方法检测福尔马林固定-石蜡包埋的非小细胞肺癌组织中hENT1 mRNA表达水平,并比较其表达水平与接受吉西他滨化疗的患者临床病理及生存期之间的关系。hENT1 mRNA表达水平与非小细胞肺癌患者的临床及肿瘤病理特征无相关性。结果：hENT1 mRNA高表达组患者经含吉西他滨方案化疗后中位无进展生存期17.5月、总生存期36月,两组间无进展生存期（P=0.420）、总生存期（P=0.707）。但是从生存曲线分析,hENT1 mRNA高表达的NSCLC患者可能从吉西他滨治疗中获益,可能获得更长无进展生存期的趋势。COX多因素回归分析显示TNM分期与肺癌患者总生存期（P=0.02）、无进展生存期（P=0.008）显著相关。hENT1 mRNA表达水平与非小细胞肺癌肿瘤病理特征无相关性,可能与肿瘤恶性生物学行为无关。结论：hENT1 mRNA的表达水平可能是含吉西他滨药物化疗的NSCLC患者预后的影响因素,肿瘤组织的分期可能是影响NSCLC患者预后的独立预测因素。     

High expression of FOXC1 is associated with poor clinical outcome in non-small cell lung cancer patients

The aim of this study was to detect FOXC1 expression in human non-small cell lung cancer (NSCLC) and to analyze its association with prognosis of NSCLC patients. Expressional levels of FOXC1 mRNA and protein in 30 cases of NSCLC and corresponding non-tumor tissue samples were examined by quantitative real-time PCR and Western blotting. Immunohistochemistry was performed to detect the expression of FOXC1 in 125 NSCLC tissues. We found that the expression levels of FOXC1 mRNA and protein in NSCLC tissues were significantly higher than those in corresponding non-tumor tissues. High-level FOXC1 expression was correlated with poor tumor differentiation, tumor–node–metastasis stage, and lymph node metastasis. Patients with high expression levels of FOXC1 showed lower overall survival rate than those with low expression levels. Multivariate analysis showed that high FOXC1 protein expression was an independent prognostic factor for NSCLC patients. Our study suggests that over-expression of FOXC1 may play an important role in the progression of NSCLC, and FOXC1 expression may offer a valuable marker for predicting the outcome of patients with NSCLC.     

Expression of TrkB and BDNF is associated with poor prognosis in non-small cell lung cancer

High expression levels of TrkB and BDNF are associated with aggressive malignant behavior in tumor cells and a poor prognosis in patients with various types of cancer. In this study, we aimed to identify the relationship between TrkB and BDNF expression and clinicopathological variables and prognosis in non-small cell lung cancer (NSCLC). We evaluated TrkB and BDNF expression in the tumor cells of 102 NSCLC patients by immunohistochemistry. Out of all clinicopathological factors examined, only vascular invasion was significantly correlated with TrkB (P=0.010) and BDNF (P=0.015) expression. TrkB-positive tumors had significantly worse disease-free survival (P=0.0094) and overall survival (P=0.0019) than TrkB-negative tumors, and TrkB expression was an independent prognostic factor for disease-free survival (HR 3.735, 95%C.I. 1.560-11.068, P=0.002) and overall survival (HR 4.335, 95%C.I. 1.534-15.963, P=0.004) in multivariate analysis. Finally, our analysis revealed that co-expression of TrkB and BDNF conferred poorer prognosis compared with overexpression of either protein alone. Our results indicate that expression of TrkB and BDNF is associated with poor prognosis in NSCLC patients.     

