Purpose: High frequency ultrasound imaging, 10–30 MHz, has the capability to assess tumor response to radiotherapy in mouse tumors as early as 24 h after treatment administration. The advantage of this technique is that the image contrast is generated by changes in the physical properties of dying cells. Therefore, a subject can be imaged before and multiple times during the treatment without the requirement of injecting specialized contrast agents. This study is motivated by a need to provide metrics of comparison between the volume and localization of cell death, assessed from histology, with the volume and localization of cell death surrogate, assessed as regions with increased echogeneity from ultrasoundimages.
Methods: The mice were exposed to radiationdoses of 2, 4, and 8 Gy. Ultrasoundimages were collected from each tumor before and 24 h after exposure to radiation using a broadband 25 MHz center frequency transducer. After radiotherapy,tumors exhibited hyperechoic regions in ultrasoundimages that corresponded to areas of cell death in histology. The ultrasound and histological images were rigidly registered. The tumors and regions of cell death were manually outlined on histological images. Similarly, the tumors and hyperechoic regions were outlined on the ultrasoundimages. Each set of contours was converted to a volumetric mesh in order to compare the volumes and the localization of cell death in histological and ultrasoundimages.
Results: A shrinkage factor of was calculated from the difference in the tumor volumes evaluated from histological and ultrasoundimages. This was used to correct the tumor and cell death volumes assessed from histology. After this correction, the average absolute difference between the volume of cell death assessed from ultrasound and histological images was and the volume overlap was .
Conclusions: The method provided metrics of comparison between the volume of cell death assessed from histology and that assessed from ultrasoundimages. It was applied here to evaluate the capability of ultrasound imaging to assess early tumor response to radiotherapy in mouse tumors. Similarly, it can be applied in the future to evaluate the capability of ultrasound imaging to assess early tumor response to other modalities of cancer treatment. The study contributes to an understanding of the capabilities and limitation of ultrasound imaging at noninvasively detecting cell death. This provides a foundation for future developments regarding the use of ultrasound in preclinical and clinical applications to adapt treatments based on tumor response to cancer therapy.
Dr. Kristy Brock and Dr. Gregory Czarnota are each supported through a Cancer Care Ontario Research Chair and Dr. Michael Kolios is supported through a Canada Research Chair. Part of the work was supported by American Institute of Ultrasound in Medicine’s Endowment for Education and Research Grant and Canadian Institutes of Health Research Strategic Training Fellowship Excellence in Radiation Research for the 21st Century to Dr. Roxana Vlad. The authors thank Dr. Azza Al-Mahrouki and Anoja Giles for technical support, MORFEUS team for valuable discussion, and Dr. Fei-Fei Liu for providing some of the cell lines used in this work.
II.A. Xenograft tumor models
II.B. Administration of ionizing radiation
II.C. Ultrasound data acquisition
II.D. Whole-mount section preparation and 3D volume reconstruction
II.E. Data analysis
III.A. Qualitative assessment
III.B. Quantitative assessment
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