Quantifying Antivascular Effects of Monoclonal Antibodies to Vascular Endothelial Growth Factor: Insights from Imaging

O’Connor, James P.B.; Carano, Richard A.D.; Ross, Jed; Ho, Calvin C.K.; Jackson, Alan; Parker, Geoffrey; Rose, Christopher; Peale, Franklin; Friesenhahn, Michel; Mitchell, Claire L.; Watson, Yvonne; Roberts, Caleb; Hope, Lynn; Cheung, Susan; Reslan, Hani Bou; Go, Mary Ann T.; Pacheco, Glenn; Wu, Xiumin; Cao, Tiesen; Ross, Sarajane; Buonaccorsi, Giovanni A.; Davies, Karen; Hasan, Jurjees; Thornton, Paula; Puerto, Olivia del; Ferrara, Napoleone; Bruggen, Nicholas van; Jayson, Gordon C

doi:10.1158/1078-0432.ccr-09-0731

Cited by 146 publications

(140 citation statements)

References 36 publications

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“…The anti-VEGF antibody used in this study blocks both human and murine VEGF-A to ensure that both tumor-and stromaderived VEGF are inhibited. This anti-VEGF antibody has been shown to suppress tumor growth, vascular density (7,31), dynamic contrast-enhanced ultrasound estimates of blood volume (7), and the perfusion-and permeability-sensitive dynamic contrast-enhanced MRI parameter K trans (33). A humanized anti-VEGF antibody (Avastin V R ; Genentech, Inc.) is currently approved for treatment of multiple human cancers.…”

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confidence: 99%

Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis

Ungersma

Pacheco²,

et al. 2010

Magnetic Resonance in Med

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Imaging of tumor microvasculature has become an important tool for studying angiogenesis and monitoring antiangiogenic therapies. Ultrasmall paramagnetic iron oxide contrast agents for indirect imaging of vasculature offer a method for quantitative measurements of vascular biomarkers such as vessel size index, blood volume, and vessel density. Here, this technique is validated with direct comparisons to ex vivo micro-CT angiography and histologic vessel measurements, showing significant correlations between in vivo vascular MRI measurements and ex vivo structural vessel measurements. The sensitivity of the MRI vascular parameters is also demonstrated, in combination with a multispectral analysis technique for segmenting tumor tissue to restrict the analysis to viable tumor tissue and exclude regions of necrosis. It is shown that this viable tumor segmentation increases sensitivity for detection of significant effects on blood volume and vessel density by two antiangiogenic therapeutics (anti-VEGF and anti-neuropilin-1) on an HM7 colorectal tumor model. Anti-VEGF reduced blood volume by 36 6 3% (P < 0.0001) and vessel density by 52 6 3% (P < 0.0001) at 48 h posttreatment; the effects of anti-neuropilin-1 were roughly half as strong with a reduction in blood volume of 18 6 6% (P < 0.05) and a reduction in vessel density of 33 6 5% (P < 0.05) at 48 h posttreatment.

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confidence: 99%

Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis

Ungersma

Pacheco²,

et al. 2010

Magnetic Resonance in Med

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“…There remain considerable technical issues around measuring K trans related to data collection and analysis techniques although the K trans estimation technique outlined in this review is becoming a standard accepted approach and there is some degree of consensus on protocol standardisation [22,33]. Measurement reproducibility is approximately 5-10% of the coefficient of variation [34,35], similar to figures from competing techniques such as DSC-MRI, and this probably limits the sensitivity of the technique.…”

