title: Evaluation of high frequency ultrasound methods and contrast agents for characterising tumor response to anti-angiogenic treatment.
abstract: OBJECTIVE
  To compare non-enhanced and contrast-enhanced high-frequency 3D Doppler ultrasound with contrast-enhanced 2D and 3D B-mode imaging for assessing tumor vascularity during antiangiogenic treatment using soft-shell and hard-shell microbubbles.
  
  
  METHODS
  Antiangiogenic therapy effects (SU11248) on vascularity of subcutaneous epidermoid-carcinoma xenografts (A431) in female CD1 nude mice were investigated longitudinally using non-enhanced and contrast-enhanced 3D Doppler at 25 MHz. Additionally, contrast-enhanced 2D and 3D B-mode scans were performed by injecting hard-shell (poly-butyl-cyanoacrylate-based) and soft-shell (phospholipid-based) microbubbles. Suitability of both contrast agents for high frequency imaging and the sensitivity of the different ultrasound methods to assess early antiangiogenic therapy effects were investigated. Ultrasound data were validated by immunohistology.
  
  
  RESULTS
  Hard-shell microbubbles induced higher signal intensity changes in tumors than soft-shell microbubbles in 2D B-mode measurements (424 ± 7 vs. 169 ± 8 A.U.; p<0.01). In 3D measurements, signals of soft-shell microbubbles were hardly above the background (5.48 ± 4.57 vs. 3.86 ± 2.92 A.U.), while signals from hard-shell microbubbles were sufficiently high (30.5 ± 8.06 A.U). Using hard-shell microbubbles 2D and 3D B-mode imaging depicted a significant decrease in tumor vascularity during antiangiogenic therapy from day 1 on. Using soft-shell microbubbles significant therapy effects were observed at day 4 after therapy in 2D B-mode imaging but could not be detected in the 3D mode. With non-enhanced and contrast-enhanced Doppler imaging significant differences between treated and untreated tumors were found from day 2 on.
  
  
  CONCLUSIONS
  Hard-shell microbubble-enhanced 2D and 3D B-mode ultrasound achieved highest sensitivity for assessing therapy effects on tumor vascularisation and were superior to B-mode ultrasound with soft-shell microbubbles and to Doppler imaging.
authors.affiliation: Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen, Germany. arix@ukaachen.de
authors.forename: Anne
authors.initials: A
authors.lastname: Rix
authors.forename: Wiltrud
authors.initials: W
authors.lastname: Lederle
authors.forename: Monica
authors.initials: M
authors.lastname: Siepmann
authors.forename: Stanley
authors.initials: S
authors.lastname: Fokong
authors.forename: Florian F
authors.initials: FF
authors.lastname: Behrendt
authors.forename: Jessica
authors.initials: J
authors.lastname: Bzyl
authors.forename: Christoph
authors.initials: C
authors.lastname: Grouls
authors.forename: Fabian
authors.initials: F
authors.lastname: Kiessling
authors.forename: Moritz
authors.initials: M
authors.lastname: Palmowski
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003287:Contrast Media; D005260:Female; D021621:Imaging, Three-Dimensional / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D045423:Microbubbles; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000209:etiology; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016896:Treatment Outcome; D014463:Ultrasonography / Q000379:methods
chemical_list: D020533:Angiogenesis Inhibitors; D003287:Contrast Media