The VEGFR-2 protein and the VEGFR-2 rs1870377 A>T genetic polymorphism are prognostic factors for gastric cancer

Objective: Angiogenesis is one of the key processes in the development of malignant tumors. The vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) signaling pathway regulates branching angiogenesis in cancer. In this study, we analyzed the associations of VEGF/VEGFR-2 proteins and VEGFR-2 genetic variations with the prognosis of gastric cancer (GC).

Method: We collected the clinical information of patients with GC and extracted genomic DNA from paraffin-embedded tissues. Immunohistochemical methods were used to detect the expression of VEGF and VEGFR-2 in GC tissues. Four single nucleotide polymorphisms of VEGFR-2 were detected by the TaqMan assay. The Kaplan-Meier method and Cox regression model were applied to analyze the associations between clinicopathological characteristics, VEGFR-2 polymorphisms and GC prognosis.

Results: A total of 256 cases of GC were included in our study. VEGFR-2 (+) and VEGFR-2 (++/+++) protein expression levels were detected in 83 and 135 cases, respectively. High expression of the VEGFR-2 protein was associated with the poor prognosis of GC (log-rank test P = 0.026). No statistical significance was observed for the association between VEGF and the prognosis of GC. The VEGFR-2 rs1870377 A > T genetic polymorphism was discovered to be associated with the prognosis of GC (AA vs. AT, HR = 1.69, 95% CI = 1.06–2.68, P = 0.027).

Conclusion: Our study suggested that the high expression of VEGFR-2, as well as the VEGFR-2 rs1870377 A > T genetic polymorphism, may be prognostic markers for GC.     

Prognostic and predictive value of vascular endothelial growth factor and its soluble receptors, VEGFR-1 and VEGFR-2 levels in the sera of small cell lung cancer patients

OBJECTIVES: Small cell lung cancer (SCLC) has a rapid growth rate and is characterized by early metastases. Tumor growth is dependent on angiogenesis. Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis. Whether surveillance of pre- and post-treatment serum VEGF and especially its receptors VEGF-1 and VEGF-2 levels in SCLC patients have impact on clinical outcome is unknown. METHODS: From February 2001 to January 2003, 39 consecutive patients with histological proven SCLC were enrolled into the study. Pre-treatment (n: 39) and post-treatment (n: 25) samples of the same patients were collected at the time of their response evaluation. The levels of VEGF and its receptors VEGFR-1 and VEGFR-2 were measured in the serum by quantitative sandwich enzyme immunoassay technique. RESULTS: The median pre-treatment serum VEGF, VEGFR-1, and VEGFR-2 levels which were significantly higher than the normal controls were 1,200 pg/ml (range, 1,414.3 +/- 956.2 pg/ml), 85 pg/ml (range, 97.8 +/- 70.7 pg/ml), and 11,550 pg/ml (range, 14,481 +/- 6,267 pg/ml), respectively. We detected a poor but positive correlation between VEGF and VEGFR-2 (r: 0.46, p: 0.003). Pre-treatment low serum VEGF (<728.5 pg/ml) value (p: 0.02) and good response to treatment (p: 0.008) were found as good prognostic factors by multivariate analysis. CONCLUSIONS: Low serum VEGF concentration is a significant and independent prognostic factor in SCLC patients. Surveillance of VEGF and its receptors to predict chemotherapy response is not useful. Whether the levels of serum VEGF and its receptors VEGFR-1 and VEGFR-2 have value in detecting treatment modalities of SCLC need further studies.     

355例晚期非小细胞肺癌预后因素分析

目的 回顾分析355例晚期非小细胞肺癌（NSCLC）的预后因素，为探索个体化治疗提供参考依据。方法 1988年3月至2000年10月35例经组织学或细胞学确诊的、未经治疗的晚期NSCLC患者（Ⅲ期134例，37.75%；Ⅳ期221例，62.25%），至少接受2周期化疗。观察疗效和生存期，分析预后因素。结果 全组无CR病例，PR101例，SD147例，有效率为28.45%，肿瘤控制率为69.86%，中位生存期为16月。1、2、3和5年生存率分别为58.41%、29.35%、14.60%和8.60%。Ⅳ期患者只闰生存期为14月，1、2、3和5年生存率分别为54.62%、25.59%、12.70%和6.73%。COX比例风险模型分析显示治疗后ECOG评分改善＋稳定（P＝0.0440)和二线化疗失败后原方案加用γ－IFN或TAM及原发灶放疗等可能有利于生存期的改善。     

