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Hunt, Stephen J.; Gade, Terence; Soulen, Michael C.; Pickup, Stephen; Sehgal, Chandra M.

Antivascular Ultrasound Therapy : Magnetic Resonance Imaging Validation and Activation of the Immune Response in Murine Melanoma : Magnetic Resonance Imaging Validation and Activation of the Immune Response in Murine Melanoma

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  • Media type: E-Article
  • Title: Antivascular Ultrasound Therapy : Magnetic Resonance Imaging Validation and Activation of the Immune Response in Murine Melanoma : Magnetic Resonance Imaging Validation and Activation of the Immune Response in Murine Melanoma
  • Contributor: Hunt, Stephen J.; Gade, Terence; Soulen, Michael C.; Pickup, Stephen; Sehgal, Chandra M.
  • imprint: Wiley, 2015
  • Published in: Journal of Ultrasound in Medicine
  • Language: English
  • DOI: 10.7863/ultra.34.2.275
  • ISSN: 0278-4297; 1550-9613
  • Origination:
  • Footnote:
  • Description: <jats:sec><jats:title>Objectives</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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 (<jats:italic>P</jats:italic> &lt; .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 (<jats:italic>P</jats:italic> &lt; .05) and 3 (<jats:italic>P</jats:italic> &lt; .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<jats:sup>+</jats:sup> cells, indicating tumor hypoxia (<jats:italic>P</jats:italic> &lt; .01), and of CD45<jats:sup>+</jats:sup>/CD3<jats:sup>+</jats:sup> cells in tumors after treatment, in keeping with increased T‐cell infiltration (<jats:italic>P</jats:italic> &lt; .01).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Antivascular US treatment effects extend beyond direct cytotoxicity from hemorrhagic necrosis to include ischemia‐mediated cytotoxicity, enhanced small molecule retention, and intratumoral immune activation.</jats:p></jats:sec>