基于2D-COSY为中心的多模态MRI联合影像组学预测IDH突变型胶质瘤术后无进展生存预后研究

Mutations in isocitrate dehydrogenase gene (IDH) characterize the majority of grade II and III gliomas and secondary glioblastomas. Independent of tumor grade, gliomas harboring IDH mutations are associated with a more favorable prognosis. However, the outcome of IDH-mutant glioma patients including progression free survival (PFS) and overall survival varies greatly across individuals. In our preliminary study, we found that early Cho/NAA ratios demonstrated the best discriminatory ability in stratifying postoperative IDH-mutant glioma patients who progressed before or after 2 years. 2HG/Cr ratios, while significantly reduced after the start of chemoradiation or chemotherapy, were only weakly associated with 2-year PFS of the patients. In this study, we conduct a prospective single-institution longitudinal study in postoperative patients with histologically confirmed IDH-mutant glioma receiving standard chemoradiation or chemotherapy: 1) 2D-COSY MRS and other multimodal MRI are acquired prior to chemoradiation or chemotherapy and then at scheduled time points posttreatment. 2) A machine-learning algorithm will be used to generate a model predictive of the postoperative PFS in IDH-mutant gliomas based on the metabolites derived from 2D-COSY, multimodal features extracted from MRI images by radiomic methods, as well as the clinical features. The key prognostic factors for the PFS will also be abstracted. It is hoped that the results of our study will facilitate better clinical management and more accurate PFS prediction of patients with IDH-mutant gliomas.

IDH突变发生于绝大多数较低级别胶质瘤和继发性胶质母细胞瘤中，且IDH突变型胶质瘤患者总生存期显著长于野生型患者。然而，IDH突变型胶质瘤患者个体结局参差不齐。我们前期研究发现术后早期Cho/NAA能预测IDH突变型胶质瘤患者化疗或放化疗开始后2年PFS结局；虽然IDH突变特异性代谢物2HG水平于放疗或放化疗开始后明显下降，早期2HG/Cr对2年PFS结局的预测价值有限。本课题拟开展：1.前瞻性纳入术后拟行化疗或放化疗的IDH突变型胶质瘤患者，于治疗开始前、后对患者定期随访，采用2D-COSY为中心的多模态MRI采集胶质瘤的代谢物和影像图像，并使用影像组学的方法从图像中提取影像学特征；2.使用机器学习从代谢物、影像学和临床特征中寻找IDH突变型胶质瘤术后PFS关键的预后指标，建立术后PFS预测模型。我们的结果将为IDH突变型胶质瘤患者科学临床管理和精确结局预测提供重要的理论依据。

本项目的主要研究内容分为3个部分：.1 探索基于代谢物、影像学和临床特征，建立IDH突变型胶质瘤术后PFS预测模型；.我们共纳入了170例IDH突变型胶质瘤术后患者。末次随访时，进展的胶质瘤患者54例。患者无进展生存的中位数为1177天，1年、2年及3年内进展患者分别为17例、30例、40例。我们将继续完成影像资料组学分析，并构建PFS预测模型。.2 探索术前胶质瘤相关癫痫（TAS）发生的危险因素及TAS与患者PFS的相关性；.我们回顾性纳入了891例胶质瘤患者（TAS 225例）。Logistic回归分析表明年龄≥40岁（OR = 0.37），WHO分级升高（OR = 0.34），肿瘤跨越中线（OR = 0.42），IDH突变（OR = 2.87），Ki67高表达（OR = 0.38），ATRX阳性（OR = 0.49）同TAS发生显著相关，其中年龄≥40岁、肿瘤跨越中线和IDH野生型是TAS的独立危险因素。我们进一步筛选了于协和医院定期复查的患者440例（TAS 125例）。Cox生存分析结果表明TAS发生是患者无进展生存的独立保护因素（HR = 0.538）。.3 探索基于MRS检测胱硫醚以靶向诊断胶质瘤1p/19q共缺失突变；.胶质瘤1p/19q共缺失突变导致肿瘤细胞内胱硫醚浓度升高，胱硫醚可以被MRS检测到，然而天门冬氨酸与胱硫醚的谱线在PRESS MRS中高度重叠，影响了胱硫醚的准确定量。.我们虚拟激发了PRESS序列不同TE时胱硫醚和天门冬氨酸的MRS，结果表明（TE1, TE2）=（17, 28）ms时，胱硫醚和天门冬氨酸2.72 ppm处峰区别最大，最有利于胱硫醚的准确检测。体外模体扫描MRS与虚拟激发谱线形态一致。在体试验结果表明45 ms TE PRESS序列能更准确检测胱硫醚，测得的胱硫醚浓度值与MEGA-PRESS的检测结果具有更高相关性（相关系数0.71）。