以表观扩散系数为核心的磁共振功能分子成像 在反映胃癌化疗期间肿瘤微结构和代谢机制中的作用

Some of the most common clinical problems are if the first line therapy maintains the efficacy, when patients will develop drug resistance, how to determine a reasonable timing to adjust the treatment regime etc. Current routine clinical treatments are still replying on morphological indexes to evaluate the efficacy of chemotherapy, which not only possibly delays the precious timing of treatment plan adjustment but also leads to costly medical care burden. Among diagnostic imaging modalities, magnetic resonance imaging (MRI) provides excellent spatial resolution and soft tissue contrast, where diffusion weighted imaging (DWI) has been demonstrated to probe pathological microstructure within tumor tissue, though it is sensitive to artifacts such as field susceptibility and body motion. Priorly we have demonstrated capabilities of generating high quality DWI images and detecting apparent diffusion coefficient (ADC) with four times less variation than the control group. Here we propose to utilize advanced MRI techniques to explore the roles of microstructural and metabolic changes of tumor tissue in predicting chemotherapy response of gastric cancer in animal models and then utilize the parameters to early intervene the treatment plans. We will first optimize imaging protocols of multiple b-value and multiple diffusion direction DWI sequence in order to model diffusion D,perfusion f and kurtosis K indexes, as well as chemical exchange saturation (CEST) sequence to probe metabolic heterogeneity. The specific aims of the proposed research are: (1) To evaluate longitudinal changes of these functional indexes during the chemotherapy and to test the hypothesis that these changes happen in early stage of the chemotherapy and could predict the final response judged by morphological indexes; (2) To test the hypothesis that the functional indexes can guide to intervene chemotherapy treatment plans in early stage and improve the outcome of the gastric cancer treatment. We will use logistic regression model to test the effectiveness of each function parameter in early prediction of therapeutic response.

目前胃癌化疗仍依靠形态学来评估疗效，缺乏早期敏感的判断指标。以扩散受限为基础的磁共振功能成像参数已被证明可以反应肿瘤微结构在化疗早期出现的变化。我们前期突破了在实验动物上获得稳定准确的ADC值的限制，使空腔脏器肿瘤的在体功能成像研究成为可能。但根据磁共振多模态功能参数分析肿瘤微结构和代谢功能在化疗中的变化如何导向化疗策略的改变，其后是否可以有效减小肿瘤负荷等问题仍是实际应用这些功能参数的疑问。本课题中我们计划通过优化DWI序列来建模曲线分析组织显微结构扩散、灌注和峰度所表现出的肿瘤异质性，并通过化学交换饱和CEST序列来量化分析移动蛋白质含量和组织平均PH值等代谢指标，在此基础上的实验研究目的包括: 1. 化疗前和期间评估功能成像指标的纵向变化, 以验证这些参数指标或组合可以预测及早期评估化疗疗效的假设; 2. 验证功能成像参数可以引导对胃癌化疗计划的早期干预, 以提高疗效的假设。

胃癌在中国的发病率位于所有恶性肿瘤中的第三位。常见临床问题包括一线药物是否有效，何时出现耐药，以及如何确定合理时机来调整治疗方案等等。目前临床常规仍然依靠形态指标来评估疗效，导致治疗时机延误和个人及社会负担的增加。磁共振成像中的扩散加权成像（DWI）已被证明可以探查肿瘤内病理显微组织，最早可于化疗后3天敏感的提示肿瘤组织结构的变化，我们前期运用藻酸盐模具大幅提高DWI图像质量和表观扩散系数（ADC）的准确性和稳定性。基于此我们运用以ADC值为核心的磁共振成像技术做为化疗的评价指标来考察其在胃癌化疗中的预测作用，利用其纵向变化特点对化疗计划进行早期干预。在本研究中，我们用小鼠模型验证了表观扩散系数（ADC）值在预测5-FU耐药胃癌化疗反应和优化化疗方案中的可行性。实验组5-FU治疗6天后ADC值逐渐升高，但治疗后10天开始下降，随后用紫杉醇替代化疗。5-Fu治疗后10天体积变化率明显增加（从35%增加到45%），化疗后用紫杉醇替代化疗。两组治疗后16天末，实验组的肿瘤负担明显低于对照组（1.619mm3 vs 1.71mm3，P<0.05）。我们发现，根据ADC的早期变化，预先用紫杉醇替代5-FU可有效地减轻肿瘤负担，这意味着ADC值有可能作为预测胃癌化疗反应和优化化疗方案的可靠生物指标。