Hunt Stephen J, Gade Terence, Soulen Michael C, Pickup Stephen, Sehgal Chandra M
Department of Radiology (S.J.H., T.G., M.C.S., S.P., C.M.S.), Penn Image-Guided Interventions Laboratory (S.J.H., T.G.), and Penn Ultrasound Research Laboratory (S.J.H., C.M.S.), Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania USA.
J Ultrasound Med. 2015 Feb;34(2):275-87. doi: 10.7863/ultra.34.2.275.
The purpose of this study was to investigate the treatment effects of antivascular ultrasound (US) with dynamic contrast-enhanced magnetic resonance imaging (MRI), contrast-enhanced sonography, and histopathologic analysis in a murine melanoma model.
Subcutaneous K1735 murine melanoma tumors were grown in syngeneic C3H/HeN mice. Quantitative tumor perfusion characteristics were measured before antivascular US treatment with both dynamic contrast-enhanced MRI and high-resolution contrast-enhanced sonography. Tumors were subsequently treated with 1 or 3 minutes of continuous low-intensity US after intravenous administration of a US contrast agent. Treatment effects were assessed by quantitative dynamic contrast-enhanced MRI, contrast-enhanced sonography, histopathologic analysis, and immunohistochemistry.
Low-intensity antivascular US treatment resulted in approximately a doubling and tripling of the time to peak enhancement on dynamic contrast-enhanced MRI in the 1- and 3-minute treatment groups, respectively, along with a significant decrease in contrast wash-out (P < .01). There was a potent reduction in tumor perfusion on contrast-enhanced sonography, with approximately 40% and 70% reductions in the tumor area perfused as assessed by contrast-enhanced sonography after 1 (P < .05) and 3 (P < .01) minutes of antivascular US. The pathologic and histologic changes spatially correlated with the regions of diminished perfusion seen on contrast-enhanced sonography and dynamic contrast-enhanced MRI. Antivascular US therapy resulted in a significant increase in the number of hypoxia-inducible factor 1A(+) cells, indicating tumor hypoxia (P < .01), and of CD45(+)/CD3(+) cells in tumors after treatment, in keeping with increased T-cell infiltration (P < .01).
Antivascular US treatment effects extend beyond direct cytotoxicity from hemorrhagic necrosis to include ischemia-mediated cytotoxicity, enhanced small molecule retention, and intratumoral immune activation.
本研究旨在通过动态对比增强磁共振成像（MRI）、对比增强超声检查和组织病理学分析，在小鼠黑色素瘤模型中研究抗血管超声（US）的治疗效果。
将皮下K1735小鼠黑色素瘤肿瘤接种于同基因C3H/HeN小鼠体内。在用抗血管超声治疗前，采用动态对比增强MRI和高分辨率对比增强超声检查测量肿瘤灌注的定量特征。随后在静脉注射超声造影剂后，对肿瘤进行1或3分钟的连续低强度超声治疗。通过定量动态对比增强MRI、对比增强超声检查、组织病理学分析和免疫组织化学评估治疗效果。
低强度抗血管超声治疗分别使1分钟和3分钟治疗组的动态对比增强MRI上的峰值增强时间增加了约一倍和两倍，同时对比剂洗脱显著减少（P <.01）。对比增强超声检查显示肿瘤灌注显著降低，抗血管超声治疗1分钟（P <.05）和3分钟（P <.01）后，通过对比增强超声检查评估的肿瘤灌注区域分别减少了约40%和70%。病理和组织学变化在空间上与对比增强超声检查和动态对比增强MRI上灌注减少的区域相关。抗血管超声治疗导致缺氧诱导因子1A(+)细胞数量显著增加，表明肿瘤缺氧（P <.01），并且治疗后肿瘤中CD45(+)/CD3(+)细胞数量增加，这与T细胞浸润增加一致（P <.01）。
抗血管超声治疗效果不仅包括出血坏死引起的直接细胞毒性，还包括缺血介导的细胞毒性、增强的小分子滞留和肿瘤内免疫激活。