非小细胞肺癌患者血清中VEGF和Ang-2的表达和临床意义

目的:检测非小细胞肺癌（NSCLC）患者血清中血管内皮生长因子（VEGF）和血管生成素-2（Ang-2）的含量,探讨血清中VEGF和Ang-2与肿瘤血管生成的关系及其临床意义。方法:收集40例NSCLC患者血清和肿瘤组织,以40例健康志愿者血清为对照,采用ELISA方法检测血清中VEGF和Ang-2的含量,应用免疫组化法检测肿瘤组织中的微血管密度（MVD）,分析血清中VEGF和Ang-2与肿瘤血管生成、临床病理资料和预后的相关性。结果:NSCLC患者血清中VEGF［（625.6±312.5）pg/ml］和Ang-2［（2450.2±1021.1）pg/ml］的含量明显高于正常对照组血清中VEGF［（321.4±102.6）pg/ml］和Ang-2［（1020.6±421.6）pg/ml］的含量（P<0.05）。NSCLC患者血清中VEGF和Ang-2的含量均与肿瘤的MVD呈正相关(r=0．525,P<0.01;r=0．612,P<0.01)。NSCLC患者血清中VEGF和Ang-2的含量与肿瘤大小、淋巴结转移及临床分期有关（P<0.05）。血清中VEGF和Ang-2高表达的患者总生存时间明显低于低表达患者（P<0.05）。结论:VEGF和Ang-2 在NSCLC的血管生成和发展中发挥重要作用,两者可作为NSCLC诊断和预后判断的潜在的分子标志物。     

Ang-2、VEGF及VEGFR3在喉鳞癌中的表达及其临床意义

 目的 研究喉鳞癌组织中促血管生成素-2(Angiopoietin-2,Ang-2)、血管内皮生长因子（vascular endothelial growth factor,VEGF）及受体-3（VEGFR-3）的表达及其与临床病理学特征间的关系。 方法 采用免疫组织化学方法检测喉鳞癌患者癌组织及癌旁正常组织中促血管生成素-2（Ang 2）、血管内皮生长因子（VEGF）及血管内皮生长因子受体-3（VEGFR-3）的表达。 结果 Ang-2、VEGF及VEGFR-3在喉鳞癌组织中表达显著高于癌旁正常组织（P均<0.01）;Ang-2表达在肿瘤病理分化程度及有无淋巴结转移上差异无统计学意义（P>0.05）, VEGF与VEGFR 3的表达在病理分化程度上的比较差异无统计学意义（P>0.05）,而有无淋巴结转移上的比较差异有统计学意义（P<0.05）; Pearson积差相关性分析：喉鳞癌组织中Ang-2与VEGF的表达呈正相关（r=0.8193,P<0.01）;VEGF与VEGFR-3的表达也呈正相关（r=0.7365,P<0.01）。 结论 Ang-2、VEGF及VEGFR-3与肿瘤的血管生成和成熟密切相关,它们在喉鳞癌组织中的过表达可能在喉鳞癌的发展过程中起重要作用。     

Bee venom inhibits tumor angiogenesis and metastasis by inhibiting tyrosine phosphorylation of VEGFR-2 in LLC-tumor-bearing mice

