针对多发性内分泌肿瘤-1型中的胰腺神经内分泌肿瘤的系统临床研究

发布时间：2018-06-07 00:13

本文选题：多发性内分泌肿瘤-1型 + 胰腺神经内分泌肿瘤　；参考：《吉林大学》2017年博士论文

【摘要】：目的:本博士论文拟通过三个部分的临床研究来明确生化标志物Cg A、PP、胰高血糖素和胃泌素在MEN-1患者中诊断PNETs的能力,内源性和外源性的雌激素暴露在女性MEN-1患者中对PNETs的保护性作用以及手术治疗对于MEN-1患者中PNETs的治疗效果。方法:第一部分通过受试者工作曲线分析来评估每个生化标志物预测PNETs可能性的能力,受试者工作曲线分析和逻辑回归模型联合用于确认4个标志物合用诊断PNETs的能力。受试者工作曲线下面积在0.60-0.80间被认为具有中等诊断价值,在0.80-1.00间被认为具有较好诊断价值。Spearman相关分析用于评估连续参数(PNETs诊断年龄、PNETs肿瘤大小及数目)和每个生化标志物间的相关性。Wilcoxon秩和检验被用于评估二分变量(性别、PNETs肿瘤位置、肿瘤功能状态、AJCC分期、淋巴结转移及淋巴血管侵犯)和每个生化标志物间的相关性。使用Wilcoxon符号秩和检验比较手术前后每个生化标志物间的差异。Cox比例风险回归分析被用于评估OS(从PNETs诊断后)与各个生化标志物间的相关性。第二部分通过单变量Cox比例风险回归模型和随时间变化的协同变量来评估雌激素暴露和女性PNETs发生的相关性,单变量Cox比例风险模型被用于评估女性PNETs患者中累积雌激素暴露和OS间的相关性,Kaplan-Meier被用于分析根据其它月经生育特点分组的OS分布情况,组间比较使用时序检验,Fisher精确检验和Wilcoxon秩和检验被用于评估不同女性PNETs组间雌激素暴露因素的不同。第三部分使用Fisher’s精确检验来比较PNETs类型的分类变量,Kruskal-Wallis检验被用于连续变量的比较。有关PFS和OS的分析使用Kaplan-Meier乘积限估计,分类变量的比较使用时序检验。结果:第一部分中Cg A、PP、胰高血糖素和胃泌素的受试者工作曲线下面积分别为59.5%、64.1%、77.0%和75.9%。Cg A、PP和胃泌素联合应用的受试者工作曲线下面积为59.6%。第二部分中根据每个患者最大PNETs肿瘤的最大横截面直径中位数(1.55厘米)将所有PNETs患者分成≤1.55厘米和1.55厘米两组,我们发现≤1.55厘米组患者的累积雌激素暴露值(291)显著高于1.55厘米组患者的累积雌激素暴露值(240)(P=0.043)。第三部分中多变量分析结果显示PNETs诊断时伴有远处转移的患者与PNETs诊断时为局部疾病的患者相比死亡率更高(危险率=3.40;P=0.042)。与胰岛素瘤患者相比,胰高血糖素瘤患者(危险率=20.15;P=0.020)和胰多肽瘤患者(危险率=13.07;P=0.036)死亡率更高。结论:我们的研究结果表明Cg A、PP、胰高血糖素和胃泌素对于在MEN-1患者中诊断PNETs的临床应用价值十分有限(即使联合应用);因此,它们不足以替代当前的影像学检查手段;雌激素暴露对于女性PNETs的肿瘤形成、发展及总体生存并没有明确的保护性作用,但是可能控制肿瘤的生长,这点要通过更多的研究证实;MEN-1患者中PNETs的OS与PNETs类型及PNETs诊断时疾病的侵袭性相关,对于MEN-1患者中的PNETs应尽早诊断,在合适的患者中应积极实施手术治疗。PNETs是MEN-1患者最主要的疾病特异性死亡原因,然而由于此疾病的罕见性以及对其认识的不足,目前只有很少针对它的临床研究。临床医生主要依赖于专家共识指南以及对散发性PNETs研究的推论来指导MEN-1-PNETs患者的临床管理,但是后一种方法非常不切实际,因为MEN-1-PNETs与散发性PNETs间存在诸多不同。针对MEN-1-PNETs的特异性筛选、准确的治疗前预后评估及合理的外科手术治疗对于减少发病率和死亡率是至关重要的。目前临床上亟需针对以上方面进行系统性、多中心、前瞻性的对照研究。
[Abstract]:Objective: This doctoral thesis intends to identify biochemical markers Cg A, PP, glucagon, and gastrin in the diagnosis of PNETs in patients with MEN-1, and the protective effect of endogenous and exogenous estrogen exposure on PNETs in female MEN-1 patients and the therapeutic efficacy of surgical treatment for PNETs in MEN-1 patients. Method: the first part evaluates the ability of each biochemical marker to predict the possibility of PNETs through the analysis of the subjects' work curve. The subjects' work curve analysis and the logistic regression model are combined to confirm the ability of the 4 markers to combine with the diagnostic PNETs. The subjects under the working curve of the subjects are considered to have a moderate diagnostic price between 0.60-0.80. Value, the.Spearman correlation analysis between 0.80-1.00 was considered to be of good diagnostic value for evaluating continuous parameters (PNETs diagnostic age, PNETs tumor size and number) and the correlation.Wilcoxon rank between each biochemical marker was used to evaluate two variables (sex, PNETs tumor location, tumor function state, AJCC staging, lymph node rotation). Correlation between migration and lymphatic vascular invasion) and each biochemical marker. Wilcoxon sign rank sum test compared the difference between each biochemical marker before and after the operation.Cox proportional risk regression analysis was used to assess the correlation between OS (from PNETs) and the various biochemical markers. The second part through the single variable Cox ratio risk return. The correlation between estrogen exposure and female PNETs was assessed by model