基于超声RF信号的微泡次谐波散射联合谐波造影灌注分析在肿瘤组织间隙液压评价及其调控治疗中的应用研究

Since interstitial fluid pressure (IFP) in most human tumors is highly elevated and will lead to resistance to chemotherapy and radiotherapy, the evaluation of tumor IFP is very important for the assessment of tumor biological characteristics and patient’s prognosis. However, currently there is no effective and noninvasive technique to assess tumor IFP. Our previous studies showed that there is good linear relationship between hydrostatic pressure and subharmonic amplitude and dynamic contrast-enhanced ultrasound could be used to quantify tumor perfusion. However, to the best of our knowledge, there is no article presenting the value of combined subharmonic signal and harmonic perfusion analysis from microbubbles in the evaluation of tumor IFP and its regulation. The purpose of this study is to determine whether combined subharmonic signal and harmonic perfusion analysis from microbubbles enables evaluation of tumor IPF and its regulation, and to compare to the measurements of tumor hypoxia, perfusion, interstitial fibrosis, microvessel density, proliferation activity and metastasis by histopathology, which will provide a noninvasive and cheap imaging technique to the evaluation of tumor biological characteristics, the determination of treatment protocol and the regulation of IFP, and this will improve the cancer treatment.

组织间隙液压异常升高是恶性实体瘤的特点并影响肿瘤的放化疗疗效，其测定对肿瘤生物学特性及预后评估具有重要意义，但目前缺乏无创监测肿瘤组织间隙液压的有效手段。课题组前期研究已证实微泡次谐波散射与环境压力之间高度的线性关系以及谐波造影血流灌注评价肿瘤灌注的有效性。那么微泡次谐波散射联合谐波造影血流灌注分析能否有效评价肿瘤组织间隙液压并在其调控治疗中发挥作用，目前尚未见报道。本研究拟建立体内外模型，优化声场参数，通过分析超声RF信号同时计算微泡的次谐波散射幅度和谐波造影血流灌注参数、结合病理评价组织缺氧、血流灌注、间质纤维化、微血管密度、肿瘤增殖活性、转移等，以传统穿刺法测量组织间隙液压为标准，探讨微泡次谐波散射联合谐波造影血流灌注分析在肿瘤组织间隙液压评价及其调控治疗中的作用，为肿瘤生物学特性评估、治疗方案制定、组织间隙液压调控治疗提供有效、无创、价廉的监测手段，对提高肿瘤治疗效果具有重要意义。

肿瘤组织间隙液压升高是恶性肿瘤微环境的重要特征之一，监测肿瘤间隙液压对肿瘤生物学特性及疗效、预后评估具有重要意义，但目前缺少无创监测肿瘤间隙液压的有效手段。本研究基于微泡次谐波散射幅度对环境压力有较好敏感性及谐波造影血流灌注参数评价肿瘤灌注的有效性基础，构建体外动态循环系统，分析微泡次谐波散射信号幅度对压力敏感性最高时的入射声压和频率，优化谐波造影条件，以穿刺法测量组织间隙液压为标准，探究次谐波散射与谐波造影血流灌注参数在肿瘤组织间隙液压评价中的作用，旨在为评估肿瘤生物学特性、拟定治疗方案、监测疗效提供的有效、无创的手段。本研究在体外水箱实验中经过声场参数调节，获得较好的次谐波幅度测压敏感性且误差较小，为下一步临床转化提供有力的研究基础；同时通过体内实验发现谐波血流灌注参数与肿瘤间隙液压之间的较好相关性。但在小鼠皮下移植瘤体内实验中，基于线阵探头的次谐波造影与肿瘤间隙压之间的相关性较差，未能继续深入开展次谐波造影评估肿瘤间隙压调控治疗的研究。调整为分析临床肝癌患者肝实质和门脉次谐波散射幅度与ICG滞留率的关系，结果显示门脉和肝实质的次谐波成像峰值强度能在一定程度上预测肝功能储备情况。本研究证实了微泡次谐波散射信号对于压力估测的可行性及有效性，但对于体内组织间隙液压评价及调控的研究由于次谐波声场参数复杂，需要改进实验设备及调整实验参数才能进一步验证。