Bee venom (BV) treatment is the therapeutic application of honeybee venom (HBV) for treating various diseases in Oriental medicine. In the present work, the authors investigated the functional specificity of BV as an angiogenesis inhibitor using in vitro models and in vivo mouse angiogenesis and lung metastasis models. BV significantly inhibited the viability of Lewis lung carcinoma (LLC) cells but did not affect peripheral blood mononuclear lymphocytes (PBML) cells. BV also inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration and capillary-like tube formation of human umbilical vein endothelial cells (HUVECs). Western blotting analysis showed that BV inhibited AKT and MAPK phosphorylation in LLC cells and HUVECs and down regulated expression of VEGF and VEGFR-2 of LLC cells and HUVECs. Also, BV effectively disrupted VEGF-induced neovascularization in Matrigel plugs in our in vivo angiogenesis assay. When given subcutaneously, BV also significantly suppressed tumor angiogenesis through inhibition of VEGF and VEGFR-2 in LLC model. Mice bearing subcutaneous LLC tumors were treated with 1 μg/ml or 10 μg/ml of BV. They showed reductions ranging between 49% and 62% in primary tumor volume and reduction of spontaneous pulmonary metastasis occurrences. Furthermore, BV treatment in the spontaneous lung metastases model after primary tumor excision prolonged their median survival time from 27 to 58 days. These results suggest that the tumor-specific anti-angiogenic activity of BV takes effect during different stages of tumor progression by blocking the tyrosine phosphorylation of VEGFR-2, and validate the application of BV in lung cancer treatment.     

Bevacizumab and erlotinib: a promising new approach to the treatment of advanced NSCLC

Biologic agents that target molecules involved in tumor growth, progression, and pathological angiogenesis--such as the human epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF)--have demonstrated efficacy in patients with non-small cell lung cancer (NSCLC). Erlotinib (Tarceva); OSI Pharmaceuticals, Inc., Melville, NY, Genentech, Inc., South San Francisco, CA, and F. Hoffmann-La Roche Ltd, Basel, Switzerland), a highly selective tyrosine kinase inhibitor that inhibits EGFR, and bevacizumab (Avastin); Genentech, Inc., South San Francisco, CA, and F. Hoffmann-La Roche Ltd, Basel, Switzerland), a VEGF-targeted recombinant humanized monoclonal antibody, have displayed very encouraging activity in a randomized phase II trial in patients with previously treated NSCLC. Because erlotinib and bevacizumab act on two different pathways critical to tumor growth and dissemination, administering these drugs concomitantly may confer additional clinical benefits to cancer patients with advanced disease, by virtue of their complementary (or additive) antitumor activity. The combination of bevacizumab plus erlotinib may prove to be a viable second-line alternative to chemotherapy or erlotinib monotherapy in patients with NSCLC. The benefits of the combination may be further enhanced by selecting for patients who are likely to respond to this therapy. While a number of potential predictive markers have been identified for erlotinib, their value remains to be confirmed in prospective trials. In addition, the application of such personalized therapy will also depend on the availability of validated screening methods.     

The relevance of cell type- and tumor zone-specific VEGFR-2 activation in locally advanced colon cancer

Background

For the successful therapeutic use of inhibitors of the vascular endothelial growth factor receptor (VEGFR) pathway detailed knowledge of the mechanisms leading to tumor progression is indispensable. The main goal of this study was to determine the relevance of the VEGFR-2 activating pathway for colon carcinoma (CC) metastasis. The initial event is ligand-induced receptor activation through tyrosine autophosphorylation.

Methods

VEGFR-2, its ligands VEGF-C and VEGF-D and the phosphorylated (activated) receptor forms pVEGFR-2^Tyr1175 and pVEGFR-2^Tyr1214 were investigated immunohistochemically in different tumor compartments (intratumoral (zone 1) - invasive front (zone 2) – extratumoral soft tissue (zone 3)) and various cell types (tumor cells, inflammatory cells, macro- and microvasculature) in 84 non-metastatic, lymphogenous-metastatic and haematogenous-metastatic CC.

