Improved Detection of preclinical Colorectal Liver Metastases by High Resolution Ultrasound including Molecular Ultrasound Imaging using the targeted Contrast Agent BR55.
OBJECTIVE
Aim of the present study was to investigate the sensitivity of high resolution ultrasound (HRU), standard contrast-enhanced ultrasound (CEUS) and CEUS using a novel vascular endothelial growth factor receptor 2 (VEGFR2)-targeted contrast agent for the detection of hepatic metastases in a mouse model of colorectal cancer using clinical standard technology.


METHODS
The human colon cancer cell line HT29, transfected with luciferase cDNA for in vivo bioluminescence monitoring, was injected intrasplenically into CB17.SCID mice. Mice were monitored weekly by bioluminescence and after 2 and 4.5 weeks by HRU and CEUS. Contrast media (untargeted BR1, targeted BR55) was applied and digital cine loops from the arterial phase (15 - 45 sec), portal venous phase (50 - 120 s) and late phases (3 - 5 min, 1hour) of the whole liver were analyzed. Data were correlated with postmortem histopathology.


RESULTS
Without contrast enhancement, lesions > 4 mm were reliably detected. After use of untargeted CEUS, lesions > 2 mm were reliably detected and enhanced rim vascularization and late-phase wash-out was shown. With BR55, lesions > 0.8 mm were reliably detected with excellent documentation of vascularization. A persistent contrast enhancement was seen > 30 min after injection. Contrast-enhancement patterns with BR55 significantly correlated with CD31 (R2 = 0.74) and VEGFR2-immunohistochemistry (R2 = 0.66).


CONCLUSIONS
Detection of metastases by HRU and CEUS was earlier and more accurate than monitoring via bioluminescence. In vivo monitoring of hepatic micrometastases can thus be performed without prior modification of cancer cells using standard technology.
Surgery, University Hospital Regensburg, Germany.
C
C
Hackl
Internal Medicine I, University Hospital Regensburg, Germany.
D
D
Schacherer
Surgery, University Hospital Regensburg, Germany.
M
M
Anders
Surgery, University Hospital Regensburg, Germany.
L M
LM
Wiedemann
Internal Medicine II, University Hospital Regensburg, Germany.
A
A
Mohr
Surgery, University Hospital Regensburg, Germany.
H J
HJ
Schlitt
Radiology, University Hospital Regensburg, Germany.
C
C
Stroszczynski
Geneva Research Center and Manufacturing Site, Bracco Suisse SA, Geneva, Switzerland.
F
F
Tranquart
Radiology, University Hospital Regensburg, Germany.
E M
EM
Jung
D000818:Animals; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging*; D003287:Contrast Media; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007089:Image Enhancement; D055666:Lipopeptides / Q000008:administration & dosage*; D008099:Liver / Q000000981:diagnostic imaging*; D008113:Liver Neoplasms / Q000000981:diagnostic imaging* / Q000556:secondary*; D008163:Luminescent Measurements; D051379:Mice; D008815:Mice, Inbred Strains; D045423:Microbubbles; D057054:Molecular Imaging; D009368:Neoplasm Transplantation; D014463:Ultrasonography; D040301:Vascular Endothelial Growth Factor Receptor-2
D003287:Contrast Media; D055666:Lipopeptides; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2