Abstract
Dynamic MR biomarkers (T2*-weighted or susceptibility-based and T1-weighted or relaxivity-enhanced) have been applied to assess tumor perfusion and its response to therapies. A significant challenge in the development of reliable biomarkers is a rigorous assessment and optimization of reproducibility. The purpose of this study was to determine the measurement reproducibility of T1-weighted dynamic contrast-enhanced (DCE)-MRI and T2*-weighted dynamic susceptibility contrast (DSC)-MRI with two contrast agents (CA) of different molecular weight (MW): gadopentetate (Gd-DTPA, 0.5 kDa) and Gadomelitol (P792, 6.5 kDa). Each contrast agent was tested with eight mice that had subcutaneous MDA-MB-231 breast xenograft tumors. Each mouse was imaged with a combined DSC-DCE protocol three times within one week to achieve measures of reproducibility. DSC-MRI results were evaluated with a contrast to noise ratio (CNR) efficiency threshold. There was a clear signal drop (>95% probability threshold) in the DSC of normal tissue, while signal changes were minimal or non-existent (<95% probability threshold) in tumors. Mean within-subject coefficient of variation (wCV) of relative blood volume (rBV) in normal tissue was 11.78% for Gd-DTPA and 6.64% for P792. The intra-class correlation coefficient (ICC) of rBV in normal tissue was 0.940 for Gd-DTPA and 0.978 for P792. The inter-subject correlation coefficient was 0.092. Calculated Ktrans from DCE-MRI showed comparable reproducibility (mean wCV, 5.13% for Gd-DTPA, 8.06% for P792). ICC of Ktrans showed high intra-subject reproducibility (ICC = 0.999/0.995) and inter-subject heterogeneity (ICC = 0.774). Histograms of Ktrans distributions for three measurements had high degrees of overlap (sum of difference of the normalized histograms <0.01). These results represent homogeneous intra-subject measurement and heterogeneous inter-subject character of biological population, suggesting that perfusion MRI could be an imaging biomarker to monitor or predict response of disease.
Highlights
Tumor angiogenesis is a pathophysiological process involving the development of new capillaries and hyperpermeable blood vessels [1]
Tumors were allowed to grow for three weeks and measured using electronic calipers and tumor volumes calculated as p/6[(short axis in mm)26(long axis in mm)]
dynamic contrast-enhanced (DCE)-MRI results were obtained for both contrast agents in all animals
Summary
Tumor angiogenesis is a pathophysiological process involving the development of new capillaries and hyperpermeable blood vessels [1]. It is important to be able to accurately monitor angiogenesis and its response to therapy [3]. MR perfusion techniques using contrast agents (CAs) detect hemodynamic parameters by monitoring the rate of wash-in and wash-out of CAs in the tumor tissue [5]. The common perfusion technique is relaxivity-based DCE-MRI which has been widely used to investigate angiogenesis within tumors, and in particular the response to antiangiogenic therapy. Kinetic models have been applied in order to derive estimates of tissue perfusion and permeability based on the slope of the tumor wash-in and/or wash-out curves [5,6]. Many applications of quantitative DCEMRI to detect response to anti-angiogenic and anti-vascular drug treatments assume that these methods are reproducible and can be used to predict biological changes [7]. We hypothesized that the larger CA, P792, is more sensitive to permeability over blood flow, but has a lower contrast-to-noise ratio (CNR) due to slow extravasation
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