Mixed-effects modeling of clinical DCE-MRI data: application to colorectal liver metastases treated with bevacizumab.

Purpose: Most dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data are evaluated for individual patients with cohorts analyzed to detect significant changes from baseline values, repeating the process at each posttreatment timepoint. Our study aimed to develop a statistically valid model for the complete time course of DCE-MRI data in a patient cohort.

Materials And Methods: Data from 10 patients with colorectal cancer liver metastases were analyzed, including two baseline scans and four post-bevacizumab scans.

The power of FDG-PET to detect treatment effects is increased by glucose correction using a Michaelis constant.

Background: We recently showed improved between-subject variability in our [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) experiments using a Michaelis-Menten transport model to calculate the metabolic tumor glucose uptake rate extrapolated to the hypothetical condition of glucose saturation: MRglucmax=Ki*(KM+[glc]), where Ki is the image-derived FDG uptake rate constant, KM is the half-saturation Michaelis constant, and [glc] is the blood glucose concentration. Compared to measurements of Ki alone, or calculations of the scan-time metabolic glucose uptake rate (MRgluc = Ki * [glc]) or the glucose-normalized uptake rate (MRgluc = Ki*[glc]/(100 mg/dL), we suggested that MRglucmax could offer increased statistical power in treatment studies; here, we confirm this in theory and practice.

Methods: We compared Ki, MRgluc (both with and without glucose normalization), and MRglucmax as FDG-PET measures of treatment-induced changes in tumor glucose uptake independent of any systemic changes in blood glucose caused either by natural variation or by side effects of drug action.

18F-FDG PET as a surrogate biomarker in non-small cell lung cancer treated with erlotinib: newly identified lesions are more informative than standardized uptake value.

Unlabelled: This study assesses the predictive value of (18)F-FDG PET for overall survival in lung cancer patients treated with a targeted drug.

Methods: (18)F-FDG PET was performed in 125 second- or third-line non-small cell lung cancer (NSCLC) patients with a baseline Eastern Cooperative Oncology Group performance status less than 3 before treatment with erlotinib (150 mg daily) and 2 wk into treatment. The predictive value of (18)F-FDG PET, clinical parameters, and epithelial growth factor receptor (EGFR) mutation status for survival duration was evaluated by fitting accelerated failure time models.

Quantitation of glucose uptake in tumors by dynamic FDG-PET has less glucose bias and lower variability when adjusted for partial saturation of glucose transport.

Background: A retrospective analysis of estimates of tumor glucose uptake from 1,192 dynamic 2-deoxy-2-(18F)fluoro-D-glucose-positron-emission tomography [FDG-PET] scans showed strong correlations between blood glucose and both the uptake rate constant [Ki] and the metabolic rate of glucose [MRGluc], hindering the interpretation of PET scans acquired under conditions of altered blood glucose. We sought a method to reduce this glucose bias without increasing the between-subject or test-retest variability and did this by considering that tissue glucose transport is a saturable yet unsaturated process best described as a nonlinear function of glucose levels.

Methods: Patlak-Gjedde analysis was used to compute Ki from 30-min dynamic PET scans in tumor-bearing mice.

Maximizing tumour exposure to anti-neuropilin-1 antibody requires saturation of non-tumour tissue antigenic sinks in mice.

Background And Purpose: Neuropilin-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.

Noncompartmental kinetic analysis of DCE-MRI data from malignant tumors: Application to glioblastoma treated with bevacizumab.

Dynamic contrast enhanced MRI contrast agent kinetics in malignant tumors are typically complex, requiring multicompartment tumor models for adequate description. For consistent comparisons among tumors or among successive studies of the same tumor, we propose to estimate the total contrast agent-accessible volume fraction of tumor, including blood plasma, v(pe), and an average transfer rate constant across all tumor compartments, K(trans.av), by fitting a three-compartment tumor model and then calculating the area under the tumor impulse-response function (= v(pe)) and the ratio area under the tumor impulse response function over mean residence time in tumor (= K(trans.

An automated method for nonparametric kinetic analysis of clinical DCE-MRI data: application to glioblastoma treated with bevacizumab.

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.

Erythropoietin dosing in children with chronic kidney disease: based on body size or on hemoglobin deficit?

There are no investigations demonstrating that body size-adapted doses of erythropoietin (EPO) are as equally effective in children as in adults. A treatment starting with 150 IU/kg body weight per week leads to an insufficient rise in hemoglobin levels in anemic children with chronic kidney disease (CKD). Nevertheless, this strategy is widely used and seems to be the reason for a high percentage of young anemic children in spite of EPO treatment.

Simultaneous sustained release of fludarabine monophosphate and Gd-DTPA from an interstitial liposome depot in rats: potential for indirect monitoring of drug release by magnetic resonance imaging.

Introduction: Cytostatic depot preparations are interstitially administered for local chemotherapy and prevention of tumor recurrence. It would be of interest to monitor in patients as to when, to what extent, and exactly where, the drug is actually released. Liposomes containing a hydrophilic cytostatic and a hydrophilic contrast agent might be expected to release both agents simultaneously.

Recombinant human erythropoietin for the treatment of renal anaemia in children: no justification for bodyweight-adjusted dosage.

Background: Drug doses for children are usually calculated by reducing adult doses in proportion to bodyweight. The clinically effective dose of recombinant human erythropoietin (epoetin) in children, however, seems to be higher than predicted by this calculation.

Objective: To determine the quantitative relationship between epoetin dose, bodyweight and response in children with end-stage renal disease.

Noninvasive methods to study drug distribution.

Positron emission tomography (PET) and nuclear magnetic resonance spectroscopy (MRS) are two techniques that allow the noninvasive monitoring of drug distribution in living systems (humans, animals), and dynamic contrast-enhanced magnetic resonance imaging (dMRI) provides noninvasive physiological information relevant for drug distribution. PET yields series of cross-sectional images that can be used to monitor the absolute radioactivity concentrations in tissues pixel-by-pixel, but does not allow direct identification of each of the products present. MRS produces spectra showing changes in the concentration of both the parent drug and of the metabolites separately for a sensitive volume, but does not provide a simple means for measuring absolute concentrations.