Gregory S. Karczmar

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.

Prostate Cancer: Differentiation of Central Gland Cancer from Benign Prostatic Hyperplasia by Using Diffusion-weighted and Dynamic Contrast-enhanced MR Imaging

PURPOSE To analyze the diffusion and perfusion parameters of central gland (CG) prostate cancer, stromal hyperplasia (SH), and glandular hyperplasia (GH) and to determine the role of these parameters in the differentiation of CG cancer from benign CG hyperplasia. MATERIALS AND METHODS In this institutional review board-approved (with waiver of informed consent), HIPAA-compliant study, 38 foci of carcinoma, 38 SH nodules, and 38 GH nodules in the CG were analyzed in 49 patients (26 with CG carcinoma) who underwent preoperative endorectal magnetic resonance (MR) imaging and radical prostatectomy. All carcinomas and hyperplastic foci on MR images were localized on the basis of histopathologic correlation. The apparent diffusion coefficient (ADC), the contrast agent transfer rate between blood and tissue (K(trans)), and extravascular extracellular fractional volume values for all carcinoma, SH, and GH foci were calculated. The mean, standard deviation, 95% confidence interval (CI), and range of each parameter were calculated. Receiver operating characteristic (ROC) and multivariate logistic regression analyses were performed for differentiation of CG cancer from SH and GH foci. RESULTS The average ADCs (× 10(-3) mm(2)/sec) were 1.05 (95% CI: 0.97, 1.11), 1.27 (95% CI: 1.20, 1.33), and 1.73 (95% CI: 1.64, 1.83), respectively, in CG carcinoma, SH foci, and GH foci and differed significantly, yielding areas under the ROC curve (AUCs) of 0.99 and 0.78, respectively, for differentiation of carcinoma from GH and SH. Perfusion parameters were similar in CG carcinomas and SH foci, with K(trans) yielding the greatest AUCs (0.75 and 0.58, respectively). Adding K(trans) to ADC in ROC analysis to differentiate CG carcinoma from SH increased sensitivity from 38% to 57% at 90% specificity without noticeably increasing the AUC (0.79). CONCLUSION ADCs differ significantly between CG carcinoma, SH, and GH, and the use of them can improve the differentiation of CG cancer from SH and GH. Combining K(trans) with ADC can potentially improve the detection of CG cancer. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100021/-/DC1.

Evaluation of Diffusion-weighted MR Imaging for Detection of Bowel Inflammation in Patients with Crohn's Disease

RATIONALE AND OBJECTIVES The aims of this study were to determine the feasibility of diffusion-weighted magnetic resonance imaging (DWI) in the detection of bowel inflammation and to investigate the changes in apparent diffusion coefficient (ADC) values in the inflamed bowel in patients with Crohns disease. MATERIALS AND METHODS Eleven patients who underwent magnetic resonance enterography (including DWI) for Crohns disease and colonoscopy or surgery within 4 weeks of examination were recruited. Two radiologists reviewed diffusion-weighted images and ADC maps to evaluate for inflammation in each bowel segment (terminal ileum, cecum, ascending colon, transverse colon, descending colon, and rectosigmoid colon) and measured the ADC values of each bowel segment. Endoscopic and pathologic results were correlated with DWI findings. RESULTS Fifty-three segments (19 with inflammation, 34 normal) were included. DWI detected inflammation in 18 of 19 segments (94.7%) and showed normal results in 28 of 34 segments (82.4%). On diffusion-weighted images, bowel segments with inflammation revealed higher signal compared to normal segments. Artifact levels were none or minimal in 10 of 11 patients (90.9%) and moderate in one patient. On quantitative analysis, ADC values of inflamed and normal bowel were measured as 0.47 - 2.60 x 10(-3) and 1.39 - 4.03 x 10(-3) mm(2)/s, respectively (P < .05). CONCLUSION DWI with parallel imaging is a feasible technique for the detection of inflammation in patients with Crohns disease. ADC values are decreased in inflamed bowel segments, indicating restricted diffusion.