and time variant synergistic variables. The single variable Cox proportional risk model was used to assess the correlation between cumulative estrogen exposure and OS in female PNETs patients. Kaplan-Meier was used to analyze the distribution of OS according to the other menstrual characteristics and the comparison between groups. Using time series test, Fisher accurate test and Wilcoxon rank sum test were used to assess the differences in estrogen exposure factors between different women PNETs groups. The third part uses the Fisher 's accurate test to compare the PNETs type classification variables, Kruskal-Wallis test is used for continuous variables. The analysis of PFS and OS uses Kaplan-Meier. Result: the area under the working curve under the working curve of Cg A, PP, glucagon, and gastrin was 59.5%, 64.1%, 77%, and 75.9%.Cg A, PP and gastrin under the working curve of 59.6%. second in the 59.6%. second part of each patient, according to the largest PNETs of each patient. The median (1.55 cm) diameter of the maximum cross section of the tumor (1.55 cm) divided all the patients into groups of less than 1.55 cm and 1.55 cm two. We found that the cumulative estrogen exposure value of the patients in the group of less than 1.55 cm (291) was significantly higher than the cumulative estrogen exposure value (240) (240) of the 1.55 cm group (240). In the third part, the results of multivariate analysis showed PNETs diagnosis. Patients with distant metastases were higher in mortality than those with local disease (risk rate of =3.40; P=0.042) when diagnosed with PNETs. Compared with patients with insulinoma, the mortality of pancreatic hyperglycemic tumor patients (risk rate =20.15; P=0.020) and pancreatic polypeptide tumors (risk rate =13.07; P= 0.036) was higher. Conclusion: our results showed Cg A, P. P, glucagon and gastrin are very limited in the clinical application of PNETs in MEN-1 patients (even if combined); therefore, they are not enough to replace the current imaging methods; estrogen exposure does not have a clear protective effect on the formation, development and overall survival of female PNETs, but it may be controlled. The growth of the tumor is confirmed by more studies; the OS of PNETs in MEN-1 patients is associated with the type of PNETs and the invasiveness of the disease at the diagnosis of PNETs. The PNETs should be diagnosed as early as possible in the MEN-1 patients, and the surgical treatment of.PNETs in the appropriate patients is the most important cause of the disease specific death of the MEN-1 patients, however, the cause of the disease is the main cause of the disease. The inadequacy of the disease and its lack of understanding have only rarely been directed at its clinical study. Clinicians rely mainly on expert consensus guidelines and the inference of sporadic PNETs studies to guide the clinical management of MEN-1-PNETs patients, but the latter method is very unrealistic because MEN-1-PNETs is stored with sporadic PNETs. In a variety of differences. Specific screening for MEN-1-PNETs, accurate preoperative assessment of prognosis and reasonable surgical treatment are essential to reduce morbidity and mortality. A systematic, multicenter, prospective, controlled study is urgently needed in these aspects.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R735.9

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