Claes An, Gambarota Giulio, Hamans Bob, van Tellingen Olaf, Wesseling Pieter, Maass Cathy, Heerschap Arend, Leenders William
Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Int J Cancer. 2008 May 1;122(9):1981-6. doi: 10.1002/ijc.23306.
Proper delineation of gliomas using contrast-enhanced magnetic resonance imaging (CE-MRI) poses a problem in neuro-oncology. The blood brain barrier (BBB) in areas of diffuse-infiltrative growth may be intact, precluding extravasation and subsequent MR-based detection of the contrast agent gadolinium diethylenetriaminepenta-acetic acid (Gd-DTPA). Treatment with antiangiogenic compounds may further complicate tumor detection as such compounds can restore the BBB in angiogenic regions. The increasing number of clinical trials with antiangiogenic compounds for treatment of gliomas calls for the development of alternative imaging modalities. Here we investigated whether CE-MRI using ultrasmall particles of iron oxide (USPIO, Sinerem) as blood pool contrast agent has additional value for detection of glioma in the brain of nude mice. We compared conventional T1-weighted Gd-DTPA-enhanced MRI to T2*-weighted USPIO-enhanced MRI in mice carrying orthotopic U87 glioma, which were either or not treated with the antiangiogenic compound vandetanib (ZD6474, ZACTIMA). In untreated animals, vessel leakage within the tumor and a relatively high tumor blood volume resulted in good MRI visibility with Gd-DTPA- and USPIO-enhanced MRI, respectively. Consistent with previous findings, vandetanib treatment restored the BBB in the tumor vasculature, resulting in loss of tumor detectability in Gd-DTPA MRI. However, due to decreased blood volume, treated tumors could be readily detected in USPIO-enhanced MRI scans. Our findings suggest that Gd-DTPA MRI results in overestimation of the effect of antiangiogenic therapy of glioma and that USPIO-MRI provides an important complementary diagnostic tool to evaluate response to antiangiogenic therapy of these tumors.
利用对比增强磁共振成像（CE-MRI）准确描绘胶质瘤在神经肿瘤学中是个难题。在弥漫性浸润生长区域，血脑屏障（BBB）可能保持完整，阻止造影剂钆双乙三胺五乙酸（Gd-DTPA）外渗及随后基于磁共振的检测。用抗血管生成化合物治疗可能使肿瘤检测进一步复杂化，因为这类化合物可恢复血管生成区域的血脑屏障。用于治疗胶质瘤的抗血管生成化合物的临床试验数量不断增加，这就需要开发替代成像模式。在此，我们研究了使用超小氧化铁颗粒（USPIO，Sinerem）作为血池造影剂的CE-MRI对裸鼠脑内胶质瘤检测是否具有额外价值。我们将传统的T1加权Gd-DTPA增强MRI与T2*加权USPIO增强MRI在携带原位U87胶质瘤的小鼠中进行比较，这些小鼠接受或未接受抗血管生成化合物凡德他尼（ZD6474，ZACTIMA）治疗。在未治疗的动物中，肿瘤内的血管渗漏和相对较高的肿瘤血容量分别导致Gd-DTPA和USPIO增强MRI有良好的磁共振成像可见性。与先前的研究结果一致，凡德他尼治疗恢复了肿瘤血管系统中的血脑屏障，导致Gd-DTPA MRI中肿瘤不可检测。然而，由于血容量减少，在USPIO增强MRI扫描中可以很容易地检测到接受治疗的肿瘤。我们的研究结果表明，Gd-DTPA MRI会高估胶质瘤抗血管生成治疗的效果，而USPIO-MRI为评估这些肿瘤的抗血管生成治疗反应提供了一种重要的补充诊断工具。
