Noninvasive Contrast-enhanced US Quantitative Assessment of Tumor Microcirculation in a Murine Model: Effect of Discontinuing Anti-VEGF Therapy
Noninvasive Contrast-enhanced US Quantitative Assessment of Tumor Microcirculation in a Murine Model: Effect of Discontinuing Anti-VEGF Therapy
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DOI：
10.1148/radiol.09090728
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发表时间：
2010-02-01
期刊：
影响因子：
19.7
通讯作者：
Lucidarme, Olivier
中科院分区：
文献类型：
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作者：
Guibal, Aymeric;Taillade, Laurent;Lucidarme, Olivier
目的：通过超声造影剂增强扫描，确定贝伐单抗治疗结束后，移植于小鼠体内的肾肿瘤多快开始血管重建。材料和方法：所有实验均由地区伦理委员会批准。将人肿瘤细胞株SK-NEP-1于第0天移植于50只裸鼠的左肾内。42只小鼠发展成肿瘤，对32只存活的小鼠进行了纵向随访。从第13天开始，14个对照组接受双周生理盐水；11只小鼠接受双周贝伐单抗治疗，直到第35天(连续)；7只小鼠接受双周贝伐单抗治疗，直到第22天，然后是双周安慰剂，直到第35天(停止)。分别于第13、14、22、27、35天行超声增强扫描。当注射的造影剂分布达到平衡时，在成像平面内应用高声压脉冲破坏毛细管床中的微气泡。监测再灌注，并根据肿瘤内和匹配深度的肾皮质感兴趣区的SIS的线性平均值获得时间-信号强度(SI)曲线。根据再灌流曲线计算的动力学参数反映了局部灌注，并相对于邻近肾皮质的灌注进行了归一化。在第35天，将每组获得的正常血流灌注与其他组进行比较，并与坏死率和微血管密度进行组织学评估。结果：最低切除平均肿瘤重量(+/-标准差)对应最长的贝伐单抗治疗持续时间：1.4g+/-1.1(持续治疗)，2.3g+/-2.1(停止治疗)和3.7g+/-1.9(对照)(P=.01)。在第35天，各自的对照组和持续治疗组的坏死区面积相当且显著扩大：37%+/-14和32%+/-17比停止治疗组(15%+/-9；P<；0.05)大。在停止治疗(第22天)后，停止治疗组的正常化血流灌注随时间显著增加(P=0.02)。结论：在该小鼠肿瘤模型中，非侵入性测量的增强超声参数显示肿瘤在停止抗血管生成治疗后发生了血管重建。
Purpose: To determine, by using contrast material-enhanced ultrasonography (US), how quickly renal tumors grafted in mice begin to revascularize after stopping bevacizumab treatment.Materials and Methods: All experiments were approved by the regional ethics committee. A human tumor cell line SK-NEP-1 was grafted at day 0 in the left kidney of 50 nude mice. Forty-two mice developed tumors and longitudinal follow-up was performed on 32 surviving mice. From day 13, 14 controls received biweekly saline; 11 mice received biweekly bevacizumab until day 35 (continuous); and seven received biweekly bevacizumab until day 22, then biweekly placebo until day 35 (discontinued). Contrast-enhanced US was performed on days 13, 14, 22, 27, and 35. Once the injected contrast material distribution reached an equilibrium phase, high acoustic pressure pulses were applied to destroy microbubbles in the capillary bed in the imaged plane. Reperfusion was monitored, and time-signal intensity (SI) curves were obtained from the linear average of SIs in intratumoral and matched-depth renal cortex regions of interest. A kinetic parameter calculated from reperfusion curves reflects local perfusion, normalized with respect to adjacent renal cortex perfusion. Normalized perfusion obtained from each group was compared with that from the other groups and with necrosis percentages and microvascular density assessed histologically at day 35. Comparisons were made by using analyses of variance and Tukey-Kramer tests.Results: The lowest excised mean tumor weights (+/- standard deviation) corresponded to the longest bevacizumab-treatment duration: 1.4 g +/- 1.1 (continuous-treatment) compared with 2.3 g +/- 2.1 (discontinued) and 3.7 g +/- 1.9 (control) (P = .01). On day 35, the respective control and continuously treated groups had comparable and significantly larger necrotic areas: 37% +/- 14 and 32% +/- 17 larger than the discontinued-treatment group (15% +/- 9; P < .05). Normalized perfusion increased significantly with time (P = .02) in the discontinued-treatment group after therapy ceased (day 22).Conclusion: Noninvasively measured contrast-enhanced US parameters demonstrated tumor revascularization after stopping antiangiogenic therapy in this murine tumor model.