食管鳞状细胞癌的生物学预后因素研究

发布时间：2018-07-01 09:44

本文选题：食管鳞状细胞癌 + 淋巴—单核细胞比例　；参考：《华中科技大学》2016年博士论文

【摘要】：目的：食管鳞状细胞癌(esophageal squamous cell carcinoma, ESCC)是常见的食管癌组织类型,每年约造成15万例死亡,在肿瘤相关死亡中列第4位。目前用于预测食管鳞癌预后的临床指标尚不精确。本研究旨在讨论术前外周血淋巴—单核细胞比例(lymphocyte-monocyte ratio, LMR)、中性—淋巴细胞比例(neutrophil-lymphocyte ratio, NLR)、血小板—淋巴细胞比例(platelet-lymphocyte ratio, PLR)与食管鳞状细胞癌预后的相关性。材料与方法：本研究纳入178例接受食管鳞癌根治术的患者,按患者术前1周血常规检查结果计算NLR、PLR及LMR,采用中位数将其分别分成两组,并用Kaplan-Meier曲线及log-rank检验分别分析高NLR、PLR、LMR组与低NLR、PLR、LMR组之间总生存时间(overall survival, OS)及无病生存时间(disease-free survival, DFS)的差异。使用Cox回归模型进行预后相关因素与OS、DFS的关联分析。结果：本研究纳入178例食管鳞癌患者,其中女性39例,男性139例,中位年龄是56岁,中位随访时间是39月。Kaplan-Meier曲线分析显示低LMR组总生存时间(P=0.187)和无病生存时间(P=0.400)较高LMR组短,差异无统计学意义。多因素分析显示食管鳞癌患者LMR与总生存时间(HR= 0.733,95% CI:0.397-1.353,P=0.321)及无病生存时间(HR= 0.850,95% CI:0.491-1.473, P=0.562)均无显著相关。结论：本研究首次证明LMR不能作为可手术的食管鳞癌患者独立的预后标志。此外,本研究为进一步探索炎症细胞与免疫细胞在食管鳞癌微环境中的作用提供支持。目的：食管癌是我国发病率第4的恶性肿瘤,鳞状细胞癌占食管癌的90%以上,但目前食管鳞状细胞癌(esophageal squamous cell carcinoma, ESCC)的五年生存率不足15%。目前用于预测食管鳞癌预后的临床指标尚不精确。本研究旨在讨论肿瘤组织浸润淋巴细胞与食管鳞状细胞癌预后的相关性。材料与方法：本研究纳入127例接受食管鳞癌根治术的患者,由两位食管癌方向的病理医生分别独立对HE切片中肿瘤上皮浸润淋巴细胞(intraepithelial tumor-infiltrating lymphocytes, iTILs)及肿瘤基质浸润淋巴细胞上皮浸润淋巴细胞(stromal tumor-infiltrating lymphocytes, sTILs)比例评分,并采用Kaplan-Meier曲线及log-rank检验分别分析iTILs与sTILs与总生存时间(overall survival, OS)及无病生存时间(disease-free survival, DFS)的关系。使用Cox回归模型进行预后相关因素与OS、DFS的关联分析。结果：参与评分的121例食管鳞癌患者包括25例女性和96例男性患者,中位年龄是58岁,中位随访时间是34月。92.6%的肿瘤组织中发现了不少于10%的基质浸润淋巴细胞(范围,10%到90%),84.3%的肿瘤组织中发现了不少于10%的上皮浸润淋巴细胞(范围,10%到40%)。Kaplan-Meier曲线分析显示基质浸润淋巴细胞比例升高,总生存时间(P0.001)及无病生存时间(P=0.025)显著增加。多因素分析显示多因素分析显示基质浸润淋巴细胞与OS (P0.001, HR= 0.968,95% CI 0.955-0.981)及DFS (P= 0.005, HR= 0.982,95% CI 0.970-0.995)相关,差异有统计学意义。结论：肿瘤组织HE切片上基质浸润淋巴细胞评分是食管鳞癌根治术后患者独立的预后因素。目的：食管鳞状细胞癌(esophageal squamous cell carcinoma,ESCC)是常见的食管癌组织类型,每年约造成15万例死亡,在肿瘤相关死亡中列第4位。目前用于预测食管鳞癌预后的临床指标尚不精确。本研究旨在讨论食管鳞癌组织p14ARF/MDM2/p53信号通路单核苷酸多态性与预后的关系。材料与方法：本研究纳入124例接受食管鳞癌根治术的患者,从患者术后肿瘤组织的石蜡切片中提取DNA,并采用质谱法检测p14ARF/MDM2/p53信号通路上6个位点的单核苷酸多态性(single nucleotide polymorphism,SNP)。采用Kaplan-Meier曲线及log-rank检验分别分析SNP位点基因型与总生存时间(overall survival,OS)及无病生存时间(disease-free survival,DFS)的差异。使用Cox回归模型进行预后相关因素与OS、DFS的关联分析。结果：本研究纳入124例食管鳞癌患者,其中女性28例,男性96例,中位年龄是58岁,中位随访时间是37月。Kaplan-Meier曲线分析显示p144ARF rs3814960位点TC/CC基因型患者较TT基因型患者总生存时间(P=0.001)和无病生存时间(P=0.001)显著减少。MDM2 rs34886328位点A/- +AA基因型患者较-/-基因型患者总生存时间(P=0.0004)和无病生存时间(P=0.0001)显著增加。Cox回归模型多因素分析结果显示p14ARF rs3814960位点TC/CC基因型患者总生存时间(]HR=2.765,95% CI: 1.330-5.750,P=0.006,Pc=0.030)和无病生存时间(HR=2.449,95% CI:1.301-4.608,P =0.005,Pc=0.025)较TT基因型患者显著减少。MDM2 rs34886328位点A/-+AA基因型患者总生存时间(]HR=0.272,95% CI:0.131-0.564,P=4.7×10-4,Pc=0.003)和无病生存时间(]HR=0.217,95% CI:0.109-0.429,P=1.1×10-5,Pc=6.6×10-5)较-/-基因型患者显著增加结论：本研究首次证明可手术的食管鳞癌患者肿瘤组织中p14ARF rs3814960和MDM2rs34886328位点多态性与预后相关,在以后的研究中经大样本人群验证可作为食管鳞状细胞癌独立的预后标志。目的：我国90%以上的食管癌属于食管鳞癌,每年有25万新发病例,约造成15万例死亡,在肿瘤相关死亡中列第4位。目前用于预测食管鳞癌预后的临床指标尚不精确。HPV在宫颈癌发生发展中起重要作用,也是口咽癌、肛管癌、宫颈癌独立的预后因素。本研究旨在探索食管鳞癌患者肿瘤组织HPV感染亚型与预后的相关性。材料与方法：本研究纳入135例接受食管鳞癌根治术的患者,提取术后食管鳞癌组织石蜡切片中的DNA,采用基质辅助激光解析／电离飞行时间质谱法(MALDI-TOF MS)及PCR法检测DNA样品中的14种HPV亚型(HPV16、18、31、33、35、39、45、51、52、56、58、59、66、68),并使用SPSS 16.0软件进行统计学分析。结果：本研究纳入135例食管鳞癌患者,其中26例为女性,109例为男性患者,中位年龄是58岁。MALDI-TOF MS法检测发现仅有1例患者感染了HPV16,占患者总数的0.74%。其余13种HPV在135例食管鳞癌患者肿瘤组织中均未检出。PCR法检测135例食管鳞癌患者肿瘤组织DNA中,仅有1例存在HPV感染。结论：由于本研究样本量小,且食管鳞癌组织中HPV感染率较低,因此我们尚无法证实肿瘤组织HPV感染与食管鳞癌预后的关系。此外,由于食管癌发病率和HPV感染率具有较大地区性差异,我们推测在不同地区HPV感染在食管鳞癌致病过程中的作用可能并不相同,HPV可能不是我国中部地区食管鳞状细胞癌患者的重要致病因素。
