超声造影评估乳腺癌新辅助化疗的相关基础研究

Neoadjuvant chemotherapy (NAC) is used in clinical for treating breast cancer widely, when the incidence of breast cancer increases more and more in China, especially in large city. There are some questions in uisng of NAC.One of them is that some patients receive poor effect and need to chang NAC plan as early as possible, but all image technology nowaday, like ultrasound, mammography, magnatic resonance imaging (MRI) and PET/CT, can't evaluate and predict NAC effect in early stage precisely and individually. In our pre study, we gave same patient contrast enhanced ultrasound (CEUS) examination before and after NAC on same location of tumor. Then we found that some variable quantities of CEUS, such as infusion time, 75% wash-out time, peak index, peak time and aera under curve (AUC), had differences during NAC, even statistical differences in infusion time, 75% wash-out time and peak index. Although we didn't know the mechanism and the value of these variation, we have a hypothesis: the activity and the quantity of tumor microvessels are affected by chemotherapeutics in NAC, and on the image level, the affection can be performanced by CEUS through enhanced agent, which is only in blood pool in human body and average diameter is 2.5 μm, easy passing microvessels, with the prediction of the NAC effects in early stage. To verify this hypothesis, we are going to study nude mouse modes inoculated with MCF-7 human breast cancer strains, and clinical breast cancer patients modes which will accepet NAC. To clarify the histology basis of CEUS in tumor NAC, we will study the correlation between the variation of CEUS variable quantities and tumor microvessel density (MVD), vascular endothelial growth factor receptor (VEGFR)-1/2/3. To evaluate NAC by CEUS, we will study the correlation between variation of CEUS variable quantities and tumor biological characteristics, such as tumor proliferation index, tumor apoptosis index, pathological result and grading, clinical TNM and staging. Our research try to study the correlation between NAC and CEUS, on the basis of tumor microcirculation and histological factors. Meanwhile, we are not only study the results of NAC in clinical, but also study tumor biological characteristics variation during NAC. The result of our reseach will bring a new way to evaluate and predict NAC by imaging technique,and will be valuable in clinical and social lives.

新辅助化疗（NAC）广泛应用于临床乳腺癌治疗，但是部分病例因药物敏感性的不同需要及时调整方案，而现有影像技术均无法早期评估、预测化疗的疗效。本课题组在前期研究中发现，乳腺癌NAC前后超声造影的部分指标存在统计学差异，但是其机理和具体价值尚需进一步探讨。由此我们提出假说：乳腺癌NAC中，肿瘤内的微血管数量和活性受化疗药物影响，在超声层面表现为造影变量的改变，二者间的相关性可用来预测化疗的疗效。为验证这一假说，我们将用接种MCF-7的裸鼠模型和临床乳腺病例，通过NAC过程：研究肿瘤微血管密度（MVD）及其相关生长因子受体（VEGFR-1/2/3）的变化与造影变量之间的相关性，阐明造影变量变化的组织学基础；研究造影变量与肿瘤生物学特性（肿瘤增殖、凋亡指数，病理分级，临床TNM分期）改变之间的相关性，揭示造影评估NAC疗效的规律。本研究将为NAC的早期预测提供全新的思路和模式，具有重要的医学价值。

乳腺癌在我国女性群体中发病率居恶性肿瘤之首，严重威胁到人群的健康，成为当代社会的重要杀手。乳腺癌的治疗已经不是简单的手术切除，而演变为多学科综合治疗，其中新辅助化疗已经成为治疗中的首选。新辅助化疗（NAC）广泛应用于临床乳腺癌治疗，但是部分病例因药物敏感性的不同需要及时调整方案，而现有影像技术均无法早期评估、预测化疗的疗效。本课题组在前期临床研究中发现，乳腺癌NAC 前后超声造影的部分指标存在统计学差异，但是其机理和具体价值尚需进一步探讨。由此我们提出假说：乳腺癌NAC 中，肿瘤内的微血管数量和活性受化疗药物影响，在超声层面表现为造影变量的改变，二者间的相关性可用来预测化疗的疗效。为验证这一假说，我们将用动物模型，通过NAC 过程：研究肿瘤微血管密度（MVD）及其相关生长因子受体（VEGFR-1/2/3）的变化与造影变量之间的相关性，阐明造影变量变化的组织学基础；研究造影变量与肿瘤生物学特性（肿瘤增殖、凋亡指数，病理分级）改变之间的相关性，揭示造影评估NAC 疗效的规律。本研究将为NAC 的早期预测提供全新的思路和模式，具有重要的医学价值。课题完成了两项研究。首先是SD大鼠皮下种植walker-256模型接受5-FU化疗前后，超声造影数据和病理结果的相关性分析，这个研究重点考察超声造影评价肿瘤化疗效果的可行性，结果我们发现，造影指标和部分病理指标之间存在相关性。然后我们建立裸鼠皮下种植MCF-7乳腺癌模型，然后完整的使用人乳腺癌新辅助化疗方案ACT，依照动物实验剂量设计给药，选取前一研究提示的部分有效的病理指标，进行造影指标与病理指标相关性分析，发现超声造影指标与病理指标，尤其是肿瘤的微血管指标具有一致性，可以在早期肿瘤大小没有发生改变的情况下，提示肿瘤的转归。研究的文章“Contrast-ehanced ultrasound evaluate the effect of chemotherapy in a rat model of walker256”已接受，文章“Does Contrast-ehanced ultrasound can evaluated neoadjuvant chemotherapy early in breast cancer? The study on animal mode”在修回中，目前课题培养在读博士研究生一名，在读硕士研究生两名。