基于超声造影评价临床乳腺癌新辅助化疗的相关实验研究

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 using of NAC. One of them is that some patients receive poor effect and need to change NAC plan as early as possible, but all image technology nowadays, like ultrasound, mammography, magnetic 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, area under curve (AUC) and the form of curve, 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 clinical breast cancer patients modes which will accept NAC by methods such as CEUS, immunohistochemical techniques, biochemistrical techniques, and cell apoptosis in situ. 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 tries 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 research 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）广泛用于临床乳腺癌治疗，但部分病例因药物敏感性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NAC的疗效。本课题组前期研究发现，乳腺癌NAC前后超声造影的部分指标存在统计学差异，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，二者间的相关性可预测化疗的疗效。 为验证这一假说，我们拟针对临床乳腺癌NAC病例，采用超声造影、免疫组化、生物化学和原位细胞凋亡等技术：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）变化的相关性，揭示造影和NAC疗效的关系；探索造影评测NAC的可行性方案。本研究将为NAC早期预测提供全新的思路和模式，具有重要的医学价值。

新辅助化疗是乳腺癌的常规治疗手段，然而部分肿瘤在化疗结束后退缩小于30%，甚至出现继续增长。现有的疗效评价依赖于术后病理，但是对于缓解较差的肿瘤耽搁了治疗时间，因此如何准确的早期预测对于化疗方案不敏感的肿瘤成为临床一大难点。我们尝试寻找一种方便简单的影像医学方法，可以准确评价乳腺癌新辅助化疗的疗效，早期预测肿瘤在化疗后的缓解情况。. 本项目围绕超声造影这一核心方法，辅助多种超声新技术，全程跟踪检查乳腺癌新辅助化疗病例，提取各项超声造影指标和超声模式的诊断指标，提取肿瘤病灶的组织学、生物学、病理学、分子学等指标，进行二者间的相关性分析。本项目从肿瘤的组织学和生物学基础上证实了超声造影指标的变化与肿瘤变化之间存在相关性，可以评价和预测乳腺癌新辅助化疗的疗效；从临床角度总结了超声造影指标变化与肿瘤病理缓解之间的关系，获得了多项用于临床的超声造影参数特征；在临床应用方面获得了超声光散射和弹性辅助造影预测乳腺癌新辅助化疗的诊断指标阈值和数据；围绕乳腺癌新辅助化疗，证明了超声对于腋下淋巴结诊断的价值并总结了有效的方法；同时立足于未来，探索了人工智能评估新辅助化疗及其分子分型的可能。. 项目的完成，提出了将超声造影及新技术用于乳腺癌新辅助化疗结果的评估和早期预测，证实具有良好的效果和可行性，最终获得了一套全新的有效的经济的影像方案。项目的完成对于乳腺癌的治疗甚至未来的精准医疗，都具有重要的临床价值和社会意义。