Rationale and Objectives
This study was designed to test the feasibility of contrast pulse sequencing imaging for contrast-enhanced grayscale ultrasound in assessing the effects of antiangiogenic therapy.
Materials and Methods
Mice with subcutaneously implanted H22 mouse hepatoma were treated with thalidomide or placebo by oral gavage over 7 days, starting at 24 hours after implantation. Contrast pulse sequencing ultrasound imaging was performed on day 8 to evaluate maximal cross-sectional area and nonenhanced area. Immediately after imaging, mice were euthanized, and tumor tissue was removed for fixation in a 10% formalin solution. The section equivalent to the ultrasound imaging plane was stained with hematoxylin and eosin to allow for the assessment of the largest cross-sectional area and necrotic area.
Results
There was no significant difference in tumor volume between the two groups. The difference of largest cross-sectional area determined by the two methods was not significant between control and treated tumors ( P > .05). The nonenhanced area and its percentage evaluated by ultrasound were significantly larger in treated tumors than in control tumors ( P < .05). The necrotic area and its percentage estimated by pathology slice were also significantly larger in treated tumors than in control tumors ( P < .05). The largest cross-sectional area determined by the two methods was well correlated ( r = 0.815, P < .001). There was good correlation between the nonenhanced area on ultrasound and the necrotic area on pathology slides ( r = 0.909, P < .001). The percentage of nonenhanced area was well correlated with the percentage of necrotic area ( r = 0.910, P < .001).
Conclusion
Contrast-enhanced grayscale ultrasound with contrast pulse sequencing imaging provides a tool for early monitoring of antiangiogenic treatment of tumors, before apparent change in tumor size.
One of the most important recent developments in the field of oncology is the introduction of vascular targeting agents into clinical medicine. Contrary to cytotoxic agents, angiogenic inhibitors do not act directly on tumor cells but on endothelial cells, which very frequently induce lesion necrosis with no change in the volume of the initial tumor . The morphologic criteria normally used (World Health Organization or Response Evaluation Criteria in Solid Tumors) may not be the most appropriate endpoints for evaluating antiangiogenic agents . Additionally, these treatments have important side effects and high prices. As a consequence, animal and clinical trials will urgently require the development of reliable and noninvasive methods for the early evaluation of therapeutic efficacy.
Currently, histologic determination of the mean intratumoral microvessel density is the most commonly used method for assessing angiogenesis , but it is also the most invasive procedure. An additional limitation of this approach is that it does not provide information on effective perfusion through a vessel. Moreover, it reflects only a single point in time and cannot be used as a way of monitoring in vivo changes induced by antiangiogenic therapy. Importantly, although microvessel density can be used to predict disease progression, it has no value in monitoring or predicting response to antiangiogenic therapy .
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Materials and methods
Animal Model
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Ultrasound Imaging Protocol
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Histologic Analysis
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Statistical Analysis
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Results
B-mode Imaging
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Contrast-Enhanced Grayscale Ultrasound
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Histology
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Comparison of Contrast-Enhanced Grayscale Ultrasound and Histology
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Discussion
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