[Abstract]:Objective: esophageal squamous cell carcinoma (ESCC) is a common type of esophageal carcinoma, which causes 150 thousand deaths each year and fourth in tumor related deaths. The current clinical indicators for predicting the prognosis of esophageal squamous cell carcinoma are not yet accurate. Lymphocyte-monocyte ratio, LMR), the relationship between the neutral lymphocyte proportion (neutrophil-lymphocyte ratio, NLR), the proportion of platelet - lymphocyte (platelet-lymphocyte ratio, PLR) and the prognosis of esophageal squamous cell carcinoma. Materials and methods: This study was included in 178 patients undergoing radical resection of esophageal squamous cell carcinoma and 1 weeks before the operation. The results of routine examination were calculated NLR, PLR and LMR, which were divided into two groups by the median, and the difference between the high NLR, PLR, LMR group and low NLR, PLR, LMR group and disease free survival time between the high NLR, LMR group and the LMR group were analyzed respectively by the Kaplan-Meier curve and log-rank test. Results: the correlation analysis of prognostic factors and OS, DFS. Results: 178 cases of esophageal squamous cell carcinoma were included in this study, of which 39 cases were female, 139 cases were male, the median age was 56 years, and the median follow-up time was 39 months.Kaplan-Meier curve analysis showed that the total survival time of the low LMR group (P=0.187) and the higher LMR group with the disease free survival time (P=0.400) were shorter, and the difference was not statistically significant Multivariate analysis showed no significant correlation between LMR and total survival time (HR= 0.733,95% CI:0.397-1.353, P=0.321) and disease-free survival time (HR= 0.850,95% CI:0.491-1.473, P=0.562) in esophageal squamous cell carcinoma. Conclusion: This study is the first to prove that LMR can not be used as an independent prognostic marker in operable esophageal squamous cell carcinoma. In addition, this study To further explore the role of inflammatory cells and immune cells in the microenvironment of squamous cell carcinoma of the esophagus. Objective: esophageal cancer is a malignant tumor of fourth in China. Squamous cell carcinoma accounts for more than 90% of the cancer of the esophagus, but the five year survival rate of esophageal squamous cell carcinoma (ESCC) is less than 15%. at present. The clinical indicators for predicting the prognosis of esophageal squamous cell carcinoma are not accurate. The purpose of this study was to discuss the correlation between tumor tissue infiltrating lymphocytes and the prognosis of squamous cell carcinoma of the esophagus. Materials and methods: This study included 127 patients undergoing radical resection of esophageal squamous cell carcinoma, and two pathologists in the direction of esophageal cancer were independent of the tumor in the HE section. The proportion of intraepithelial tumor-infiltrating lymphocytes (iTILs) and tumor matrix infiltrating lymphocyte epithelial infiltrating