Results

VEGF-D produced by tumor cells has an autocrine affinity for its receptor VEGFR-2. In tumor budding regions VEGF-D-induced receptor activation by autophosphorylation at Tyr1214 seems to be a possible initial event of the VEGFR-2-mediated signaling pathway, but without effect on metastatic behaviour. In inflammatory cells of almost all CC VEGFR-2 phosphorylation at Tyr 1175 and Tyr 1214 was detectable without accompanying receptor expression, suggesting receptor activation without cell surface expression. Peritumoral inflammatory cells also expressed paracrine acting VEGF-C. The autocrine VEGF-D/VEGFR-2 signaling axis and receptor autophosphorylation at Tyr1214 appear to be main events for capillaries in all three tumor zones and for small vessels in zone 1 and 2. Independent of the metastatic status a large number of cases with capillary immunopositivity in the angiogenically active invasive front was documented, especially for VEGF-D, VEGFR-2 and pVEGFR-2^Tyr1214. VEGFR-2 positive extratumoral capillaries were significantly more common in distant metastatic CC. In all tumor compartments the investigated biomolecules were also detected in different frequencies in the macrovasculature, which is responsible for sufficient tumor vascularization. In addition, vascular paracrine-acting VEGF-C production was widely detected, but without zone and vessel-type dependence.

Conclusions

The VEGFR-2 activating pathway is closely involved in tumor cell-associated, vessel-mediated and immuno-inflammatory processes in colon carcinoma and appears to contribute to tumor survival and growth as well as maintenance of the infiltrative phenotype rather than to promote metastasis.     

Platinum rechallenge in patients with advanced NSCLC: A pooled analysis

Introduction

The sole agents pemetrexed (PEM), docetaxel and anti-EGFR agents are approved second-line therapies for non-small cell lung cancer (NSCLC) after failure with cisplatin-based doublets. The potential usefulness of platinum-based doublets as rechallenge for second-line chemotherapy has not yet been established.

Methods

Studies that enrolled NSCLC platinum pre-treated patients were identified using electronic databases (MEDLINE and EMBASE). Pemetrexed and taxanes (TAXs)-based platinum combinations were considered. A systematic review was conducted using Comprehensive Meta-Analysis (version 2.2.064) software to calculate the event rate of response and 95% confidence interval. Median weighted progression-free survival (PFS) and overall survival (OS) time for PEM and TAXs-based doublets were compared by two-sided Student's t test. We tested for significant heterogeneity by Cochran's chi-square test and I² index.

Results

Eleven studies published between 1999 and 2012 were included in this analysis with a total of 607 patients enrolled; 468 were treated with PEM-doublets and 139 with TAXs-doublets. The overall response rate was 27.5% with a higher response rate of 37.8% (range, 29.7–46.7%) for TAXs-based treatment vs. 22% (range, 13.4–34.1%) for PEM-based combinations; (p < 0.0001). Median PFS and OS were 3.9 and 8.7 months with weighted PFS of 3.9 vs. 5.3 months (p < 0.0001) and similar OS for PEM vs. TAXs-based doublets.

Conclusions

With the limitations of small and not randomised trials included, this pooled analysis shows that NSCLC patients who relapsed after a first-line platinum-based chemotherapy obtain a tumour response of 27% from a platinum rechallenge containing PEM or TAXs. Response rate and median PFS appear better with TAXs-than with PEM-doublets.     

Association of plasma VEGF-A, soluble VEGFR-1 and VEGFR-2 levels and clinical response and survival in advanced colorectal cancer patients receiving bevacizumab with modified FOLFOX6

For individualized bevacizumab-based therapy, non-invasive biomarkers are necessary. This study assessed the predictive value of plasma vascular endothelial growth factor (VEGF)-A, soluble VEGF receptor (sVEGFR)-1 and sVEGFR-2 levels as biomarkers for clinical response and survival in advanced colorectal cancer (CRC) patients treated with bevacizumab and modified FOLFOX6 (mFOLFOX6). Forty-six unresectable advanced CRC patients and 20 healthy controls were included in this study. CRC patients were treated with bevacizumab and mFOLFOX6. Pretreatment plasma VEGF-A, sVEGFR-1 and sVEGFR-2 levels were measured using the multiplex immunoassay. Plasma VEGF-A, sVEGFR-1 and sVEGFR-2 levels were significantly higher in CRC patients than in the healthy subjects. The plasma sVEGFR-1 levels in the responder patients [complete response (CR)/partial response (PR)] and stable disease (SD) patients were significantly lower than those in the progressive disease (PD) patients (CR/PR vs. PD, p=0.025; SD vs. PD, p=0.032), while the plasma VEGF-A and sVEGFR-2 levels did not show any significant differences between the two groups of patients. Patients with higher sVEGFR-1 levels showed a significantly poorer progression-free survival (PFS) and overall survival (OS) than those with lower VEGFR-1 levels. In contrast, VEGF-A and sVEGFR-2 did not show any significant relationship between PFS and OS according to the status of each level. In the multivariate Cox proportional hazard regression analysis, sVEGFR-1 levels showed a significant relationship between PFS and OS. These results suggest that plasma sVEGFR-1 levels have a predictive value for clinical response and survival in advanced CRC patients treated with bevacizumab and mFOLFOX6. Larger scale studies are needed to further validate our results.     

