血清碱性成纤维生长因子在晚期NSCLC中的表达和临床价值

目的碱性成纤维生长因子(bFGF)作为非小细胞肺癌(NSCLC)重要的血管新生因子,参与疾病的发生和发展。本研究检测bFGF在NSCLC患者血清中的表达,探讨bFGF在NSCLC患者疾病分期、治疗反应和预后中的价值。方法采用ELISA方法检测66例晚期NSCLC患者和15例健康体检者血清bFGF的表达水平,并和临床指标进行比较分析。结果 NSCLC患者血清bFGF的表达水平显著高于正常对照组(3.2vs 20.1 pg/ml,P0.001);在治疗结束后bFGF水平逐步下降(20.1 vs 10.6 pg/ml,P0.05);生存分析发现NSCLC患者治疗前血清bFGF水平和患者无疾病进展生存显著相关,血清bFGF20 pg/ml患者的PFS显著短于bFGF水平较低患者(5.6月vs 9.6月,P0.001)。结论 NSCLC患者血清bFGF水平和疾病发生发展、疾病分期和疾病生存有关,可以作为NSCLC血管新生和预后的新指标。     

Prognostic value of stromal decorin expression in patients with breast cancer: a meta-analysis

Background

Numbers of studies have investigated the biological functions of decorin (DCN) in oncogenesis, tumor progression, angiogenesis and metastasis. Although many of them aim to highlight the prognostic value of stromal DCN expression in breast cancer, some controversial results still exist and a consensus has not been reached until now. Therefore, our meta-analysis aims to determine the prognostic significance of stromal DCN expression in breast cancer patients.

Methods

PubMed, EMBASE, the Web of Science and China National Knowledge Infrastructure (CNKI) databases were searched for full-text literatures met out inclusion criteria. We applied the hazard ratio (HR) with 95% confidence interval (CI) as the appropriate summarized statistics. Q-test and I² statistic were employed to estimate the level of heterogeneity across the included studies. Sensitivity analysis was conducted to further identify the possible origins of heterogeneity. The publication bias was detected by Begg’s test and Egger’s test.

Results

There were three English literatures (involving 6 studies) included into our meta-analysis. On the one hand, both the summarized outcomes based on univariate analysis (HR: 0.513; 95% CI: 0.406-0.648; P<0.001) and multivariate analysis (HR: 0.544; 95% CI: 0.388-0.763; P<0.001) indicated that stromal DCN expression could promise the high cancer-specific survival (CSS) of breast cancer patients. On the other hand, both the summarized outcomes based on univariate analysis (HR: 0.504; 95% CI: 0.389-0.651; P<0.001) and multivariate analysis (HR: 0.568; 95% CI: 0.400-0.806; P=0.002) also indicated that stromal DCN expression was positively associated with high disease-free survival (DFS) of breast cancer patients. No significant heterogeneity or publication bias was observed within this meta-analysis.

Conclusions

The present evidences indicate that high stromal DCN expression can significantly predict the good prognosis in patients with breast cancer. The discoveries from our meta-analysis have better be confirmed in the updated review pooling more relevant investigations in the future.     

Infrequent ERBB2 mutations in Chinese patients with non-small cell lung cancer

ERBB2 mutations have been reported to occur in a subset of patients with lung adenocarcinomas or lung squamous cell carcinomas for some ethnicities, but it is unclear for Chinese patients with lung squamous cell carcinomas up to now. We retrospectively evaluated the status of ERBB2 mutations in a large cross-sectional cohort of 212 Chinese patients with non-small cell lung cancer (NSCLC) diagnosed in several hospitals from southern China during a time period of 1.5 years by polymerase chain reaction (PCR)-based direct sequencing and PCR-single strand conformation polymorphism (PCR-SSCP) analysis. ERBB2 mutation was found in 1 of 49 lung adenocarcinomas (2.0%) and none in lung squamous cell carcinomas and lung adenosquamous carcinomas. It implies the occurrence of ERBB2 mutations is infrequent in Chinese patients with NSCLC, especially in lung squamous cell carcinomas.     