lymphocytes (stromal tumor-infiltrating lymphocytes, sTILs) was scored. The Kaplan-Meier curve and log-rank test were used to analyze iTILs and sTILs and total survival time. OS) and disease-free survival time (disease-free survival, DFS). A Cox regression model was used to analyze the correlation between prognostic factors and OS, DFS. Results: 121 cases of esophageal squamous cell carcinoma included 25 women and 96 male patients with a median age of 58 years, and a median follow-up time of 34 month.92.6% in tumor tissues. No less than 10% of the stromal infiltrating lymphocytes (range, 10% to 90%), 84.3% of the tumor tissues found not less than 10% of the epithelial infiltrating lymphocytes (range, 10% to 40%).Kaplan-Meier curve analysis showed that the proportion of stromal infiltrating lymphocytes increased, the total survival time (P0.001) and the disease-free survival time (P=0.025) increased significantly. Multiple factor analysis showed that the number of infiltrating lymphocytes increased significantly. The multifactor analysis showed that the stromal infiltrating lymphocytes were related to OS (P0.001, HR= 0.968,95% CI 0.955-0.981) and DFS (P= 0.005, HR= 0.982,95% CI 0.970-0.995). The difference was statistically significant. Conclusion: the matrix infiltrating lymphocyte score on the tumor tissue section is an independent prognostic factor after radical resection of the carcinoma of food. Esophageal squamous cell carcinoma (ESCC) is a common type of esophageal carcinoma, which causes 150 thousand deaths per year and fourth in tumor related deaths. The clinical indicators used to predict the prognosis of esophageal squamous cell carcinoma are not accurate. The purpose of this study is to discuss the single nucleus of p14ARF/MDM2/p53 signaling pathway in esophageal squamous cell carcinoma. The relationship between glucoside polymorphism and prognosis. Materials and methods: This study included 124 patients undergoing radical resection of esophageal squamous cell carcinoma, extracted DNA from the paraffin section of the tumor tissue after operation, and detected the single nucleotide polymorphisms (single nucleotide polymorphism, SNP) of the 6 loci on the p14ARF/MDM2/p53 signaling pathway by mass spectrometry. The use of Kap Lan-Meier curve and log-rank test were used to analyze the difference between the genotype of SNP loci and the total survival time (overall survival, OS) and the disease free survival time (disease-free survival, DFS). A Cox regression model was used to analyze the correlation between the prognostic factors and OS and DFS. Results: 124 cases of esophageal squamous cell carcinoma were included in this study, of which 28 cases, male, male, male, male and female. The median age was 58 years, and the median follow-up time was 37 months.Kaplan-Meier curve analysis showed that the total survival time (P=0.001) and the disease free survival time (P=0.001) of the p144ARF rs3814960 locus TC/CC genotype patients significantly reduced the total survival time of the patients with the A/- + AA genotype of.MDM2 rs34886328 loci (P=) (P=) (P=). 