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Vascular endothelial growth factor receptor 2 (VEGFR-2) and α ß integrin are the most frequently addressed targets in molecular imaging of tumor angiogenesis. In preclinical studies, molecular imaging of angiogenesis has shown potential to detect and differentiate benign and malignant lesions of the breast. Thus, in this retrospective clinical study employing patient tissues, the diagnostic value of VEGFR-2, α ß integrin and vascular area fraction for the diagnosis and differentiation of breast neoplasia was evaluated. To this end, tissue sections of breast cancer ( n = 40), pre-invasive ductal carcinoma in situ (DCIS; n = 8), fibroadenoma ( n = 40), radial scar ( n = 6) and normal breast tissue ( n = 40) were used to quantify (1) endothelial VEGFR-2, (2) endothelial α ß integrin and (3) total α ß integrin expression, as well as (4) the vascular area fraction. Sensitivity and specificity to differentiate benign from malignant lesions were calculated for each marker by receiver operating characteristics (ROC) analyses. Whereas vessel density, as commonly used, did not significantly differ between benign and malignant lesions (AUROC: 0.54), VEGFR-2 and α ß integrin levels were gradually up-regulated in carcinoma versus fibroadenoma versus healthy tissue. The highest diagnostic accuracy for differentiating carcinoma from fibroadenoma was found for total α ß integrin expression (AUROC: 0.76), followed by VEGFR-2 (AUROC: 0.71) and endothelial α ß integrin expression (AUROC: 0.68). In conclusion, total α ß integrin expression is the best discriminator between breast cancer, fibroadenoma and normal breast tissue. With respect to vascular targeting and molecular imaging of angiogenesis, endothelial VEGFR-2 appeared to be slightly superior to endothelial α ß for differentiating benign from cancerous lesions. [ABSTRACT FROM AUTHOR]

Objectives: Tumour xenografts of well-discernible sizes can be examined well by molecular ultrasound. Here, we investigated whether very early breast carcinomas express sufficient levels of VEGFR2 for reliable molecular ultrasound imaging with targeted microbubbles. Methods: MCF-7 breast cancer xenografts were orthotopically implanted in nude mice ( n = 26). Tumours measuring from 4 mm (2 mm diameter) up to 65 mm (5 mm diameter) were examined with automated 3D molecular ultrasound using clinically translatable VEGFR2-targeted microbubbles (BR55). Additionally, the relative tumour blood volume was assessed with non-targeted microbubbles (BR38). In vivo ultrasound data were validated by quantitative immunohistochemistry. Results: Very small lesions 2 mm in diameter showed the highest binding of VEGFR2-specific microbubbles. In larger tumours significantly less BR55 accumulated ( p = 0.023). Nonetheless, binding of VEGFR2-targeted microbubbles was still high enough for imaging. The relative blood volume was comparable at all tumour sizes. Both findings were confirmed by immunohistochemistry. Additionally, a significantly enhanced number of large and mature vessels were detected with increasing tumour size ( p < 0.01), explaining the decrease in VEGFR2 expression during tumour growth. Conclusions: 3D molecular ultrasound using BR55 is very well suited to depicting the angiogenic activity in very small breast lesions, suggesting its potential for detecting and characterising these lesions. Key Points: • Xenografts implanted into nude mice offer new insights into breast cancer. • Small MCF-7 breast xenografts (2 mm) exhibit greater VEGFR2 expression than larger tumours. • 3D molecular ultrasound with BR55 microbubbles accurately depicts the high angiogenic activity. • Detecting and characterising small cancers with molecular ultrasound may become possible. [ABSTRACT FROM AUTHOR]

Abstract: Our aim was to prospectively compare two post-processing techniques for dynamic contrast-enhanced ultrasound and to evaluate their impact for monitoring antiangiogenic therapy. Thus, mice with epidermoid carcinoma xenografts were examined during administration of polybutylcyanoacrylate-microbubbles using a small animal ultrasound system (40MHz). Cine loops were acquired and analyzed using time–intensity (TI) and maximum intensity over time (MIOT) curves. Influences of fast (50μl/2s) vs. slow (50μl/10s) injection of microbubbles on both types of curves were investigated. Sensitivities of both methods for assessing effects of antiangiogenic treatment (SU11248) were examined. Correlative histological analysis was performed for vessel-density. Mann–Whitney test was used for statistical analysis. Microbubble injection rates significantly influenced upslope, time-to-peak and peak enhancement of conventional TI curves (p <0.05) but had almost no impact on maximum enhancement of MIOT curves (representing relative blood volume). Additionally, maximum enhancement of MIOT curves captured antiangiogenic therapy effects more reliably and earlier (already after 1 day of therapy; p <0.05) than peak enhancement of TI curves. Immunohistochemistry validated the significantly (p <0.01) lower vessel densities in treated tumors and high correlation (R 2 =0.95) between vessel-density and maximum enhancement of MIOT curves was observed. In conclusion, MIOT is less susceptible to variations of the injection''s speed. It enables to assess changes of the relative blood volume earlier and with lower standard deviations than conventional TI curves. It can easily be translated into clinical practice and thus may provide a promising tool for cancer therapy monitoring. [Copyright &y& Elsevier]