The Different Effect of VEGF Polymorphisms on the Prognosis of Non-Small Cell Lung Cancer according to Tumor Histology

Vascular endothelial growth factor (VEGF) contributes to tumor angiogenesis. The role of VEGF single nucleotide polymorphisms (SNPs) in lung cancer susceptibility and its prognosis remains inconclusive and controversial. This study was performed to investigate whether VEGF polymorphisms affect survival outcomes of patients with early stage non-small cell lung cancer (NSCLC) after surgery. Three potentially functional VEGF SNPs (rs833061T>C, rs2010963G>C, and rs3025039C>T) were genotyped. A total of 782 NSCLC patients who were treated with surgical resection were enrolled. The association of the SNPs with overall survival (OS) and disease free survival (DFS) was analyzed. In overall population, none of the three polymorphisms were significantly associated with OS or DFS. However, when the patients were stratified by tumor histology, squamous cell carcinoma (SCC) and adenocarcinoma (AC) had significantly different OS (Adjusted hazard ratio [aHR] = 0.76, 95% CI = 0.56–1.03 in SCC; aHR = 1.33, 95% CI = 0.98–1.82 in AC; P for heterogeneity = 0.01) and DFS (aHR = 0.75, 95% CI = 0.58–0.97 in SCC; aHR = 1.26, 95% CI = 1.00–1.60 in AC; P for heterogeneity = 0.004) according to the rs833061T>C genotypes. Our results suggest that the prognostic role of VEGF rs833061T>C may differ depending on tumor histology.     

Natural Progression of Ground-glass Nodules after Curative Resection for Non-small Cell Lung Cancer

BackgroundThis retrospective study investigated the natural course of synchronous ground-glass nodules (GGNs) that remained after curative resection for non-small-cell lung cancer (NSCLC).MethodsProspectively collected retrospective data were reviewed concerning 2,276 patients who underwent curative resection for NSCLC between 2008 and 2017. High-resolution computed tomography or thin-section computed tomography data of 82 patients were included in the study. Growth in size was considered the most valuable outcome, and patients were grouped according to GGN size change. Patient demographic data (e.g., age, sex, and smoking history), perioperative data (e.g., GGN characteristics, histopathology and pathological stage of the resected tumours), and other medical history were evaluated in a risk factor analysis concerning GGN size change.ResultsThe median duration of follow-up was 36.0 months (interquartile range, 23.0–59.3 months). GGN size decreased in 6 patients (7.3%), was stationary in 43 patients (52.4%), and increased in 33 patients (40.2%). In univariate analysis, male sex, the GGN size on initial CT, part-solid GGN and smoking history (≥ 10 pack-years) were significant risk factors. Among them, multivariate analysis revealed that lager GGN size, part-solid GGN and smoking history were independent risk factors.ConclusionDuring follow-up, 40.2% of GGNs increased in size, emphasising that patients with larger GGNs, part-solid GGN or with a smoking history should be observed.     

克唑替尼治疗非小细胞肺癌的研究

非小细胞肺癌（NSCLC）是肺癌常见类型,早期诊断难度较大,5年生存率低。克唑替尼作为抑制Met/ALK/ROS的ATP竞争性的多靶点蛋白激酶抑制剂,是治疗NSCLC的分子靶向药物,在控制变性淋巴瘤激酶（ALK）阳性NSCLC患者疾病发展中具有重要意义,可有效延长患者无进展生存期,且较化疗毒副反应更小,患者耐受性高,但克唑替尼的耐药性也是临床关注重点。本文主要对克唑替尼治疗NSCLC、克唑替尼药理作用及其临床效果、耐药后治疗等进行综述,旨在为更好的发挥该药治疗效果,为临床治疗NSCLC提供参考依据。     

