小细胞肺癌的临床回顾及免疫治疗相关靶点的研究

发布时间：2018-12-27 18:07

【摘要】：背景和目的:小细胞肺癌是肺癌中恶性程度最高的肿瘤,只占全部肺癌中的13-15%,但预后极差,多年来其治疗没有取得突破性的进展。随着以抗PD-1/PD-L1为代表的新型癌症免疫治疗抗体和CAR-T新型免疫治疗技术的出现,在全身各种肿瘤中,包括非小细胞肺癌都表现出显著的疗效,而小细胞肺癌中相关的研究较少。在本研究中,首先对本科室2008年以来的小细胞肺癌患者的临床资料进行了系统回顾和分析;其次,应用免疫组化法对其中的具有较好石蜡标本的26例患者,共28例石蜡切片,进行了PD1、PD-L1和间皮素的蛋白表达分析,其中两组互为原发灶和转移灶初步探讨了免疫治疗相关靶基因在小细胞肺癌中的蛋白表达情况和其临床特征。材料和方法:收集了2008年以来我科就诊经手术或者活检取得标本并由病理科确诊为小细胞肺癌的患者共有96例,除去围手术期死亡、或者其他原因而未能得到随诊结果的患者,最终有77例患者纳入了临床病例分析。临床资料包括年龄、性别、吸烟史、原发肿瘤的占位处、肿瘤具体的常见转移部位(包括骨转移、脑转移、肝转移、肾上腺转移)。临床肿瘤分期采用2009年颁布的第七版肺癌TNM分期进行分期。随访方式主要采用电话随访和门诊随诊的方式进行。进一步在77例患者中选取有足够石蜡标本患者26例,共28例石蜡块,其中有两对石蜡标本互为原发灶和转移灶癌组织。用免疫组化的方法对PD-1,PD-L1和间皮素进行检测,分析各个蛋白的表达与患者的临床特征,并进一步用Kaplan-Meier曲线分析各个蛋白的表达与患者的生存关系,转移灶中表达与原发灶不一致的以原发灶的表达情况为准。用Fisher精确检验的方法分析各个基因蛋白的表达与临床特征之间的相关性,所用统计学软件为SPSS21.0,P值小于0.05认为有统计学意义。结果:1、在临床特征分析中发现:小细胞肺癌好发于男性,吸烟的患者;但是患者的预后与其性别、年龄、肿瘤发生部位、或者吸烟史没有明显的相关性。2、分析患者发生转移部位的数据提示,脑转移的发生率最高,骨转移和肝转移次之,肾上腺转移居末。3、进一步分析发现在68例未进行预防性颅脑照射的患者中,18例患者出现脑转移,其发生率为26.47%,而在6例行预防性颅脑照射的患者中,只有1例患者发生了脑转移,其发生率为16.67%。此结果提示颅脑照射可能对预防脑转移具有一定帮助,但两组比较无显著性统计学差异(P0.05),这可能与患者病例数目较少有关,需要进一步验证。4、对于晚期小细胞肺癌的患者,接受治疗(手术+化疗,化疗+手术+化疗,单纯化疗)患者中位生存期为12月(5-72个月),不接受治疗中位生存期在3个月之内。此结果提示患者接受治疗能够获得明显延长的生存期;但手术+化疗、化疗+手术+化疗和单纯化疗三者之间,生存期没有显著性区别。5、PD-1和PD-L1在28例小细胞肺癌中的阳性表达率分别为50%(13/26)和53.8%(14/26);间皮素的阳性表达率为46.2%(12/26),且在肿瘤间血管内皮观察到了间皮素的表达。经统计学分析发现三者之间的表达无相关性(P0.05);PD-1的表达可能和患者预后负相关,但是需要扩大样本量来验证。PD-L1和间皮素则没有显示出相同的结果。6、PD-L1、PD1和间皮素三者的蛋白表达在小细胞肺癌的原发灶和转移灶中存在肿瘤异质性,即部分仅仅在原发灶中呈阳性表达,而在转移灶中却呈阴性,反之亦然。结论:1、小细胞肺癌好发于男性,吸烟的患者;患者的预后与其性别、年龄、肿瘤发生部位、或者吸烟史没有明显的相关性。2、脑转移是小细胞肺癌最常发生的转移部位。3、预防性颅脑照射对预防脑转移可能具有帮助作用;4、对于晚期小细胞肺癌的患者,接受包括手术+化疗、化疗+手术+化疗和单纯化疗的治疗能够明显延长患者的生存期;但不同的治疗方式之间不存在生存期的显著差异。5、PD-1、PD-L1和间皮素在小细胞肺癌中存在阳性表达,但三者的表达不存在相关性;PD-1的表达可能和患者预后负相关。6、PD-L1、PD1和间皮素三者的蛋白表达在小细胞肺癌的原发灶和转移灶中存在肿瘤异质性。
[Abstract]:BACKGROUND & OBJECTIVE: Small cell lung cancer is the most malignant tumor in lung cancer, accounting for 13-15% of all lung cancer, but the prognosis is very poor. With the advent of novel cancer immunotherapy antibodies and CAR-T new immunotherapeutic techniques, which are represented by anti-PD-1/ PD-L1, non-small cell lung cancer, including non-small cell lung cancer, has a significant therapeutic effect in various tumors of the whole body, while the associated studies in small cell lung cancer are less. In this study, the clinical data of small cell lung cancer patients since 2008 were systematically reviewed and analyzed. The protein expression of PD-L1 and m-skin was analyzed, and the expression of protein in small-cell lung cancer and its clinical characteristics were discussed in the two groups. Materials and Methods: A total of 96 patients with small cell lung cancer by surgery or biopsy have been collected since 2008, and 96 patients have been diagnosed as small cell lung cancer by the pathology department. In the end, 77 patients were included in the clinical case analysis. The clinical data included age, sex, smoking history, the position of the primary tumor, the common metastatic site of the tumor (including bone metastasis, brain metastasis, liver metastasis, and adrenal metastasis). The staging of TNM staging was performed in the seventh edition of lung cancer, which was promulgated in 2009. The follow-up was followed by telephone follow-up and out-patient follow-up. Twenty-six patients with enough paraffin were selected in 77 patients, and 28 paraffin blocks, of which two pairs of paraffin specimens were primary and metastatic tumor tissues. The expression of each protein and the clinical characteristics of the patient were analyzed by using the method of immunohistochemistry, and the expression of each protein and the survival relationship of the patient were further analyzed by the Kaplan-Meier curve. The expression of the original range which is not consistent with the original range is subject to the expression of the original range. The correlation between the expression of each gene protein and the clinical features was analyzed by Fisher's exact test. The statistical software used was SPSS21. 