多模态的磁共振弹性成像和超短TE磁共振成像联合评价肝细胞癌的侵袭性

The assessment of invasiveness of hepatocellular carcinoma (HCC) plays a critical role in selecting treatment options and evaluating prognosis. However, assessing the invasiveness of HCC is almost dependent on pathological examination, lacking of a noninvasive and reliable assessment method. Studies has shown that tumor stiffness of HCC and collagen content could be important indicators for evaluating invasiveness of HCC. This research will focus on combining tumor physical micro-environment and stiffness measured by multi-frequency multi-parametric 3D magnetic resonance elastography (MRE) (stiffness value, storage modulus, loss modulus, volumetric strain, phase angle, damping ratio and tumor boundary, etc.) and collagen content in HCC tumor tissues measured by ultra-TE-MR imaging (UTE-MRI) to evaluate the invasiveness of HCC based on clinical samples. Then, further change the expression of tumor stiffness genes in HCC cell lines and build animal model that is related to extracellular matrix stiffness and the interstitial fluid pressure. Measuring the stiffness value and several other parameters by multi-frequency 3D MRE and the collagen content by UTE-MRI. Combined with the pathological analysis of collagen contents and invasiveness markers of tumors, and reveal the mechanism of the relationship among tumor physical micro-environment and stiffness, intra-tumor collagen content and HCC invasiveness. This research has important clinical significance for clarifying the value of the combination of multi-frequency 3D MRE and UTE-MRI in the assessment of invasiveness of HCC, and provide a new predictive maker for the invasiveness of HCC.

肝细胞癌（HCC）的侵袭性是治疗方案选择和预后评估的重要依据。临床评价HCC侵袭性依赖病理诊断，缺乏无创、可靠的手段。研究表明HCC硬度及胶原含量等为评估HCC侵袭性的重要指标。本项目拟联合临床样本的多频率MR弹性成像(MRE)的硬度、储存模量、损耗模量、容积张力、相位角、阻尼系数的定量值及肿瘤边界等检测肿瘤的硬度、微环境以及超短TE(UTE)-MRI检测HCC肿瘤的胶原成分，评估其与HCC侵袭性的关系。并建立重组肝癌细胞株移植瘤动物模型，调控HCC硬度相关基因的表达来改变胶原的排列和间质流体压力，采用多频率MRE和UTE-MRI测量肿瘤的硬度、胶原含量等定量值，并结合病理学结果以及侵袭性相关标志物，阐明HCC侵袭性与肿瘤硬度、胶原含量等多参数之间的分子调控机理。本项目对于确定MRE和UTE-MRI联合评估HCC侵袭性的诊断价值具有重要的临床意义，也为HCC治疗决策提供重要依据。

肝癌（HCC）的侵袭性是治疗方案选择和预后评估的重要依据，但目前侵袭性评估依赖病理诊断，缺乏无创、可靠的手段，为HCC诊断和治疗中亟待解决的关键科学问题。本项目针对该关键科学问题展开了如下研究，相关研究成果共计发表SCI论文21篇，权威国际会议摘要30篇（oral 12篇）。.（1）针对HCC的临床诊断问题，课题组探索并针对全球2018版HCC影像诊断指南（LI-RADS v2018）临床应用难点建立了提高多参数MRI对不典型低侵袭性HCC、小HCC诊断的敏感性和准确性的修订优化方案，并被Radiology（IF=29.15）引用；Wolfgang Schima对我们建立HCC的诊断方案给予肯定评价（述评，AJR. 2022; 218:698）。同时申请人作为国内唯一专家参与了全球HCC诊断LI-RADS v2018手册的制定。此外发现深度学习有助提高CT检查对HCC的准确诊断，并在维持诊断效能的同时减少辐射剂量，肝病顶级杂志Journal of Hepatology（IF=30.08）认为该发现有助于优化HCC诊断方案。.（2）在评估HCC侵袭性及预后的工作中，课题组发现3D MRE、CSE-MRI及IOP技术与多参数MRI影像特征可术前评估HCC分化程度、微血管侵犯等，表明多模态MRI可无创定量定性评估反映HCC侵袭性的病理学特征，有助于改善评估HCC侵袭性主观性强、重复性低的现状。同期研究发现3D MRE测量的肿瘤硬度与盆腔肿瘤侵袭性生物学行为高度相关，表明3D MRE是一种无创评估恶性肿瘤侵袭性的有效手段。此外，发现3D MRE测量的HCC及背景肝的硬度值分别为HCC术后早/晚期复发的高风险因素；肿瘤边缘不规则及肝胆期瘤周低信号等可在治疗前识别CD8与PDL1状态判断免疫激活情况，有助于针对高侵袭性中晚期HCC患者制定合理的治疗措施以提高疗效及预后。.（3）开发了一种多功能聚合物PEG-b-PLLys-g-(ss-IPEI)，通过负载透明质酸酶等来降低间质液粘性等改善肿瘤物理微环境，促进药物靶向输送发挥长期高效抗肿瘤特性，同时合成了一种纳米蛋白材料可协助进行HCC诊断定位和确定激光治疗的时间窗，联合饥饿治疗发挥的抗肿瘤效应，并发现反映肝脏物理微环境的3D MRE多力学参数可对肝纤维化严重程度及疗效进行评估，为进一步研究HCC侵袭性提供了依据。