Expression of paired basic amino acid-cleaving enzyme 4 (PACE4) correlated with prognosis in non-small cell lung cancer (NSCLC) patients

Background

Paired basic amino acid-cleaving enzyme 4 (PACE4) was shown to enhance tumor cells proliferation and invasive. This study provides the first investigation of PACE4 expression in non-small cell lung cancer (NSCLC) and the correlation with clinicopathologic features, prognostic indicators of 172 cases.

Methods

Quantitative real-time PCR (RT-PCR) and immunofluorescence (IF) were applied to detect PACE4 expression in NSCLC and 16HBE cell lines, then 172 consecutive NSCLC and 15 normal lung tissues were studied through immunohistochemistry (IHC). The association between PACE4 expression and clinicopathological parameters was evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of PACE4 expression on survival.

Results

PACE4 expression in NSCLC were significantly higher than normal lung cell and tissues (P<0.05). PACE4 had cytoplasmic expression and was observed in 111 of the 172 (64.5%) NSCLC patients. Clinicopathologically, PACE4 expression was significantly associated with lymph node metastasis (N stage) (P=0.007), and clinical stage (P=0.024). Multivariable analysis confirmed that PACE4 expression increased the hazard of death after adjusting for other clinicopathological factors [hazards ratio (HR): 1.584; 95% confidence interval (CI): 1.167-2.151; P<0.001]. Overall survival (OS) was significantly prolonged in PACE4 negative group when compared with PACE4 positive group (5-year survival rates, 23.1% vs. 54.5%, log-rank test, χ²=17.717, P<0.001), as was disease-free survival (DFS) (5-year survival rates, 23.4% vs. 55.4%, log-rank test, χ²=20.486, P<0.001).

Conclusions

Our results suggest that positive expression of PACE4 is an independent factor for NSCLC patients and it might serve as a potential prognostic biomarker for patients with NSCLC.     

Clinicopathological and prognostic significance of programmed cell death ligand1 (PD-L1) expression in patients with non-small cell lung cancer: a meta-analysis

Objective

Programmed cell death 1 (PD-1) and one of its ligands, PD-L1, are key immune checkpoint proteins. Evidences showed PD-L1 is an emerging biomarker for immunotherapy by anti-PD-1 and anti-PD-L1 antibody in non-small cell lung cancer (NSCLC). To investigate the association of PD-L1 protein expression with clinicopathological features and its impact on survival outcome, we conducted a meta-analysis.

Methods

A comprehensive literature search of electronic databases (up to July 10, 2014) was performed. Correlation between PD-L1 expression and clinicopathological features and overall survival (OS) was analyzed by synthesizing the qualified data. Publication biases were examined.

Results

A total of 1,550 NSCLC patients from 9 studies were included. The pooled odds ratios (ORs) indicated high PD-L1 expression was associated with poor tumor differentiation [OR =0.53, 95% confidence interval (CI): 0.39-0.72, P<0.0001]. Whereas, none of other clinicopathological characteristics [gender, smoking status, histological type, invasive depth of tumor, status of lymph node metastasis and tumor node metastasis (TNM) stage] were correlated with PD-L1 expression in current analysis. The combined hazard ratio (HR) for OS showed high expression of PD-L1 impaired the OS in NSCLC (HR_{positive/negative} =1.47, 95% CI: 1.19-1.83, P=0.0004).

Conclusions

Our meta-analysis indicated PD-L1 protein expression in NSCLC was not associated with common clinicopathological characteristics, except tumor differentiation. It was a poor prognostic biomarker for NSCLC. Further research should be performed to investigate the precise clinicopathological and prognostic significance of PD-L1 in NSCLC under uniform testing standard.     

晚期NSCLC患者外周血EGFR基因检测的meta分析

目的 系统评价使用晚期非小细胞肺癌患者(non-small cell lung cancer,NSCLC)血液行表皮生长因子受体(epidermal growth factor receptor,EGFR)检测的临床价值.方法 检索SCI、PubMed、Medline、中国生物医学文献数据库及中国学术期刊全文数据库中发表的使用晚期NSCLC血液行EGFR检测的研究.敏感度、特异度及综合工作者受试曲线(symmetric receiveroperator characteristic curve,SROC)等统计指标评估血液检测的诊断特性.结果 本研究共纳入13篇文献,2 349例晚期NSCLC患者样本,血液EGFR突变检测的敏感度与特异度分别为61％ (95％ CI:0.49～0.72)和96％ (95％CI:0.90～0.99),SROC曲线下面积为0.85(95％ CI:0.82～0.88).结论 当晚期NSCLC患者组织获取困难时,血液特别是血浆可替代组织进行EGFR基因检测.     

