Frederick Kelcz

Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Pharmacodynamic Measure of Response After Acute Dosing of AG-013736, an Oral Angiogenesis Inhibitor, in Patients With Advanced Solid Tumors: Results From a Phase I Study

PURPOSE Identifying suitable markers of biologic activity is important when assessing novel compounds such as angiogenesis inhibitors to optimize the dose and schedule of therapy. Here we present the pharmacodynamic response to acute dosing of AG-013736 measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). PATIENTS AND METHODS Thirty-six patients with advanced solid tumors were treated with various doses of AG-013736. In addition to standard measures of objective disease response and pharmacokinetic analysis, DCE-MRI scans were acquired at baseline and repeated at cycle 1--day 2 after the scheduled morning dose of the AG-013736 in 26 patients. Indicators of a vascular response, such as the volume transfer constant (K(trans)) and initial area under the curve (IAUC), were calculated to assess the effect of treatment on tumor vascular function. RESULTS Evaluable vascular response data were obtained in 17 (65%) of 26 patients. A linear correlation was found in which the percentage change from baseline to day 2 in K(trans) and IAUC was inversely proportional to AG-013736 exposure. Using a conservative a priori assumption that a > or = 50% decrease in K(trans) was indicative of an objective vascular response, a 50% decrease in K(trans) was achieved and corresponded to a plasma AUC(0-24) of > 200 ng . h/mL. CONCLUSION A sufficient decrease in tumor vascular parameters was observed at a dose chosen for additional phase II testing by conventional toxicity criteria. In addition, the day 2 vascular response measured using DCE-MRI seems to be a useful indicator of drug pharmacology, and additional research is needed to determine if it is a suitable marker for predicting clinical activity.

Magnetic resonance imaging reveals functional diversity of the vasculature in benign and malignant breast lesions

Tumor perfusion through the microvascular network can be imaged noninvasively by dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI). The objective of the current study was to quantify the microvascular perfusion parameters in various human breast lesions and to determine whether they varied between benign lesions and malignancy and whether they were altered with increased invasiveness.

Extraneous factors affecting resistive index.

Recently, numerous studies have referred to the resistive index as an accurate indicator of acute renal transplant rejection. We encountered several factors other than rejection that resulted in an elevation of the resistive index in both clinical and experimental situations. Any compressive effect on the kidney will elevate the resistive index. This compression may arise from an adjacent mass such as a fluid collection, most commonly hematoma, or even from excessive pressure transmitted via the transducer by a heavy-handed technician. Resistive index elevation also has been demonstrated in experimentally induced hypotension. Technically inaccurate scanning can yield a falsely low resistive index, but these previously mentioned entities can falsely elevate it, leading to an incorrect diagnosis of acute rejection.

Computed tomographic measurement of the xenon brain-blood partition coefficient and implications for regional cerebral blood flow: a preliminary report.

The calculation of regional cerebral blood flow requires, in addition to the measurement of the clearance, a knowledge of the regional brain-blood partition coefficient. The usual 133Xe washout techniques do not measure this latter parameter but use published values for normal brain tissue. This may lead to large errors in pathological tissue because the partition coefficient changes significantly in brain tumors. Investigations have begun into the use of CT and stable xenon to produce a cross sectional view of the brain in terms of its brain-blood partition coefficients. Results of experiments using an iodine phantom and xenon inhalation in animals are presented.

Frequency of malignancy in lesions classified as probably benign after dynamic contrast-enhanced breast MRI examination.

To determine the chance of malignancy in lesions classified as “probably benign” by dynamic magnetic resonance imaging (MRI), in a heterogeneous population.

Critical role of spatial resolution in dynamic contrast-enhanced breast MRI†

The spatial resolution of three‐dimensional (3D) gradient‐echo T1‐weighted images, from 40 women with 25 malignant and 23 benign lesions, was purposely degraded to determine the role of spatial resolution in recording, analysis, and diagnosis of dynamic contrast‐enhanced breast MRI. Images were recorded and analyzed at pixel resolution according to the 3TP method (Degani et al., Nat Med 1997;3:780–782). Reduction in spatial resolution degraded the appearance of foci with fast wash‐in and fast washout dynamics. This resulted in an increase in false‐negative diagnoses. The sensitivity for differentiating between malignant and benign lesions, using threshold criteria defined by the 3TP analysis, of 76% decreased to 60% and 24% for a 2‐ and 4‐fold reduction in spatial resolution, respectively, without affecting significantly the high specificity (96–100%). In order to minimize false‐negative diagnoses of contrast‐enhanced breast MRI and maintain high specificity, it is essential to record and analyze the dynamic behavior at high spatial resolution. J. Magn. Reson. Imaging 2001;13:862–867.