中性粒细胞/淋巴细胞比值与介入治疗中晚期非小细胞肺癌患者预后的相关性

目的 探讨介入治疗中晚期非小细胞肺癌（NSCLC）的患者的中性粒细胞/淋巴细胞比值（NLR）与其预后的相关性。方法 回顾性分析我院介入科2014年1月1日~2017年1月1日收治的68例行介入治疗的中晚期非小细胞肺癌患者的临床资料。计算术前NLR值,并通过建立ROC生存曲线分为高NLR组（NLR≥3.8）和低NLR组（NLR＜3.8）,比较两组的无进展生存时间及总生存时间,同时对可能影响患者预后的危险因素行单因素及多因素分析。结果 所有患者在接受介入治疗后,中位总生存时间为421 d;其中高NLR组中位总生存时间为292 d,低NLR组中位总生存时间为506 d,差异有统计学意义（P＜0.05）;同时高NLR组中位无进展生存时间为152 d,低NLR组中位无进展生存时间为341 d,差异有统计学意义（P＜0.05）。在单因素分析中,存在远处转移、介入手术次数＜3次及NLR≥3.8均是影响总生存时间和无进展生存时间的危险因素（P＜0.05）;在多因素分析中,存在远处转移、NLR≥3.8是影响总生存时间的独立危险因素（P＜0.05）;存在远处转移、介入手术次数＜3次及NLR≥3.8是影响无进展生存时间的独立危险因素（P＜0.05）。结论 术前NLR可作为介入治疗中晚期NSCLC患者的预后指标,NLR高者预后差。     

非小细胞肺癌患者血清PCNA和癌组织NapsinA表达及与病理类型的关系

目的 研究分析非小细胞肺癌(NSCLC)患者血清细胞增殖抗原(PCNA)及癌组织NapsinA表达与患者病理类型的关系.方法 选取2016年2月至2017年2月我院收治的NSCLC患者100例为观察组,另取同期健康体检者50例为对照组.采用酶联免疫吸附法分别检测两组人员的血清PCNA水平,并分析PCNA与NSCLC患者临床病理特征的关系.采用免疫组化SP方法检测观察组癌组织以及癌旁组织的NapsinA表达情况,分析与患者临床病理特征的关系.结果 观察组患者的血清PCNA水平为(444.2 ±26.7) pg/mL,显著高于正常对照组的(290.5±16.2) pg/mL.癌组织NapsinA表达阳性率为80.00％ (80/100),显著低于癌旁正常组织的100.00％ (100/100).NSCLC分化程度为低中分化、TNM分期为Ⅲ～Ⅳ期以及有淋巴结转移患者的血清血清PCNA水平分别为(469.5±27.3) pg/mL、(472.5±26.8)pg/mL、(477.1±26.2) pg/mL,均显著高于高分化、TNM分期为Ⅰ～Ⅱ期以及无淋巴结转移患者.NSCLC病理类型为腺癌、高中分化、TNM分期为Ⅰ～Ⅱ期以及无淋巴结转移患者的NapsinA表达阳性率分别为100.00％ (72/72)、100.00％ (46/46)、95.24％(40/42)、92.31％ (48/52),均显著高于鳞癌与大细胞癌、分化程度为低中分化、TNM分期为Ⅲ～Ⅳ期、有淋巴结转移患者.以上对比均P ＜0.05差异有统计学意义.结论 NSCLC患者血清PCNA水平与病理类型无相关性,而癌组织NapsinA在腺癌中的表达显著高于鳞癌以及大细胞癌,上述两指标可作为判断患者分化程度、TNM分期及淋巴结转移的参考指标.而癌旁组织NapsinA阳性率对区分患者病情程度不具备参考价值     

非小细胞肺癌根治术后复发及进展影响因素的回顾性分析

目的 探讨非小细胞肺癌根治术后早期复发及进展的影响因素。方法 回顾性分析2013年1月~2016年12月NSCLC根治术后复发患者120例的临床资料,通过采用单因素及多因素研究方法,从中寻找影响患者无复发时间间隔早晚的因素。结果 单因素分析显示:患者年龄、TNM分期、血钠水平、术后一线化疗方案、术后化疗周期数是术后早期复发的影响因素。Logistic回归模型多因素分析仅提示年龄为术后早期复发的影响因素。结论 对于年龄超过65岁,首发症状为胸痛,且存在血清钠异常的非小细胞肺癌患者其术后复发时间可能更短,应提高其随访频率。     

siRNA干扰Notch1抑制肺癌干细胞脊柱转移瘤的生长

目的研究Notch受体1(Notch receptor 1,Notch1)在肺癌脊柱转移瘤中的表达,并探讨Notch1 siRNA对肺癌干细胞(lung cancer stem cells,LCSCs)迁移能力和脊柱转移瘤生长的影响。方法通过Western blotting法检测Sox2、Oct4和Notch1蛋白在肺癌脊柱转移瘤组织中的表达水平。通过lipofectamine 2000将Notch1 siRNA转染到肺癌干细胞(A549-CSC),Transwell法检测Notch1 siRNA对A549-CSC迁移能力的影响;将BALB/C裸鼠分为两组:control siRNA组和Notch1 siRNA组,分别通过左心室注射control siRNA和Notch1 siRNA转染的A549-CSC,通过Mic-CT检测小鼠脊柱转移瘤的生长。结果Western blot检测结果显示,Sox2、Oct4和Notch1蛋白在脊柱转移瘤组织中的表达显着高于癌旁对照组(P<0.01);Transwell结果显示,与control siRNA组比较,Notch1 siRNA组细胞迁移率显著降低(P<0.01);Mic-CT结果显示,与control siRNA组比较,Notch1 siRNA组小鼠脊柱转移瘤生长显著降低。结论siRNA干扰Notch1能够抑制LCSCs迁移能力,抑制小鼠肺癌脊柱转移瘤的生长。     

