吸纯氧后BOLD-fMRI监测胶质瘤乏氧微环境

The tumors' hypoxia microenvironment is characteristic and generally seen.Hypoxia microenvironment plays a crucial role in malignant progression and restricts curative efficacy.However, the existing modalities are far from effective in evaluating the hypoxia in tumor.Our preliminary research has revealed that: free oxygen is paramagnetic and the signal of brain tissue changes significantly after inhalation of pure oxygen. Prominent signal difference has been detected between areas with differed perfusion levels. As an example of tumor with hypoxia, the current research is planning to establish glioma model (originated from u251 glioma cell lines) of rats, which are then seperately developping to be hyperoxia, normal and hypoxia groups.Oxygen enhanced BOLD-magnetic resonance imaging is to be performed during paradigm of pure oxygen inhalation. The results of BOLD-fMRI are to be compared to those form PET/CT imaging and oxygen electrode evaluation (reference standard). The HIF-1、VEGF、CXCL12/CXCR4、CXCL12/CXCR7 levels in three group would be detected and compared with immunohistochemistry, whose correlation with the results of fMRI and hemodynamics reveals the molecular-level basis of oxygen-enhanced BOLD-fMRI. The results will be introduce and extend to most types of tumor and other disease condition, such as ischemia and infarction. The aim of the research is to establish and optimize the oxygen related BOLD-fRMI to better demonstrate hypoxia microenvironment in tumor.The results could be extend to most types of tumor and other disease condition, such as ischemia and infarction.

乏氧是肿瘤微环境最普遍存在的现象。它与肿瘤发生发展关系密切，且影响放化疗的疗效。然而目前尚无有效无创敏感的评价肿瘤乏氧的理想方法。前期工作发现：游离氧有顺磁性，吸入纯氧后脑组织信号明显变化，正常和异常血供区的信号有显著差异。本研究计划以胶质瘤为例，分组建立乏氧、正常及富氧的三组u251细胞系大鼠胶质瘤模型；成瘤后利用纯氧吸入法增加不同供氧区肿瘤组织的游离氧含量差异，同时用BOLD-fMRI显示（称"游离氧功能磁共振成像"）。fMRI结果将与PET/CT乏氧显像、氧电极法结果比较，不断优化成像方法。用免疫组化检测及比较三组胶质瘤HIF-1α、VEGF、CXCL12/CXCR4及CXCR7的表达，并讨论与游离氧显像及肿瘤血流动力学参数的相关性，从机制上深化成像原理。研究最终目的在于建立肿瘤乏氧影像学评价新方法。这对于认识肿瘤发病机制、临床判断肿瘤乏氧及指导个体化治疗和判断预后均意义深远。

这项研究的目的是利用氧增强功能磁共振来探测肿瘤内部缺氧情况是否可行，并观察吸氧后肿瘤组织学分析，氧分压变化与磁共振图像中信号强度变化百分比（percent of signal intensity changes，PSIC）是否相关。我们首先建立大鼠C6原位胶质瘤模型。部分大鼠原位胶质瘤模型在氧增强功能磁共振后进行血管密度、GLUT-1染色等免疫组化分析，部分大鼠在氧功能磁共振结束后密切观察其生存期。根据氧增强功能磁共振图像，可以得到所有原位胶质瘤图像的时间-信号强度曲线以及PSIC地图。高PSIC感兴趣区（high-ROI,平均PSIC > 10%) 和PSIC感兴趣区（low-ROI，平均PSIC <10%)在PSIC地图上随机选出. 为了确定PSIC地图分辨肿瘤缺氧区的准确性，我们另外建立了大鼠体表胶质瘤模型来直接测量肿瘤内氧分压，观察信号变化与氧分压的关系。所有的肿瘤的PSIC地图都显示了异质性。对于原位肿瘤，时间-信号强度曲线表明高PSIC感兴趣区内信号强度上升程度高于低PSIC感兴趣区。表现为低百分比（平均PSIC <10%)的区域百分比与GLUT-1染色阳性区域承正相关 (r =0.71; P<0.05)。信号轻度百分比与区域内血管密度成正相关 (r=0.88;P<0.05)，根据肿瘤内低PSIC区域的百分比把原位肿瘤分为三组，发现生存期有显著差异 (log-rank P = 0.035)。体表肿瘤的时间-氧分压与时间-信号强度曲线变化相似。PSIC与氧分压变化成正相关 (r =0.82; P<0.05)。这些结果表明氧增强磁共振可以用于评估C6胶质瘤内部的缺氧情况，在这些模型中，PSIC值与生存期相关，说明PSIC可以作为一个判定胶质瘤预后的手段。