Carboplatin-based chemotherapy in patients with advanced non-small cell lung cancer and a poor performance status

BACKGROUND: Poor performance status patients with advanced non-small cell lung cancer (NSCLC) have frequently been excluded from clinical trials due to the perception that they would have excessive treatment-related toxicity and a limited life expectancy. METHODS: A retrospective review of two multicenter trials centered at the University of North Carolina of patients who were treated with platinum-based chemotherapy for advanced NSCLC was conducted. Patients were divided into two subgroups based on Karnofsky performance status (KPS). Patients with a KPS = 70 were considered to have poor performance status, while patients with a KPS > or =80 were considered to have good performance status. RESULTS: Of the 387 patients, 19% (n = 73) had a poor performance status. The response rate (complete and partial responses) was similar between the two sub-groups (26% versus 28%); however, there was a difference in survival (p = 0.0004, log-rank test) between the groups. The median survival and 1-year survival rate for the poor performance status patients was 4.9 months and 21%, while the good performance status patients had a median survival of 8.4 months and a 1-year survival rate of 31%. The rate of National Cancer Institute (NCI) Common Toxicity Criteria (CTC) toxicities was similar between the two groups (p = 0.33). The percentage of patients receiving <4 cycles of therapy in the poor and good performance status was 55 and 39%, respectively (p = 0.012). CONCLUSIONS: Patients with poor performance status treated with platinum based chemotherapy have a similar rate of toxicity compared to good performance status patients. Their overall survival was lower despite a similar response to chemotherapy.     

Wnt1 overexpression associated with tumor proliferation and a poor prognosis in non-small cell lung cancer patients

The Wnt family genes encode multifunctional signaling glycoproteins that are involved in the regulation of a wide variety of normal and pathological processes including tumorigenesis. In order to clarify the clinical significance of the intratumoral Wnt1 expression in non-small cell lung cancer (NSCLC), we performed an immunohistochemical study on the Wnt1 expression in NSCLCs in relation to the tumor proliferation. The intratumoral Wnt1 protein expression appeared in a cytoplasmic staining pattern. Of the 151 NSCLCs studied, 61 carcinomas (40.4%) were Wnt1-positive. Regarding the tumor biology of the intratumoral Wnt1 expression, the Ki-67 proliferation index was significantly higher in Wnt1-positive than in Wnt1-negative tumors (P=0.0062). Furthermore, regarding the expression of c-Myc, one of the proliferation-regulating Wnt targets, the percentage of c-Myc-positive tumor cells was significantly higher in Wnt1-positive than in Wnt1-negative tumors (P=0.0019). The Ki-67 proliferation index was significantly higher in c-Myc-positive than in c-Myc-negative tumors (P=0.0239). The overall survival was significantly lower in patients with Wnt1-positive NSCLCs than in patients with Wnt1-negative NSCLCs (P=0.0003). A Cox regression analysis demonstrated that the Wnt1 status was a significant prognostic factor for NSCLC patients (hazard ratio 1.983; P=0.0061). Our results revealed that the Wnt1 overexpression affects the tumor proliferation in NSCLCs, partly via the upregulation of c-Myc.     

Reduced expression of thrombospondin-1 correlates with a poor prognosis in patients with non-small cell lung cancer

Thorombospondin-1 (TSP-1) is a 450 kDa extracellular matrix glycoprotein, with anti-angiogenic activity. We analyzed the relationship in TSP-1 expression and Microvessel count (MVC), and also clinical factors, using immunohistochemical methods for non-small cell cancer (NSCLC). Histopathologically, there was inverse correlation between TSP-1 expression and MVC for squamous cell carcinoma, but not for adenocarcinoma cases. Among 199 completely resected cases of NSCLC, the 5-year survival was 77.0% when the expression of TSP-1 was maintained and 55.1% when the expression were reduced, respectively (P=0.0046). When compared with TSP-1 expression in the high MVC subgroup, there was significantly shorter survival time when TSP-1 expression was reduced (P=0.0091), and no significant difference was seen for the low MVC subgroup. Multivariate analysis revealed that expression of TSP-1 is as a prognostic factor of NSCLC. Our present data suggest that TSP-1 might not be a direct anti-angiogenic factor and the TSP-1 expression is a prognostic indicator of NSCLC.     

