We describe a standard set of quantity names and symbols related to the estimation of kinetic parameters from dynamic contrast-enhanced T 1 -weighted magnetic resonance imaging data, using diffusable agents such as gadopentetate dimeglumine (Gd-DTPA). These include a) the volume transfer constant K trans (min ؊1 ); b) the volume of extravascular extracellular space (EES) per unit volume of tissue v e (0 F v e F 1); and c) the flux rate constant between EES and plasma k ep (min ؊1 ). The rate constant is the ratio of the transfer constant to the EES (k ep ‫؍‬ K trans / v e ). Under flow-limited conditions K trans equals the blood plasma flow per unit volume of tissue; under permeability-limited conditions K trans equals the permeability surface area product per unit volume of tissue. We relate these quantities to previously published work from our groups; our future publications will refer to these standardized terms, and we propose that these be adopted as international standards.

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Here, we describe an automated nonparametric method for evaluating gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) kinetics, based on dynamic contrast-enhanced-MRI scans of glioblastoma patients taken before and after treatment with bevacizumab; no specific model or equation structure is assumed or used. Tumor and venous blood concentration-time profiles are smoothed, using a robust algorithm that removes artifacts due to patient motion, and then deconvolved, yielding an impulse response function. In addition to smoothing, robustness of the deconvolution operation is assured by excluding data that occur prior to the plasma peak; an exhaustive analysis was performed to demonstrate that exclusion of the prepeak plasma data does not significantly affect results. All

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BACKGROUND AND PURPOSENeuropilin-1 (NRP1) is a VEGF receptor that is widely expressed in normal tissues and is involved in tumour angiogenesis. MNRP1685A is a rodent and primate cross-binding human monoclonal antibody against NRP1 that exhibits inhibition of tumour growth in NPR1-expressing preclinical models. However, widespread NRP1 expression in normal tissues may affect MNRP1685A tumour uptake. The objective of this study was to assess MNRP1685A biodistribution in tumour-bearing mice to understand the relationships between dose, non-tumour tissue uptake and tumour uptake. EXPERIMENTAL APPROACHNon-tumour-bearing mice were given unlabelled MNRP1685A at 10 mg·kg -1. Tumour-bearing mice were given 111 In-labelled MNRP1685A along with increasing amounts of unlabelled antibody. Blood and tissues were collected from all animals to determine drug concentration (unlabelled) or radioactivity level (radiolabelled). Some animals were imaged using single photon emission computed tomography -X-ray computed tomography. KEY RESULTSMNRP1685A displayed faster serum clearance than pertuzumab, indicating that target binding affected MNRP1685A clearance. I.v. administration of In-labelled MNRP1685A to tumour-bearing mice yielded minimal radioactivity in the plasma and tumour, but high levels in the lungs and liver. Co-administration of unlabelled MNRP1685A with the radiolabelled antibody was able to competitively block lungs and liver radioactivity uptake in a dose-dependent manner while augmenting plasma and tumour radioactivity levels. CONCLUSIONS AND IMPLICATIONSThese results indicate that saturation of non-tumour tissue uptake is required in order to achieve tumour uptake and acceptable exposure to antibody. Utilization of a rodent and primate cross-binding antibody allows for translation of these results to clinical settings. AbbreviationsAUC, area under the antibody serum concentration versus time