miR-1254靶向GLTSCR2调控非小细胞肺癌增殖和活力

目的探讨miR-1254、GLTSCR2与非小细胞肺癌凋亡和增殖活力的关系。方法检测非小细胞肺癌和正常肺细胞中miR-1254与GLTSCR2的表达;运用TargetScan在线分析miR-1254与GLTSCR2的相关性;利用luciferase assay检测miR-1254是否靶向调控GLTSCR2;转染miR-1254 mimics或miR-1254 inhibitor进非小细胞肺癌A549细胞,通过Western blot检测GLTSCR2的表达量和非小细胞肺癌A549细胞凋亡标志蛋白表达情况;通过CCK-8试验检测不同条件下A549细胞的增殖活力。结果非小细胞肺癌A549的miR-1254相对表达量最高(P <0.05); GLTSCR2在非小细胞肺癌A549和H1299表达量最低(P<0.05);miR-1254靶向GLTSCR2的3'UTR的193-200区域;miR-1254过表达时,GLTSCR2的表达量下降(P<0.05),细胞凋亡相关蛋白BAK的表达量明显下降(P<0.05),而BCL-2的表达量明显上升(P<0.05),并且CASPASE9/CLEAVED-CAS9的比例明显上升(P<0.05),细胞增殖活力明显上升(P<0.05);敲低miR-1254后,GLTSCR2的表达量明显上升(P<0.05),细胞凋亡相关蛋白BAK的表达量明显上升(P<0.05),而BCL-2的表达量明显下降(P <0. 05),并且CASPASE9/CLEAVED-CAS9的比例明显下降(P <0.05),细胞增殖活力明显下降(P<0.05)。结论 miR-1254能通过降低GLTSCR2的表达来降低非小细胞肺癌细胞凋亡以及提高非小细胞肺癌A549的增殖和活力。     

Prognostic value of the neutrophil to lymphocyte ratio in lung cancer: A meta-analysis

Recently, a series of studies explored the correlation between the neutrophil to lymphocyte ratio and the prognosis of lung cancer. However, the current opinion regarding the prognostic role of the neutrophil to lymphocyte ratio in lung cancer is inconsistent.We performed a meta-analysis of published articles to investigate the prognostic value of the neutrophil to lymphocyte ratio in lung cancer. The hazard ratio (HR) and its 95% confidence interval (CI) were calculated.An elevated neutrophil to lymphocyte ratio predicted worse overall survival, with a pooled HR of 1.243 (95%CI: 1.106−1.397; P_{heterogeneity}=0.001) from multivariate studies and 1.867 (95%CI: 1.487−2.344; P_{heterogeneity}=0.047) from univariate studies. Subgroup analysis showed that a high neutrophil to lymphocyte ratio yielded worse overall survival in non-small cell lung cancer (NSCLC) (HR=1.192, 95%CI: 1.061−1.399; P_{heterogeneity}=0.003) as well as small cell lung cancer (SCLC) (HR=1.550, 95% CI: 1.156−2.077; P_{heterogeneity}=0.625) in multivariate studies.The synthesized evidence from this meta-analysis of published articles demonstrated that an elevated neutrophil to lymphocyte ratio was a predictor of poor overall survival in patients with lung cancer.     

抗血管生成药物在非小细胞肺癌中的应用及研究进展

新生血管的形成是肿瘤生长、进展、转移的基础,此过程涉及各类受体介导的细胞信号通路,其中刺激血管生成作用最强的生长因子是血管内皮生长因子（VEGF）。随着VEGF作用的深入认识和血管靶向治疗的临床实践,以抗新生血管为核心的治疗策略取得显著成效。现将抗血管药物的作用机制及其在治疗非小细胞肺癌中的研究进展作简要综述。     

