基于多模态磁共振的胰腺癌细胞外间质演变机制及新辅助治疗后预后评估模型研究

Neoadjuvent therapy (NAT) has played an increasing role in locally advanced and borderline resectable pancreatic adenocarcinoma in recent years. It has been shown that neoadjuvent chemotherapy and radiation therapy could improve the overall survival. Tumor downstaging could be achieved in approximately 30% patients, whose R0 resection rate and survival rate were close to those who had resectable pancreatic cancer initially. CT assessment of pancreatic cancer resectability was considered highly accurate, however, the accuracy decreased sharply for re-staging post-NAT patients, due to radiation-induced pancreatitis and post-treatment fibrosis, which could not be differentiated from tumor infiltration by CT. The tumor microenvironment of pancreatic adenocarcinoma is comprised of cancer cells, stromal stellate cells and an abundance of extracellular matrix (ECM). Stellate cell activation and interplay between cancer cells and stellate cells trigger signal pathways， leading to alteration of ECM protein production, resulting in desmoplasia. Pancreatic cancer ECM produces and supplies the cancer cells with metabolites, and promotes an inflammatory state, recruiting immune cells that facilitate or inhibit cancer growth. ECM is therefore playing a complicated yet essential role in the mechanism of invasiveness and drug-resistance of pancreatic cancer. The alteration of ECM components reflects the response to treatment and predicts patient outcome. Our hypothesis is that in patients with pancreatic adenocarcinoma, the ECM component at baseline and the pattern of ECM evolution under NAT varies in different individuals, which leads to the different post-NAT outcome concerning re-staging and overall survival. Multi-parametric MRI employing quantitative imaging, functional diffusion and perfusion imaging, and biophysiological imaging, has the potential to realize the in vivo visualization of intrinsic ECM composition, which allows the observation, classification and follow-up of ECM evolution under NAT down to the molecular scale. The MRI features and parameters will be correlated with pre-, under- and post-NAT ECM components of patients with pancreatic adenocarcinoma, and a prediction model of patient prognosis will be built using multivariate analysis. The validity of the model will be further tested and optimized using data from prospectively collected patients. The goal is to develop a precision imaging tool for pancreatic cancer patients receiving NAT, both to explore cancer microenvironment evolution mechanism, and to support clinical decision making.

新辅助治疗在局部进展和交界可切除性胰腺癌中应用日益广泛，可改善患者总体预后，使约30%患者重获手术机会。然而传统影像学手段不能准确评价胰腺癌新辅助治疗的效果。胰腺癌的间质微环境近年来受到关注。星形细胞激活，通过一系列信号通路，导致细胞外间质成分发生重大改变，增加胰腺癌的血管浸润风险，并增强其耐药性。治疗过程中的细胞外间质成分改变从微观水平反映治疗效果，预示临床预后。我们推测不同患者的胰腺癌间质存在本底差异和治疗过程中的演变模式差异，这种个体差异性与新辅助治疗后肿瘤可切除性及总生存期有关。磁共振mapping、弥散及灌注成像、生物物理特性成像等综合应用，有望实现胰腺癌间质成分在活体的可视化精准评估，探索肿瘤间质演化的规律。本项目拟通过多模态磁共振与胰腺癌新辅助治疗前/中/后的间质成分进行关联分析，结合患者临床结局建立回归模型，并进行验证和优化，为胰腺癌精准个体化评估提供理论依据和影像工具。

胰腺癌特有的纤维增生反应与肿瘤进展、耐药性和临床预后有关。星形细胞激活，细胞外间质中肿瘤相关的纤维胶原成分增多，有利于癌细胞发生血管和周围组织浸润，使肿瘤的手术可切除性和化疗敏感性降低。.本研究评估了胰腺癌和正常胰腺实质的生物机械特征，并展示了基于组织硬度的MRE对胰腺癌的检出效能优于常规增强CT；评价了多模态MRI对胰腺癌和自身免疫性胰腺炎的诊断效能，发现MRE的硬度指数和液化指数能够客观、准确地实现两种疾病的鉴别诊断；评价了多模态MRI参数与胰腺癌细胞外间质纤维化程度和肿瘤相关纤维母细胞含量的相关性，发现细胞外间质占比（ECV）和硬度指数均与病理的肿瘤纤维化指标存在相关性，而液化指数与肿瘤的淋巴血管侵犯有关。肿瘤大小和硬度指数是胰腺癌术后早期复发的独立风险因素。未能接受手术的患者和手术患者之间肿瘤大小、硬度指数和液化指数均存在显著差异，液化指数是未手术患者总生存期的独立风险因素。.基于本项目建成的胰腺疾病临床-影像-病理数据库，还进行了多模态MRI与胰腺纤维化及胰十二指肠切除术后严重胰瘘风险的相关性评估，以及多模态MRI与胰腺肿瘤术后血糖不耐受风险的相关性评估。研究发现胰腺硬度和ECV均与胰腺纤维化程度有关，胰腺硬度是术后严重胰瘘的独立危险因素。术后新发糖尿病的患者，胰腺平扫T1弛豫值和ECV更高，ECV是术后血糖不耐受的独立危险因素。.基于以上工作，我们初步证实了多模态MRI能够比增强CT更出色地检出胰腺癌，实现与其他疾病的鉴别诊断，并预测胰腺术后并发症的风险。通过与病理标本的关联分析，发现多模态MRI能反映胰腺癌细胞外间质的个体差异，在此基础上初步建立了基于多模态MRI的胰腺癌预后模型。作为一种无创量化的影像学工具，多模态MRI在胰腺癌的诊疗过程中的多个环节体现出优势。通过筛选胰腺癌术后复发高危患者和总生存期更短的患者，施行个体化治疗决策，可能有助于胰腺癌总体预后的改善。