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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]

Objectives: To implement a retrospective intrinsic landmark-based (ILB) gating protocol for contrast-enhanced ultrasound (CEUS) and to compare its efficiency to non-gated, manually gated and extrinsically gated CEUS. Methods: CEUS of the liver was performed in healthy mice ( n = 5) and in NEMO knockout mice with dysplastic livers ( n = 5). In healthy animals, first-pass kinetics of non-specific microbubbles was recorded. Knockout mice were analysed regarding retention of VEGFR2-specific microbubbles. For retrospective gating, a landmark which showed respiratory movement was encircled as a region of interest (ROI). During inspiration, the signal intensity within the ROI altered, which served as gating signal. To evaluate the accuracy, non-gated, extrinsically gated and ILB-gated time-intensity curves were created. For each curve, descriptive parameters were calculated and compared to the gold standard (manual frame-by-frame gating). Results: No significant differences in the variation of ILB- and extrinsically gated time-intensity curves from the gold standard were observed. Non-gated data showed significantly higher variations. Also the variation of molecular ultrasound data was significantly lower for ILB-gated compared to non-gated data. Conclusion: ILB gating is a robust and easy method to improve data accuracy in functional and molecular ultrasound liver imaging. This technique can presumably be translated to contrast-enhanced ultrasound examinations in humans. Key Points: • Quantitative analysis of the uptake of contrast agents during ultrasound is complex. • Intrinsic landmark-based gating (ILB) offers a simple implementable method for motion correction. • Results using ILB-gating are comparable to extrinsic gating using external biomonitoring devices. • Functional and molecular imaging of mobile organs will benefit from ILB gating. [ABSTRACT FROM AUTHOR]

Objectives: To characterise clinically translatable long-circulating (BR38) and VEGFR2-targeted (BR55) microbubbles (MB) and to assess their ability to discriminate breast cancer models with different aggressiveness.Methods: The circulation characteristics of BR38 and BR55 were investigated in healthy mice. The relative blood volume (rBV) of MDA-MB-231 (n = 5) or MCF-7 (n = 6) tumours was determined using BR38. In the same tumours in-vivo binding specificity of BR55 was tested and VEGFR2 expression assessed. Data validation included quantitative immunohistological analysis.Results: BR38 had a longer blood half-life than BR55 (>600 s vs. 218 s). BR38-enhanced ultrasound showed greater vascularisation in MDA-MB-231 tumours (p = 0.022), which was in line with immunohistology (p = 0.033). In-vivo competitive binding experiments proved the specificity of BR55 to VEGFR2 (p = 0.027). Binding of BR55 was significantly higher in MDA-MB-231 than in MCF-7 tumours (p = 0.049), which corresponded with the VEGFR2 levels found histologically (p = 0.015). However, differences became smaller when normalising the levels of BR55 to the rBV.Conclusions: BR38 and BR55 are well suited to characterising and distinguishing breast cancers with different angiogenesis and aggressiveness. Long-circulating BR38 MB allow extensive 3-dimensional examinations of larger or several organs. BR55 accumulation faithfully reflects the VEGFR2 status in tumours and depicts even small differences in angiogenesis. [ABSTRACT FROM AUTHOR]

US is a low-cost, real-time imaging modality that is the most used diagnostic tool in paediatric radiology. Reasons include the improved US image quality in children as compared to adults and the demand for avoiding X-rays as much as possible because children are more sensitive to radiation than adults. Stabilized microbubbles have been approved as US contrast agents for adults and show great potential in improving the diagnostic accuracy for many diseases. Initial studies show that in paediatric radiology contrast-enhanced US could also be beneficial for more than just the diagnosis of vesicoureteral reflux, if US contrast agents were approved for children. Molecular US imaging utilizes microbubbles conjugated to biomolecules that target intravascular disease-specific molecules. Many preclinical studies show that molecular US imaging is a highly sensitive tool to detect neovascularisation, inflammation and cardiovascular diseases. Its main advantages are the higher informative value, the longer persistence of the label at the target lesion and the chance to work with lower contrast agent dosages. Now, clinical translation of molecular US appears at the horizon. This review article reports on the current status of molecular US imaging and discusses its potential for paediatric radiology. [ABSTRACT FROM AUTHOR]