TrkB/BDNF在非小细胞肺癌组织中的表达及临床意义

目的:探讨肿瘤标记物TrkB/BDNF在非小细胞肺癌癌组织中的表达及其临床意义。方法:采用免疫组化(SP法)和Realtime-PCR方法检测非小细胞肺癌组织和癌旁组织中TrkB/BDNF的mRNA表达水平,并分析其在相关临床因素间的差异。结果:非小细胞肺癌癌组织TrkB/BDNF表达阳性,且明显高于癌旁组织。TrkB/BDNFmRNA水平在有否脑转移和不同TNM分期之间存在明显差异(P<0.05);而在性别、年龄、吸烟、肿瘤大小、分化程度、病理组织学类型间无显著差异(P>0.05)。结论:TrkB/BDNF在非小细胞肺癌癌组织中高表达,并与其脑转移、TNM分期有关,两者可能在非小细胞肺癌的侵袭及转移(尤其脑转移)中发挥重要作用。     

Clinical Significance of Aberrant Wnt7a Promoter Methylation in Human Non-Small Cell Lung Cancer in Koreans

The Wnt signaling pathway has regulatory roles in cell proliferation, differentiation, and polarity. Aberrant Wnt pathway regulation can lead to abnormal cell proliferation and cancer, and loss of Wnt7a expression has been demonstrated in lung cancer cell lines. E-cadherin keeps intercellular integrity and prevents metastasis. Therefore, E-cadherin has been known as a prognostic factor in cancer. In the present study, we investigated the E-cadherin expression status by immunohistochemical stain and the Wnt7a promoter methylation status in human non-small cell lung carcinoma (NSCLC) by methylation-specific PCR. We also analyzed their correlations with clinicopathological factors. Methylation of the Wnt7a gene promoter was detected in the lung tissues of 32 of 121 (26.4%) patients with NSCLC. Wnt7a promoter methylation was correlated with advanced tumor stage (P = 0.036) and distant metastasis (P = 0.037). In addition, Wnt7a promoter methylation showed correlation with loss of E-cadherin expression (P < 0.001). However, Wnt7a promoter methylation was not closely related with gender, age, histological type, or smoking habit. Even though Wnt7a methylation could not show significant correlation with the long term survival of the patients with limited follow up data, these findings suggest that loss of the Wnt7a gene induced by promoter methylation might be another prognostic factor for NSCLC and that restoration of Wnt7a may be a promising treatment for NSCLC.

Graphical Abstract

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茶多酚对高转移性肺癌细胞与内皮细胞粘附及粘附分子表达的影响

目的：探讨茶多酚抗肿瘤转移作用。方法：应用共聚焦显微镜和流式细胞仪荧光标记法，体外研究高转移性肺癌细胞（PG细胞）与血管内皮细胞的粘附性、粘附分子表达以及共多酚抗肿瘤转移作用。结果：茶多酚可明显抑制PG细胞表达CD44、CD54的表达。茶多酚对PG细胞与激活和静息血管内皮细胞的粘附性也具有明显的抑制作用，并可抑制粘附分子CD44、CD54的表达，呈剂量依赖关系。结论：茶多酚的抗粘附作用可能与其抗肿瘤转移有关。     

TSGF和CEA检测对非小细胞肺癌诊断的临床价值

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Intramedullary Spinal Cord Metastasis in Renal Cell Carcinoma: A Case Report of the Surgical Experience

Intramedullary spinal cord metastasis (ISCM) from renal cell carcinoma (RCC) is rare manifestation and most of them are treated by adjuvant treatment modalities like radiotherapy. Despite the radio-resistance of RCC itself, focal radiotherapy has been preferred as the first-line treatment modality of ISCM from RCC and only a few cases underwent surgical treatment. We describe a case of ISCM from RCC, which underwent surgical excision and pathologically confirmed. A 44-yr-old man was presented with rapid deterioration of motor weakness during focal radiotherapy for ISCM from RCC. After the surgery for removal of the tumor mass and spinal cord decompression, his motor power was dramatically improved to ambulate by himself. We report the first published Korean case of ISCM from RCC confirmed pathologically and describe our surgical experience and his clinical characteristics.     

