Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Ultrasonics. 2011 Apr;51(3):382-9. doi: 10.1016/j.ultras.2010.11.004. Epub 2010 Nov 18.
The purpose of this study was to prospectively compare noninvasive, quantitative measures of vascularity obtained from four contrast enhanced ultrasound (US) techniques to four invasive immunohistochemical markers of tumor angiogenesis in a large group of murine xenografts. Glioma (C6) or breast cancer (NMU) cells were implanted in 144 rats. The contrast agent Optison (GE Healthcare, Princeton, NJ) was injected in a tail vein (dose: 0.4ml/kg). Power Doppler imaging (PDI), pulse-subtraction harmonic imaging (PSHI), flash-echo imaging (FEI), and Microflow imaging (MFI; a technique creating maximum intensity projection images over time) was performed with an Aplio scanner (Toshiba America Medical Systems, Tustin, CA) and a 7.5MHz linear array. Fractional tumor neovascularity was calculated from digital clips of contrast US, while the relative area stained was calculated from specimens. Results were compared using a factorial, repeated measures ANOVA, linear regression and z-tests. The tortuous morphology of tumor neovessels was visualized better with MFI than with the other US modes. Cell line, implantation method and contrast US imaging technique were significant parameters in the ANOVA model (p<0.05). The strongest correlation determined by linear regression in the C6 model was between PSHI and percent area stained with CD31 (r=0.37, p<0.0001). In the NMU model the strongest correlation was between FEI and COX-2 (r=0.46, p<0.0001). There were no statistically significant differences between correlations obtained with the various US methods (p>0.05). In conclusion, the largest study of contrast US of murine xenografts to date has been conducted and quantitative contrast enhanced US measures of tumor neovascularity in glioma and breast cancer xenograft models appear to provide a noninvasive marker for angiogenesis; although the best method for monitoring angiogenesis was not conclusively established.
本研究旨在前瞻性地比较四种对比增强超声（CEUS）技术获得的无创、定量血管生成指标与四种侵袭性免疫组化肿瘤血管生成标志物在一大组鼠异种移植模型中的相关性。将胶质瘤（C6）或乳腺癌（NMU）细胞植入 144 只大鼠中。尾静脉注射对比剂 Optison（GE Healthcare，新泽西州普林斯顿）（剂量：0.4ml/kg）。使用 Aplio 扫描仪（东芝美国医疗系统公司，加利福尼亚州托斯汀）和 7.5MHz 线性阵列进行功率多普勒成像（PDI）、脉冲减法谐波成像（PSHI）、闪烁回声成像（FEI）和微流成像（MFI；一种随时间创建最大强度投影图像的技术）。从对比超声的数字剪辑中计算肿瘤新生血管的分数，而从标本中计算相对染色面积。使用析因、重复测量方差分析、线性回归和 z 检验比较结果。与其他超声模式相比，MFI 更好地显示肿瘤新生血管的迂曲形态。细胞系、植入方法和对比超声成像技术是方差分析模型中的显著参数（p<0.05）。在 C6 模型中，线性回归确定的最强相关性是 PSHI 与 CD31 染色面积百分比（r=0.37，p<0.0001）之间的相关性。在 NMU 模型中，FEI 与 COX-2 之间的相关性最强（r=0.46，p<0.0001）。用各种超声方法获得的相关性之间没有统计学上的显著差异（p>0.05）。总之，迄今为止进行了最大的对比增强超声鼠异种移植研究，在胶质瘤和乳腺癌异种移植模型中，肿瘤新生血管的定量对比增强超声测量似乎提供了一种非侵入性的血管生成标志物；尽管尚未确定监测血管生成的最佳方法。