Diffusion-Weighted and Dynamic Contrast-Enhanced MRI of Prostate Cancer: Correlation of Quantitative MR Parameters With Gleason Score and Tumor Angiogenesis

OBJECTIVE The objective of our study was to investigate whether quantitative parameters derived from diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE-MRI) correlate with Gleason score and angiogenesis of prostate cancer. MATERIALS AND METHODS Seventy-three patients who underwent preoperative MRI and radical prostatectomy were included in our study. A radiologist and pathologist located the dominant tumor on the MR images based on histopathologic correlation. For each dominant tumor, the apparent diffusion coefficient (ADC) value and quantitative DCE-MRI parameters (i.e., contrast agent transfer rate between blood and tissue [K(trans)], extravascular extracellular fractional volume [v(e)], contrast agent backflux rate constant [k(ep)], and blood plasma fractional volume on a voxel-by-voxel basis [v(p)]) were calculated and the Gleason score was recorded. The mean blood vessel count, mean vessel area fraction, and vascular endothelial growth factor (VEGF) expression of the dominant tumor were determined using CD31, CD34, and VEGF antibody stains. Spearman correlation analysis between MR and histopathologic parameters was conducted. RESULTS The mean tumor diameter was 15.2 mm (range, 5-28 mm). Of the 73 prostate cancer tumors, five (6.8%) had a Gleason score of 6, 46 (63%) had a Gleason score of 7, and 22 (30.1%) had a Gleason score of greater than 7. ADC values showed a moderate negative correlation with Gleason score (r = -0.376, p = 0.001) but did not correlate with tumor angiogenesis parameters. Quantitative DCE-MRI parameters did not show a significant correlation with Gleason score or VEGF expression (p > 0.05). Mean blood vessel count and mean vessel area fraction parameters estimated from prostate cancer positively correlated with k(ep) (r = 0.440 and 0.453, respectively; p = 0.001 for both). CONCLUSION There is a moderate correlation between ADC values and Gleason score and between k(ep) and microvessel density of prostate cancer. Although the strength of the correlations is insufficient for immediate diagnostic utility, these results warrant further investigation on the potential of multiparametric MRI to facilitate noninvasive assessment of prostate cancer aggressiveness and angiogenesis.

Quantitative tumor oxymetric images from 4D electron paramagnetic resonance imaging (EPRI): methodology and comparison with blood oxygen level-dependent (BOLD) MRI.

This work presents a methodology for obtaining quantitative oxygen concentration images in the tumor‐bearing legs of living C3H mice. The method uses high‐resolution electron paramagnetic resonance imaging (EPRI). Enabling aspects of the methodology include the use of injectable, narrow, single‐line triaryl methyl spin probes and an accurate model of overmodulated spectra. Both of these increase the signal‐to‐noise ratio (SNR), resulting in high resolution in space (1 mm)3 and oxygen concentrations (∼3 torr). Thresholding at 15% the maximum spectral amplitude gives leg/tumor shapes that reproduce those in photographs. The EPRI appears to give reasonable oxygen partial pressures, showing hypoxia (∼0–6 torr, 0–103 Pa) in many of the tumor voxels. EPRI was able to detect statistically significant changes in oxygen concentrations in the tumor with administration of carbogen, although the changes were not increased uniformly. As a demonstration of the method, EPRI was compared with nearly concurrent (same anesthesia) T  2* /blood oxygen level‐dependent (BOLD) MRI. There was a good spatial correlation between EPRI and MRI. Homogeneous and heterogeneous T  2* /BOLD MRI correlated well with the quantitative EPRI. This work demonstrates the potential for EPRI to display, at high spatial resolution, quantitative oxygen tension changes in the physiologic response to environmental changes. Magn Reson Med 49:682–691, 2003.

Imaging vascular function for early stage clinical trials using dynamic contrast-enhanced magnetic resonance imaging.

AbstractMany therapeutic approaches to cancer affect the tumour vasculature, either indirectly or as a direct target. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has become an important means of investigating this action, both pre-clinically and in early stage clinical trials. For such trials, it is essential that the measurement process (i.e. image acquisition and analysis) can be performed effectively and with consistency among contributing centres. As the technique continues to develop in order to provide potential improvements in sensitivity and physiological relevance, there is considerable scope for between-centre variation in techniques. A workshop was convened by the Imaging Committee of the Experimental Cancer Medicine Centres (ECMC) to review the current status of DCE-MRI and to provide recommendations on how the technique can best be used for early stage trials. This review and the consequent recommendations are summarised here. Key Points • Tumour vascular function is key to tumour development and treatment • Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascular function • Thus DCE-MRI with pharmacokinetic models can assess novel treatments • Many recent developments are advancing the accuracy of and information from DCE-MRI • Establishing common methodology across multiple centres is challenging and requires accepted guidelines