非小细胞肺癌患者血清血管内皮生长因子水平的变化及与临床的关系

目的研究非小细胞肺癌患者血清血管内皮生长因子(VEGF)水平的变化及与临床分期和病理类型的关系。方法三组研究对象为非小细胞肺癌组患者96例,支气管、肺良性病变组40例,健康对照组30例,采用ELISA法进行血清VEGF的检测。结果非小细胞肺癌组的血清VEGF水平显著高于其它两组(P<0.01);非小细胞肺癌患者血清VEGF水平随临床分期的递增而逐步升高,各期间比较差异有显著性(P<0.05);不同病理类型非小细胞肺癌患者血清的VEGF水平之间无显著性差异(P>0.05)。结论非小细胞肺癌患者的血清VEGF水平升高和随临床分期递增而明显升高的改变对非小细胞肺癌的临床分期和预后产生了重要影响,而这种改变并不受病理类型的影响,有助于我们对非小细胞肺癌患者的治疗效果和预后进行判断。     

A decade of advances in treatment for advanced non-small cell lung cancer

The last decade has heralded a paradigm shift in the evaluation and treatment of advanced non-small cell lung cancer (NSCLC). No longer are patients with NSCLC considered a homogeneous population treated in the same way; rather, clinical characteristics, histology, and an expanding array of molecular markers are increasingly being used to individualize therapy. Both histology and tumor epidermal growth factor receptor mutational status currently have firmly established roles in determining initial and salvage therapy for advanced NSCLC. Several other biomarkers are the focus of ongoing prospective randomized clinical trials customizing both traditional chemotherapy and newer molecularly targeted agents.     

Elevated platelet count is a strong predictor of poor prognosis in stage I non-small cell lung cancer patients

Stage I non-small cell lung cancer (NSCLC) show a highly variable biological behavior which cannot be accurately predicted by the current available prognostic markers. Platelet plays a significant role in cancer cell growth, progression and metastasis. This study aimed to investigate whether preoperative platelet count correlate with clinical prognosis in localized NSCLC. A retrospective clinical analysis was designed for a total of 234 stage I NSCLC patients in our hospital between October 2006 and December 2009. Pre-operative platelet count was measured. The association of platelet count with clinical pathological factors and patient outcome was evaluated. A significant correlation was detected between platelet count and tumor cell differentiation and T stage. Patients with elevated platelet count had an elevated risk of disease progression and death compared to patients with normal platelet count. The hazard ratio was 5.314 (95% confidence interval [CI] 2.750–10.269) for disease progression and 3.139 (95% CI 1.227–8.034) for death. The trend linking increasing platelet count with risk was also statistically significant for both the outcomes (p?<?0.05). These finding demonstrate that preoperative platelet count is a useful predictor of high risk progression and poor prognosis in stage I NSCLC patients.     

The role of SOX-2 on the survival of patients with non-small cell lung cancer

Background

Lung cancer is the most commonly diagnosed cancer as well as the leading cause of cancer death worldwide. Observational studies on the prognostic role of SOX-2 in non-small-cell lung cancer (NSCLC) are controversial.

Methods

To clarify the impact of SOX-2 in NSCLC survival, we performed this meta-analysis that included eligible studies. The combined hazard ratios and their corresponding 95% confidence intervals (95% CI) were calculated in terms of overall survival.

Results

A total of seven studies with 1,944 patients were evaluable for this meta-analysis. The studies were categorized by histology, disease stage and patient race. Our results suggested that SOX-2 overexpression had a favorable impact on survival of patients with NSCLC, the HR (95% CI) was 0.57 (0.48 to 0.65). However, highly significant heterogeneity was detected among these studies (I²=76.7%, P=0.000).

Conclusions

SOX-2 overexpression indicates a favorable prognosis for patients with NSCLC.     