Reproducibility of perfusion parameters in dynamic contrast-enhanced MRI of lung and liver tumors: Effect on estimates of patient sample size in clinical trials and on individual patient responses

OBJECTIVE Dynamic contrast-enhanced MRI (DCE-MRI) is a potentially useful noninvasive technique for assessing tissue perfusion, particularly in the context of solid tumors and targeted antiangiogenic and antivascular therapies. Our aim was to determine the reproducibility of perfusion parameters derived at DCE-MRI of tumors of the lung and liver, the most common sites of metastasis. SUBJECTS AND METHODS Patients with lung and liver tumors underwent two sequential DCE-MRI examinations 2-7 days apart without any intervening therapy. The volume transfer constant between blood plasma and the extravascular extracellular space (K(trans)) and blood-normalized initial area under the signal intensity-time curve (initial AUC(BN)) were computed with a two-compartment pharmacokinetic model. Differences in parameters were assessed with within-patient coefficients of variation. RESULTS Twenty-three patients had evaluable tumors (12 lung, 11 liver). The within-patient coefficients of variation for K(trans) and initial AUC(BN) for liver lesions were 8.9% and 9.9% and for lung lesions were 17.9% and 18.2%. Sample sizes for reductions in these parameters from 10% to 50% were estimated to range from two to 102 subjects. Estimates of confidence that changes observed in a given patient were due to intervening therapy rather than variability of the technique were calculated to range from 71% to 87% if a 20% reduction in a parameter was observed. CONCLUSION The rate of reproducibility of DCE-MRI parameters is in the range of 10%-20% and is influenced by lesion location, parameters being significantly more reproducible in the liver than in the lung. These findings provide the foundation for interpretation of results and design of clinical trials in which DCE-MRI studies are used to assess objective responses.

Absorption-edge fluoroscopy using a three-spectrum technique.

We have recently reported on a 1-kVp, two-filter image subtraction method for visualizing low concentrations of elements like iodine which have K-shell absorption edges in the diagnostic x-ray energy range. However, in the application of this technique to human thyroid imaging, superimposed images due to variations in tissue and bone thickness presented serious difficulties. In this paper, a technique is described for implementing a 3-kVp, three-filter approach. Using carefully chosen spectra and logarithmic image processing, images are produced which are compatible with our previously described two-stage storage-tube subtraction device. Proper manipulation of the resulting difference images results in a final absorption-edge image in which only the element of interest is visualized, with unwanted background images suppressed. Computer calculations are presented to illustrate the relative sizes of difference signals arising from the element of interest and from tissue and bone backgrounds. Phantom studies using iodine concentrations as small as 1 mg/cm2, with variations of 10 cm of tissue and 2 g/cm2 of bone, suggest that the theory is sound and that, with straightforward apparatus modifications, images of good quality should be possible.

Improvement in Breast Lesion Characterization With Dynamic Contrast-Enhanced MRI Using Pharmacokinetic Modeling and Bookend T 1 Measurements

Dynamic contrast‐enhanced breast MR imaging was performed on 14 patients (five cancerous lesions, nine benign) with slice‐selective spoiled gradient‐recalled echo (2D SPGR) imaging. Adiabatic saturation recovery T1 measurements were performed before (T1pre) and after (T1post) 2D SPGR imaging. These two “bookend” T1 measurements were used to calibrate the equations which were employed to convert the time course of the 2D SPGR signal strength to T1‐vs.‐time, which in turn was used to compute the gadolinium concentration‐vs.‐time ([C](t)) in the lesion. The extraction‐flow product (EF) was computed for each lesion by pharmacokinetic modeling of [C](t). For this study, EF provided a sensitivity and specificity for cancer of 100% and 78%, respectively. When only T1pre was used to estimate [C](t) (which assumes a priori knowledge of the shape and amplitude of the slice profile), the sensitivity and specificity fell to 80% and 56%, respectively. This is presumably due to unexpected variations in the shape and/or amplitude of the slice profile, which could be caused by factors such as patient‐to‐patient variations in breast geometry or inconsistently set transmit gains. Therefore, both T1pre and T1post measurements are necessary for optimum sensitivity and specificity using pharmacokinetic analysis. Magn Reson Med 51:1066–1070, 2004.

Accurate and rapid quantitative dynamic contrast‐enhanced breast MR imaging using spoiled gradient‐recalled echoes and bookend T1 measurements

A method is presented that converts dynamic T1‐weighted spoiled gradient‐recalled echo (SGRE) image intensities into estimates of T1 without the errors associated with imperfections in the slice profile and transmitter coil magnetic field (B1). The method involves T1 measurements performed before and after a series of dynamic SGRE images. These measurements serve to calibrate and correct the SGRE signal strength equation used to estimate T1. Simulations and phantom experiments were performed to test the method for slice‐selective (two‐dimensional) and slab‐selective (three‐dimensional) imaging, as well as for imaging performed with optimized and un‐optimized B1. For nearly all test conditions, T1 was estimated accurately (within 10%) over a range of T1 values expected in vivo (∼1200 → 300 msec). This method should be useful for quantifying dynamic SGRE imaging for many different applications including breast MR imaging. Magn Reson Med 42:746–753, 1999.