Rapid T 1 -weighted 3D spoiled gradient-echo (GRE) data sets were acquired in the abdomen of 23 cancer patients during a total of 113 separate visits to allow dynamic contrast-enhanced MRI (DCE-MRI) analysis of tumor microvasculature. The arterial input function (AIF) was measured in each patient at each visit using an automated AIF extraction method following a standardized bolus administration of gadodiamide. The AIFs for each patient were combined to obtain a mean AIF that is representative for any individual. T 1 -weighted dynamic contrast-enhanced (DCE)-MRI is an established method for assessing microvascular changes associated with disease in tissues. It is most commonly used in cancer imaging (1-15), but has also been applied in a range of inflammatory conditions (16,17,41) and in cerebral (18) and cardiac (19) ischemia. Quantitative DCE-MRI has the potential to provide physiological information related to the functional status of tissue microvasculature. This information is available via the application of a tracer kinetic model-usually a compartmental model that describes the rate of transfer of contrast agent between the blood pool and the extracellular extravascular space (EES) (20).All models of contrast agent kinetics require the concentration of contrast agent in the blood pool (the arterial input function (AIF)) to be determined. Simple models assume a simplified functional form for the AIF, and additionally assume that the same functional form is valid for all individuals (16,21). However, it has been shown that using a simplified standard AIF leads to large systematic errors in model output parameters such as the volume transfer constant K trans and blood volume v b (22,42). Additionally, it is generally assumed that interpatient variability in factors such as heart rate and kidney function will lead to differences in the true form of AIF between individuals. An AIF that is accurately measured in each patient studied is therefore the accepted aim for kinetic modeling using contrast agents, even if it one that is met in only a minority of studies (6,13,23).In many settings it is not possible to perform an AIF measurement reliably, due either to data acquisition constraints or the lack of a suitable artery within the imaging field of view (FOV) from which to obtain an AIF. In such cases it would be desirable to utilize an assumed form of AIF that provides sufficient information to allow an accurate estimation of model parameters. Here we present a functional form of AIF that meets this requirement. We obtained this AIF from a population of 67 individually measured AIFs from the abdomens of 23 patients. We also show that the variability associated with the population of AIFs is low. Finally, we show that the use of the new functional form of the population AIF improves the reproducibility of tracer kinetic model parameters, and conclude that it is valid to use an assumed form of AIF if it is not possible to acquire AIFs from individual patients. MATERIALS AND METHODS PatientsTwenty-three patients (...

Single nanopore electrodes and nanopore electrode arrays have been fabricated using a focused ion beam (FIB) method. High aspect ratio pores (approximately 150-400-nm diameter and 500-nm depth) were fabricated using direct-write local ion milling of a silicon nitride layer over a buried platinum electrode. This local milling results in formation of a recessed platinum electrode at the base of each nanopore. The electrochemical properties of these nanopore metal electrodes have been characterized by voltammetry. Steady-state voltammograms were obtained for a range of array sizes as well as for single nanopore electrodes. High-resolution scanning electron microscopy imaging of the arrays showed that the pores had truncated cone, rather than cylindrical, conformations. A mathematical model describing diffusion to an electrode located at the base of a truncated conical pore was developed and applied to the analysis of the electrode geometries. The results imply that diffusion to the pore mouth is the dominant mass transport process rather than diffusion to the electrode surface at the base of the truncated cone. FIB milling thus represents a simple and convenient method for fabrication of prototype nanopore electrode arrays, with scope for applications in sensing and fundamental electrochemical studies.

Purpose: Little is known concerning the onset, duration, and magnitude of direct therapeutic effects of anti-vascular endothelial growth factor (VEGF) therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early-phase clinical trials. Experimental Design: Preclinical studies were done using ex vivo microcomputed tomography and in vivo ultrasound imaging to characterize tumor vasculature in a human HM-7 colorectal xenograft model treated with the anti-VEGF antibody G6-31. Clinical evaluation was by quantitative magnetic resonance imaging in 10 patients with metastatic colorectal cancer treated with bevacizumab. Results: Microcomputed tomography experiments showed reduction in perfused vessels within 24 to 48 h of G6-31 drug administration (P ≤ 0.005). Ultrasound imaging confirmed reduced tumor blood volume within the same time frame (P = 0.048). Consistent with the preclinical results, reductions in enhancing fraction and fractional plasma volume were detected in patient colorectal cancer metastases within 48 h after a single dose of bevacizumab that persisted throughout one cycle of therapy. These effects were followed by resolution of edema (P = 0.0023) and tumor shrinkage in 9 of 26 tumors at day 12. Conclusion: These data suggest that VEGF-specific inhibition induces rapid structural and functional effects with downstream significant antitumor activity within one cycle of therapy. This finding has important implications for the design of early-phase clinical trials that incorporate physiologic imaging. The study shows how animal data help interpret clinical imaging data, an important step toward the validation of image biomarkers of tumor structure and function. (Clin Cancer Res 2009;15(21):6674-82)