Overexpression of TMPRSS4 in non-small cell lung cancer is associated with poor prognosis in patients with squamous histology

Background:

Mortality rates in lung cancer patients have not decreased significantly in recent years, even with the implementation of new therapeutic regimens. One of the main problems is that a large proportion of patients present local or distant metastasis at the time of diagnosis. The need for identification of novel biomarkers and therapeutic targets for a more effective management of lung cancer led us to investigate TMPRSS4, a protease reported to promote tumour growth and metastasis.

Material and methods:

In all, 34 lung cancer cell lines were used to evaluate the TMPRSS4 expression. Cell migration and clonogenic assays, and an in-vivo lung metastasis model were used for functional analysis of the TMPRSS4 downregulation in H358, H441 and H2170 cell lines. The TMPRSS4 expression analysis in normal and malignant lung tissue samples was performed by qPCR. Five different microarray-based publicly available expression databases were used to validate our results and to study prognosis.

Results:

The TMPRSS4 knock down in H358, H441 and H2170 cells resulted in a significant reduction in proliferation, clonogenic capacity and invasion. A significant (P<0.05) decrease in the lung colonisation and growth was found when mice were injected with TMPRSS4-depleated H358-derived clones, as compared with controls. Expression of TMPRSS4 showed a >30-fold increase (P<0.001) in tumours in comparison with non-malignant samples. Levels in tumours with squamous cell carcinoma (SCC) histology were found to be significantly higher (P<0.001) than those with adenocarcinoma (AC) histology, which was confirmed in data retrieved from the microarrays. Kaplan–Meier curves demonstrated that high levels of TMPRSS4 were significantly associated (P=0.017) with reduced overall survival in the patients with SCC histology, whereas no correlation was found for the AC histology.

Conclusion:

Our results demonstrate that TMPRSS4 has a role in the lung cancer development. The potential use of TMPRSS4 as a biomarker for lung cancer detection or as a predictor of patient''s outcome warrants further investigation.     

Expression of fibroblast growth factor 9 is associated with poor prognosis in patients with resected non-small cell lung cancer

Objectives

Fibroblast growth factor (FGF) 9 is a member of the FGF family, which modulates cell proliferation, differentiation, and motility. Recent studies show that the activation of FGF signals including FGF9 is associated with the pathogenesis of several cancers; however, its clinicopathological and biological significance in non-small cell lung cancer (NSCLC) is unclear. The purpose of this study was to clarify the characteristics of NSCLC with FGF9 expression.

Materials and Methods

We evaluated the expression of FGF9 in resected NSCLC specimens and corresponding non-tumorous lung tissue samples using cDNA microarray and evaluated its clinicopathological characteristics.

Results

Nine out of 90 NSCLC specimens (10%) had “high” FGF9 expression compared with corresponding non-cancerous lung tissues. Histologically, of the 9 NSCLC specimens with high FGF9 expression, 5 were adenocarcinoma, whereas none were squamous cell carcinoma. FGF9 expression was not associated with sex, smoking history, or clinical stage. However, in patients with high and low FGF9 expression, the postoperative recurrence rates were 78% and 24% (p = 0.033), respectively. Overall survival was significantly shorter in patients with high FGF9 expression than in those with low FGF9 expression (p < 0.001).

Conclusion

Our data indicate that FGF9 may be a novel unfavorable prognostic indicator and a candidate therapeutic target of NSCLC.     

MYC protein expression is associated with poor prognosis in diffuse large B cell lymphoma patients treated with RCHOP chemotherapy

This study aims to investigate the prognostic significance of the MYC protein expression in diffuse large B cell lymphoma (DLBCL) patients treated with RCHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). A total of 60 patients with DLBCL from 2008 to 2013 were included. Formalin-fixed, paraffin-embedded DLBCL samples were analyzed for MYC protein expression and divided into high or low MYC group. The MYC protein expression and the international prognostic variables were evaluated. The high MYC protein expression predicted a shorter 3-year estimated overall survival (OS) and progression-free survival (PFS) versus the low MYC protein expression (57 % vs. 96 %, P?<?0.001 and 50 % vs. 96 %, P?=?0.001, respectively). Multivariate analysis confirmed the prognostic significance of the MYC protein expression for both OS (HR, 11.862; 95 % CI, 1.462–96.218; P?=?0.021) and PFS (HR, 6.073; 95 % CI, 1.082–34.085; P?=?0.040). MYC protein expression with International Prognostic Index (IPI) score distinguished patients into three risk groups with different 3-year OS rates (χ ² 23.079; P?<?0.001) and distinct 3-year PFS rates (χ ² 15.862; P?<?0.001). This study suggests that the MYC protein expression is an important inferior prognostic factor for survival in patients with DLBCL treated with RCHOP. The combinative model with IPI score and MYC protein expression could stratify DLBCL patients into prognostically relevant subgroups more effectively than either the IPI or the MYC alone.     

