Quantitative contrast-enhanced ultrasound for imaging antiangiogenic treatment response in experimental osteolytic breast cancer bone metastases.
OBJECTIVE
The aim of this study was to investigate the feasibility of using contrast-enhanced ultrasound (CEUS) in experimental breast cancer bone metastases and its utilization for assessment of early antiangiogenic treatment response in these lesions.


METHODS
Nude rats bearing bone metastases (n = 20) were treated with the antiangiogenic tyrosine kinase inhibitor sunitinib daily from days 30 to 35 after MDA-MB-231 tumor cell inoculation (n = 10) and compared with sham-treated controls (n = 10). Imaging with ultrasound (US) and magnetic resonance imaging (MRI) was performed on days 30, 32, and 35 after tumor cell inoculation to determine tumor volume and parameters of vascularization in bone metastases. Contrast-enhanced US images were used to calculate wash-in and wash-out values, peak enhancement, and area under the curve from time intensity curves. In addition, a quantitative analysis software was used to determine regional blood volume and flow as well as filling times within bone metastases. For comparison, dynamic contrast-enhanced MRI provided amplitude A and exchange rate constant kep, respectively. Immunohistological analysis of the vasculature in bone metastases followed in vivo imaging experiments.


RESULTS
Although no changes in tumor volume were assessed in the observation time, significantly decreased values for peak enhancement, area under the curve, and wash-out were determined by CEUS in animals treated with sunitinib at day 35 after tumor cell inoculation. Analysis of CEUS images with quantitative analysis software showed significantly lower values for regional blood volume and regional blood flow as well as higher values for filling time in treated animals as early as 2 days after therapy onset. Dynamic contrast-enhanced MRI revealed significantly decreased values for parameter A at day 35 and kep at days 32 and 35 after tumor cell inoculation for treated animals. Immunohistology of bone metastases revealed significantly larger vessels and decreased positive area fraction for von Willebrand Factor in animals treated with sunitinib.


CONCLUSIONS
Contrast-enhanced US is feasible in experimental breast cancer bone metastases and depicts early antiangiogenic treatment response in advanced osteolytic lesions.
Department of Medical Physics in Radiology, German Cancer Research Center, Heidelberg, Germany.
Maximilian
M
Merz
Dorde
D
Komljenovic
Wolfhard
W
Semmler
Tobias
T
Bäuerle
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000556:secondary*; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000473:pathology; D003287:Contrast Media; D004195:Disease Models, Animal; D005240:Feasibility Studies; D005260:Female; D008279:Magnetic Resonance Imaging; D009389:Neovascularization, Pathologic; D010014:Osteolysis; D051381:Rats; D011923:Rats, Nude; D018709:Statistics, Nonparametric; D014463:Ultrasonography
D020533:Angiogenesis Inhibitors; D003287:Contrast Media