【作者】 吴婷；

【导师】 陈强；

【作者基本信息】 福建医科大学 ， 肿瘤学， 2018， 硕士

【摘要】 背景:肺癌(lung cancer,LC)又称为支气管肺癌,是指原发在支气管粘膜或腺体的恶性肿瘤。这些年来,由于环境和饮食污染日益加重,LC发生率逐年上升,并且呈年轻化趋势,成为严重影响我国居民健康的疾病之一。2015年中国癌症统计数据结果提示男性和女性死亡率的最高的均是肺癌。而非小细胞肺癌(non-small cell lung cancer,NSCLC)占肺癌中绝大部分比例,约80%-85%。目前,临床上对于肺癌的诊断以细胞学、组织病理学为金标准,以影像学作为辅助诊断,对于治疗疗效的评价绝大多数以影像学为主。但是细胞学、组织病理学检查时均具备一定的创伤性,并且诊断周期较长、重复性较差,常伴有多种并发症。而影像学检查费用相对较高,且存在一定的辐射,早期或潜在的血行转移往往容易漏诊,对疗效的评估也存在一定的局限性。因此,迫切需要一种操作相对简单、价格低廉、创伤性小的检查解决上述问题,国内外有研究证实肿瘤标志物(tumor marker,TM)测定对帮助患者早期发现肿瘤及指导临床治疗具有重要的意义。但是,单一血清肿瘤标志物诊断特异性、敏感性较低,导致临床诊断价值有限。为了弥补上述不足,本课题拟将细胞质胸苷激酶(thymidine kinase 1,TK1)、癌胚抗原(carcinoembryonic antigen,CEA)与D-二聚体(D-Dimer,D-D)进行联合检测用于晚期非小细胞肺癌诊断及疗效预测中,为临床晚期非小细胞肺癌诊断及疗效预测提供新的思路。目的:探讨TK1、CEA与D-D进行联合检测在晚期NSCLC患者中的应用效果,为晚期NSCLC诊断、疗效预测提供参考。方法:取2016年12月-2017年12月我院收治的晚期NSCLC患者67例(腺癌54例,鳞癌13例),设为观察组;取同期入院健康体检者20例,设为对照组。采用酶联免疫吸附试验测定2组细胞质胸苷激酶浓度;采用免疫比浊法测定2组D-二聚体浓度;采用化学发光法测定2组CEA浓度。根据EGFR(Epidermal Growth Factor Receptor,表皮生长因子受体)基因检测结果及患者的经济情况,对观察组67例患者进行至少2周期的化疗或1疗程的靶向治疗,在第3周期化疗前或第2疗程靶向治疗前进行TK1、CEA及D-D浓度进行测定;同期进行影像学检查,按RECIST 1.1版进行疗效评价,根据评价情况分为PD(Progressive Disease,疾病进展)组及DC(Disease Control,疾病控制)组,分析TK1、CEA及D-D联合测定在晚期非小细胞肺癌患者中的诊断效果及临床治疗疗效预测的价值。结果:1、本研究共纳入87例样本,男女比例、吸烟情况、年龄分布无统计学差异(p>0.05)。2、肺腺癌患者中TK1、CEA、D-D浓度均高于对照组,差异具有统计学意义(p<0.05);作ROC曲线分析,TK1、CEA、D-D单独检测和两两联合、三指标联合均有诊断价值(p<0.05),单项检测CEA的曲线下面积及youden指数最大,两两联合或三指标联合其曲线下面积及youden指数较单项检测增大,其中D-D联合TK1的曲线下面积最大,Youden指数最大,诊断灵敏度和特异度均较高。3、肺鳞癌患者与对照组TK1及CEA浓度差异无统计学意义(p>0.05);肺鳞癌D-D浓度与对照组差异有统计学意义(p<0.05),此次研究其Youden指数及曲线下面积均显著低于肺腺癌组。4、经2周期化疗或1疗程靶向治疗后对TK1、CEA、D-D变化进行比较,肺腺癌患者影像学评估PD组患者的TK1、CEA、D-D较治疗前升高,差异具有统计学意义(p<0.05),而影像学评估DC组患者的TK1、CEA、D-D较治疗前降低,差异具有统计学意义(p<0.05);肺鳞癌患者影像学评估PD和DC组患者的TK1、D-D、CEA在治疗前后差异均无统计学意义(p>0.05)。5、肺腺癌疾病控制的DC患者肿瘤标志物下降,PD患者肿瘤标志物升高,患者中PD和DC的TK1、CEA、D-D变化率有统计学差异(p<0.05)。作ROC曲线分析,三项单独和联合检测都有预测肺腺癌疗效价值(p<0.05),单项检测D-D的曲线下面积及youden指数最大,联合检测曲线下面积及youden指数较单项指标检测大,其中D-二聚体联合TK1的曲线下面积较大,Youden指数最高,灵敏度和特异度也较高。6、肺鳞癌患者PD和DC的TK1、CEA、D-D变化率无差异(p>0.05),作ROC曲线分析,三项指标变化率均无肺鳞癌疗效预测价值(p>0.05)。结论:1.TK1、CEA、D-二聚体检测对晚期肺腺癌的诊断及疗效预测具有一定的价值,单项检测CEA的诊断价值最高,D-D的疗效预测价值最高。TK1、CEA对晚期肺鳞癌未见诊断价值,D二聚体对晚期肺鳞癌具有一定的诊断价值,但其诊断价值低于肺腺癌。TK1、CEA、D-二聚体检测对晚期肺鳞癌未见疗效预测价值。2.TK1、CEA、D-二聚体联合检测可提高对晚期肺腺癌诊断及疗效预测的价值,其中TK1联合D-二聚体意义较大,可有助于临床协助诊断及疗效预测。3.由于本研究中纳入的样本量较少,尤其是肺鳞癌的样本量太小,今后有待于继续增加样本量进行论证。更多还原

【Abstract】 Background: Lung cancer(LC),also known as bronchial lung cancer,is a malignant tumor that originates in the bronchial mucosa or glands.In recent years,the incidence of LC has been increasing year by year because of the worsening of environmental and dietary pollution,and it has become one of the diseases that seriously affect the health of the residents in our country.China’s cancer statistics in 2015 show that lung cancer is the highest mortality rate for both men and women.And NSCLC(non-small cell lung cancer)accounts for about 80% to 85% in lung cancer.At present,cytology,histopathology is the gold standard diagnosis of lung cancer.Imaging is an auxiliary diagnosis and can use to evaluate the efficiency of the treatment.However,the cytology and histopathological examination have a certain degree of trauma,and longer diagnosis cycle,poor repeatability,and often