0 and the P value was less than 0.05. Results: 1. In the clinical analysis, it was found that the small cell lung cancer is good for the male and the smoker, but the prognosis of the patient is not related to the sex, age, tumor, or smoking history. The incidence of the brain metastasis was the highest, the bone metastasis and the liver metastasis were the second, and the adrenal metastasis was the last. 3. The further analysis found that in the 68 patients without the prophylactic head irradiation, 18 patients had a brain metastasis, the incidence of which was 26. 47%, and in the 6 cases of the patients with the prophylactic head irradiation, Only one patient had a brain metastasis, with a rate of 16.67%. The results suggest that the brain irradiation may be helpful to the prevention of brain metastasis, but there is no significant difference between the two groups (P0.05). This may be related to the number of patients with advanced small cell lung cancer and need further verification. 4. For patients with advanced small cell lung cancer, treatment (operation + chemotherapy, The survival of the patients was 12 months (5-72 months) in the patients with chemotherapy + surgery + chemotherapy and simple chemotherapy, and the median survival in the treatment was within 3 months. The positive expression of PD-1 and PD-L1 in 28 small cell lung cancer was 50% (13/ 26) and 53.8% (14/ 26). The positive expression of the mesothelin was 46.2% (12/ 26), and the expression of the mesothelin was observed between the tumor and the vascular endothelium. It was found that there was no correlation between the expression of PD-1 and the prognosis of the patients (P0.05). The expression of PD-1 may be negatively correlated with the prognosis of the patients, but the sample size needs to be expanded to verify. The results showed that the expression of PD-L1, PD-L1, PD1, and eppelin in the primary and metastatic foci of small-cell lung cancer showed the heterogeneity of the tumor, that is, the partial expression of PD-L1, PD-L1, and eppelin was positive in the primary and negative, and vice versa. Conclusion: 1. Small cell lung cancer is good for men and smokers. The prognosis of patients with small cell lung cancer is not related to their sex, age, tumor, or smoking history. Preventive brain irradiation may be helpful to the prevention of brain metastasis; 4. For patients with advanced small cell lung cancer, the treatment of patients with advanced small cell lung cancer, including operation + chemotherapy, chemotherapy + surgery + chemotherapy and simple chemotherapy, can significantly prolong the survival of patients. However, there was no significant difference in the survival time between different treatment modes. 5, PD-1, PD-L1 and m-skin were positive in small cell lung cancer, but there was no correlation between the expression of PD-1 and the prognosis of the patients. The protein expression of PD1 and eppelin has tumor heterogeneity in the primary and metastatic foci of small cell lung cancer.
【学位授予单位】：天津医科大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R734.2

【相似文献】