Genetic interaction of P2X7 receptor and VEGFR-2 polymorphisms identifies a favorable prognostic profile in prostate cancer patients

VEGFR-2 and P2X₇ receptor (P2X₇R) have been described to stimulate the angiogenesis and inflammatory processes of prostate cancer. The present study has been performed to investigate the genetic interactions among VEGFR-2 and P2X₇R SNPs and their correlation with overall survival (OS) in a population of metastatic prostate cancer patients. Analyses were performed on germline DNA obtained from blood samples and SNPs were investigated by real-time PCR technique. The survival dimensionality reduction (SDR) methodology was applied to investigate the genetic interaction between SNPs. One hundred patients were enrolled. The SDR software provided two genetic interaction profiles consisting of the combination between specific VEGFR-2 (rs2071559, rs11133360) and P2X₇R (rs3751143, rs208294) genotypes. The median OS was 126 months (95% CI, 115.94–152.96) and 65.65 months (95% CI, 52.95–76.53) for the favorable and the unfavorable genetic profile, respectively (p < 0.0001). The genetic statistical interaction between VEGFR-2 (rs2071559, rs11133360) and P2X₇R (rs3751143, rs208294) genotypes may identify a population of prostate cancer patients with a better prognosis.     

Human Recombinant Endostatin Combined with Cisplatin Based Doublets in Treating Patients with Advanced NSCLC and Evaluation by CT Perfusion Imaging

Aims: To study the effectiveness of human recombinant endostatin injection (Endostar®) combined withcisplatin doublets in treating advanced non-small cell lung cancer (NSCLC), and to evaluate outcome by CTperfusion imaging. Methods: From April 2011 to September 2014, 76 patients with advanced NSCLC whowere treated with platinum-based doublets were divided into group A (36 patients) and group B (40 patients).Endostar® 15mg/day was administered 4 days before chemotherapy and combined with chemotherapy from day5 in group A, and combined with chemotherapy from the first day in Group B. Endostar® in the two groups wasinjected intravenously for 14 days. Results: Treatment effectiveness in the two groups differed with statisticalsignificance (p<0.05). Effectiveness evaluated by CT perfusion imaging, BF, BV, MTT and PS also demonstratedsignificant differences (all p<0.05). Adverse reactions in the two groups did not significantly vary (p> 0.05).Conclusions: The response rate with Endostar® administered 4 days before chemotherapy and combined withchemotherapy from day 5 in group A was better than Endostar® combined with chemotherapy from the firstday, and CT perfusion imaging could be a reasonable method for evaluation of patient outcomes.     

Expressions of Beta-Catenin, SUFU and VEGFR-2 Proteins in MeduUoblastoma

Objective： to investigate the expressions of beta-catenin, SUFU and VEGFR-2 proteins in medulloblastoma. Methods： Immunohistochemical staining with SP method was conducted to determine the expressions of beta-catenin, SUFU and VEGFR-2 in 33 cases of medulloblastoma and 10 normal cerebellar tissues. Results： the abnormal expression rates of beta-catenin and VEGFR-2 in medulloblastoma were significantly higher than that in normal tissue. While the positive expression of SUFU gene in medulloblastoma was significantly lower than that in 10 normal cerebellar tissues, A significant negative correlation was found between beta-catenin and SUFU proteins and a positive correlation between beta-catenin and VEGFR-2 was found in medulloblastoma. Conclusion： Beta-catenin, VEGFR-2 and SUFU have important effects on the pathogenesis and development of medulloblastoma.     

