Antivascular Ultrasound Therapy Magnetic Resonance Imaging Valication anc Activation of the Immune Response in Murine Melanoma

作者：Hunt Stephen J^*; Gade Terence; Soulen Michael C; Pickup Stephen; Sehgal Chandra M

来源：Journal of Ultrasound in Medicine, 2015, 34(2): 275-287.

DOI：10.7863/ultra.34.2.275

• cancer
• immune
• dynamic contrast-enhanced magnetic resonance imaging
• microbubble
• therapeutic ultrasound

Objectives The purpose of this study was to investigate the treatment effects of anti-vascular ultrasound (US) with dynamic contrast-enhanced magnetic resonance imaging (MRI), contrast-enhanced sonography, and histopathologic analysis in a murine melanoma model.
Methods Subcutaneous 1(1735 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.
Results 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 hypmda (P<.01), and of CD45(+)/CD3(+) cells in tumors after treatment, in keeping-with increased T-cell infiltration (P<.01).
Conclusions Antivascular US treatment effects extend beyond direct cytotoxicity from hemorrhagic necrosis to include ischemia-mediated cytotoxicity, enhanced small molecule retention, and intratumoral immune activation.

• 出版日期2015-2