Milica Medved

Dynamic Contrast-Enhanced Magnetic Resonance Imaging Pharmacodynamic Biomarker Study of Sorafenib in Metastatic Renal Carcinoma

PURPOSE Sorafenib is an antiangiogenic agent with activity in renal cancer. We conducted a randomized trial to investigate dynamic contrast magnetic resonance imaging (DCE-MRI) as a pharmacodynamic biomarker. PATIENTS AND METHODS Patients were randomly assigned to placebo or 200 or 400 mg twice per day of sorafenib. DCE-MRI was performed at baseline and 4 weeks. DCE-MRI parameters, area under the contrast concentration versus time curve 90 seconds after contrast injection (IAUC(90)), and volume transfer constant of contrast agent (K(trans)) were calculated for a metastatic site selected in a blinded manner. Primary end point was change in K(trans). RESULTS Of the 56 assessable patients, 48 underwent two MRIs; 44 MRIs were assessable for study end points. Mean K(trans) log ratios were 0.131 (standard deviation [SD], 0.315), -0.148 (SD, 0.382), -0.271 (SD, 0.499) in placebo, 200- and 400-mg cohorts, respectively (P = .0077 for trend) corresponding to changes of +14%, -14%, and -24%. IAUC(90) log ratios were 0.041 (SD, 0.197), -0.040 (SD, 0.132), -0.356 (SD, 0.411), respectively (P = .0003 for trend), corresponding to changes of +4%, -4%, and -30%. Using a log-rank test, IAUC(90) and K(trans) changes were not associated with progression-free survival (PFS). Patients with high baseline K(trans) had a better PFS (P = .027). CONCLUSION IAUC(90) and K(trans) are pharmacodynamic biomarkers for sorafenib, but variability is high and magnitude of effect is less than previously reported. Changes in DCE-MRI parameters after 4 weeks of sorafenib are not predictive of PFS, suggesting that these biomarkers are not surrogate end points. The value of baseline K(trans) as a prognostic or predictive biomarker requires additional study.

Estimating the arterial input function using two reference tissues in dynamic contrast‐enhanced MRI studies: Fundamental concepts and simulations

In dynamic contrast‐enhanced MRI (DCE‐MRI) studies, an accurate knowledge of the arterial contrast agent concentration as a function of time is crucial for the estimation of kinetic parameters. In this work, a novel method for estimating the arterial input function (AIF) based on the contrast agent concentration‐vs.‐time curves in two different reference tissues is described. It is assumed that the AIFs of the two tissues have the same shape, and that simple models with two or more compartments, and unknown kinetic parameters, can describe their tracer concentration‐vs.‐time curves. Based on the principle of self‐consistency, one can relate the two tracer concentration‐vs.‐time curves to estimate their common underlining AIF, together with the kinetic parameters of the two tissues. In practice, the measured concentration‐vs.‐time curves have noise, and the AIFs of the two tissues are not exactly the same due to different dispersion effects. These factors will produce errors in the AIF estimate. Simulation studies show that despite the two error sources, the double‐reference‐tissue method provides reliable estimates of the AIF. Magn Reson Med 52:1110–1117, 2004.

Semiquantitative analysis of dynamic contrast enhanced MRI in cancer patients: Variability and changes in tumor tissue over time†

To evaluate variability of a simplified method for measuring semiquantitative DCE‐MRI parameters in patients with cancer and to explore effects of treatment with a putative anti‐angiogenic compound.

Phase II study of the Flk-1 tyrosine kinase inhibitor SU5416 in advanced melanoma.

Purpose: Vascular endothelial growth factor (VEGF) expression is prognostic in melanoma, and the activity of VEGF is mediated in part through the receptor tyrosine kinase Flk-1. A Phase II study of SU5416, a preferential inhibitor of Flk-1, was carried out in patients with metastatic melanoma to determine clinical response, tolerability, and changes in tumor vascular perfusion. Experimental Design: Patients with documented progressive disease and ≤1 prior therapy were eligible. Central nervous system metastases were allowed if stable off medication. SU5416 (145 mg/m2) was administered via a central catheter twice weekly for 8 weeks. Premedication with dexamethasone, diphenhydramine, and a H2 blocker was required because of the Cremophor vehicle. Tumor vascular perfusion was assessed before treatment and during week 8 by dynamic contrast magnetic resonance imaging, and plasma was analyzed for VEGF. Results: Thirty-one patients were enrolled. Two-thirds had received prior therapy, 21 had visceral metastasis, and 14 had an elevated lactate dehydrogenase. Mean absolute lymphocyte counts were decreased (P = 0.002), and glucose levels were increased (P = 0.001) posttherapy, presumably because of steroid premedication. Four vascular adverse events were observed. Of 26 evaluable patients, 1 experienced a partial response, 1 had stable disease, and 5 had a mixed response. Dynamic contrast magnetic resonance imaging in 5 evaluable patients showed decreased tumor perfusion at week 8 (P = 0.024), and plasma VEGF levels were elevated compared with pretherapy (P = 0.008). Conclusions: SU5146 appears to be relatively well tolerated in this population. Although the modest clinical activity and potential effects on tumor vascularity may support additional exploration of VEGF as a target in melanoma, effects from steroid premedication limit further investigation of this agent.