非小细胞肺癌患者血浆Cripto-1的水平及临床意义

目的探讨非小细胞肺癌患者(NSCLC)血浆中CR-1的表达水平与患者临床病理特征之间的关系,及其对肺癌预后的判断价值。方法收集35例正常人血浆,40例良性肺部疾病患者和102例NSCLC患者血浆,用酶联免疫吸附法(ELISA)检测血浆CR-1表达水平。结果NSCLC患者血浆CR-1水平远高于健康对照组(P<0.05),良性肺部疾病患者血浆CR-1浓度虽也有一定的升高,但较之肺癌组低,二者间差异有显著性(P<0.05)。肺癌患者血浆CR-1水平与淋巴结转移状态和临床分期有关(P<0.01)。血浆CR-1与患者生存期密切相关,生存>12个月患者血浆CR-1明显低于<12个月者(P<0.01)。结论血浆CR-1与NSCLC的病程进展及生存期相关,是一种有价值的预后判断指标。     

Molecular genetic alterations in egfr CA-SSR-1 microsatellite and egfr copy number changes are associated with aggressiveness in thymoma

Background

The key role of egfr in thymoma pathogenesis has been questioned following the failure in identifying recurrent genetic alterations of egfr coding sequences and relevant egfr amplification rate. We investigated the role of the non-coding egfr CA simple sequence repeat 1 (CA-SSR-1) in a thymoma case series.

Methods

We used sequencing and egfr-fluorescence in situ hybridization (FISH) to genotype 43 thymomas; (I) for polymorphisms and somatic loss of heterozygosity of the non-coding egfr CA-SSR-1 microsatellite and (II) for egfr gene copy number changes.

Results

We found two prevalent CA-SSR-1 genotypes: a homozygous 16 CA repeat and a heterozygous genotype, bearing alleles with 16 and 20 CA repeats. The average combined allele length was correlated with tumor subtype: shorter sequences were significantly associated with the more aggressive WHO thymoma subtype group including B2/B3, B3 and B3/C histotypes. Four out of 29 informative cases analysed for somatic CA-SSR-1 loss of heterozygosity showed allelic imbalance (AI), 3/4 with loss of the longer allele. By egfr-FISH analysis, 9 out of 33 cases were FISH positive. Moreover, the two integrated techniques demonstrated that 3 out of 4 CA-SSR-1-AI positive cases with short allele relative prevalence showed significantly low or high chromosome 7 “polysomy”/increased gene copy number by egfr-FISH.

Conclusions

Our molecular and genetic and follow up data indicated that CA-SSR-1-allelic imbalance with short allele relative prevalence significantly correlated with EGFR 3+ immunohistochemical score, increased egfr Gene Copy Number, advanced stage and with relapsing/metastatic behaviour in thymomas.     

Impact of EGFR mutation status on tumor response and progression free survival after first-line chemotherapy in patients with advanced non-small-cell lung cancer: a meta-analysis

Objectives

Non-small-cell lung cancer (NSCLC) patients harboring sensitive epidermal growth factor receptor (EGFR) mutations derive greater benefits from EGFR-tyrosine kinase inhibitors (EGFR-TKIs) than those with wild type tumors. However, whether EGFR mutation status is associated with the efficacy of cytotoxic chemotherapy or prognosis in advanced NSCLC patients remained controversial. Thus, we sought to conduct a meta-analysis to answer this question.

Methods

Electronic databases were searched for eligible literatures. The primary outcomes were objective response rate (ORR) and 6-month progression-free survival (PFS) rate. The pooled odds ratio (OR) was calculated using random-effects model. Subgroup analyses stratified by study types, EGFR mutation detection methods, chemotherapy regimens, and patient origins were proposed.

Results

A total of 14 studies involving 1,772 advanced NSCLC patients with known EGFR mutation status who had received first-line chemotherapy were included. Patients with positive EGFR mutation had numerically higher ORR than wild type patients (36.2% vs. 30.1%) without significant differences (OR 1.24, 95% CI, 0.90 to 1.70; P=0.19). However, patients with EGFR mutants had significantly superior 6-month PFS rate than wild-type patients (58.6% vs. 47.2%; OR 1.88, 95% CI, 1.33 to 2.65; P=0.0003). Results of the subgroup analyses were concordant with the overall ones.