非小细胞肺癌多耐药基因产物(P-gp)表达与多种预后因素的关系

探讨非小细胞肺癌（NSCLC）多药耐药基因-1（MDR-1）产物P-糖蛋白（P-gp）在术前未经治疗的非小细胞肺癌组织中的表达及与多种预后因素间的关系。采用免疫组化法检测P-gp在56例NSCLC组织中的表达及其与性别、病理类型、病理分级、淋巴结状况、细胞增殖指数（Ki67）、肿瘤细胞修复能力（TOPOⅡ、MGMT）、表皮生长因子受体（EGFR）、肿瘤的免疫状态（HSP70）以及参与肿瘤恶变、凋亡及转移的癌基因和抑癌基因（P53、Bcl-2、C-erb-2、MDM2）的相关性。结果显示,P-gp在非小细胞肺癌组织中的阳性表达率是53.6%（30/56）,P-gp与TOPOⅡ之间（r=0.279,P=0.037）、P-gp与EG-FR之间（r=0.320,P=0.016）、P-gp与HSP70之间（r=0.279,P=0.037）以及P-gp与C-erb2之间（r=0.249,P=0.043）有相关性。结论：非小细胞肺癌组织中P-gp的表达与多种基因的表达密切相关。采用MDR-1逆转剂可增加非小细胞肺癌的化疗敏感性,行多基因联合检查可为预测非小细胞肺癌预后及指导化疗提供实验依据。     

Changes in the Demographics and Prognoses of Patients with Resected Non-Small Cell Lung Cancer: A 20-Year Experience at a Single Institution in Korea

The demographics and prognosis of non-small cell lung cancer patients have changed during the last few decades. We conducted this study to assess the change in demographics and prognosis in resected non-small cell lung cancer patients during a 20-yr single-institution study in Korea. We retrospectively reviewed the medical records of 2,076 non-small cell lung cancer patients who underwent pulmonary resection between 1990 and 2009. Their clinical characteristics and survival were analyzed over a five-year period. With time, the proportions of female, adenocarcinoma, stage IA, and lobectomy patients increased, whereas the proportions of male, squamous cell carcinoma, stage IIIA, and pneumonectomy patients decreased. These demographic changes caused improved prognosis. The five-year survival rate of all patients was 53.9%. The five-year survival rate increased from 31.9% in 1990-1994, to 43.6% in 1995-1999, 51.3% in 2000-2004, and 69.7% in 2005-2009 (P < 0.001). In conclusion, among patients with resected non-small cell lung cancer, the proportions of female, adenocarcinoma, stage IA, and lobectomy patients have increased, and the five-year survival rate has gradually improved during the last 20 yr in Korea.     

康艾注射液联合化疗治疗晚期非小细胞肺癌的临床研究

目的 探讨康艾注射液配合多西他赛、顺铂治疗晚期非小细胞肺癌的客观疗效和安全性。方法 将解放军武汉总医院2015年2月～2018 年2月收治的100例晚期非小细胞肺癌患者按随机数字表法分为两组,每组50例。对照组给予多西他赛、顺铂化疗,治疗组在对照组基础上加康艾注射液治疗。连续治疗2个疗程后评估疗效、生活质量、中医症状和不良反应。结果 治疗组的有效率为46.00%,高于照组的44.00%,但差异无统计学意义（P＞0.05）;治疗组在生活质量改善优于对照组（68.00% vs 48.00%）（P＜0.05）。治疗组纳呆、神疲乏力、呕吐三组中医症状均较对照组有改善（P＜0.05）。治疗组化疗不良反应减轻方面优于对照组（P＜0.05）。结论 康艾注射液联合多西他赛、顺铂治疗晚期非小细胞肺癌在稳定性、改善生活质量、减轻毒副反应方面存在一定优势,值得进一步深入研究。     

Predicting Recurrence Using the Clinical Factors of Patients with Non-small Cell Lung Cancer After Curative Resection

We present a recurrence prediction model using multiple clinical parameters in patients surgically treated for non-small cell lung cancer. Among 1,578 lung cancer patients who underwent complete resection, we compared the early-recurrence group with the 3-yr non-recurrence group for evaluating those factors that influence early recurrence within one year after surgery. Adenocarcinoma and squamous cell carcinoma were analyzed independently. We used multiple logistic regression analysis to identify the independent clinical predictors of recurrence and Cox''s proportional hazard regression method to develop a clinical prediction model. We randomly divided our patients into the training and test subsets. The pathologic stages, tumor cell type, differentiation of tumor, neoadjuvant therapy and age were significant factors on the multivariable analysis. We constructed the model for the training set with adenocarcinoma (n=236) and squamous cell carcinoma (n=305), and we applied it to the test set with adenocarcinoma (n=110) and squamous cell carcinoma (n=154). It was predictive for the in adenocarcinoma (P<0.001) and the squamous cell carcinoma (P=0.037), respectively. Our results showed that our recurrence prediction model based on the clinical parameters could significantly predict the individual patients who were at high risk or low risk for recurrence.