Multiple reference tissue method for contrast agent arterial input function estimation.

A precise contrast agent (CA) arterial input function (AIF) is important for accurate quantitative analysis of dynamic contrast‐enhanced (DCE)‐MRI. This paper proposes a method to estimate the AIF using the dynamic data from multiple reference tissues, assuming that their AIFs have the same shape, with a possible difference in bolus arrival time. By minimizing a cost function, one can simultaneously estimate the parameters and underlying AIF of the reference tissues. The method is computationally efficient and the estimated AIF is smooth and can have higher temporal resolution than the original data. Simulations suggest that this method can provide a reliable estimate of the AIF for DCE‐MRI data with a moderate signal‐to‐noise ratio (SNR) and temporal resolution, and its performance increases significantly as the SNR and temporal resolution increase. As demonstrated by its clinical application, sufficient reference tissues can be easily obtained from normal tissues and subregions segmented from a tumor region of interest (ROI), which suggests this method can be generally applied to cancer‐based DCE‐MRI studies to estimate the AIF. This method is applicable to general kinetic models in DCE‐MRI, as well as other CE imaging modalities. Magn Reson Med, 2007.

New model for analysis of dynamic contrast-enhanced MRI data distinguishes metastatic from nonmetastatic transplanted rodent prostate tumors.

Dynamic contrast‐enhanced MRI (DCEMRI) data were acquired from metastatic and nonmetastatic tumors in rodents to follow the uptake and washout of a low‐molecular‐weight contrast agent (Gd‐DTPA) and a contrast agent with higher molecular weight (P792). The concentration vs. time curves calculated for the tumor rims and centers were analyzed using the two‐compartment model (TCM) and a newly developed empirical mathematical model (EMM). The EMM provided improved fits to the experimental data compared to the TCM. Parameters derived from the empirical model showed that the contrast agent washout rate was significantly slower in metastatic tumors than in nonmetastatic tumors for both Gd‐DTPA (P < 0.03) and P792 (P < 0.04). The effects of the tumor on blood flow in “normal” tissue immediately adjacent to the tumors were evident: Gd‐DTPA uptake and washout rates were much lower in muscle near the tumor (P < 0.05) than normal muscle farther from the tumor. The results suggest that accurate fits of DCEMRI data provide kinetic parameters that distinguish between metastatic and relatively benign cancers. In addition, a comparison of the dynamics of Gd‐DTPA and P792 provides information regarding the microenvironment of tumors. Magn Reson Med 51:487–494, 2004.

Reproducibility assessment of a multiple reference tissue method for quantitative dynamic contrast enhanced–MRI analysis

Bone metastases of 16 prostate cancer patients were scanned twice 1 week apart by dynamic contrast enhanced (DCE) –MRI at 2‐s resolution using a two‐dimensional gradient‐echo pulse sequence. With a multiple reference tissue method (MRTM), the local tissue arterial input function (AIF) was estimated using the contrast agent enhancement data from tumor subregions and muscle. The 32 individual AIFs estimated by the MRTM, which had considerable intra‐patient and inter‐patient variability, were similar to directly measured AIFs in the literature and using the MRTM AIFs in a pharmacokinetic model to derive estimated individual cardiac outputs provided physiologically reasonable results. The MRTM individual AIFs gave better fits with smaller sum of squared errors and equally reproducible estimate of kinetic parameters compared with a previous reported population AIF measured from remote arteries. The individual MRTM AIFs were also used to obtain a mean local tissue AIF for the unique population of this study, which further improved the reproducibility of the estimated kinetic parameters. The MRTM can be applied to DCE‐MRI studies of bone metastases from prostate cancers to provide an AIF from which reproducible quantitative DCE‐MRI parameters can be derived, thus help standardize DCE‐MRI studies in cancer patients. Magn Reson Med, 2009.