Section: Analysis Of T 1 Wdce-mri Datamentioning

confidence: 99%

Dynamic contrast-enhanced imaging techniques: CT and MRI

O’Connor¹,

Tofts²,

Miles³

et al. 2011

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ABSTRACT. Over the last few decades there has been considerable research into quantifying the cerebral microvasculature with imaging, for use in studies of the human brain and various pathologies including cerebral tumours. This review highlights key issues in dynamic contrast-enhanced CT, dynamic contrast-enhanced MRI and arterial spin labelling, the various applications of which are considered elsewhere in this special issue of the British Journal of Radiology. The tumour microvasculature can readily be imaged using X-ray, CT and MRI techniques. This review concentrates on three main methods. Dynamic contrast-enhanced CT (DCE-CT) and dynamic contrastenhanced MRI (DCE-MRI) are well-established techniques, where data acquisition and analysis are comparable despite inherent differences in signal production and mechanism of tissue contrast enhancement (reviewed in [1,2]). Although they can be performed on conventional clinical scanners, they require specialist image analysis to extract biomarkers of tumour vascular function. In distinction, arterial spin labelling (ASL) offers a highly specific method of measuring cerebral perfusion without exogenous contrast agent (CA) administration, but is at present a research technique. The practical applications of these techniques are considered elsewhere in this special issue. Basic principles of dynamic contrast-enhanced imagingDCE imaging describes the acquisition of a baseline image(s) without contrast enhancement followed by a series of images acquired over time after an intravenous bolus of conventional CA. The presence of CA within cerebral blood vessels and tissues affects measured X-ray attenuation on CT in a linear fashion and the calculated signal intensity on MRI in a non-linear manner. Thus, the temporal changes in contrast enhancement effectively provide a time-concentration curve, which can be analysed to quantify a range of physiological parameters that indicate the functional status of the vascular system within tumours and adjacent tissues. These parameters reflect the two-compartment pharmacokinetics exhibited by CA, comprising intravascular and extravascular components. During the first-pass of the CA through the circulation (typically 45-60 s after injection), CA is predominantly intravascular allowing evaluation of perfusion (i.e. blood flow per unit volume or mass of tissue), relative blood volume (rBV) and mean transit time. During the subsequent 2-10 min, there is increasing passage of CA into the extravascular space, and imaging during this delayed phase enables measurement of vascular permeability and relative extravascular volume. DCE-CT image acquisition protocolsA number of distinct DCE-CT techniques have been developed, reflecting the different analysis methodologies adopted by commercial software packages for perfusion CT. The main acquisition factors to be considered are summarised in Table 1. For DCE-CT, the need to keep the radiation burden as low as practicable is a constraint on the total number of images acquired and the X-ray exposure ...

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“…Any histologic sample is necessarily a tiny fraction of a tumor; vessel measurements done on biopsies or single slices from a tumor may be skewed by tumor heterogeneity and interior regions of necrosis. Ex vivo micro-CT angiography has been used to quantify vascular structure in whole tumors (6,7) but provides only a single measurement time point and detects only structural information about the presence of vasculature, rather than functional information about how that vasculature was perfused in vivo. Contrast-enhanced micro-CT angiography can be done in vivo with a rapid volume scanning system, but the resolution limit of the CT signal limits the size of detectable vessels; microvasculature smaller than 30-50 mm cannot be visualized (8).…”

mentioning

confidence: 99%

“…The anti-VEGF antibody used in this study blocks both human and murine VEGF-A to ensure that both tumor-and stroma-derived VEGF are inhibited. This anti-VEGF antibody has been shown to suppress tumor growth, vascular density (7,31), dynamic contrast-enhanced ultrasound estimates of blood volume (7), and the perfusion-and permeability-sensitive dynamic contrast-enhanced MRI parameter K trans (33). A humanized anti-VEGF antibody (Avastin; Genentech, Inc., South San Francisco, CA) is currently approved for treatment of multiple human cancers.…”

mentioning

confidence: 99%

Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis

Pacheco²,

et al. 2011

Magnetic Resonance in Med

Self Cite

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*Imaging of tumor microvasculature has become an important tool for studying angiogenesis and monitoring antiangiogenic therapies. Ultrasmall paramagnetic iron oxide contrast agents for indirect imaging of vasculature offer a method for quantitative measurements of vascular biomarkers such as vessel size index, blood volume, and vessel density (Q). Here, this technique is validated with direct comparisons to ex vivo micro-computed tomography angiography and histologic vessel measurements, showing significant correlations between in vivo vascular MRI measurements and ex vivo structural vessel measurements. The sensitivity of the MRI vascular parameters is also demonstrated, in combination with a multispectral analysis technique for segmenting tumor tissue to restrict the analysis to viable tumor tissue and exclude regions of necrosis. It is shown that this viable tumor segmentation increases sensitivity for detection of significant effects on blood volume and Q by two antiangiogenic therapeutics [anti-vascular endothelial growth factor (anti-VEGF) and anti-neuropilin-1] on an HM7 colorectal tumor model. Anti-vascular endothelial growth factor reduced blood volume by 36 6 3% (p < 0.0001) and Q by 52 6 3% (p < 0.0001) at 48 h post-treatment; the effects of anti-neuropilin-1 were roughly half as strong with a reduction in blood volume of 18 6 6% (p < 0.05) and a reduction in Q of 33 6 5% (p < 0.05) at 48 h post-treatment. Magn Reson Med 63:1637-1647,

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Quantifying Antivascular Effects of Monoclonal Antibodies to Vascular Endothelial Growth Factor: Insights from Imaging

Cited by 146 publications

References 36 publications

Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis

Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis

Dynamic contrast-enhanced imaging techniques: CT and MRI

Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis

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