Expressions of Beta-Catenin,SUFU and VEGFR-2 Proteins in Medulloblastoma

Objective:to investigate the expressions of beta-catenin,SUFU and VEGFR-2 proteins in medulloblastoma.Methods:Immunohistochemical staining with SP method was conducted to determine the expressions of beta-catenin,SUFU and VEGFR-2 in 33 cases of medulloblastoma and 10 normal cerebellar tissues.Results:the abnormal expression rates of beta-catenin and VEGFR-2 in medulloblastoma were significantly higher than that in normal tissue.While the positive expression of SUFU gene in medulloblastoma was significantly lower than that in 10 normal cerebellar tissues.A significant negative correlation was found between beta-catenin and SUFU proteins and a positive correlation between beta-catenin and VEGFR-2 was found in medulloblastoma.Conclusion:Beta-catenin,VEGFR-2 and SUFU have important effects on the pathogenesis and development of medulloblastoma.     

Gefitinib as first-line treatment for patients with advanced non-small-cell lung cancer with activating Epidermal Growth Factor Receptor mutation: implications for clinical practice and open issues

Randomized trials comparing gefitinib with chemotherapy as first-line treatment in patients with EGFR mutated advanced NSCLC support gefitinib as a new, highly effective treatment option in this setting. However, its use in clinical practice has several relevant implications and open issues. In order to choose the best treatment, a molecular characterization is now mandatory, as part of baseline diagnostic procedures. Every effort should be made in order to obtain sufficient tissue. If a clinical enrichment has to be performed for selecting patients to test for EGFR mutation, a reasonable proposal is to test all non-squamous tumors, and patients with squamous tumors only if never smokers. In patients with EGFR mutated tumor, one major issue is the decision about immediate use of gefitinib as first-line, or after failure of standard chemotherapy. First-line gefitinib, compared to chemotherapy, is associated with longer progression-free survival, higher response rate, better toxicity profile and quality of life, and its administration as first-line warrants that all patients have the chance of receiving an EGFR inhibitor. Evidence about the efficacy of erlotinib in the same setting will be soon available, however, at the moment, there are no direct comparisons between gefitinib and erlotinib in EGFR mutated patients. Treatment with gefitinib is usually well tolerated. Typical side effects in most cases are of mild to moderate intensity, and usually manageable with temporary interruption of treatment. When indicated gefitinib appears feasible also in special populations, like elderly or unfit patients, characterized by a significantly poorer risk/benefit ratio with standard chemotherapy. Personalized medicine for patients with lung cancer is now a reality, and patients with EGFR mutation should be treated with first-line EGFR tyrosine kinase inhibitor.     

血管内皮生长因子联合肿瘤标记物检测在非小细胞肺癌诊断中的应用价值

目的探讨血管内皮生长因子联合肿瘤标记物检测在非小细胞肺癌诊断中的应用价值。方法收取非小细胞肺癌患者52例作为研究对象,另收取43例良性肺部感染患者及45例健康体检者进行对照。对3组患者血管内皮生长因子C(VEGF-C)、癌胚抗原(CEA)、糖类抗原125(CA125)以及糖类抗原153(CA153)表达水平进行检测。结果肺癌组VEGF-C、CEA、CA125及CA153表达量均明显高于良性对照组及健康对照组,差异具有统计学意义(P<0.05);良性对照组VEGF-C表达水平明显高于健康对照组(P<0.05),而肿瘤标记物表达水平与健康对照组无统计学差异(P>0.05)。VEGF-C与肿瘤标记物联合检测可显著提高灵敏度、特异度及准确度,与各单项检测比较差异具有统计学意义(P<0.05)。有淋巴结转移的肺癌患者VEGF-C明显高于未转移患者,差异有统计学意义(P<0.05);而二者肿瘤标记物水平无统计学差异(P>0.05)。结论 VEGF-C联合肿瘤标记物检测对非小细胞肺癌诊断及淋巴结转移判断均有重要意义。     

