Macrophage uptake rate of Sonazoid in breast lymphosonography is highly conserved in healthy controls

Subcutaneous microbubble administration in connection with contrast enhanced ultrasound (CEUS) imaging is showing promise as a noninvasive and sensitive way to detect tumor draining sentinel lymph nodes (SLNs) in patients with breast cancer. Moreover, there is potential to harness the results from these approaches to directly estimate cancer burden, since some microbubble formulas, such as the Sonazoid used in this study, are rapidly phagocytosed by macrophages, and the macrophage concentration in a lymph node is inversely related to the cancer burden. This work presents a mathematical model that can approximate a rate constant governing macrophage uptake of Sonazoid,k_i, given dynamic CEUS Sonazoid imaging data. Twelve healthy women were injected with 1.0 ml of Sonazoid in an upper-outer quadrant of one of their breasts and SLNs were imaged in each patient immediately after injection, and then at 0.25, 0.5, 1, 2, 4, 6, and 24 h after injection. The mathematical model developed was fit to the dynamic CEUS data from each subject resulting in a mean ± sd of 0.006 ± 0.005 h^-1and 0.4 ± 0.1 h^-1for relative lymphatic flow (EF_l) andk_i, respectively. Furthermore, the roughly 25% sd of thek_imeasurement was similar to the sd that would be expected from realistic noise simulations for a stable 0.4 h^-1value ofk_i, suggesting that macrophage concentration is highly consistent among cancer-free SLNs. These results, along with the significantly smaller variance ink_imeasurement observed compared to relative lymphatic flow suggest thatk_imay be a more precise and promising approach of estimating macrophage abundance, and inversely cancer burden. Future studies comparing tumor-free to tumor-bearing nodes are planned to verify this hypothesis.