0.0004) and a significant increase in the.Cox regression model with the disease free survival time (P=0.0001). The results of the.Cox regression model showed that the total survival time (]HR=2.765,95% CI: 1.330-5.750, P=0.006, Pc=0.030) and the disease-free survival time of the p14ARF rs3814960 locus were significantly lower than those of the genotype patients. The total survival time (]HR=0.272,95% CI:0.131-0.564, P=4.7 x 10-4, Pc=0.003) and disease-free survival time (]HR=0.217,95% CI:0.109-0.429, P=1.1 x 10-5, Pc=6.6 x 10-5) in patients with the MDM2 rs34886328 locus A/-+AA genotype were significantly higher than those in the type / - genotype patients. This study was the first to prove that the tumor tissue of the patients with esophageal squamous cell carcinoma could be operated for the first time. The polymorphism of rs3814960 and MDM2rs34886328 loci is associated with the prognosis. In future studies, a large sample population can be used as an independent prognostic marker for esophageal squamous cell carcinoma. Objective: more than 90% of the esophageal cancer in China belongs to esophageal squamous cell carcinoma, with more than 25 million new cases each year, resulting in about 150 thousand deaths, and fourth in tumor related deaths. The clinical indicators used to predict the prognosis of squamous cell carcinoma of the esophagus are still inaccurate and.HPV plays an important role in the development of cervical cancer. It is also an independent prognostic factor for oropharyngeal, anal and cervical cancer. The purpose of this study was to explore the correlation between the subtype of HPV infection and the prognosis of the tumor tissues of the patients with esophageal squamous cell carcinoma. Materials and methods: the study was included in 135 cases. DNA in paraffin section of esophageal squamous cell carcinoma was extracted after radical resection of esophageal squamous cell carcinoma. 14 HPV subtypes (HPV16,18,31,33,35,39,45,51,52,56,58,59,66,68) in DNA samples were detected by matrix assisted laser desorption / ionization time of flight mass spectrometry (MALDI-TOF MS) and PCR method, and SPSS 16 software was used for statistical analysis. Fruit: 135 cases of esophageal squamous cell carcinoma were included in this study, of which 26 were female and 109 were male. The median age was 58 year old.MALDI-TOF MS detection. Only 1 patients were infected with HPV16, and the other 13 HPV in the total number of 0.74%. were not detected by.PCR in 135 cases of esophageal squamous cell carcinoma in 135 cases of esophageal squamous cell carcinoma. In the tumor tissue DNA, only 1 cases have HPV infection. Conclusion: because of the small sample size and low HPV infection rate in the squamous cell carcinoma of the esophagus, we can not confirm the relationship between the HPV infection and the prognosis of the squamous cell carcinoma of the esophagus. In addition, we speculate that the incidence of esophageal cancer and the rate of HPV infection have great regional differences. The role of HPV infection in the pathogenesis of esophageal squamous cell carcinoma may not be the same. HPV may not be an important pathogenic factor for patients with squamous cell carcinoma of the esophagus in Central China.
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R735.1

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