COX-2、VEGF在NSCLC中的表达及与微血管生成的关系

目的探讨肺癌组织中COX-2、VEGF的表达及与血管生成和临床病理特征的关系。方法收集85例肺癌和20例肺良性病变标本,免疫组化S-P法检测COX-2、VEGF蛋白及MVD的表达并作相关分析。结果COX-2、VEGF、MVD在肺癌中的阳性表达率显著高于肺良性病变组织(P<0.05);COX-2表达与肺癌的组织学类型、分化程度和淋巴结转移相关(P<0.05);VEGF表达与肺癌分化程度和淋巴结转移相关(P<0.05);COX-2、VEGF、MVD呈两两正相关。结论COX-2、VEGF参与了肺癌的发生发展过程,COX-2可能通过上调VEGF促进肺癌的血管新生和发生发展。     

NSCLC患者血清Ang2与VEGF动态变化的关系

目的 探讨非小细胞肺癌（NSCLC）患者病程中血管生成素2（Ang2）和血管内皮生长因子（VEGF）的变化情况,评价在肿瘤发生、进展、预后的临床意义。方法 对82例首诊未经治疗的NSCLC患者行ELISA法定量检测外周血Ang2与VEGF水平。结果 NSCLC患者外周血Ang2与VEGF水平较对照组明显升高［Ang2：（1326.8±942.9）pg/ml vs. （445.0±213.0） pg/ml, P<0.01;VEGF：（846.8±459.6）pg/ml vs. （691.3±369.6） pg/ml, P<0.05］。Ang2在早期NSCLC开始明显升高,但在各进展期之间比较差异无统计学意义,进入晚期后在越接近死亡的患者Ang2又再有上升趋势。VEGF在早期未见升高,进入进展期后逐渐升高,在未有远处转移的患者,原发灶直径越大,VEGF越高。COX回归分析显示临床分期与VEGF是NSCLC生存预后的独立危险因素(P<0.05）。结论 NSCLC患者血清Ang2与 VEGF均明显升高, 对早期NSCLC患者检测血清Ang2较VEGF有更好的辅助诊断价值,在NSCLC进展期检测血清VEGF较Ang2更有助于评价肿瘤进展情况,在NSCLC晚期检测血清Ang2升高较VEGF更能提示临终期。     

The identification of KRAS mutations at codon 12 in plasma DNA is not a prognostic factor in advanced non-small cell lung cancer patients

Background

Qualitative analysis of circulating DNA in the blood is a promising non-invasive diagnostic and prognostic tool. Our aim was to study the association between the presence of KRAS mutations at codon 12 and several clinical variables in advanced non-small cell lung cancer (NSCLC) patients.

Methods

We examined 308 stage IIIB and IV NSCLC patients who were treated with cisplatin and docetaxel. Blood samples were collected before chemotherapy, and circulating DNA was extracted from the plasma using commercial adsorption columns. The KRAS mutational status was determined by an RT-PCR method that is based on allelic discrimination.

Results

The median age of the patients was 60 years [31-80], 84% were male, 98% had a performance status of 0-1 and 84% of the patients were in stage IV. The histological subtypes were as follows: 30% squamous cell carcinoma (SCC), 51% adenocarcinoma (ADC) and 19% others. Of the 277 response-evaluated patients, 1% achieved a complete response (CR), 26% achieved a partial response (PR), 34% had stable disease (SD) and 39% had progressive disease (PD). Additionally, 27 (8.8%) patients had KRAS mutations; 26 had a KRAS codon 12 TGT mutation, and 1 had a codon 12 GTT mutation. Plasmatic KRAS mutations were found in patients presenting SCC or ADC. Patients with KRAS mutations in plasma DNA had a median progression free survival (PFS) of 5.77 months [3.39-8.14], whereas for patients with wild-type (wt) KRAS, the PFS was 5.43 months [4.65-6.22] (p = 0.277). The median overall survival (OS) in KRAS-mutated patients was 9.07 months [4.43-13.70] vs 10.03 months [8.80-11.26] in wt patients (p = 0.514).

Conclusions

In advanced NSCLC patients, there were no significant differences between patients with or without KRAS mutations in plasma-free DNA with respect to the baseline characteristics, response rates, PFS or OS.