Conclusions

This comprehensive analysis revealed that advanced NSCLC patients with sensitivity EGFR mutation had higher 6-month PFS rate and potentially greater ORR compared with wild-type patients after first-line chemotherapy. It suggested that EGFR mutation status should be considered a significant factor for patient stratification in evaluating the efficacy of antitumor agents in addition to EGFR-TKIs.     

Prognostic value of KRAS and BRAF mutations in curatively resected colorectal cancer

AIM: To investigate the prognostic role of KRAS and BRAF mutations after adjustment for microsatellite instability(MSI) status in Japanese colorectal cancer(CRC) population.METHODS: We assessed KRAS and BRAF mutations and MSI status in 813 Japanese patients with curatively resected, stage Ⅰ-Ⅲ CRC and examined associations of these mutations with disease-free survival(DFS) and overall survival(OS) using uni- and multivariate Cox proportional hazards models.RESULTS: KRAS and BRAF mutations were detected in 312(38%) of 812 and 40(5%) of 811 tumors, respectively. KRAS mutations occurred more frequently in females than in males(P = 0.02), while the presence of BRAF mutations was significantly associated with the female gender(P = 0.006), proximal tumor location(P 0.001), mucinous or poorly differentiated histology(P 0.001), and MSI-high tumors(P 0.001). After adjusting for relevant variables, including MSI status, KRAS mutations were associated with poorer DFS(HR = 1.35; 95%CI: 1.03-1.75) and OS(HR = 1.46; 95%CI: 1.09-1.97). BRAF mutations were poor prognostic factors for DFS(HR = 2.20; 95%CI: 1.19-4.06) and OS(HR = 2.30; 95%CI: 1.15-4.71). Neither the BRAF by MSI interaction test nor the KRAS by MSI interaction test yielded statistically significant results for DFS and OS.CONCLUSION: KRAS and BRAF mutations are associated with inferior survival, independent of MSI status, inJapanese patients with curatively resected CRC.     

非小细胞肺癌患者临床疗效及预后的影响因素

目的 研究非小细胞肺癌(NSCLC)的临床疗效及相关预后因素.方法 2013年6月-2020年6月,于复旦大学附属华东医院呼吸科治疗的155例NSCLC患者,分为手术组(n=47)和非手术组(n=108).比较2组的临床特征,随访观察患者的中位总生存时间(OS)、中位无进展生存(PFS)及生存率,分析影响NSCLC预后...     

重庆地区非小细胞肺癌表皮生长因子受体突变检测与临床病理特征分析

目的探讨重庆市地区非小细胞肺癌（NSCLC）患者表皮生长因子受体（EGFR）突变状态及其与临床病理特征的关系。方法收集55例NSCLC患者的癌组织或胸水标本,采用扩增阻滞突变系统（ARMS）检测EGFR外显子18、19、20和21突变状态。结果55例患者中,EGFR突变14例,突变率25．45％;其中,男、女突变率分别为12．50％、43．48％（P=0．013）;吸烟、不吸烟患者突变率分别为11．11％、39．29％（P=0．017）;外显子19突变8例（57．14％,8／14）,外显子21突变5例（35．71％,5／14）,外显子18、20同时突变1例（7．15％,1／14）。结论在重庆市地区NSCLC患者中,女性、非吸烟者EGFR突变率较高,EGFR基因突变以外显子19和21为主。     