MR Imaging–guided Focal Laser Ablation for Prostate Cancer: Phase I Trial

PURPOSE To evaluate the feasibility and safety of magnetic resonance (MR) imaging-guided laser-based thermotherapy in men with clinically low-risk prostate cancer and a concordant lesion at biopsy and MR imaging. MATERIALS AND METHODS This HIPAA-compliant phase I prospective study was approved by the institutional review board. Informed consent was obtained from all patients. Transperineal MR imaging-guided focal laser ablation for clinically low-risk prostate cancer was performed in patients with a Gleason score of 7 or less in three or fewer cores limited to one sextant obtained with transrectal ultrasonography (US)-guided biopsy and a concordant lesion at MR imaging. Lesions were targeted with a laser ablation system. Periprocedural complications were recorded. The International Prostate Symptom Score (IPSS) and the Sexual Health Inventory for Men (SHIM) score were collected before and after the procedure. MR imaging-guided biopsy of the ablation zone was performed 6 months after treatment. The prostate-specific antigen level, IPSS, and SHIM score before and after ablation were compared by using the Wilcoxon signed rank test. RESULTS Treatment was successfully completed in nine patients (procedure duration, 2.5-4 hours; mean laser ablation duration, 4.3 minutes). Immediate contrast-enhanced posttreatment MR imaging showed a hypovascular defect in eight patients. Self-resolving perineal abrasion and focal paresthesia of the glans penis each occurred in one patient. The mean (± standard deviation) IPSS and SHIM score at baseline were 5.8 ± 5.3 and 19.0 ± 8.0, respectively. Average score changes were not significantly different from zero during follow-up (P = .18-.99). MR imaging-guided biopsy of the ablation zone showed no cancer in seven patients (78%) and Gleason grade 6 cancer in two (22%). CONCLUSION Transperineal MR imaging-guided focal laser ablation appears to be a feasible and safe focal therapy option for clinically low-risk prostate cancer.

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.

The interaction of adriamycin with small unilamellar vesicle liposomes. A fluorescence study.

The interaction of the antineoplastic agent adriamycin with sonicated liposomes composed of phosphatidylcholine alone and with small amounts (1-6%) of cardiolipin has been studied by fluorescence techniques. Equilibrium binding data show that the presence of cardiolipin increases the amount of drug bound to liposomes when the bilayer is below its phase transition temperature and when the ionic strength is relatively low (0.01 M). At higher ionic strength (0.15 M) and above the Tm (i.e. conditions which are closer to the physiological state) the binding of the drug to the two liposome types is nearly the same. Thus the differences in the interactions of adriamycin with cardiolipin-containing membranes, as opposed to those composed of phosphatidylcholine alone, are not due simply to increased binding but rather to an altered membrane structure when this lipid is present. Quenching of adriamycin fluorescence by iodide shows that bound drug is partially, but not completely, buried in the liposomal membrane. Both in the presence and absence of cardiolipin the bulk of the adriamycin is more accessible to the quencher below the Tm than above it; that is, a solid membrane tends to exclude the drug from deep penetration. Above the Tm, the presence of cardiolipin alters the nature of liposome-adriamycin interaction. Here the fluorescence quenching data suggest that the presence of small amounts of cardiolipin (3%) in a phosphatidylcholine matrix creates two types of binding environments for drug, one relatively exposed and the other more deeply buried in the membrane. The temperature dependence of the adriamycin fluorescence and the liposome light scattering reveal that cardiolipin alters the thermal properties of the bilayer as well as its interaction with adriamycin. At low ionic strength lateral phase separations may occur with both pure phosphatidylcholine and when 3% cardiolipin is present; under these conditions the bound adriamycin exists in two kinds of environment. It is notable that only adriamycin fluorescence reveals this phenomenon; thebulk property of liposome light scattering reports only on the overall membrane phase change. These data suggest that under certain conditions the drug binding sites in the membranes are decoupled from the bulk of the lipid bilayer.

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.