accompanied with various complications.Imaging examination have relatively high cost and a certain radiation,the early or potential blood transfer is often miss diagnose,and the evaluation of curative effect aslo have some limitations.Therefore,there is an urgent need for a relatively simple operation,low cost,small trauma to solve the above problems.Studies at home and abroad have confirmed that the detection of tumor marker(TM)is of great significance in helping patients to find tumor early and guiding clinical treatment.However,the low specificity and sensitivity of single serum tumor markers lead to limited clinical diagnostic value.In order to make up for the deficiency mentioned above,it is proposed that combined detection of thymidine kinase 1,D-dimer and CEA can be used in the diagnosis and curative effect prediction of advanced non-small cell lung cancer and provide a new idea for the diagnosis and curative.effect prediction.Objective: To investigate the effect of combined detection of TK1,CEA,and D-D in patients with advanced NSCLC,and provide a reference for the diagnosis and curative effect prediction of advanced NSCLC.Methods:From December 2016 to December 2017,sixty seven patients with advanced NSCLC(fifty four adenocarcinoma and thirteen squamous cell carcinoma)in our hospital were selected as observation group,and twenty patients who were health examination in the same period were selected as control group.In the two groups,the concentration of thymidine kinase1 was determined by enzyme linked immunosorbent assay(Elisa),The concentration of D-dimer was determined by immunoturbidimetry,and the concentration of CEA was determined by chemiluminescence assay.According to the results of EGFR gene detection and the financial situation of patients,67 patients in observation group were treated with chemotherapy therapy for at least2 cycles or one course of targeted therapy,before the third cycle of chemotherapy or before the second course of targeted therapy the concentrations of TK1,D-D and CEA were measured and the imaging examinations were performed at the same time,observation group divided into PD(Progressive Disease)group and DC(Disease Control)group according to the RECIST 1.1.To analysis the diagnostic effect and curative effect prediction of combined detection of TK1,CEA,D-Dimer in advanced non-small cell lung cancer.Results:1.There was no significant difference in the sex ratio,smoking status and age distribution in eighty seven samples(p > 0.05).2.The concentrations of TK1,CEA and D-D in patients with lung adenocarcinoma were significantly higher than those in the control group.The difference is statistically significant(p > 0.05).The ROC curve analysis showed that TK1,D-D,CEA detected alone or combined with every two or three were have diagnostic value in lung adenocarcinoma(p < 0.05).CEA has the largest area under curve and youden index in single detection.The area under curve and youden index of combination of two or three indexs were larger than that of single detection,and the area under curve and youden index of D-D combined with TK1 was the largest,the diagnostic