High-Resolution Computed Tomography of Single Breast Cancer Microcalcifications in Vivo

Abstract

Microcalcification is a hallmark of breast cancer and a key diagnostic feature for mammography. We recently described the first robust animal model of breast cancer microcalcification. In this study, we hypothesized that high-resolution computed tomography (CT) could potentially detect the genesis of a single microcalcification in vivo and quantify its growth over time. Using a commercial CT scanner, we systematically optimized acquisition and reconstruction parameters. Two ray-tracing image reconstruction algorithms were tested: a voxel-driven "fast" cone beam algorithm (FCBA) and a detector-driven "exact" cone beam algorithm (ECBA). By optimizing acquisition and reconstruction parameters, we were able to achieve a resolution of 104 μm full width at half-maximum (FWHM). At an optimal detector sampling frequency, the ECBA provided a 28 μm (21%) FWHM improvement in resolution over the FCBA. In vitro, we were able to image a single 300 μm × 100 μm hydroxyapatite crystal. In a syngeneic rat model of breast cancer, we were able to detect the genesis of a single microcalcification in vivo and follow its growth longitudinally over weeks. Taken together, this study provides an in vivo "gold standard" for the development of calcification-specific contrast agents and a model system for studying the mechanism of breast cancer microcalcification.

Bisphosphonate-functionalized gold nanoparticles for contrast-enhanced X-ray detection of breast microcalcifications

“…The injection volume and HA concentration were readily tailored providing a straightforward and reproducible model for creating microcalcifications of known HA concentration for investigating X-ray contrast agents. Breast microcalcifications have also been biologically-induced in mice and rats via implanted cancer cells [44] and delivery of exogenous growth factors [45–47], respectively, but these models require separate measurements to quantify the HA concentration or microcalcification burden rather than offering a priori control.…”

“…In vivo models of breast microcalcifications have been developed in mice using implanted tumor cells [44] and in rats using exogenous growth factors [45–47]. These models are more biologically-relevant and will be useful for future investigations for the targeted delivery of BP-Au NPs and radiographic imaging in vivo .…”

Contrast-Enhanced X-ray Detection of Breast Microcalcifications in a Murine Model Using Targeted Gold Nanoparticles

“…The in vivo murine model of microcalcifications developed in this study was an extension of an ex vivo tissue model we previously reported . Other in vivo models of breast microcalcifications have been previously developed in rodents using implanted tumor cells and exogenous growth factors. − These models are more biologically relevant for the spontaneous formation and growth of microcalcifications, but the amount of mineral that is deposited varies between animals and requires additional verification. Furthermore, the formation of microcalcifications in these models is preceded by tumor formation, in contrast to the normal disease progression, and the presence of tumor tissue may create additional model variability due to differences in the X-ray attenuation of the background tissue between animals.…”

Diagnostic PET Imaging of Mammary Microcalcifications Using 64Cu-DOTA-Alendronate in a Rat Model of Breast Cancer

“…In contrast to mice, with an adult size of 300-500 g, rats are large enough for structures, such as microcalcifications, to be differentiated by PET within a mammary gland. It has been reported that aging rats develop microcalcifications in their mammary glands (21) and, more recently, that they can even be implanted with, or stimulated to grow, mammary calcifications (22). Here, we report the use of aged, female, retired breeder Sprague-Dawley rats as models for both normal and pathologic human breast tissue microcalcifications without any artificial microcalcification growth induction.…”