贫血对晚期非小细胞肺癌患者化疗疗效及预后的影响

背景与目的癌性贫血是非小细胞肺癌(non-small cell lung cancer,NSCLC)的常见并发症,不但严重影响NSCLC患者的生活质量(quality of life,QOL),还影响其化疗疗效和预后,本研究通过统计NSCLC患者化疗前后贫血发生率,分析其危险因素,探讨贫血对NSCLC患者QOL及化疗疗效和预后的影响。方法回顾性分析我院2007年1月-2008年12月期间住院的140例NSCLC患者化疗前后血红蛋白水平变化,探讨发生贫血的危险因素,分析其与化疗疗效、预后的关系;并应用QOL量表EORTCQLQ-C30中文版评价贫血对NSCLC患者QOL的影响。结果 140例NSCLC患者,化疗2周期后贫血发生率明显高于化疗前(71.4%vs47.1%,P<0.001),贫血严重程度随着化疗周期的增加而加重。单因素和多因素Logistic回归分析显示,年龄、临床分期、PS评分、白蛋白水平与治疗前发生癌性贫血密切相关;而多因素Logistic分析显示,仅白蛋白水平是引发治疗后贫血的危险因素。贫血者与非贫血者的QOL量表得分在症状、躯体功能及整体生活质量均有显著差异(P<0.05)。无论化疗前发生的...     

Sarcopenia is related to poor prognosis in patients after trimodality therapy for locally advanced non-small cell lung cancer

International Journal of Clinical Oncology - The association between sarcopenia and prognosis in patients with locally advanced non-small cell lung cancer (NSCLC) undergoing trimodality therapy,...     

BNIP3 expression is linked with hypoxia-regulated protein expression and with poor prognosis in non-small cell lung cancer.

BNIP3 is a proapoptotic protein regulated by hypoxia-inducible factor 1. We analyzed BNIP3 expression in 105 tumor samples from early operable, non-small lung cancer and the relationship of expression to hypoxia-inducible factor 1alpha, other hypoxia-regulated pathways, and prognosis. There was strong cytoplasmic expression in >10% of cells in 40 of 105 cases. BNIP3 expression was associated significantly with high hypoxia-inducible factor 1alpha (P = 0.003), carbonic anhydrase 9 (P = 0.04), and was inversely associated with bcl-2 expression (P = 0.009). High BNIP3 expression was a major independent factor for overall survival. Thus, high expression of a hypoxia regulated proapoptotic pathway was associated with a selection of an aggressive phenotype in vivo.     

Reduced expression of claudin-7 is associated with poor outcome in non-small cell lung cancer

Claudin-7 is a tight junction protein that plays an important role in tumorigenesis, tumor invasion and metastasis. We examined the clinical significance of claudin-7 expression in 75 postsurgical non-small cell lung cancer (NSCLC) patients. Claudin-7 expression was measured immunohistochemically and was found to be high in 25 patients (33.3%) and low in 50 (66.7%). Survival was significantly poorer in patients with claudin-7-low than in those with claudin-7-high NSCLCs (P=0.024). In particular, survival was significantly poorer in patients with claudin-7-low than in those with claudin-7-high squamous cell carcinomas (P=0.011). A reduced expression of claudin-7 was associated with poor outcome in NSCLCs. Claudin-7 may thus be a useful biomarker and a potential therapeutic target in patients with NSCLC.