Sensitivity to tumor microvasculature without contrast agents in high spectral and spatial resolution MR images

Contrast‐enhanced (CE)‐MRI is sensitive to cancers but can produce adverse reactions and suffers from insufficient specificity and morphological detail. This research investigated whether high spectral and spatial resolution (HiSS) MRI detects tumor vasculature without contrast agents, based on the sensitivity of the water resonance line shape to tumor blood vessels. HiSS data from AT6.1 tumors inoculated in the hind legs of rats (N = 8) were collected pre‐ and post–blood pool contrast agent (iron‐oxide particles) injection. The waterline in small voxels was significantly more asymmetric at the tumor rim compared to the tumor center and normal muscle (P < 0.003). Composite images were synthesized, with the intensity in each voxel determined by the Fourier component (FC) of the water resonance having the greatest relative image contrast at that position. We tested whether regions with high contrast in FC images (FCIs) contain vasculature by comparing FCIs with CE‐MRI as the “gold standard” of vascular density. The FCIs had 75% ± 13% sensitivity, 74% ± 10% specificity, and 91% ± 4% positive predictive value (PPV) for vasculature detection at the tumor rim. These results suggest that tumor microvasculature can be detected using HiSS imaging without the use of contrast agents. Magn Reson Med 61:291–298, 2009.

MR Imaging of the Prostate and Adjacent Anatomic Structures before, during, and after Ejaculation: Qualitative and Quantitative Evaluation

PURPOSE To determine the possibility of obtaining high-quality magnetic resonance (MR) images before, during, and immediately after ejaculation and detecting measurable changes in quantitative MR imaging parameters after ejaculation. MATERIALS AND METHODS In this prospective, institutional review board-approved, HIPAA-compliant study, eight young healthy volunteers (median age, 22.5 years), after providing informed consent, underwent MR imaging while masturbating to the point of ejaculation. A 1.5-T MR imaging unit was used, with an eight-channel surface coil and a dynamic single-shot fast spin-echo sequence. In addition, a quantitative MR imaging protocol that allowed calculation of T1, T2, and apparent diffusion coefficient (ADC) values was applied before and after ejaculation. Volumes of the prostate and seminal vesicles (SV) were calculated by using whole-volume segmentation on T2-weighted images, both before and after ejaculation. Pre- and postejaculation changes in quantitative MR parameters and measured volumes were evaluated by using the Wilcoxon signed rank test with Bonferroni adjustment. RESULTS There was no significant change in prostate volumes on pre- and postejaculation images, while the SV contracted by 41% on average (median, 44.5%; P = .004). No changes before and after ejaculation were observed in T1 values or in T2 and ADC values in the central gland, while T2 and ADC values were significantly reduced in the peripheral zone by 12% and 14%, respectively (median, 13% and 14.5%, respectively; P = .004). CONCLUSION Successful dynamic MR imaging of ejaculation events and the ability to visualize internal sphincter closure, passage of ejaculate, and significant changes in SV volumes were demonstrated. Significant changes in peripheral zone T2 and ADC values were observed.

High Spectral and Spatial Resolution MRI of Breast Lesions: Preliminary Clinical Experience

OBJECTIVE In previous research, high spectral and spatial resolution (HiSS) echo-planar spectroscopic imaging (EPSI) was successfully applied to the human breast, obtaining improved contrast, anatomic detail, and sensitivity to contrast agents. To test HiSS in the clinical setting, we used HiSS MRI to image 30 women with suspicious breast lesions. SUBJECTS AND METHODS Women with suspicious breast lesions were scanned before and after contrast administration using EPSI at 1.5 T (0.63-mm in-plane resolution, 2.6-Hz spectral resolution). Images with intensity proportional to the water signal peak height in each voxel were synthesized and compared with standard clinical fat-saturated and early dynamic subtraction images. Pre- and postcontrast HiSS images were compared to assess the effect of the contrast agent on water resonance structure. RESULTS HiSS images scored significantly better than standard clinical images in lesion conspicuity, margin definition, and internal definition, even though they were acquired before contrast agent injection. Fat suppression was more complete and uniform and detail was shown on HiSS images more clearly than on conventional fat-saturation images. Thus, HiSS images often allowed easier evaluation of the lesion. Contrast agent-affected changes were often spatially and spectrally inhomogeneous. CONCLUSION HiSS scans were successfully integrated into standard clinical examinations and provided diagnostically useful images before contrast agent injection. Thus, it might be possible to characterize suspicious lesions on the basis of precontrast high-resolution spectral information. This information and information about the effect of contrast agents could potentially improve the specificity of breast MRI.