sensitivity and specificity are high.3.The TK1 and CEA concentrations were not statistically significant in lung Squamous cell carcinoma and control groups(p > 0.05),and the D-D concentration of lung squamous cell carcinoma and the control group was statistically significant(p <0.05),suggesting that it is helpful to the diagnosis of lung squamous cell carcinoma.But this study its Youden index and the area under the curve were significantly lower than those in lung adenocarcinoma group.4.After two cycles of chemotherapy or one course of targeted therapy,in lung Adenocarcinoma patients the concentration of TK1 and CEA,D-D in imaging evaluated PD group were higher than those before treatment,the concentration of TK1 and CEA,D-D in imaging evaluated DC group were lower than those before treatment.The difference was statistically significant(p < 0.05);but in lung squamous Cell carcinoma patients both PD or DC group,there was no significant difference of concentration of TK1,CEA,D-D before and after treatment.(p > 0.05).5.In lung adenocarcinoma patients tumor markers in DC patients decreased and tumor markers increased in PD patients,there was statistical difference in the change rate of PD and DC between TK1,CEA,D-D(p < 0.05).According to the ROC curve,detected alone or combined with every two or three were haves values in evaluating the curative effect of lung adenocarcinoma(p < 0.05).D-D have the largest under curve and youden index in single detection.The area under curve and youden index of combination of two or three indexs were larger than that of single detection.D dimer combined with TK1 have the larger area under the curve,and the youden index was the highest,the sensitivity and specificity were also higher.6.There was no difference in the change rate of TK1,CEA,and D-D between PD and DC in patients with lung squamous cell carcinoma(p > 0.05).The ROC curve analysis showed that none of the three indexes could predict the curative effect of lung squamous cell carcinoma(p > 0.05).Conclusion:1.The detection of TK1,CEA,D-dimer have a certain value in the diagnosis and evaluation of curative effect of advanced lung adenocarcinoma.In single detection CEA have the highest diagnostic value,D-D have the highest predictive value of efficacy.TK1,CEA have no diagnostic value in advanced lung squamous cell carcinoma(p>0.05),D-dimer have a certain value in the diagnosis of advanced lung squamous cell carcinoma,but its diagnostic value may be lower than that of lung adenocarcinoma.The detection of TK1,CEA,D-dimer haven’t see value in the prediction of the therapeutic effect in advanced lung squamous cell carcinoma(SCC).2.The detection combined with TK1,CEA and D-dimer can improve the value diagnosis and prediction of curative effect in advanced lung adenocarcinoma.TK1 combined with D-dimer is of great significance,which can be helpful to clinical diagnosis and prediction of curative effect.3.Due to the small sample size included in this study,especially the lung squamous cell carcinoma sample size is too small,we will continue to increase the sample size to demonstrate our results in the future.更多还原