Genetic modifiers of EGFR dependence in non-small cell lung cancer

Lung adenocarcinomas harboring activating mutations in the epidermal growth factor receptor (EGFR) represent a common molecular subset of non-small cell lung cancer (NSCLC) cases. EGFR mutations predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and thus represent a dependency in NSCLCs harboring these alterations, but the genetic basis of EGFR dependence is not fully understood. Here, we applied an unbiased, ORF-based screen to identify genetic modifiers of EGFR dependence in EGFR-mutant NSCLC cells. This approach identified 18 kinase and kinase-related genes whose overexpression can substitute for EGFR in EGFR-dependent PC9 cells, and these genes include seven of nine Src family kinase genes, FGFR1, FGFR2, ITK, NTRK1, NTRK2, MOS, MST1R, and RAF1. A subset of these genes can complement loss of EGFR activity across multiple EGFR-dependent models. Unbiased gene-expression profiling of cells overexpressing EGFR bypass genes, together with targeted validation studies, reveals EGFR-independent activation of the MEK-ERK and phosphoinositide 3-kinase (PI3K)-AKT pathways. Combined inhibition of PI3K-mTOR and MEK restores EGFR dependence in cells expressing each of the 18 EGFR bypass genes. Together, these data uncover a broad spectrum of kinases capable of overcoming dependence on EGFR and underscore their convergence on the PI3K-AKT and MEK-ERK signaling axes in sustaining EGFR-independent survival.The term “oncogene addiction” has been used to describe the phenomenon whereby tumor cells exhibit singular reliance on an oncogene or oncogenic pathway for their survival, despite the accumulation of multiple genetic lesions (1). In non-small cell lung cancer (NSCLC), this principle is perhaps best exemplified with the finding that epidermal growth factor receptor (EGFR) mutations predict response to EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, and thus represent a dependency in the subset of tumors harboring these alterations (2–6). However, though EGFR-mutant NSCLCs typically respond dramatically to EGFR TKIs, clinical responses are not universal, even within this genetically defined cohort, with the rate of objective response estimated to be ∼71% (5, 6). Furthermore, the overwhelming majority of patients who initially respond to EGFR inhibitors ultimately develop resistance to therapy (7). A deeper understanding of the genetic underpinnings of EGFR addiction, and how EGFR-mutant cells can overcome reliance on EGFR, may improve clinical outcomes.Here, we have applied an unbiased screening approach to identify genetic modifiers of EGFR dependence in NSCLC. Mounting evidence supports the existence of several genetic modifiers of EGFR dependence in EGFR-mutant NSCLC, which can reduce the degree to which these tumors rely on EGFR and thereby contribute to EGFR TKI resistance (8). Examples include amplification of the MET receptor tyrosine kinase (RTK) (9), activation of the NF-κB pathway (8), amplification of the HER2 (ERBB2) RTK (10), amplification of the CRKL gene (11), and activation of the AXL kinase (12). Notably, MET bypass can be reciprocally achieved via EGFR activation in MET-dependent cells (13), and analogous examples of reciprocal kinase switching have been reported in other kinase-driven cancer models (14, 15). These and other findings suggest that compensatory kinase switching may be a more general way in which oncogene-dependent cancers overcome reliance on their primary driver kinase (14, 16), but the full-range of kinases capable of mediating EGFR bypass has not been systematically studied.Recent advances in large-scale functional genetic libraries have made it possible to query a wide range of genetic perturbations for their ability to modulate specific cellular phenotypes in mammalian systems (17, 18). Using the model of EGFR-mutant, erlotinib-sensitive NSCLC cells, we have performed a systematic ORF-based screen to identify kinase and kinase-related genes whose overexpression can complement loss of EGFR activity in an EGFR-dependent context. Our findings indicate broad potential for EGFR substitution in the setting of EGFR dependence, with compensatory mechanisms commonly conferring EGFR-independent activation of the PI3K-AKT and MEK-ERK signaling pathways. Importantly, this approach has recovered known mechanisms of erlotinib resistance as well as identified novel mediators of EGFR bypass in EGFR-mutant NSCLC. These data support the idea that the EGFR-dependent state can be redundantly driven by diverse genetic inputs that commonly converge on shared downstream signaling nodes.     

非小细胞肺癌EGFR靶向治疗的研究进展

肺癌是目前世界上发病率和病死率最高的癌症,其中非小细胞肺癌(NSCLC)占肺癌的85％以上.近10年来,随着对肿瘤生物学的深入研究,作为NSCLC治疗靶点的多个基因突变已被识别,其中表皮生长因子受体(EGFR)基因的突变频率最高,因此,EGFR基因的靶向治疗也逐渐成为NSCLC治疗的主力军.本文将就目前NSCLC中的EGFR基因突变及其靶向治疗药物进行简要阐述.